Medicine, Faculty of
Population and Public Health (SPPH), School of
DSpace
UBCV
Chen, Yixian
Doctor of Philosophy - PhD
University of British Columbia
Background: Certain diabetes medications have been linked to reduced risk of breast, colorectal, and pancreatic cancers, although findings are inconclusive, reflecting limitations in the methodology of previous studies. Objective: To evaluate associations between classes, subclasses and individual diabetes medications, and risks of breast, colorectal, and pancreatic cancers. Methods: Using linked administrative health data from the Province of British Columbia, a cohort of over 3 million people aged 35-100 (1996-2019) was constructed. Diabetes medication use was parameterized as binary, continuous, and categorical variables. Duration-response and dose-response associations were determined using cumulative duration and cumulative dose (years receiving the defined daily doses). Medication use was treated as time-varying, with a 1-year lag, over the follow-up period. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between new use of diabetes medications and occurrence of breast, colorectal, and pancreatic cancers. In a subset of participants from the British Columbia Generations Project (BCGP), risk estimates were further adjusted for sociodemographic and lifestyle variables. An active comparator analysis was employed to mitigate confounding by indication. Results: Metformin (HR=1.04, 95%CI=1.04-1.05) and insulin secretagogues (HR=1.02, 95%CI=1.01-1.02), especially gliclazide and glyburide, were found to be linked to an increased risk of colorectal cancer. A higher dose of basal insulin was associated with a higher pancreatic cancer risk (HR=1.05, 95%CI=1.04-1.06). Conversely, ever use of SGLT-2 inhibitors was related to a lower breast cancer risk than never use (HR=0.64, 95%CI=0.48-0.85). Many of these associations persisted after adjusting for sociodemographic and lifestyle factors in the BCGP subset. In the active comparator analysis, similar associations were identified when compared to alternative diabetes medications. Conclusion: Multiple diabetes medications were associated with breast, colorectal, and pancreatic cancer risk, highlighting the possible need to consider long-term health implications of these commonly prescribed medications.
DIABETES MEDICATION USE AND RISK OF BREAST, COLORECTAL, AND PANCREATIC CANCER: A POPULATION-BASED COHORT STUDY by Yixian Chen BSc Hons, Brock University, 2017 MSc, Brock University, 2020 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Population and Public Health) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2023 © Yixian Chen, 2023 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Diabetes medication use and risk of breast, colorectal, and pancreatic cancer: a population-based cohort study submitted by Yixian Chen in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Population and Public Health Examining Committee: Dr. Rachel Murphy, Assistant Professor, School of Population and Public Health, UBC Co-supervisor Dr. Trevor Dummer, Associate Professor, School of Population and Public Health, UBC Co-supervisor Dr. Parveen Bhatti, Associate Professor, School of Population and Public Health, UBC Supervisory Committee Member Dr. Kimberlyn McGrail, Professor, School of Population and Public Health, UBC University Examiner Dr. Tricia Tang, Associate Professor, Department of Medicine, UBC University Examiner iii Abstract Background: Certain diabetes medications have been linked to reduced risk of breast, colorectal, and pancreatic cancers, although findings are inconclusive, reflecting limitations in the methodology of previous studies. Objective: To evaluate associations between classes, subclasses and individual diabetes medications, and risks of breast, colorectal, and pancreatic cancers. Methods: Using linked administrative health data from the Province of British Columbia, a cohort of over 3 million people aged 35-100 (1996-2019) was constructed. Diabetes medication use was parameterized as binary, continuous, and categorical variables. Duration-response and dose-response associations were determined using cumulative duration and cumulative dose (years receiving the defined daily doses). Medication use was treated as time-varying, with a 1-year lag, over the follow-up period. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between new use of diabetes medications and occurrence of breast, colorectal, and pancreatic cancers. In a subset of participants from the British Columbia Generations Project (BCGP), risk estimates were further adjusted for sociodemographic and lifestyle variables. An active comparator analysis was employed to mitigate confounding by indication. Results: Metformin (HR=1.04, 95%CI=1.04-1.05) and insulin secretagogues (HR=1.02, 95%CI=1.01-1.02), especially gliclazide and glyburide, were found to be linked to an increased iv risk of colorectal cancer. A higher dose of basal insulin was associated with a higher pancreatic cancer risk (HR=1.05, 95%CI=1.04-1.06). Conversely, ever use of SGLT-2 inhibitors was related to a lower breast cancer risk than never use (HR=0.64, 95%CI=0.48-0.85). Many of these associations persisted after adjusting for sociodemographic and lifestyle factors in the BCGP subset. In the active comparator analysis, similar associations were identified when compared to alternative diabetes medications. Conclusion: Multiple diabetes medications were associated with breast, colorectal, and pancreatic cancer risk, highlighting the possible need to consider long-term health implications of these commonly prescribed medications. v Lay Summary Breast and colorectal cancers are among the most common cancers in Canada, while pancreatic cancer has one of the highest mortality rates. As such, understanding factors that may increase or decrease the risk of these cancers is important. Using a large population-based dataset, we examined whether classes, subclasses or individual diabetes medications impact the risk of developing breast, colorectal and pancreatic cancers. The findings showed that metformin use was associated with a higher risk of colorectal cancer. Insulin secretagogues, particularly gliclazide and glyburide, were associated with increased risk of colorectal cancer. Use of basal insulins was associated with a greater risk of pancreatic cancer. SGLT-2 inhibitors were, however, linked to a reduced risk of breast cancer. This study suggests possible risks and benefits of diabetes medication that may in the future, help inform medical professionals and treatments for people with diabetes. vi Preface This dissertation embodies the original work of the author, Yixian Chen. The research delineated in Chapters 4 to 7 received approval from the Research Ethics Boards of the University of British Columbia and British Columbia Cancer Agency Research (H20-02366). Yixian Chen assumed responsibility for all facets described within this dissertation encompassing identification of research objectives, study design, data preparation and analysis, results interpretation and presentation, and the composition of all chapters. All dissertation work was executed under the supervisory guidance of the Ph.D. committee. A version of Chapter 3 of the thesis has been published as “ Chen, Y. et al. Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years. Sci Rep 13, 1–12 (2023)”. The primary literature search was conducted by Yixian Chen, with Surim Son and Fidela Mushashi acting as second reviewers. Yixian Chen performed the meta-analysis and authored the manuscript. Constructive feedback for the development of this chapter was provided by Drs. Parveen Bhatti, Trevor Dummer, and Rachel Murphy. vii Table of Contents Abstract ......................................................................................................................................... iii Lay Summary .................................................................................................................................v Preface ........................................................................................................................................... vi Table of Contents ........................................................................................................................ vii List of Tables ............................................................................................................................. xvii List of Figures ............................................................................................................................ xxii List of Abbreviations ............................................................................................................... xxiii Acknowledgements .................................................................................................................. xxvi Dedication ................................................................................................................................ xxvii Chapter 1: Introduction ................................................................................................................1 1.1 General overview ............................................................................................................ 1 1.2 Rational ........................................................................................................................... 2 1.3 Objectives ....................................................................................................................... 2 1.4 Dissertation outline ......................................................................................................... 3 Chapter 2: Literature review ........................................................................................................5 2.1 Type 2 diabetes ............................................................................................................... 5 2.1.1 Epidemiology of type 2 diabetes................................................................................. 5 2.1.2 Risk factors for type 2 diabetes ................................................................................... 6 2.1.3 Diagnosis and management of type 2 diabetes ......................................................... 11 2.1.3.1 Lifestyle management ....................................................................................... 11 2.1.3.2 Diabetes medications ........................................................................................ 12 viii 2.1.3.2.1 Biguanides (i.e., metformin) ....................................................................... 13 2.1.3.2.2 Incretin-based medicines ............................................................................. 13 2.1.3.2.3 Sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors) ................ 14 2.1.3.2.4 Alpha-glucosidase inhibitors (AGIs) .......................................................... 15 2.1.3.2.5 Insulin secretagogues (sulfonylureas and meglitinides).............................. 15 2.1.3.2.6 Thiazolidinediones ...................................................................................... 16 2.1.3.2.7 Insulins and analogues ................................................................................ 16 2.2 Breast, colorectal, and pancreatic cancers .................................................................... 17 2.2.1 Epidemiology of breast, colorectal and pancreatic cancers ...................................... 17 2.2.1.1 Breast cancer ..................................................................................................... 17 2.2.1.2 Colorectal cancer .............................................................................................. 18 2.2.1.3 Pancreatic cancer .............................................................................................. 19 2.2.2 Risk factors for breast, colorectal, and pancreatic cancers ....................................... 20 2.2.2.1 Breast cancer ..................................................................................................... 20 2.2.2.2 Colorectal cancer .............................................................................................. 22 2.2.2.3 Pancreatic cancer .............................................................................................. 25 Chapter 3: Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years ......................................................................27 3.1 Introduction ................................................................................................................... 27 3.2 Methods......................................................................................................................... 28 3.2.1 Study designs ............................................................................................................ 28 3.2.2 Participants ................................................................................................................ 28 3.2.3 Exposures .................................................................................................................. 29 ix 3.2.4 Comparators .............................................................................................................. 29 3.2.5 Outcomes .................................................................................................................. 29 3.2.6 Publication characteristics ........................................................................................ 29 3.2.7 Search strategies........................................................................................................ 30 3.2.8 Study selection .......................................................................................................... 30 3.2.9 Data extraction .......................................................................................................... 30 3.2.10 Quality assessment ................................................................................................ 31 3.2.11 Data synthesis ....................................................................................................... 31 3.3 Results ........................................................................................................................... 32 3.3.1 Literature search........................................................................................................ 32 3.3.2 Study characteristics ................................................................................................. 34 3.3.3 Association between diabetes and cancer risk .......................................................... 35 3.4 Discussion ..................................................................................................................... 39 Chapter 4: Methods .....................................................................................................................42 4.1 Data sources .................................................................................................................. 42 4.2 Study population ........................................................................................................... 48 4.3 Exposure assessment ..................................................................................................... 50 4.4 Outcome assessment ..................................................................................................... 51 4.5 Potential confounders.................................................................................................... 53 4.6 Statistical analysis ......................................................................................................... 54 4.6.1 Primary analysis ........................................................................................................ 55 4.6.2 Sensitivity analyses ................................................................................................... 55 4.6.2.1 Additional adjustment for other diabetes medications...................................... 55 x 4.6.2.2 Washout and lag periods ................................................................................... 56 4.6.2.3 BCGP analysis .................................................................................................. 57 4.6.2.4 Active comparator analysis ............................................................................... 62 4.6.3 Cancer subtype analysis ............................................................................................ 63 Chapter 5: Diabetes medications and risk of breast cancer: a population-based cohort study ..............................................................................................................................................64 5.1 Chapter overview .......................................................................................................... 64 5.2 Introduction ................................................................................................................... 65 5.3 Methods......................................................................................................................... 66 5.3.1 Data sources .............................................................................................................. 66 5.3.2 Study population ....................................................................................................... 66 5.3.3 Exposure assessment ................................................................................................. 67 5.3.4 Outcome assessment ................................................................................................. 67 5.3.5 Potential confounders................................................................................................ 68 5.3.6 Statistical analysis ..................................................................................................... 68 5.3.6.1 Primary analysis ................................................................................................ 68 5.3.6.2 Sensitivity analyses ........................................................................................... 69 5.3.6.2.1 Additional adjustment for other diabetes medications ................................ 69 5.3.6.2.2 Washout and lag periods ............................................................................. 69 5.3.6.2.3 BCGP analysis............................................................................................. 69 5.3.6.2.4 Active comparator analysis ......................................................................... 70 5.3.6.3 Breast cancer subtype analysis.......................................................................... 70 5.4 Results ........................................................................................................................... 70 xi 5.4.1 Findings from the primary analysis .......................................................................... 74 5.4.1.1 Biguanides (i.e., metformin) – Class ................................................................ 76 5.4.1.2 SGLT-2 inhibitors – Class ................................................................................ 76 5.4.1.3 Insulin secretagogues – Class ........................................................................... 77 5.4.1.4 Sulfonylureas – Subclass .................................................................................. 77 5.4.1.5 Gliclazide – Individual ...................................................................................... 78 5.4.1.6 Insulins and analogues – Class ......................................................................... 78 5.4.1.7 Basal insulins – Subclass .................................................................................. 79 5.4.1.8 Bolus insulins – Subclass .................................................................................. 79 5.4.2 Findings from sensitivity analyses ............................................................................ 79 5.4.2.1 Additional adjustment for other diabetes medications...................................... 79 5.4.2.2 Washout and lag periods ................................................................................... 82 5.4.2.3 BCGP analysis .................................................................................................. 84 5.4.2.4 Active comparator analysis ............................................................................... 88 5.4.3 Findings from cancer subtype analysis ..................................................................... 88 5.5 Discussion ..................................................................................................................... 90 5.5.1 Key findings .............................................................................................................. 90 5.5.2 Comparison with other studies.................................................................................. 91 5.5.3 Strengths and limitations........................................................................................... 92 5.6 Conclusion .................................................................................................................... 93 Chapter 6: Diabetes medications and risk of colorectal cancer: a population-based cohort study ..............................................................................................................................................94 6.1 Chapter overview .......................................................................................................... 94 xii 6.2 Introduction ................................................................................................................... 95 6.3 Methods......................................................................................................................... 96 6.3.1 Data sources .............................................................................................................. 96 6.3.2 Study populations...................................................................................................... 96 6.3.3 Exposure assessment ................................................................................................. 97 6.3.4 Outcome assessment ................................................................................................. 97 6.3.5 Potential confounders................................................................................................ 98 6.3.6 Statistical analysis ..................................................................................................... 98 6.3.6.1 Primary analysis ................................................................................................ 98 6.3.6.2 Sensitivity analyses ........................................................................................... 99 6.3.6.2.1 Additional adjustment for other diabetes medications ................................ 99 6.3.6.2.2 Washout and lag periods ............................................................................. 99 6.3.6.2.3 BCGP analysis............................................................................................. 99 6.3.6.2.4 Active comparator analysis ....................................................................... 100 6.3.6.3 Colorectal cancer subtype analysis ................................................................. 100 6.4 Results ......................................................................................................................... 100 6.4.1 Findings from the primary analysis ........................................................................ 103 6.4.1.1 Biguanides (i.e., metformin) – Class .............................................................. 105 6.4.1.2 Insulin secretagogues – Class ......................................................................... 106 6.4.1.3 Sulfonylureas – Subclass ................................................................................ 106 6.4.1.4 Gliclazide – Individual .................................................................................... 107 6.4.1.5 Glyburide – Individual .................................................................................... 108 6.4.1.6 Thiazolidinediones – Class ............................................................................. 108 xiii 6.4.1.7 Rosiglitazone – Individual .............................................................................. 109 6.4.1.8 Insulins and analogues – Class ....................................................................... 109 6.4.1.9 Basal insulins – Subclass ................................................................................ 110 6.4.1.10 Bolus insulins – Subclass ............................................................................ 111 6.4.2 Findings from sensitivity analyses .......................................................................... 111 6.4.2.1 Additional adjustment for other diabetes medications.................................... 111 6.4.2.2 Washout and lag periods ................................................................................. 114 6.4.2.3 BCGP analysis ................................................................................................ 117 6.4.2.4 Active comparator analysis ............................................................................. 120 6.4.3 Findings from cancer subtype analysis ................................................................... 120 6.5 Discussion ................................................................................................................... 130 6.5.1 Key findings ............................................................................................................ 130 6.5.2 Comparison with other studies................................................................................ 130 6.5.3 Strengths and limitations......................................................................................... 131 6.6 Conclusion .................................................................................................................. 132 Chapter 7: Diabetes medications and risk of pancreatic cancer: a population-based cohort study ............................................................................................................................................133 7.1 Chapter overview ........................................................................................................ 133 7.2 Introduction ................................................................................................................. 134 7.3 Methods....................................................................................................................... 135 7.3.1 Data sources ............................................................................................................ 135 7.3.2 Study populations.................................................................................................... 135 7.3.3 Exposure assessment ............................................................................................... 136 xiv 7.3.4 Outcome assessment ............................................................................................... 136 7.3.5 Potential confounders.............................................................................................. 137 7.3.6 Statistical analysis ................................................................................................... 137 7.3.6.1 Primary analysis .............................................................................................. 137 7.3.6.2 Sensitivity analyses ......................................................................................... 138 7.3.6.2.1 Additional adjustment for other diabetes medications .............................. 138 7.3.6.2.2 Washout and lag periods ........................................................................... 138 7.3.6.2.3 BCGP analysis........................................................................................... 138 7.3.6.2.4 Active comparator analysis ....................................................................... 139 7.3.6.3 Pancreatic cancer subtype analysis ................................................................. 139 7.4 Results ......................................................................................................................... 139 7.4.1 Findings from the primary analysis ........................................................................ 142 7.4.1.1 Biguanides (i.e., metformin) – Class .............................................................. 145 7.4.1.2 Incretin-based medicines – Class .................................................................... 145 7.4.1.3 DPP-4 inhibitors – Subclass............................................................................ 146 7.4.1.4 Sitagliptin – Individual ................................................................................... 146 7.4.1.5 Insulin secretagogues – Class ......................................................................... 147 7.4.1.6 Sulfonylureas – Subclass ................................................................................ 147 7.4.1.7 Gliclazide – Individual .................................................................................... 148 7.4.1.8 Glyburide – Individual .................................................................................... 149 7.4.1.9 Thiazolidinediones – Class ............................................................................. 149 7.4.1.10 Rosiglitazone – Individual .......................................................................... 150 7.4.1.11 Insulins and analogues – Class ................................................................... 150 xv 7.4.1.12 Basal insulins – Subclass ............................................................................ 151 7.4.1.13 Bolus insulins – Subclass ............................................................................ 151 7.4.2 Findings from sensitivity analyses .......................................................................... 152 7.4.2.1 Additional adjustment for other diabetes medications.................................... 152 7.4.2.2 Washout and lag periods ................................................................................. 155 7.4.2.3 BCGP analysis ................................................................................................ 159 7.4.2.4 Active comparator analysis ............................................................................. 162 7.4.3 Findings from cancer subtype analysis ................................................................... 162 7.5 Discussion ................................................................................................................... 165 7.5.1 Key findings ............................................................................................................ 165 7.5.2 Comparison with other studies................................................................................ 166 7.5.3 Strengths and limitations......................................................................................... 166 7.6 Conclusion .................................................................................................................. 167 Chapter 8: Discussion and Conclusions ...................................................................................169 8.1 Key findings ................................................................................................................ 169 8.1.1 Breast cancer ........................................................................................................... 169 8.1.2 Colorectal cancer .................................................................................................... 171 8.1.3 Pancreatic cancer .................................................................................................... 173 8.2 Comparison with other studies.................................................................................... 174 8.2.1 Breast cancer ........................................................................................................... 174 8.2.1.1 The class of SGLT-2 inhibitors....................................................................... 174 8.2.1.2 The class of biguanides (i.e., metformin) ....................................................... 177 8.2.1.3 The class of insulins and analogues, and bolus insulin subclass .................... 179 xvi 8.2.2 Colorectal cancer .................................................................................................... 180 8.2.2.1 The class of biguanides (i.e., metformin) ....................................................... 180 8.2.2.2 The class of insulin secretagogues, sulfonylureas subclass, gliclazide and glyburide individual medications .................................................................................... 181 8.2.3 Pancreatic cancer .................................................................................................... 183 8.2.3.1 The class of insulin secretagogues, sulfonylureas subclass, and glyburide individual medication...................................................................................................... 183 8.2.3.2 The class of insulins and analogues, and basal and bolus insulin subclasses . 185 8.3 Strengths ..................................................................................................................... 186 8.4 Limitations .................................................................................................................. 190 8.5 Public health implications ........................................................................................... 194 8.6 Future Research .......................................................................................................... 195 8.7 Conclusions ................................................................................................................. 197 Bibliography ...............................................................................................................................199 Appendices ..................................................................................................................................220 Appendix A Supplementary tables for Chapter 3 ................................................................... 220 Appendix B Supplementary tables for Chapter 5 ................................................................... 240 Appendix C Supplementary tables for Chapter 6 ................................................................... 266 Appendix D Supplementary tables for Chapter 7 ................................................................... 304 xvii List of Tables Table 3-1. Characteristics of the 61 studies selected for inclusion in systematic review and meta-analysis of diabetes medications and cancer associations ............................................................ 34 Table 3-2. Diabetes medication classes and breast cancer risk .................................................... 36 Table 3-3. Diabetes medication classes and colorectal cancer risk .............................................. 37 Table 3-4. Diabetes medication classes and pancreatic cancer risk .............................................. 38 Table 4-1. Datasets for the study .................................................................................................. 44 Table 4-2. Classification information for diabetes medications in PharmaNet ............................ 45 Table 4-3. Ranges of duration (years) and dose (1-year-equivalent doses) for identified diabetes medications ................................................................................................................................... 52 Table 4-4. Site and morphology codes for cancer types and subtypes ......................................... 53 Table 4-5. Definition of potential confounders in adjusted models .............................................. 54 Table 4-6. Baseline characteristics at cohort entry of participants from the BCGP study ........... 58 Table 4-7. Definition of additional confounders in BCGP analysis ............................................. 60 Table 5-1. Baseline characteristics at cohort entry of the overall cohort and stratified by incident breast cancer case status at cohort entry ....................................................................................... 72 Table 5-2. Associations between select diabetes medications and the risk of breast cancer ........ 74 Table 5-3. Associations between select diabetes medications and the risk of breast cancer with adjustment for other diabetes medications .................................................................................... 80 Table 5-4. Associations between select diabetes medications and the risk of breast cancer with variation in washout and lag periods ............................................................................................ 82 xviii Table 5-5. Associations between select diabetes medications and the risk of breast cancer among people in the BCGP ...................................................................................................................... 86 Table 5-6. Associations between diabetes medication and breast cancer, an active comparator analysis among new users of medication ...................................................................................... 88 Table 5-7. Associations between select diabetes medications and the risk of breast cancer morphological subtype: ductal ...................................................................................................... 89 Table 6-1. Baseline characteristics at cohort entry of the overall cohort and stratified by incident colorectal cancer case status at cohort entry ............................................................................... 101 Table 6-2. Associations between select diabetes medications and the risk of colorectal cancer 103 Table 6-3. Associations between select diabetes medications and the risk of colorectal cancer with adjustment for other diabetes medications.......................................................................... 112 Table 6-4. Associations between select diabetes medications and the risk of colorectal cancer with variation in washout and lag periods .................................................................................. 114 Table 6-5. Associations between select diabetes medications and the risk of colorectal cancer among people in the BCGP......................................................................................................... 118 Table 6-6. Associations between diabetes medication and colorectal cancer, an active comparator analysis among new users of medication .................................................................................... 120 Table 6-7. Associations between select diabetes medications and the risk of colorectal cancer location subtype: colon ............................................................................................................... 121 Table 6-8. Associations between select diabetes medications and the risk of colorectal cancer location subtype: proximal colon ................................................................................................ 123 Table 6-9. Associations between select diabetes medications and the risk of colorectal cancer location subtype: distal colon...................................................................................................... 126 xix Table 6-10. Associations between select diabetes medications and the risk of colorectal cancer location subtype: rectum ............................................................................................................. 128 Table 7-1. Baseline characteristics at cohort entry of the overall cohort and stratified by incident pancreatic cancer case status at cohort entry .............................................................................. 140 Table 7-2. Associations between select diabetes medications and the risk of pancreatic cancer 142 Table 7-3. Associations between select diabetes medications and the risk of pancreatic cancer with adjustment for other diabetes medications.......................................................................... 152 Table 7-4. Associations between select diabetes medications and the risk of pancreatic cancer with variation in washout and lag periods .................................................................................. 156 Table 7-5. Associations between select diabetes medications and the risk of pancreatic cancer among people in the BCGP......................................................................................................... 160 Table 7-6. Associations between diabetes medication and pancreatic cancer, an active comparator analysis among new users of medication................................................................. 162 Table 7-7. Associations between select diabetes medications and the risk of pancreatic cancer morphological subtype: adenocarcinoma ................................................................................... 163 Supplementary Table A-1. MEDLINE (Ovid) search strategy .................................................. 220 Supplementary Table A-2. Characteristics of included studies assessing cancer risk with diabetes medications ................................................................................................................................. 222 Supplementary Table B-1. Associations between all diabetes medications and the risk of breast cancer .......................................................................................................................................... 240 Supplementary Table B-2. Associations between all diabetes medications and the risk of breast cancer with adjustment for other diabetes medications .............................................................. 245 xx Supplementary Table B-3. Associations between all diabetes medications and the risk of breast cancer with variation in washout and lag periods ....................................................................... 250 Supplementary Table B-4. Associations between all diabetes medications and the risk of breast cancer among people in the BCGP ............................................................................................. 255 Supplementary Table B-5. Associations between all diabetes medications and the risk of breast cancer morphological subtype: ductal ........................................................................................ 257 Supplementary Table B-6. Associations between all diabetes medications and the risk of breast cancer morphological subtype: lobular ....................................................................................... 262 Supplementary Table C-1. Associations between all diabetes medications and the risk of colorectal cancer ......................................................................................................................... 266 Supplementary Table C-2. Associations between all diabetes medications and the risk of colorectal cancer with adjustment for other diabetes medications ............................................. 271 Supplementary Table C-3. Associations between all diabetes medications and the risk of colorectal cancer with variation in washout and lag periods ...................................................... 276 Supplementary Table C-4. Associations between all diabetes medications and the risk of colorectal cancer among people in the BCGP ............................................................................ 281 Supplementary Table C-5. Associations between all diabetes medications and the risk of colorectal cancer location subtype: colon ................................................................................... 284 Supplementary Table C-6. Associations between all diabetes medications and the risk of colorectal cancer location subtype: proximal colon .................................................................... 289 Supplementary Table C-7. Associations between all diabetes medications and the risk of colorectal cancer location subtype: distal colon ......................................................................... 294 xxi Supplementary Table C-8. Associations between all diabetes medications and the risk of colorectal cancer location subtype: rectum ................................................................................. 299 Supplementary Table D-1. Associations between all diabetes medications and the risk of pancreatic cancer ......................................................................................................................... 304 Supplementary Table D-2. Associations between all diabetes medications and the risk of pancreatic cancer with adjustment for other diabetes medications ............................................. 309 Supplementary Table D-3. Associations between all diabetes medications and the risk of pancreatic cancer with variation in washout and lag periods ..................................................... 314 Supplementary Table D-4. Associations between all diabetes medications and the risk of pancreatic cancer among people in the BCGP ............................................................................ 319 Supplementary Table D-5. Associations between all diabetes medications and the risk of pancreatic cancer morphological subtype: adenocarcinoma ....................................................... 321 xxii List of Figures Figure 3-1. Flow diagram for selection of studies included in the systematic review and meta-analysis .......................................................................................................................................... 33 Figure 4-1. Illustration of an eligible individual in the study cohort ............................................ 49 Figure 5-1. Flowchart of study cohort .......................................................................................... 71 xxiii List of Abbreviations AGIs: Alpha-glucosidase Inhibitors Akt: Protein Kinase B AMPK: AMP-Activated Protein Kinase ATC: Anatomical Therapeutic Chemical BC: British Columbia BCGP: British Columbia Generations Project BMI: Body Mass Index CI: Confidence Interval Cochrane CENTRAL: Cochrane Central Register of Controlled Trials DDD: Defined Daily Dose DIN/PIN: Drug Identification Numbers / Product Identification Numbers DPP-4 inhibitors: Dipeptidyl Peptidase 4 Inhibitors Embase: Excerpta Medica DataBase ER: Estrogen Receptor FAP: Familial Adenomatous Polyposis GIP: Glucose-dependent Insulinotropic Polypeptide GLP-1 Receptor Agonists: Glucagon-like Peptide 1 Receptor Agonists GLP-1: Glucagon-like Peptide 1 GPRD: General Practice Research Database HbA1c: Glycated Hemoglobin HER2: Human Epidermal Growth Factor Receptor 2 xxiv HER2+: HER2-positive HR-/HER2+: Hormone Receptor-negative/HER2-positive HR: Hazard Ratio HR+/HER2-: Hormone Receptor-positive/HER2-negative HR+/HER2+: Hormone Receptor-positive/HER2-positive HR+: Hormone Receptor-positive HRT: Hormone Replacement Therapy ICD-O-3: International Classification of Diseases In Oncology, Third Edition IDF: International Diabetes Federation IQR: Interquartile Range KPNC: Kaiser Permanente Northern California MEDLINE: Medical Literature Analysis and Retrieval System Online MET: Metabolic Equivalent of Task MOOSE: Meta-Analysis of Observational Studies in Epidemiology MSP: Medical Services Plan mTOR: Mammalian Target of Rapamycin NOS: Newcastle-Ottawa Scale NPH insulin: Neutral Protamine Hagedorn Insulin OR: Odds Ratio PCOS: Polycystic Ovary Syndrome PHN: Personal Health Number PI3K: Phosphatidylinositide 3-Kinase PopData: Population Data BC xxv PPAR-γ agonists: Peroxisome Proliferator-activated Receptor Gamma Agonists PR: Progesterone Receptor PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses PROSPERO: International Prospective Register of Systematic Reviews RCT: Randomized Controlled Trial RR: Relative Risk SD: Standard Deviation SES: Socioeconomic Status SGLT-2 inhibitors: Sodium-glucose Cotransporter 2 Inhibitors TNBC: Triple-negative Breast Cancer WHO: World Health Organization xxvi Acknowledgements I want to express my gratitude to my supervisor, Dr. Rachel Murphy, for her guidance and expertise that shaped this research project and enriched my academic experience. I’m also thankful to my co-supervisor, Dr. Trevor Dummer, for enhancing my understanding through his contributions and collaborative approach. I appreciate Dr. Parveen Bhatti for his insightful guidance that strengthened the quality of this work. I am grateful to my mentors for their wisdom and consistent support, which has been important in my academic and personal development. Their mentorship helped me overcome challenges and reach my goals. Lastly, I want to thank my parents for their unwavering support throughout my educational journey. Their encouragement and sacrifices have been key to my achievements. I’m forever thankful for their trust in me and for fostering a sense of perseverance and dedication in me. xxvii Dedication My sincerest thanks to my family, friends, and mentors. I dedicate this thesis to you with great appreciation. Your unwavering support and belief in me have propelled me along this journey. Thank you for being the pillars upon which my dreams have been built. 1 Chapter 1: Introduction 1.1 General overview Type 2 diabetes is strongly connected to lifestyle factors, including being overweight or obese, being physically inactive, and consuming an energy-dense diet 1. Type 2 diabetes is also more prevalent in middle-aged (45 to 64 years old: prevalence 11.1%) and older populations (≥65 years: 18.2%) than in younger adults (20 to 44 years: 2.1%) 2. However, due to the rise in obesity among young adults and children, the prevalence of type 2 diabetes in younger populations has risen 3. In British Columbia (BC), Canada, both the incidence and prevalence of type 2 diabetes in young people (<20 years) increased between 2002 to 2013: the incidence rose from 3.5 to 5.2 per 100,000 people, and the prevalence increased from 9 to 21 per 100,000 3. People living with type 2 diabetes have a higher risk of developing various types of cancer, such as cancer of the colon and rectum 4, pancreas 5, liver 6, and endometrium 7. These associations could be attributed to hyperglycemia, hyperinsulinemia, and chronic inflammation that are linked with type 2 diabetes 8. All of these biologic processes are known to promote the initiation of cancer 8. While diabetes has been consistently observed to be a risk factor for many of the most common types of cancer, studies of diabetes medication use and cancer risk have produced inconsistent findings. The purpose of this study was to investigate the associations between diabetes medications and the risks of breast, colorectal, and pancreatic cancers. 2 1.2 Rational While numerous studies have investigated the association between diabetes medications and cancer, most suffer from study design limitations, such as use of self-reported data on diabetes medication use and lack of detailed information with which to assess medication dose-response relationships. Moreover, to date, most studies have focused on the association between metformin and breast cancer, ignoring the many other commonly prescribed medications and additional important cancer sites. Studies that have considered other diabetes medications have mostly grouped together heterogenous medication types, rather than considering individual medications or at least subclasses of medications with distinct mechanisms of action. These limitations have hindered our understanding of the impact of diabetes medications on cancer risk. Given the high prevalence of diabetes and the widespread use of diabetes medications, there is a critical need for studies that are better designed and inclusive of detailed data on medication use. Understanding the associations between diabetes medications and cancer risk is essential for informing clinical practice and guiding treatment of diabetes. By addressing many of the limitations of previous research, this study aims to provide a more robust and nuanced evaluation of the association between diabetes medications and cancer risk. 1.3 Objectives This study has two primary objectives: Objective 1: Conduct a systematic review of existing evidence on the associations between diabetes medications and risks of breast, colorectal, and pancreatic cancers. 3 Objective 2: Use administrative health data to evaluate associations between diabetes medications and risks of breast, colorectal, and pancreatic cancer. The second objective is further divided into five sub-objectives: Objective 2a: Estimate associations between diabetes medications with risks of breast, colorectal, or pancreatic cancer with adjustment for the use of other diabetes medications types. Objective 2b: Explore the influence of various lengths of washout and lag periods on associations. Objective 2c: Explore the effect of lifestyle-related factors on risk estimates using data from the British Columbia Generations Project (BCGP). Objective 2d: Address confounding by indication or healthy user bias through active comparator analysis. Objective 2e: Explore associations between diabetes medications and clinically important subtypes of breast, colorectal, and pancreatic cancers. 1.4 Dissertation outline This dissertation is comprised of eight chapters. The first chapter introduces the topic, outlining the general overview, rationale, and objectives. The literature review in Chapter 2 examines type 2 diabetes, its epidemiology, risk factors, and management, as well as the epidemiology and risk factors for breast, colorectal, and pancreatic cancers. The third chapter provides a systematic review and meta-analysis of the associations between diabetes medications and cancer risk. The methods and findings of the study are detailed in Chapters 4 through 7. Chapter 4 describes the data sources, study population, exposure and outcome evaluation assessments, potential 4 confounders, and statistical analysis. Chapters 5, 6, and 7 of this dissertation serve as individual stand-alone sections, each fully exploring the analyses of breast, colorectal, and pancreatic cancer, respectively. These chapters reiterate the methods delineated in Chapter 4 and brief the discussion encapsulated in Chapter 8, making each chapter a comprehensive, self-contained analysis of each separate cancer study. Chapter 8 concludes with a discussion of the key findings for each cancer, addressing the study’s strengths and limitations, comparing the results to those of other studies, and exploring the biological plausibility and implications of the findings. Appendices A to D include supplemental tables for Chapters 3, 5, 6, and 7. 5 Chapter 2: Literature review 2.1 Type 2 diabetes 2.1.1 Epidemiology of type 2 diabetes Diabetes can be classified into two main categories: type 1 and type 2. Type 1 diabetes, also known as insulin-dependent diabetes, is estimated to account for between 5 and 10% of all diagnosed cases of diabetes 9. The vast majority of people diagnosed with diabetes have type 2 diabetes, also known as non-insulin dependent diabetes. Type 2 diabetes accounts for more than 90% of all diabetes cases 10. Type 2 diabetes occurs when either or both of the following metabolic changes happen: the body develops insulin resistance, or the pancreas cannot produce enough insulin to meet the body’s demands 11. As a result, glucose accumulates in the bloodstream, causing high blood glucose levels. Since symptoms may be moderate or completely absent, identifying the onset of type 2 diabetes is difficult 10. An estimated one-third to 50% of individuals who have type 2 diabetes may be undiagnosed 10. This study focuses on type 2 diabetes, which accounts for about 90% of diabetes cases and primarily requires management with medication beyond insulin alone. As such, the term “diabetes” will be used to refer to type 2 diabetes throughout the remainder of this thesis. According to data from the International Diabetes Federation (IDF), an estimated 537 million adults (aged 20 to 79 years) worldwide were living with diabetes in 2021. This number is projected to rise to over 783 million by 2045, representing 9.8% and 11.2% of diabetes prevalence (world population standardized) 10. It is estimated that around 3 million people in Canada between the ages of 20 and 79 were living with diabetes in 2021. The prevalence of diabetes in Canada (North America and the Caribbean) would reach approximately 11.9% of the 6 adult population in the year 2021, higher than the average prevalence of diabetes worldwide 9.8% 10. The prevalence of diabetes among adults in Canada has steadily increased over the past few decades 12. The upward trend may be attributed to a number of drivers, including the increasing incidence in youth and young adults 12, the aging population, as well as updates to diagnostic criteria (lowering fasting plasma glucose threshold) 13, the recommendation of more frequent screening of diabetes 12 and increased prevalence of risk factors. As a result, diabetes ranked 7th in Canada’s leading causes of mortality 14 and is a cause of many morbidities, including cardiovascular disease, kidney failure, blindness, and amputations 15. It is anticipated that the annual financial burden of diabetes in Canada will rise to a total of 16.9 billion Canadian dollars in the year 2020 16. 2.1.2 Risk factors for type 2 diabetes Non-modifiable risk factors for diabetes include age, sex, race/ethnicity, family history, and the generation that people were born into (birth cohort). Modifiable risk factors include geographic barriers to healthcare services (e.g., living in remote regions or lack of reliable transportation), household income, overweight or obesity, physical inactivity, and consumption of an unhealthy diet. Age: Based on data from the 2008/2009 Canadian Chronic Disease Surveillance System, 88.3% of people with diabetes were over 45 years of age 17. The prevalence of diabetes among Canadians (aged at least 20 years old) was higher among older adults (65-69 years: 20.7%) than that in middle-aged adults (45-49years: 5.6%), or younger adults (20-24 years: 0.7%) 17. Age-related physiological changes, such as defects in insulin secretion, may increase an individual’s 7 risk of diabetes 18. Advancing age also exacerbates insulin resistance and hyperinsulinemia 19, which are key characteristics of diabetes. Sex: Men are more likely than women to develop diabetes. In adults aged at least 35 years, males had a higher risk of diabetes than females in all age groups 17. The precise mechanisms through which biological sex impacts the risk of diabetes are not known, though variation in body composition 20, differences in sex hormones 21, and differences in lifestyle behaviors may play a role. Women generally have more subcutaneous fat than men who tend to have more visceral fat 22, and visceral adipose tissue is more strongly associated with risk of insulin resistance than subcutaneous adipose tissue 23. Estrogen may reduce insulin resistance via regulating glucose homeostasis 21, and lower levels of circulating estrogen after menopause24 may explain the diminished gap in incidence of diabetes between men and women aged 75 and older. Lower levels of androgens in men may also be associated with an increased risk of insulin resistance 25. There are also sex differences in dietary consumption that may contribute to diabetes, with men generally having an overall lower diet quality than women 26. Race/ethnicity: Certain racial and ethnic groups have a greater risk of developing diabetes. In Canada, the prevalence of self-reported diabetes was greater among Indigenous individuals than among non-Indigenous individuals 27. The prevalence of diabetes among those of South Asian descent is greater than among whites 28. It is not well understood why race and ethnicity impact the risk of diabetes. Certain genetic predispositions, for instance, the “thrifty gene” may be associated with a higher risk of diabetes in Indigenous populations 29. Lifestyle factors, such as a poor diet and lack of physical exercise, as well as socioeconomic challenges, such as poverty and 8 insufficient access to health services, may contribute to the increased risk in specific racial and ethnic groups 30. Family history: Individuals with a family history of diabetes have a greater risk of developing the disease than those without a family history 31. Compared to people without any family history of diabetes in first-degree relatives, those with a family history had lower insulin sensitivity 32. Genetics likely play a substantial role in familial diabetes since certain inherited genes may increase the risk of developing the condition 33. Birth cohort: Numerous economic, social, and cultural transitions associated with fetal development, nutrition, physical fitness, and occupational hazard occurred rapidly in the last 100 years. Hence, birth cohort encapsulates the distinctive generation-specific exposures one might have experienced. Some of the exposures are environmental factors (e.g., endocrine‑disrupting chemicals) 34, lifestyle factors (e.g., smoking and alcohol consumption), and healthcare services (e.g., access to screening, diagnosis, and treatment) that have varied over generations, and may influence the risk of diabetes. For instance, individuals with low (<2,500 grams) or high (>4,000 grams) birth weights were at 47% and 36% higher risks, respectively, of developing diabetes in comparison to individuals with normal birth weight 35. The positive associations may reflect neonatal overfeeding in infants with low birth weight 36 and maternal hyperglycemia among mothers of high birth weight infants 37. Among singletons born between 1978 and 1994 in Canada, mean birth weight was higher in more recent birth cohorts than earlier birth cohorts 38. Changes in dietary patterns 39 and physical activity habits 40, as well as the incidence of obesity, might contribute to birth cohort effects on risk of diabetes. 9 Geographic factors and access to care: Studies show that people living in rural areas are at a greater risk for diabetes-related complications 41, and greater driving distance to primary care location is associated with poor glycemic control 42. Geographic factors, such as living in remote areas with limited access to medical facilities, might act as barriers that hinder a person’s ability to engage in diabetes screening 43 and receive treatment necessary to manage their disease 44. Income: People with lower socioeconomic status are more likely to develop diabetes 44, reflecting, in part, greater prevalence of risk factors for diabetes, such as unhealthy lifestyles (i.e., poor diet, sedentary behaviour, smoking, and increased alcohol intake 45) as well as structural factors related to health care access and opportunities for engaging in healthful activities. Despite Canada’s universal healthcare system’s goal of providing equitable care, individuals with lower socioeconomic status may face barriers that increase the risk of diabetes, such as a lack of access to diabetes prevention knowledge and information, reliable transportation, language barriers, and time constraints 46. Overweight and obesity: The World Health Organization (WHO) reported that globally, over 650 million adults aged 18 years and older are obese (body mass index [BMI]≥30 kg/m2), and 2 billion adults are overweight (BMI≥25 kg/m2) 47. Overweight and obesity are thought to contribute to diabetes via several mechanisms. For example, adiponectin normally attenuates inflammation and enhances insulin sensitivity but levels decrease with increases in body fat 48. At the same time, leptin may be become elevated with higher body fat levels, which promotes inflammatory response and insulin resistance 49. Excessive intracellular lipids in non-adipose 10 tissues such as the liver and muscles may also disrupts insulin signaling, resulting in decreased metabolism and insulin-stimulated glucose uptake 50, contributing to hyperglycemia. Physical activity and sedentary behaviour: Physical inactivity is a well-documented risk factor for diabetes 51. In 2018/2019, only 49% of Canadian adults aged 18 to 79 52 met the recommendation of engaging in at least 150 minutes of moderate-to-vigorous physical activity per week for overall health 53. Greater physical activity is associated with a lower risk of developing diabetes in men 54 and women 55. A healthy diet in tandem with physical activity can improve glucose control 56. The association between physical inactivity and the risk of diabetes might be partially mediated by body composition. Sedentary behaviour (along with a poor diet) partially contributes to a shift in body composition, greater adipose tissue, and lower lean mass. The shift towards greater adipose tissue changes the proportion of insulin receptors in adipose and muscle cells, leading to a lower rate of glucose metabolism in adipose cells compared to muscle cells 57 as glucose uptake is less efficient in adipose cells than in muscle cells 57. Dietary intake: It has been well documented that an unhealthy diet contributes to the development of diabetes 58. An unhealthy diet is typically one that is high in trans-fat, has a high glycemic load (higher amounts of rapidly digested and absorbed carbohydrates, resulting in a rapid rise in blood glucose levels), is low in cereal fibre, and fruits and vegetables and has a low ratio of polyunsaturated to saturated fat. Even after adjusting for BMI, studies have shown that men and women who consume an unhealthy diet have a higher risk of developing diabetes 59,60. The precise pathways through which a poor diet contributes to developing diabetes are unclear. There may be direct effects. For example, a diet high in carbohydrates causes blood glucose 11 levels to rise. Indirect effects are also likely, as an energy dense diet and high saturated fatty acid consumption may lead to weight gain 61, thus increasing the risk of diabetes. 2.1.3 Diagnosis and management of type 2 diabetes Blood tests, physical examinations, and patient histories are used to diagnose diabetes. According to Clinical Practice Guidelines from Diabetes Canada 62, fasting plasma glucose (≥7 mmol/L), glycated hemoglobin (HbA1c [glycated hemoglobin] ≥6.5%), 2-hour plasma glucose in a 75 g oral glucose tolerance test (≥11.1 mmol/L), or random plasma glucose levels (≥11.1mmol/L) are indicative of diabetes 62. Experts recommended screening adults at high risk for diabetes every three years, beginning at age 40 or earlier, if other risk factors are present, such as hypertension or smoking, and signs of diabetes 63. 2.1.3.1 Lifestyle management People with prediabetes (impaired fasting glucose, impaired glucose tolerance or HbA1c of 6.0 to 6.4%) 64 or who are otherwise at higher risk of diabetes may delay the onset or reduce the risk of developing diabetes through weight loss, healthy diet, and physical activity 65. These modifications are also a vital component of managing diabetes 66. In addition to improving insulin sensitivity, maintaining a healthy body weight by consuming a healthy diet and engaging in regular physical activity 53 helps lower the risk of complications from diabetes like kidney disease and cardiovascular disease 67. Dietary changes, such as consuming non-starchy vegetables, low-carbohydrate diets, and avoiding processed foods, can improve glucose levels, lipid profiles, and overall health 68. Moderate to vigorous physical activity can lower glucose 12 levels, improve insulin sensitivity 67 and reduce the risk of cardiovascular disease and all-cause mortality 69. Quitting smoking can improve glycemic control, hence reducing the risk of complications 70. Smoking cessation is also associated with a reduced risk of cardiovascular disease and all-cause mortality 71. Stress management is also important for people with diabetes because stress can elevate blood glucose levels 72. Guidelines suggest people with diabetes who manage their stress, such as through physical activity or meditation, can better manage blood glucose levels. Lack of sleep can slow glucose metabolism, making sufficient sleep essential for overall health 73. People with diabetes should strive for 7 to 8 hours of sleep each night to improve glycemic control and decrease the risk of complications from diabetes 73. 2.1.3.2 Diabetes medications Adapting and maintaining a healthy lifestyle can be challenging to adequately manage glucose levels. As a result, pharmacological interventions, such as medications, may be necessary to manage diabetes. People with diabetes are prescribed the first-line glucose-lowering medication, metformin 74. A second-line medication will be added if the patient’s glycated hemoglobin levels have not improved after three months 74. If the combination of metformin and a second-line medication cannot manage glycemic levels, another second-line medication will be added to the treatment regimen 74. Then insulin therapy will be given along with metformin with or without non-insulin medications when the previous treatment is insufficient 75. 13 There are seven classes of diabetes medications: (1) biguanides (i.e., metformin), (2) incretin-based medicines, (3) sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors), (4) alpha-glucosidase inhibitors (AGIs), (5) insulin secretagogues, (6) thiazolidinediones, and (7) insulins and analogues. For each class, the earliest approval year, prescription rate or prevalence of use, and mechanisms of action are summarized below. 2.1.3.2.1 Biguanides (i.e., metformin) Metformin’s primary effects include increasing the activity of the enzyme AMP-activated protein kinase (AMPK), decreasing the activity of the mammalian target of rapamycin (mTOR), and inhibiting hepatic glucose production 76. As a result, metformin increases the peripheral insulin sensitivity of the body, inhibits the activity of glucagon in the liver, and decreases the amount of glucose absorbed by the intestines 75. Metformin is the only biguanide currently available in Canada and has been the most commonly prescribed diabetes medication since its approval in 1972 77. Metformin monotherapy was the most prescribed glucose-lowering medication in people with newly diagnosed diabetes from 2001 to 2020 in BC 78. Women with polycystic ovary syndrome may be prescribed metformin to treat insulin resistance 79. 2.1.3.2.2 Incretin-based medicines Incretin-based medicines include glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists, also referred to as incretin mimetics) and dipeptidyl peptidase 4 (DPP-4) inhibitors (incretin enhancers). The GLP-1 receptor is a membrane-bound cell-surface receptor in pancreatic beta cells. GLP-1 receptor agonists activate the GLP-1 receptor, increases insulin secretion, and decreases glucagon secretion. The use of GLP-1 receptor agonists leads to a delay 14 in stomach emptying, a decrease in appetite, and a rise in satiety 80. DPP-4 is an enzyme that degrades the incretins (glucagon like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). Both GLP-1 and GIP stimulate insulin secretion in pancreatic beta cells. In addition, the effects of GLP-1 include reducing the secretion of glucose-dependent glucagon, slowing gastric emptying, suppressing appetite, and lowering food intake 81. Pharmacological inhibition of the DPP-4 improves glycemic control and boosts plasma incretin activity 80. In 2011, the first GLP-1 receptor agonists, exenatide, received approval from Health Canada for people with diabetes 82. Among people who were newly diagnosed with diabetes in BC, the proportion of them receiving GLP-1 receptor agonists monotherapy as initial treatment has continued to increase since 2012, reaching 14.6% in 2020 78. The first DPP-4 inhibitor, sitagliptin, was approved in 2012 in Canada 83. Among older adults aged 66 and older in Ontario, the prescription rate of sitagliptin during 2010 and 2013 fluctuated between 5% and 15% among people with newly diagnosed diabetes 84. 2.1.3.2.3 Sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors) More than 99% of the glucose that is filtered out of the blood for renal excretion is then reabsorbed in the glomerulus. SGLTs mediate the reabsorption of renal glucose, with 90% of this reabsorption being facilitated by the isoform termed SGLT-2 in the first segment of the proximal tubule. The remaining amount of reabsorption is controlled by SGLT1 which is expressed in the more distal segments (the second and the third segment) of the proximal convoluted tubule and enterocytes of the gastrointestinal tract 85. With SGLT-2 inhibitors, renal excretion of glucose is facilitated without the need for increased endogenous insulin secretion 80,86. In 2014, the first 15 SGLT-2 inhibitor (canagliflozin) was approved to treat diabetes in Canada 87. Among people newly diagnosed with diabetes in BC, less than 3% were prescribed SGLT-2 inhibitor monotherapy between 2014 to 2020 78. 2.1.3.2.4 Alpha-glucosidase inhibitors (AGIs) All AGIs slow the rate of intestinal carbohydrate digestion by competing with oligosaccharides for binding to the α-glucosidase enzyme in the brush border of the small intestine. The use of AGI delays glucose absorption, attenuates postprandial glycaemia peak, and reduces insulin levels without stimulating insulin secretion 88. Acarbose was the first and the only type of AGI approved in Canada since 1996 89. In BC, acarbose monotherapy as the first treatment was prescribed to less than 1% of people with newly diagnosed diabetes between 2001 and 2020 78. 2.1.3.2.5 Insulin secretagogues (sulfonylureas and meglitinides) The main mechanism of action of sulfonylureas is via preventing potassium from entering pancreatic beta cells by blocking ATP-sensitive potassium channels. This causes potassium to accumulate inside the cell, which in turn depolarizes the cell membrane. After that, it activates voltage-gated calcium channels and causes the pancreas to release insulin into the bloodstream by stimulating insulin secretion 75. In 1957, tolbutamide, a sulfonylurea, became available in Canada 90. Sulfonylurea monotherapy prescriptions declined from 21% in 2001 to 3% in 2013 and remained below 3% from 2013 to 2020 among adults newly diagnosed with diabetes in BC 78. 16 2.1.3.2.6 Thiazolidinediones Thiazolidinediones indirectly ameliorate insulin resistance, enhance liver and muscle insulin sensitivity, modify adipose metabolism and distribution, and decrease circulating levels of pro-inflammatory cytokine concentrations 91. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, such as thiazolidinediones, bind to PPAR receptors in the muscle, adipose, and liver cells. The expression of target genes involved in lipid and glucose metabolism is regulated by PPAR-γ receptors, which results in lower insulin resistance and improved beta cell function 75. In 2000, the first thiazolidinedione medication, pioglitazone, was approved and became available for diabetes in Canada 92. In adults newly diagnosed with diabetes in BC, thiazolidinedione monotherapy prescriptions has remained below 3% since 2010 and shrank to nearly zero after 2010 78. 2.1.3.2.7 Insulins and analogues Insulin activates insulin receptors and modulates the metabolism of carbohydrate, lipid, and protein 74. Insulin activates the intracellular tyrosine kinase domain and phosphorylates insulin receptor substrates upon contact to the insulin receptor. Activation of these substrates stimulates downstream signaling molecules, including phosphatidylinositide 3-kinase (PI3K) and protein kinase B (Akt). After binding to PI3K, Akt is phosphorylated and activated. The activation of the PI3K/Akt pathway is key to the regulation of glucose and fatty acid metabolism, gene expression, and cell growth and differentiation 93. The second most frequently prescribed diabetes medication is insulin. Animal insulins were the only option until recombinant DNA human insulin (human insulin) became accessible in 1982 94. Patients who are unable to attain target HbA1c levels with oral medications are prescribed insulin injections. Insulin therapy can 17 be used alone or in conjunction with other diabetes medications. Insulin therapy can be divided into short- (bolus insulin) and long-acting (basal insulin). In adults with diabetes in BC, although the proportion of insulins and analogues used as second-line therapy has fluctuate, it remained below 9.0% between 2001 and 2020 78. 2.2 Breast, colorectal, and pancreatic cancers The focus of this section is the examination of relationships between diabetes medication and the risk of specific cancers, including breast, colorectal and pancreatic cancer. These three cancer sites were selected because of the high incidence of breast and colorectal cancers in Canada 95, while pancreatic cancers 96 may be particularly relevant to study in relation to diabetes medications due to the role of the pancreas in physiologic processes related to diabetes. 2.2.1 Epidemiology of breast, colorectal and pancreatic cancers 2.2.1.1 Breast cancer In Canada, breast cancer is the most frequently diagnosed cancer in women, with approximately 28,000 new cases diagnosed in 2021 95. In BC, the age-standardized incidence rate of breast cancer was 116.4 cases per 100,000 women 95. Breast cancer was the second leading cause of cancer death in Canadian women after lung cancer in 2021, with approximately 5,500 deaths from the disease 95. There are several histological subtypes of breast cancer. The two histological subtypes that comprise most breast cancers, ductal and lobular carcinoma, account for roughly 75% and 15% of all cases, respectively 97. While lobular carcinoma develops in the milk-producing glands, 18 ductal carcinoma begins in the cells lining the milk ducts. Studies had revealed that particular risk factors might be connected to specific breast cancer subtypes. For instance, alcohol consumption and hormone replacement therapy have been associated with lobular carcinoma 98. While ductal carcinoma may be more strongly associated with obesity 99 and cigarette smoking 100. Based on the presence or absence of specific hormone receptors and human epidermal growth factor receptor 2 (HER2), breast cancer can be categorized into three major subtypes. About 82.2% 101 of cases have hormone receptor-positive (HR+) breast cancers, distinguished by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) and can be further categorized based on HER2 expression as HR+/HER2- or HR+/HER2+. HER2-positive (HER2+) breast cancers account for 15.7% of cases 101 and exhibit overexpression of HER2, regardless of hormone receptor status, and can be either hormone receptor-positive (HR+/HER2+) or hormone receptor-negative (HR-/HER2+). Approximately 12.1% of breast cancers 101 are triple-negative breast cancer (TNBC), a subtype that lacks expression of HER2, ER, and PR, frequently exhibiting aggressive behavior and a worse prognosis than other subtypes 102. Hormone receptor subtypes of breast cancer exhibit different biological and clinical characteristics, such as different risk factors 103 and treatment options 102. 2.2.1.2 Colorectal cancer In 2021, an estimated 24,800 new cases of colorectal cancer were diagnosed in Canada, making it the third most common cancer 95. In BC, the age-standardized incidence rate of colorectal cancer was 61.1 cases per 100,000 men and 46.7 cases per 100,000 women 95. During the mid-19 2000s, colorectal cancer mortality rates in Canada have been falling, most likely due to organized screening programs to detect easily treatable precancerous polyps and earlier-stage colorectal cancer 104. In 2021, an estimated 9,400 deaths occurred from colorectal cancer in Canada 95. The most common histological subtypes are adenocarcinoma, mucinous adenocarcinoma, and signet ring cell carcinoma. Adenocarcinoma accounts for 88% of cases 105 and is characterized by gland-forming malignant cells 106. Mucinous adenocarcinoma, which accounts for about 11% of cases 105, is distinguished by the production of extracellular mucin 106. Less than one percent of cases 105 have signet ring cell adenocarcinoma which is characterized by the presence of signet ring-shaped cells with high mucin content 106. The biological differences in cellular structure and mucin content of these subtypes contribute to variations in prognosis 107 and treatment 108. 2.2.1.3 Pancreatic cancer In Canada, an estimated 6,700 new cases of pancreatic cancer were diagnosed in 2021 95. The age-standardized incidence rate of pancreatic cancer in BC was 15.4 cases per 100,000 men and 12.0 cases per 100,000 women 95. The mortality rate for pancreatic cancer high, with a five-year net survival rate as low as 10% 95. In 2021, pancreatic cancer was estimated to be the third leading cancer cause of death among Canadian men and women, with approximately 5,700 deaths from the disease 95. Adenocarcinoma is the most common histological subtype of pancreatic cancer, comprising approximately 85% of all pancreatic cancer cases 109. Pancreatic adenocarcinoma is a type of 20 exocrine pancreatic cancer that originates in the cells that line the ducts of the pancreas 110. Early detection through screening and the discovery of biomarkers is crucial for improving survival rates for pancreatic cancer because the disease is frequently detected too late for curative resection to be effective. Total resection only provides palliative treatment, and adjuvant therapy seldom successfully cures pancreatic cancer 111. 2.2.2 Risk factors for breast, colorectal, and pancreatic cancers 2.2.2.1 Breast cancer Breast cancer is a multifaceted disease with multiple risk factors. One of the largest risk factors for breast cancer is the personal history of the disease. Women with a history of breast cancer are 55% more likely to develop another primary breast cancer than women without a history of the disease 112. A family history of breast and other cancers is also a strong risk factor. Women with a first-degree family (mother, sister, or daughter) who was diagnosed with breast cancer have a higher risk of developing the disease 113. In addition, women with a family history of other cancers, such as prostate or ovarian cancer, are more susceptible to developing breast cancer 114. Women with BRCA1 or BRCA2 gene mutations have 61.8% and 43.2% cumulative risks, respectively, of developing their first primary breast cancer by age 60, compared to 15.7% among women without these mutations 115. Ashkenazi Jewish descent has been identified as a breast cancer risk factor 116, in part due to Jewish women having a higher prevalence of BRCA mutations 117.Several genetic conditions, including Li-Fraumeni and Cowden syndrome, are also linked to higher risks of breast cancer 118. 21 Women who have never given birth or who gave birth to their first child after the age of 30 have higher risks of developing breast cancer 119. Furthermore, increases in the number of live births slightly decreases risk of developing breast cancer 120. Women who have taken hormone replacement therapy (HRT) for a prolonged period, especially estrogen-progestin combinations, have a higher risk of developing breast cancer 121. Long-term oral contraceptive use is also associated with an increased risk of breast cancer 122. A benign condition characterized by irregular cell proliferation in breast tissue, atypical hyperplasia, is also a risk factor for breast cancer 123. Women diagnosed with the condition are at a 400% higher risk of developing breast cancer 124. Several sociodemographic and lifestyle characteristics have also been linked to breast cancer. Increasing age is associated with higher cancer risk 125,126. Socioeconomic status (SES), a broad metric that combines employment, income, and education, is also related to breast cancer. Women living in regions with the lowest quintile of neighbourhood income have a lower risk of being diagnosed with breast cancer than those living in areas with the highest quintile 127. Education is an additional risk factor for breast cancer, with more educated women having a greater breast cancer incidence 128. These paradoxical associations between socioeconomic status (SES) and the risk of breast cancer can be attributable to reproductive history (e.g. later age at first birth), SES gradients in access to and engagement in cancer screening programs, and greater use of oral contraceptives and hormone replacement therapy among higher SES populations 129. Race/ethnicity or country/region of birth is also a risk factor for breast cancer. For instance, First Nations women in BC had a slightly lower risk of breast cancer (age-standardized incidence rate of 224 per 100,000 people) than non-First Nations women (240 per 100,000 people) 130. A study 22 conducted in Ontario reported women who were born in South Asia, East Asia and Pacific, Sub-Saharan Africa, or Europe and Central Asia were at a lower risk of breast cancer than long-term Canadian residents (i.e., immigrants who arrived before 1985 or those who were Canadian-born) 131. There may also be associations between marital status and breast cancer incidence, with married women having a slightly lower risk 132. Several lifestyle factors may influence breast cancer risk. Greater adiposity (overweight/obesity) is associated with an increased risk of breast cancer 133. Low physical activity is also linked to a higher risk of breast cancer 134. Cigarette smoking and low consumption of fruits and vegetables are associated with a higher risk of breast cancer 134. Women who consume any amount of alcohol have a 22% greater risk of breast cancer than those who do not consume alcohol, and each 10-gram increase in alcohol consumption is associated with a 10% increase in breast cancer risk 135. The only occupational/environmental exposure that has been consistently associated with breast cancer is ionizing radiation, with exposure during puberty or early adulthood associated with particularly high risks 136,137. 2.2.2.2 Colorectal cancer The incidence of colorectal cancer increases with age, making aging the most prominent non-modifiable risk factor. About 90% of those who are diagnosed with colorectal cancer are at least 50 years old 138. The incidence of colorectal cancer is higher in men than in women 138. The age-standardized incidence rates are 18.6 per 100,000 men and 12.8 per 100,000 women 139. A strong cohort effect has been identified in the incidence of colorectal cancer, with likelihood of developing colorectal cancer increasing with successive birth cohorts 140. This trend may be due 23 to shifts in lifestyle factors that have occurred over time 140. Having a family history of colorectal cancer is an important risk factor 141. A family history of colorectal cancer in first-degree relatives is associated with a 72% greater risk of colorectal cancer, most likely as a result of shared genetic and environmental risk factors 142. Two rare genetic conditions, Lynch syndrome and familial adenomatous polyposis (FAP) are associated with increased risks of colorectal cancer 143. FAP is characterized by the abnormal growth of hundreds of adenomatous polyps in the colon and rectum 143. If left untreated, adenomatous polyps can proceed to cancer 144. Lynch syndrome is an autosomal dominant disorder resulting from germline mutations in DNA mismatch repair genes 145, which increases the risk of colorectal cancer and other types of cancer 146. Ashkenazi Jewish heritage has also been linked to a higher risk of colorectal cancer, most likely because of a higher prevalence of gene mutations like Lynch syndrome 145. Physical inactivity, being overweight or obese, consuming alcohol, and smoking have all been associated with a greater risk of colorectal cancer 134. The waist-to-hip ratio, a measure of abdominal obesity, has been positively associated with the risk of colorectal cancer 147. In comparison to non-drinkers or occasional drinkers, people who consumed 2 to 3 drinks per day or 4 or more drinks per day had a 21% or 52% higher risk of colorectal cancer, respectively 148. A meta-analysis found that ever-smokers were at an 18% significantly higher risk of developing colorectal cancer than never-smokers 149. Heme iron, nitrate/nitrite, and heterocyclic amines that are found in red and processed meat or form during the cooking process may underlie associations between red and processed meat and colorectal cancer risk 150. Low intake of fruits 24 and vegetables, and thus lower intake of dietary fibre 134, is also associated with a higher risk of colorectal cancer 151. Several sociodemographic factors are linked to the risk of colorectal cancer as well. Compared to long-term residents (Canadian-born and immigrants who arrived before 1985), immigrants from South Asia had the lowest risk of colorectal cancer. In addition, the longer that people resided in Canada, the greater the risk 131. Several health conditions are also associated with a higher risk of colorectal cancer. Compared to people without diabetes, those who have diabetes have a 30% higher risk of developing colorectal cancer 152. Two common types of inflammatory bowel disease, ulcerative colitis and Crohn’s disease, are well-documented risk factors for colorectal cancer 153. The anatomic location of colorectal cancer, including the colon (further subdivided into the proximal and distal colon) and rectum, is a significant driver of the disease’s pathogenesis and clinical characteristics. There is an association between sedentary behavior, such as prolonged sitting or lack of exercise, and an increased risk of distal colon or rectal cancer 154. The relationship between diabetes and colorectal cancer may be stronger for proximal colon cancer than distal colon or rectal cancer 155. The positive association between obesity and colorectal cancer may be stronger for colon cancer than for rectal cancer 156. 25 2.2.2.3 Pancreatic cancer Age is a key risk factor for pancreatic cancer, with the incidence increasing drastically after the age of 50 (age-standardized incidence rates of 13.4 per 100,000 people in 50 to 59 years vs 3.9 per 100,000 people in 40-49) 157. Men are more likely to develop pancreatic cancer than women (age-standardized incidence rate of 14.7 per 100,000 men vs 12.4 per 100,000 women) 157. People who have a first-degree family member (parent, sibling, or child) with pancreatic cancer have a 3.2-fold greater risk of developing the disease themselves 158. In addition, several genetic conditions (including hereditary pancreatitis 159, Peutz-Jeghers syndrome 160 and Lynch syndrome 161) have been associated with an elevated risk of pancreatic cancer. In comparison to non-First Nations residents in BC, First Nations residents had a slightly lower risk of pancreatic cancer 130, although it is unclear if differences reflect genetic factors or barriers to healthcare access 162. Diabetes is associated with an 80% increased risk of pancreatic cancer; however, the risk is higher in individuals with a shorter duration of diabetes 163. Chronic pancreatitis, an inflammatory disorder of the pancreas, is also a risk factor for pancreatic cancer. Five years after a diagnosis of pancreatitis, patients were 7.9 times more likely to develop pancreatic cancer 96. Cigarette smoking is one of the most well-established modifiable pancreatic cancer risk factors. Compared to never-smokers, current smokers have a 77% increased risk of developing pancreatic cancer, with the risk increasing with duration and intensity of smoking 164. In addition, ten years after quitting, former smokers continue to have a higher risk of pancreatic cancer than those who have never smoked 165. Alcohol consumption is also a risk factor for pancreatic 26 cancer. Excessive alcohol consumption (>60 mL ethanol/day) was associated with a 60% increased risk of pancreatic cancer 166. A systematic review found that consuming citrus fruits was associated with a 17% lower risk of pancreatic cancer 167. Another systematic review also found an inverse relationship with pancreatic cancer in vegetables and fruits among pooled case-control studies 168. However, a pooled analysis from cohort studies suggested no association 169. A meta-analysis of cohort studies found that men who consumed red meat had a 29% increased risk of pancreatic cancer, and each 50-gram of processed meat per day was associated with a 19% increased risk 170. However, similar associations were not observed in women 170. Obesity has been associated with an increased risk of pancreatic cancer. Compared to those with a normal BMI (18.5 to 24.9 kg/m2), individuals with a BMI of 25 to 29.9 or 30 to 34.9 kg/m2 had an 18% or 20% increased risk of pancreatic cancer 171. Physical inactivity may also be associated with increased risk of pancreatic cancer. A meta-analysis revealed that individuals who engaged in greater leisure time physical activity had an 11% lower risk of pancreatic cancer compared to those who were physically inactive 172. 27 Chapter 3: Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years 3.1 Introduction The prevalence of type II diabetes, herein referred to as diabetes, continues to grow and, globally, will affect 7.7% (439 million) of adults aged 20 to 79 years old by 2030 173. Epidemiological evidence suggests that diabetes is associated with a higher risk for many cancers, from 20-30% elevated breast or colorectal cancer to 97% elevated risk of intrahepatic cholangiocarcinoma or endometrial cancer 174,175. These associations likely reflect shared etiology. For instance, tobacco use, physical inactivity, overweight, and poor diet are closely linked to cancer risk and progression 176 and risk of diabetes 177–179. Several biological mechanisms have been proposed to explain why diabetes may be associated with cancer, including inflammation, hyperglycemia, and hyperinsulinemia 180,181. Furthermore, medications for diabetes may modify the association. Multiple epidemiologic studies have evaluated the association of diabetes medications with the risk of site-specific cancers in patients with diabetes 182,183. Previous systematic reviews either synthesized the effect of a single medication class on multiple cancer sites 184–186 or the effects of multiple medication classes on overall cancer 187. No systematic reviews have synthesized multiple associations among different diabetes medication classes and cancer sites in patients with diabetes, which limits our capacity to analyze evidence in the context of various mechanisms involved with diabetes treatment and underlying causes of cancers. To this end, we conducted a systematic review and meta-analyses of the latest 28 randomized controlled trials (RCTs) and observational studies (cohort and case-control studies) that evaluated the effect of diabetes medications, namely biguanides, incretin-based medicines, alpha-glucosidase inhibitors (AGIs), insulin secretagogues, thiazolidinediones, and insulins, on the risk of developing any of study cancers, specifically breast, colorectal, or pancreatic cancers. 3.2 Methods We followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) 188 for observational studies and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 189 statement for experimental studies. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in March 2021 (registration number: CRD42021239348). 3.2.1 Study designs We included original human experimental and observational studies that evaluated the associations between diabetes medications and six site-specific cancers, representing the most common cancer and cancers with high fatality. Studies using a cross-sectional design were excluded as they cannot provide clear evidence of temporality. In this study, we reviewed the results of RCTs, cohort, and case-control studies. 3.2.2 Participants The study population for breast cancer was restricted to female biological sex due to the rareness of breast cancer in males. People with prevalent cancer or a previous history of study cancers were excluded. No other restrictions were placed on the study population. 29 3.2.3 Exposures In RCTs, diabetes medications were randomly assigned. For observational studies, the determination of the exposure to diabetes medications was made on the basis of self-report, medical records, pharmacy prescription records, or insurance claims databases. 3.2.4 Comparators In addition to people receiving no treatment or placebo, for each diabetes medication of interest, people using one or more other diabetes medications were considered to be eligible as controls. Control groups were from population-based and hospital settings in observational studies and in RCTs respectively. 3.2.5 Outcomes Cancer incidence or mortality was determined through a national record system, cancer registry or death certificates. Eligible measures of the effect included odds ratio (OR), relative risk (RR), and hazard ratio (HR). 3.2.6 Publication characteristics Searches were limited to publications dating from January 2011 onwards to synthesize the recent evidence. No language restrictions were imposed. After titles/abstracts screening, the full text of selected studies in languages other than English was translated using Google Translate. 30 3.2.7 Search strategies With the assistance of an institutional librarian, we systematically searched MEDLINE (Ovid), Embase (Ovid), Web of Science Core Collection, and Cochrane CENTRAL (Ovid). Search terms included controlled vocabulary and keywords terms related to various diabetes medications and cancer at multiple sites. Details of the search strategy for MEDLINE (Ovid) are provided in Supplementary Table A-1. 3.2.8 Study selection All titles and abstracts were imported to Covidence (www.covidence.org). The study selection comprised two stages. Firstly, all titles and abstracts were screened by reviewers (Y.C., F.M., and S.S.) for potentially eligible papers according to the above-mentioned inclusion and exclusion criteria. Studies that were excluded by more than one reviewer were excluded from this review. Secondly, full texts of all relevant studies were retrieved, and two reviewers (Y.C., F.M., or S.S.) independently screened each study for eligibility. Reasons for exclusion were documented at the full-text screening stage. 3.2.9 Data extraction Two reviewers, Y.C. and F.M. or Y.C. and S.S. extracted data from each included study using Covidence independently. Discrepancies in extracted data were resolved through discussion or consensus with a third reviewer. 31 3.2.10 Quality assessment The methodological quality of RCTs and observational studies were scrutinized independently by two reviewers and collated by the lead reviewer using Cochrane Collaboration’s tool for assessing the risk of bias 190 and the Newcastle-Ottawa scale (NOS) 191. If randomization, allocation concealment, and blinding were uncertain in an RCT, it was categorized as a high-risk study 187. Three domains assessed in observational studies were the selection of study groups, the comparability of groups, and the ascertainment of exposure or outcome of interest. A score of less than 4 or more than 6 represented a high or low risk of bias, respectively 187. 3.2.11 Data synthesis We performed meta-analyses in order to obtain the pooled relative risk (RR) using Stata software version 17.0 (Stata Corp., College Station, TX, USA). First, the findings were summarized in a narrative form, with textual description and tabulation to compare potential differences among studies. We employed a DerSimonian-Laird random-effects model 192 to pool the data from two or more studies evaluating the same class of diabetes medication and the same site of cancer. Cochran’s Q was used to test the statistical heterogeneity of the included studies, with a significance level of 0.1 193. The magnitude of heterogeneity was measured using the I2 statistic 194 with <25% and >75% corresponding to low and high heterogeneity, respectively. Analyses were performed to quantify individual associations among different medication classes and cancer sites. We performed subgroup analyses (study design, quality levels, and population regions) to determine possible sources of between-study heterogeneity. 32 3.3 Results 3.3.1 Literature search The literature search and study selection process are summarized in Figure 3-1. Of the 10,540 citations uniquely identified from databases, 323 were eligible for full-text review. After reviewing and excluding studies on lung, prostate, or liver cancer, 61 studies were selected for inclusion. A detailed description of these studies can be found in the supplementary materials (Supplementary Table A-2). A total of 134 separate associations between various diabetes medication classes and cancer sites were evaluated in the 61 studies (Table 3-1). Sodium-glucose cotransporter 2 inhibitors were included in the meta-analysis but will not be discussed in this review as no studies on cancer sites of interest were identified. 33 Figure 3-1. Flow diagram for selection of studies included in the systematic review and meta-analysis 34 Table 3-1. Characteristics of the 61 studies selected for inclusion in systematic review and meta-analysis of diabetes medications and cancer associations Breast cancer Colorectal cancer Pancreatic cancer Total 35 57 42 Study design RCT 1 1 3 Cohort 31 32 27 Case-control 3 24 12 Risk of bias Low 21 40 31 Moderate 13 16 8 High 1 1 3 Population region Asian 7 27 15 Western 28 30 24 Multiple continents 0 0 3 RCT: Randomized controlled trial. 3.3.2 Study characteristics All three RCTs were categorized as having a high risk of bias due to either lack of allocation concealment or potential selective reporting (Supplementary Table A-2). Among the 42 cohort studies, eight and 34 were categorized as moderate and low risk of bias, respectively; observation time ranged from two to 25 years and 34 studies had data spanning more than five years. Of the 16 case-control studies, seven and nine were categorized as moderate and low risk of bias, respectively. Three of the case-control studies were conducted in hospital settings. Overall, colorectal cancer (n=57) was the most commonly evaluated outcome across included studies (Table 3-1). A cohort design was used for the majority of the breast (89%) studies. Regarding colorectal cancer, approximately equivalent numbers of the studies were conducted in populations from Asian and Western regions. The majority of studies on breast and pancreatic cancer were conducted in populations from Western regions. 35 3.3.3 Association between diabetes and cancer risk Individual associations among medication classes and cancer sites and subgroup analysis results are summarized here. Overall, a number of inverse associations were found. Biguanide use was significantly associated with lower risk of colorectal cancer (n=18, RR=0.85, 95%CI=0.78-0.92, Table 3-3). Use of thiazolidinediones was associated with lower risks of breast cancer (n=6, RR=0.87, 95%CI=0.80-0.95, Table 3-2). Lower risk of breast cancer (n=15, RR=0.90, 95%CI=0.82-0.98, Table 3-2) was found among insulin users compared with nonusers. On the other hand, elevated risk of pancreatic cancer was observed with insulin secretagogue use (n=5, RR=1.26, 95%CI=1.01-1.57, Table 3-4) and insulin use (n=8, RR=2.41, 95%CI=1.08-5.36, Table 3-4). Effects were largely consistent across studies with different designs, quality levels, and population regions, though there are some notable differences. The use of insulin secretagogues was significantly associated with higher colorectal cancer risk in cohort studies (n=4, RR=1.21, 95%CI=1.04-1.40, Table 3-3), but not in case-control studies. Biguanide use was associated with a higher risk of pancreatic cancer in case-control studies but not in cohort studies (n=3, RR=1.25, 95%CI=1.03-1.50, Table 3-4). Thiazolidinedione use was associated with a lower risk of pancreatic cancer in cohort studies (n=4, RR=0.59, 95%CI=0.39-0.89, Table 3-4), whereas, in case-control studies, a non-significant increased risk of pancreatic cancer was observed (n=2, RR=1.26, 95%CI=0.79-2.02, Table 3-4). 36 Table 3-2. Diabetes medication classes and breast cancer risk RR 95%CI P value for effect P value for Egger’s test I2 (%) P value for difference between subgroups Biguanides All studies (n=8) 0.74 (0.47–1.17) 0.20 0.96 99.08 — Study design Cohort (n=6) 0.69 (0.39–1.22) 0.21 — 99.01 0.37 Case-control (n=2) 0.92 (0.72–1.18) 0.51 — 77.07 Risk of bias Low risk (n=4) 0.74 (0.36–1.51) 0.40 — 99.40 0.95 Moderate risk (n=4) 0.75 (0.54–1.06) 0.11 — 87.65 Study population Asian (n=1) 0.38 (0.36–0.39) <0.001 — — <0.001 Western (n=7) 0.84 (0.69–1.03) 0.09 — 89.12 Incretin-based medicines All studies (n=2) 0.78 (0.61–1.00) 0.05 0.46 44.34 — Study design Cohort (n=2) 0.78 (0.61–1.00) 0.05 — 44.34 — Risk of bias Low risk (n=1) 0.70 (0.56–0.87) <0.001 — — 0.18 Moderate risk (n=1) 0.90 (0.67–1.21) 0.50 — — Study population Asian (n=1) 0.70 (0.56–0.87) <0.001 — — 0.18 Western (n=1) 0.90 (0.67–1.22) 0.50 — — Insulin secretagogues All studies (n=4) 1.04 (0.90–1.20) 0.60 0.97 9.80 — Study design Cohort (n=4) 1.04 (0.90–1.20) 0.60 — 9.80 — Risk of bias Low risk (n=3) 1.11 (0.96–1.30) 0.17 — <0.001 0.07 Moderate risk (n=1) 0.83 (0.63–1.10) 0.19 — — Study population Western (n=4) 1.04 (0.90–1.20) 0.60 — 9.80 — Thiazolidinediones All studies (n=6) 0.87 (0.80–0.95) <0.001 0.75 <0.001 — Study design RCT (n=1) 0.52 (0.26–1.04) 0.07 — — 0.14 Cohort (n=5) 0.88 (0.81–0.96) <0.001 — <0.001 Risk of bias Low risk (n=4) 0.88 (0.80–0.96) 0.01 — <0.001 0.33 Moderate risk (n=1) 0.91 (0.68–1.20) 0.50 — — High risk (n=1) 0.52 (0.26–1.04) 0.07 — — Study population Asian (n=2) 0.87 (0.79–0.97) 0.01 — <0.001 0.93 Western (n=4) 0.87 (0.73–1.03) 0.10 — <0.001 Insulins All studies (n=15) 0.90 (0.82–0.98) 0.02 0.07 72.10 — Study design Cohort (n=14) 0.87 (0.79–0.96) <0.001 — 67.70 <0.001 Case-control (n=1) 1.15 (1.02–1.29) 0.03 — — Risk of bias Low risk (n=9) 0.86 (0.76–0.96) 0.01 — 78.63 0.19 Moderate risk (n=6) 0.98 (0.83–1.14) 0.75 — 46.38 Study population Asian (n=3) 0.79 (0.50–1.25) 0.31 — 41.44 0.61 Western (n=12) 0.89 (0.80–0.99) 0.04 — 76.47 37 Table 3-3. Diabetes medication classes and colorectal cancer risk RR 95%CI P value for effect P value for Egger’s test I2 (%) P value for difference between subgroups Biguanides All studies (n=18) 0.85 (0.78–0.92) <0.001 0.11 97.33 — Study design Cohort (n=11) 0.80 (0.71–0.92) <0.001 — 98.28 0.15 Case-control (n=7) 0.91 (0.82–1.00) 0.05 — 88.63 Risk of bias Low risk (n=12) 0.86 (0.78–0.95) <0.001 — 98.12 0.51 Moderate risk (n=6) 0.81 (0.70–0.94) <0.001 — 78.74 Study population Asian (n=7) 0.76 (0.62–0.94) 0.01 — 98.49 0.13 Western (n=11) 0.90 (0.84–0.96) <0.001 — 80.05 Incretin-based medicines All studies (n=5) 1.03 (1.00–1.06) 0.11 0.34 <0.001 — Study design Cohort (n=4) 1.01 (0.97–1.06) 0.58 — <0.001 0.34 Case-control (n=1) 1.04 (1.00–1.09) 0.07 — — Risk of bias Low risk (n=4) 1.03 (1.00–1.06) 0.10 — <0.001 0.36 Moderate risk (n=1) 0.06 (0.01–27.59) 0.36 — — Study population Asian (n=2) 1.03 (0.99–1.06) 0.11 — <0.001 0.78 Western (n=3) 0.99 (0.76–1.28) 0.93 — 19.23 Alpha-glucosidase inhibitors All studies (n=2) 1.13 (0.97–1.31) 0.11 0.43 93.78 — Study design Cohort (n=1) 1.21 (1.17–1.26) <0.001 — — <0.001 Case-control (n=1) 1.05 (0.98–1.11) 0.18 — — Risk of bias Low risk (n=2) 1.13 (0.97–1.31) 0.11 — 93.78 — Study population Asian (n=2) 1.13 (0.97–1.31) 0.11 — 93.78 — Insulin secretagogues All studies (n=9) 1.07 (0.95–1.21) 0.25 0.33 94.82 — Study design Cohort (n=4) 1.21 (1.04–1.40) 0.01 — 85.06 0.04 Case-control (n=5) 1.03 (0.97–1.08) 0.38 — 40.29 Risk of bias Low risk (n=6) 1.10 (0.97–1.26) 0.15 — 95.75 0.22 Moderate risk (n=3) 1.00 (0.94–1.07) 0.96 — <0.001 Study population Asian (n=4) 1.13 (0.97–1.32) 0.13 — 97.10 0.18 Western (n=5) 1.01 (0.95–1.07) 0.83 — <0.001 Thiazolidinediones All studies (n=11) 0.99 (0.96–1.03) 0.86 0.19 55.38 — Study design RCT (n=1) 0.74 (0.43–1.27) 0.27 — — 0.50 Cohort (n=4) 0.94 (0.76–1.17) 0.59 — 63.45 Case-control (n=6) 0.99 (0.96–1.03) 0.72 — 52.91 Risk of bias Low risk (n=8) 1.01 (0.96–1.06) 0.74 — 60.70 0.37 Moderate risk (n=2) 0.97 (0.91–1.04) 0.38 — 62.65 High risk (n=1) 0.74 (0.43–1.27) 0.27 — — Study population Asian (n=7) 1.01 (0.98–1.04) 0.54 — 46.96 0.08 Western (n=4) 0.87 (0.73–1.03) 0.10 — 37.73 Insulins All studies (n=12) 1.04 (0.94–1.16) 0.42 0.39 95.19 — Study design Cohort (n=8) 1.03 (0.86–1.22) 0.77 — 96.81 0.75 Case-control (n=4) 1.06 (0.97–1.15) 0.19 — 59.90 Risk of bias Low risk (n=8) 1.03 (0.91–1.17) 0.63 — 96.58 0.54 Moderate risk (n=4) 1.15 (0.83–1.61) 0.41 — 87.21 Study population Asian (n=5) 1.22 (1.01–1.46) 0.04 — 94.15 0.09 Western (n=7) 0.96 (0.79–1.18) 0.72 — 95.68 38 Table 3-4. Diabetes medication classes and pancreatic cancer risk RR 95%CI P value for effect P value for Egger’s test I2 (%) P value for difference between subgroups Biguanides All studies (n=8) 1.08 (0.77–1.52) 0.65 0.53 96.10 — Study design Cohort (n=5) 1.01 (0.62–1.64) 0.98 — 97.18 0.43 Case-control (n=3) 1.25 (1.03–1.50) 0.02 — 43.74 Risk of bias Low risk (n=5) 1.05 (0.69–1.59) 0.83 — 97.74 0.97 Moderate risk (n=3) 1.04 (0.78–1.39) 0.80 — <0.001 Study population Asian (n=3) 0.97 (0.51–1.83) 0.92 — 98.56 0.62 Western (n=5) 1.15 (0.91–1.45) 0.23 — 62.28 Incretin-based medicines All studies (n=13) 0.73 (0.47–1.11) 0.14 0.56 96.69 — Study design RCT (n=2) 0.76 (0.20–2.95) 0.69 — 28.67 0.53 Cohort (n=10) 0.70 (0.42–1.19) 0.19 — 97.33 Case-control (n=1) 0.96 (0.81–1.12) 0.58 — — Risk of bias Low risk (n=10) 0.68 (0.42–1.09) 0.11 — 97.10 0.02 Moderate risk (n=1) 1.41 (1.13–1.75) <0.001 — — High risk (n=2) 0.76 (0.20–2.95) 0.69 — 28.67 Study population Asian (n=4) 0.84 (0.41–1.69) 0.62 — 96.77 0.67 Western (n=6) 0.63 (0.24–1.65) 0.34 — 97.79 Multiple continents (n=3) 0.95 (0.81–1.12) 0.55 — <0.001 Alpha-glucosidase inhibitors All studies (n=1) 1.15 (0.99–1.34) 0.06 — — — Study design Cohort (n=1) 1.15 (0.99–1.34) 0.06 — — — Risk of bias Low risk (n=1) 1.15 (0.99–1.34) 0.06 — — — Study population Asian (n=1) 1.15 (0.99–1.34) 0.06 — — — Insulin secretagogues All studies (n=5) 1.26 (1.01–1.57) 0.04 0.79 86.08 — Study design Cohort (n=2) 1.09 (1.01–1.17) 0.02 — <0.001 0.04 Case-control (n=3) 1.46 (1.11–1.91) 0.01 — 74.71 Risk of bias Low risk (n=4) 1.31 (1.01–1.69) 0.04 — 89.37 0.31 Moderate risk (n=1) 1.06 (0.77–1.45) 0.74 — — Study population Asian (n=2) 1.09 (1.01–1.17) 0.02 — <0.001 0.04 Western (n=3) 1.46 (1.11–1.91) 0.01 — 74.71 Thiazolidinediones All studies (n=7) 0.73 (0.47–1.14) 0.17 0.66 86.70 — Study design RCT (n=1) 0.31 (0.12–0.85) 0.02 — — 0.01 Cohort (n=4) 0.59 (0.39–0.89) 0.01 — 69.18 Case-control (n=2) 1.26 (0.79–2.02) 0.33 — 67.60 Risk of bias Low risk (n=5) 0.77 (0.44–1.34) 0.35 — 89.99 0.12 Moderate risk (n=1) 0.98 (0.64–1.48) 0.91 — — High risk (n=1) 0.31 (0.12–0.86) 0.02 — — Study population Asian (n=2) 0.80 (0.37–1.75) 0.58 — 76.96 0.75 Western (n=5) 0.68 (0.35–1.34) 0.27 — 88.92 Insulins All studies (n=8) 2.41 (1.08–5.36) 0.03 0.61 99.01 — Study design Cohort (n=5) 2.92 (0.98–8.70) 0.06 — 99.25 0.43 Case-control (n=3) 1.77 (0.95–3.30) 0.07 — 92.94 Risk of bias Low risk (n=6) 2.06 (1.55–2.73) <0.001 — 77.20 0.62 Moderate risk (n=2) 3.60 (0.40–32.23) 0.25 — 99.38 Study population Asian (n=3) 2.16 (1.52–3.09) <0.001 — <0.001 0.76 Western (n=5) 2.56 (0.92–7.14) 0.07 — 99.42 39 3.4 Discussion This comprehensive meta-analysis examined associations among the most commonly prescribed diabetes medication classes and the risk of breast, colorectal, and pancreatic cancers in patients with diabetes. Evidence of increased and decreased risks of cancer was found. For example, biguanide use was associated with a moderately decreased risk of colorectal cancer. Thiazolidinedione use was found to moderately reduce the risk of breast cancer. Conversely, the use of insulin secretagogues was associated with a moderately elevated risk of pancreatic cancer. Opposing associations with different cancer sites within a medication class were also evident; insulin use was associated with a higher risk of pancreatic cancers but a lower risk of breast cancer. In addition to varied cancer-specific biologic mechanisms, these differences may be attributed to variations in research instruments and the composition of study populations (e.g., age differences) across the included studies. Several biological mechanisms have been speculated to contribute to cancer modifying effects of diabetes medications. The protective effects of biguanides on colorectal cancer may be attributed to their ability to regulate upstream and downstream molecular mechanisms involved in cellular metabolism and energy homeostasis, cell cycle arrest, oxidative stress, inflammation, and apoptosis 195. By stimulating endogenous insulin production, insulin secretagogues increase insulin-like growth factor-1 levels which may promote pancreatic cancer development by interfering with cell metabolism and stimulating cell proliferation 196. Thiazolidinediones have been shown to suppress breast cancer cell proliferation, stimulating apoptosis, and impeding tumor angiogenesis with PPAR-γ ligands 197. 40 A protective effect of insulin was observed on breast cancer in the review, but the etiology is unclear. Lack of adjustment for mammography screening suggested detection bias might be a concern. In addition, insulin use has growth-promoting and mitogenic effects on pancreatic cancer cells, which may lead to pancreatic cancer development or acceleration 198. However, the higher risk of pancreatic cancer might be also attributable to severe diabetes conditions rather than insulin use. This review represents the latest examination of associations among all currently prescribed classes of diabetes medications and the risk of cancer across multiple sites. A myriad of new diabetes medications has become available over the past two decades 199. Our approach, considering different classes of medications separately across individual cancer sites, is an important advance over previous literature reviews 184–187 that have grouped all diabetes medications and/or cancer sites together. The large sample size of included studies augmented the precision of summary effect estimates and the inclusion of large numbers of individuals from Asian and Western regions enhances the generalizability of our findings. Our review has some limitations. Evidence of heterogeneity in summary risk estimates was observed for biguanides and insulins across all cancer sites, but subgroup analyses did not reveal clear sources of this heterogeneity. It is worth stressing that study design pronouncedly impacts results. For instance, the use of insulin secretagogues showed a more prominent effect on pancreatic cancer in case-control studies than in cohort studies. When the majority of studies were case-control studies, differences observed in results between cohort and case-control studies might be attributed to recall bias. Effects of sodium-glucose cotransporter 2 inhibitors on 41 cancer risk and AGIs on breast cancer could not be explored due to the absence of data. In general, few studies of cancer risk in association with AGIs and incretin-based medicines were identified. Differences in the standard of care for diabetes across jurisdictions and the use of combination medication therapies may have impacted results. Given that severity of diabetes is typically a driver of specific medication use, the possibility of confounding by indication cannot be ruled out in the individual studies that were included in this review. We did not evaluate dose-response relationships by incorporating the duration of diabetes medication use because it is beyond the scope of this review. In conclusion, various diabetes medications might be linked to the risk of study cancers; however, the strengths of associations showed variation to some extent across studies with different designs, quality levels, and population regions. On the other hand, the preventive effect of biguanides against colorectal cancer was consistent across different studies. An increased risk associated with insulin on the pancreas was only found in populations from Asian regions. Although further studies are required, these findings suggest that it may be important to weigh the potential harms of insulin among patients with diabetes who are at high risk of pancreatic cancer due to family history or other risk factors. The choice of medication for patients with diabetes may incorporate individuals’ susceptibility to individual cancers in conjunction with established clinical considerations. Future studies may further consider the duration of medication use and dose-response relationships to consolidate current knowledge in observed associations with study cancers. 42 Chapter 4: Methods 4.1 Data sources Population Data BC (referred to hereon as PopData) organizes and provides researchers and policymakers with access to longitudinal, individual level administrative data for all residents of British Columbia (BC) 200. The study cohort was established by linking basic demographic data (Consolidation file) 201 with data on prescription medications (PharmaNet) 202, cancer diagnoses (BC Cancer Registry) 203, and mortality (BC Vital Statistics Agency) 204. Linkage was conducted primarily by using Personal Health Numbers (PHNs), which are unique lifetime identifiers provided to each individual enrolled in BCs publicly-funded health insurance program (Medical Services Plan (MSP) 200. PopData performs validation and applies stringent, standardized linkage procedures by combining deterministic and probabilistic methodologies 200. The Consolidation file is the central demographic file that holds residence and health insurance data for every person enrolled with MSP or accessing healthcare services 201. PharmaNet records all prescriptions for pharmaceuticals and medical supplies filled by British Columbia community pharmacies 202. PharmaNet does not include medications administered to patients when they are admitted into the hospital, medications dispensed directly to hospital in-patients, over-the-counter medications purchased without a prescription, or third-party coverage information and paid amounts 202. PharmaNet records include Drug Identification Numbers / Product Identification Numbers (DIN/PIN), the date of dispensing, the dosage, the quantity dispensed, and the number of days supplied of each medication. 43 Cancers diagnosed in British Columbia are reported to the BC Cancer Registry, and it is estimated that the BC Cancer Registry captures 95% of all cancer cases occurring in the province 203. BC Vital Statistics data captured all deaths registered in BC 204. In addition, a subset of the British Columbia Generations Project (BCGP) data was linked with datasets at PopData. BCGP is a longitudinal cohort study of nearly 30,000 British Columbians aged 35 to 69 who were recruited through public outreach activities 205. Between 2009 and 2016, participants in BCGP completed questionnaires on health, demographics, and lifestyle 205. These datasets are summarized in Table 4-1. The table provides a description and the time period during which the data is available. Table 4-2 provides a thorough classification of diabetes medications captured in PharmaNet. It summarizes medication class, medication subclass, individual medication name, anatomical therapeutic chemical (ATC) code, and DIN/PIN. Ethics approval Approval for the study was granted by the Research Ethics Boards of the University of British Columbia and BC Cancer (Certificate Number: H20-02366). 44 Table 4-1. Datasets for the study Datasets Description Time period PopData, PharmaNet The PharmaNet system records all prescriptions for medications and medical supplies filled by British Columbia’s community and hospital outpatient pharmacies. During office visits, physicians can record medications administered to patients, although this is not required, and the data are incomplete. PharmaNet provides several functions, including medication dispensing, monitoring, and claims processing, and it stores both medication and PharmaCare claims information 202. 1996 to 2019 PopData, BC Cancer Registry The BC Cancer Registry obtains information on all cancers diagnosed and reported by residents in British Columbia. The data is derived from the broader BC Cancer Registry Identifying Data and is obtained from various sources, including hospital reports, pathology reports, hematology reports, cancer treatment centres, and death certificates. Since cancer is a reportable condition in British Columbia, it is estimated that at least 95% of all cancer cases are captured in the registry 203. 1985 to 2019 PopData, BC Vital Statistics Agency (deaths) The BC Vital Events and Statistics Deaths dataset contains every death registered in British Columbia 204. 1996 to 2019 PopData, Consolidation file, MSP registry The Central Demographics File, commonly known as the Consolidation File, is the primary file for demographic information. It includes basic demographic information such as age, sex, residential location, and MSP registration information 201. 1986 to 2019 PopData, Consolidation file, Census geodata Census geographic areas (e.g., Census Division, Census Subdivision, Census Metropolitan Area, Census Tract, Dissemination Area, etc.) and neighbourhood income quintiles/deciles were populated based on the individual’s residential postal code 201. 1989 to 2019 BCGP Data were obtained from a longitudinal cohort of nearly 30,000 British Columbians aged 35 to 69 who participated in the Canadian Partnership for Tomorrow’s Health. The questionnaire obtained information on health status, sociodemographics, physical measurements, and lifestyle 205. 2009 to 2016 BC: British Columbia. BCGP: British Columbia Generations Project. MSP: Medical Services Plan. PopData: Population Data BC. 45 Table 4-2. Classification information for diabetes medications in PharmaNet Medication class Medication subclass Individual medication name ATC DIN/PIN list 1) Biguanides Metformin A10BA02 314552, 2045710, 2099233, 2148765, 2162822, 2162849, 2167786, 2188902, 2220628, 2223562, 2229516, 2229517, 2229656, 2229785, 2229994, 2230026, 2230027, 2230475, 2230670, 2230671, 2231058, 2231389, 2233999, 2238827, 2239081, 2239214, 2242589, 2242726, 2242783, 2242793, 2242794, 2242931, 2242974, 2246820, 2246821, 2246964, 2246965, 2252945, 2252953, 2257726, 2257734, 2265575, 2265583, 2268493, 2268507, 2269031, 2269058, 2284782, 2284790, 2300451, 2305062, 2314894, 2314908, 2331519, 2331527, 2334437, 2334445, 2339110, 2339129, 2341522, 2341603, 2343606, 2343614, 2353377, 2353385, 2361264, 2361272, 2364506, 2364514, 2365286, 2365294, 2378043, 2378051, 2378116, 2378124, 2378620, 2378639, 2378841, 2378868, 2379767, 2379775, 2380196, 2380218, 2380722, 2380730, 2385341, 2385368, 2388766, 2388774, 2406020, 2406039, 2408228, 2408236, 2409283, 2409291, 2421828, 2421836, 2438275, 2438283, 2444933, 2444941, 2446065, 2449390, 2449404, 2460653 2) Incretin-based medicines DPP-4 inhibitors Alogliptin A10BH04 2417189, 2417197, 2417200 Linagliptin A10BH05 2370921 Saxagliptin A10BH03 2333554, 2375842 Sitagliptin A10BH01 2303922, 2388839, 2388847 GLP-1 receptor agonists Albiglutide A10BJ04 2443635, 2443643 Dulaglutide A10BX14 2448599, 2448602 Exenatide A10BX04 2361809, 2361817, 2448610 Liraglutide A10BX07 2351064, 2437899, 2351056 Lixisenatide A10BJ03 2464276, 2464284, 2464349 Semaglutide A10BJ06 2471469, 2471477 3) SGLT-2 inhibitors Canagliflozin A10BX11 2425483, 2425491 Dapagliflozin A10BX09 2435462, 2435470 Empagliflozin A10BX12 2443937, 2443945 4) AGIs Acarbose A10BF01 2190885, 2190893 5) Insulin secretagogues Meglitinides Nateglinide A10BX03 2245438, 2245439, 2245440 Repaglinide A10BX02 2239924, 2239925, 2239926, 2321475, 2321483, 2321491, 2354926, 2354934, 2354942, 2355663, 2355671, 2355698, 2357453, 2357461, 2357488, 2366347, 2366355, 2366363, 2373270, 2373289, 2373297, 2415968, 2415976, 2415984, 2424258, 2424266, 2424274 Sulfonylureas Acetohexamide A10BB31 15598 Chlorpropamide A10BB02 13730, 21350, 24708, 24716, 156728, 209937, 312711, 377937, 399302, 430986, 586773 Glibenclamide (glyburide) A10BB01 12599, 454753, 720933, 720941, 808733, 808741, 1900927, 1900935, 1913654, 1913662, 1913670, 1913689, 1959352, 1959360, 1987534, 1987836, 2020734, 2020742, 2084341, 2085887, 2147521, 2147548, 2224550, 2224569, 2226804, 2226812, 2228920, 2228939, 2229595, 2229596, 2230036, 2230037, 2234513, 2234514, 2236543, 2236548, 2236733, 2236734, 2242095, 2242096, 2248008, 2248009, 2316544, 2340763, 2340771, 2345854, 2345862, 2350459, 2350467, 2363704, 2363712 Gliclazide A10BB09 765996, 2155850, 2229519, 2238103, 2242987, 2245247, 2248210, 2248453, 2254719, 2287072, 2294400, 2297795, 2336316, 2348578, 2356422, 2363518, 2405067, 2407124, 2423286, 2423294, 2429764, 2429772, 2438658, 2439328, 2449765, 2461323, 2461331, 2463571 46 Medication class Medication subclass Individual medication name ATC DIN/PIN list Glimepiride A10BB12 2245272, 2245273, 2245274, 2269589, 2269597, 2269619, 2273101, 2273128, 2273136, 2273756, 2273764, 2273772, 2274248, 2274256, 2274272, 2279061, 2279088, 2279126, 2284545, 2284553, 2295377, 2295385, 2295393, 2313596 Tolbutamide A10BB03 12602, 12610, 13889, 21849, 93033, 156663, 209872, 312762, 431168, 1987542, 1987828, 2224771, 2224798 6) Thiazolidinediones Pioglitazone A10BG03 2242572, 2242573, 2242574, 2274914, 2274922, 2274930, 2297906, 2297914, 2297922, 2298279, 2298287, 2298295, 2301423, 2301431, 2301458, 2302861, 2302888, 2302896, 2302942, 2302950, 2302977, 2303124, 2303132, 2303140, 2303442, 2303450, 2303469, 2307634, 2307642, 2307650, 2307669, 2307677, 2307723, 2312050, 2312069, 2312077, 2320754, 2320762, 2320770, 2326477, 2326485, 2326493, 2339587, 2339595, 2345366, 2345374, 2345382, 2363232, 2363240, 2363259, 2365529, 2365537, 2374013, 2374021, 2374048, 2374587, 2374595, 2375850, 2375869, 2375877, 2384906, 2384914, 2384922, 2389290, 2389304, 2389312, 2391600, 2397307, 2417049, 2417057, 2417065, 2418002, 2418010, 2418029, 2421674, 2421682, 2421690, 2434121, 2434148, 2434156 Rosiglitazone A10BG02 2241112, 2241113, 2241114, 2306166, 2306174, 2306182, 2307170, 2307189, 2307197, 2307553, 2307561, 2307588, 2326329, 2326337, 2326345, 2354144, 2354152, 2354160, 2354349, 2354357, 2354365, 2403366, 2403374, 2403382 7) Insulins and analogues Basal insulins Insulin degludec A10AE06 2467879, 2467887 Insulin detemir A10AE05 2271842, 2412829 Insulin glargine,hum.rec.anlog A10AE04 2245689, 2251930, 2294338, 2441829, 2444844, 2444852, 2461528 Insulin isophane human, NPH A10AC01 1959239, 2024225, 2024268, 2024403, 2241310, 2403447, 587737 Insulin isophane NPH,bf-pk A10AC01 1934066, 446572, 612235 Insulin isophane,pork pure A10AC03 2275864, 514551 Insulin NPH human semi-syn A10AB01 1986805, 612197, 632686 Insulin reg-isophane,NPH human A10AD01 1959212, 1962639, 1962647, 1962655, 1962663, 2024217, 2024292, 2024306, 2024314, 2024322, 2024446, 2025248, 795879, 889091, 889105, 889113 Insulin zinc extend human rec A10AE01 2024276, 644358, 733075 Insulin zinc human recombinant A10AC01 2024241, 646148 Insulin zinc,beef-pork A10AC01 1934090, 446580, 612278 Insulin zinc,pork purified A10AC03 514535 Bolus insulins Insulin aspart A10AB05 2244353, 2245397, 2377209 Insulin aspart (niacinamide) A10AB05 2460408, 2460416, 2460424 Insulin glulisine A10AB06 2279460, 2279479, 2294346 Insulin lispro A10AB04 2229704, 2229705, 2233562, 2241283, 2403412, 2439611, 2470152 Insulin regular, human A10AB01 1959220, 2024233, 2024284, 2025256, 2415089, 2466864, 586714 Insulin regular,beef-pork A10AB01 1934112, 446564, 612227 Insulin,pork purified A10AB03 2275872, 513644 Premixed insulins Insulin aspart/aspart protamin A10AD05 2265435 Insulin lispro/lispro protamin A10AD04 2240294, 2240295, 2240297, 2403420, 2403439 Insulin NPH s-s/reg insulin hm A10AD01 889121 8) Combinations of oral blood glucose lowering medications Incretin-based medicines & sodium-glucose cotransporter 2 inhibitors Linagliptin and empagliflozin A10BD19 2459752, 2459760 Incretin-based medicines & thiazolidinediones Pioglitazone and alogliptin A10BD09 2419300, 2419319, 2419327, 2419335, 2419343, 2419351 47 Medication class Medication subclass Individual medication name ATC DIN/PIN list Insulin secretagogues & thiazolidinediones Glimepiride and rosiglitazone A10BD04 2258781, 2258803, 2258811 Metformin & incretin-based medicines Metformin and alogliptin A10BD13 2417219, 2417227, 2417235 Metformin and linagliptin A10BD11 2403250, 2403269, 2403277 Metformin and saxagliptin A10BD10 2389169, 2389177, 2389185 Metformin and sitagliptin A10BD07 2333856, 2333864, 2333872, 2416786, 2416794, 2416808 Metformin & sodium-glucose cotransporter 2 inhibitors Metformin and canagliflozin A10BD16 2455404, 2455412, 2455420, 2455439, 2455447, 2455455 Metformin and dapagliflozin A10BD15 2449935, 2449943 Metformin and empagliflozin A10BD20 2456575, 2456583, 2456591, 2456605, 2456613, 2456621 Metformin & thiazolidinediones Metformin and rosiglitazone A10BD03 2247085, 2247086, 2247087, 2248440, 2248441, 2357887, 2357895, 2357909, 2357917, 2357925 AGIs: Alpha-glucosidase inhibitors. ATC: Anatomical therapeutic chemical. DIN/PIN: Drug Identification Numbers / Product Identification Numbers. DPP-4 inhibitors: Dipeptidyl peptidase 4 inhibitors. GLP-1 receptor agonists: Glucagon-like peptide 1 receptor agonists. SGLT-2 inhibitors: Sodium-glucose cotransporter 2 inhibitors. 48 4.2 Study population The study cohort was defined using the following inclusion criterion; all BC residents aged 35 years or older and registered with MSP between 1 January 1996 to 31 December 2019. The exposure data from PharmaNet dates back to 1996. The most recent outcome data from BC Cancer Registry is Dec 31, 2019. Given the low incidence of diabetes and cancer during early adulthood, an age range of 35 and 100 was selected. Individuals were excluded from the cohort if they met any of the following: (i) did not reach 35 years of age by December 31, 2019, (ii) had a cancer diagnosis (except non-melanoma skin cancer) before 1996, (iii) did not have at least 5 consecutive years of MSP registry, (iv) fewer than 5 years of follow-up data, (v) used any diabetes medications within their first full year of follow-up, i.e., 1-year washout period) 206, and (vi) cancer diagnosis, death, or censoring occurred within first full year of follow-up (i.e., 1-year lag period) 207. All individuals were followed from the year of cohort entry until first diagnosis of any cancer (except non-melanoma skin cancer), death, loss to follow-up or December 31, 2019, whichever occurred first. An eligible participant in the study cohort’s follow-up period is shown in Figure 4-1. 49 Figure 4-1. Illustration of an eligible individual in the study cohort 50 4.3 Exposure assessment The prevalence of use of the various diabetes medications at the class, subclass, and individual levels was compared to a benchmark diabetes medication, acarbose. Acarbose was chosen as the benchmark as it had the lowest number of exposed individuals across all medication classes, and below this, the number of exposed individuals would not support model convergence. The prevalence of use of individual medications was determined by calculating their “sums of quantity” and “sums of days supplied”. If either value was greater than that of the benchmark medication acarbose, the medication was evaluated individually. Otherwise, the medication was only included in analyses at the subclass and/or class levels. Based on this criterion, seven mutually exclusive medication classes, six subclasses, and seven individual medications were identified as study exposures. Each of the 20 study exposures were parameterized as follows: (i) binary (ever vs never use) 208, (ii) continuous cumulative duration (in years) 209, (iii) continuous cumulative dose (in 1-year-equivalent doses based on defined daily doses) 209, (iv) categorized cumulative duration, and (v) categorized cumulative dose, both with low, medium, or high categories compared to none) 210. Cumulative duration was calculated by summing the total number of days supplied of each medication, or class, or subclass over the follow-up period and dividing by 365.25 to obtain the total number of years the medication was prescribed. The World Health Organization’s (WHO) defined daily dose (DDD) 211, the typical daily amount used for the medication’s primary indication in adults, was used to calculate the cumulative dose. As the potencies of different 51 diabetes medications vary, the total quantity dispensed for each medication was converted to a proportion of DDD for that medication and then added up to standardize potencies. The 1-year-equivalent doses were then calculated by dividing the total DDD-standardized dose by 365.25. Duration- and dose-responses were assessed for continuous cumulative duration and continuous cumulative dose, and categorized cumulative duration and categorized cumulative dose. These definitions enabled examination of real-world scenarios where individuals are exposed to multiple medications simultaneously and transition between different medications during the follow-up period. Cumulative duration and dose categories were defined by specific ranges of duration (in years) and dose (in 1-year-equivalent doses) (Table 4-3). The values were divided into three equal categories (i.e., tertiles) of person-years for cumulative duration and dose values greater than zero. 4.4 Outcome assessment The BC Cancer Registry is regarded as the gold standard for detecting incident cancer in British Columbia, as it records an estimated 95% of all cancer cases 203. Incident cases of any cancer (except non-melanoma skin cancer) in the source population were identified by linking to the BC cancer registry using ICD-O-3 (International Classification of Diseases in Oncology, Third Edition). Main outcomes of interest included incident breast, colorectal, and pancreatic cancers, along with their respective subtypes (Table 4-4). In this study, breast cancer refers to cancers found in the breast tissue of individuals who are biologically female. 52 Table 4-3. Ranges of duration (years) and dose (1-year-equivalent doses) for identified diabetes medications Duration Dose Study exposure Medication level Mean (SD) Low, medium, and high groups Mean (SD) Low, medium, and high groups 1. Biguanides (i.e., metformin) Class 4.45 (4.32) <1.62, 1.62 to 5.59, ≥5.59 3.39 (3.98) <0.86, 0.86 to 3.82, ≥3.82 2. Incretin-based medicines Class 2.05 (2.05) <0.66, 0.66 to 2.38, ≥2.38 1.70 (1.95) <0.40, 0.40 to 1.89, ≥1.89 2.1. DPP-4 inhibitors Subclass 2.07 (2.01) <0.74, 0.74 to 2.44, ≥2.44 2.04 (2.00) <0.74, 0.74 to 2.38, ≥2.38 2.1.1. Linagliptin Individual 1.57 (1.40) <0.62, 0.62 to 1.89, ≥1.89 1.57 (1.41) <0.61, 0.61 to 1.89, ≥1.89 2.1.2. Sitagliptin Individual 1.87 (1.84) <0.66, 0.66 to 2.22, ≥2.22 1.84 (1.83) <0.63, 0.63 to 2.15, ≥2.15 2.2. GLP-1 receptor agonists Subclass 1.35 (1.56) <0.36, 0.36 to 1.40, ≥1.40 0.26 (0.46) <0.04, 0.04 to 0.21, ≥0.21 3. SGLT2 inhibitors Class 1.28 (1.13) <0.52, 0.52 to 1.48, ≥1.48 1.40 (1.47) <0.47, 0.47 to 1.52, ≥1.52 4. AGIs (i.e., acarbose) Class 1.71 (2.66) <0.25, 0.25 to 1.35, ≥1.35 0.95 (1.76) <0.09, 0.09 to 0.62, ≥0.62 5. Insulin secretagogues Class 4.33 (4.28) <1.48, 1.48 to 5.06, ≥5.06 8.36 (10.76) <1.81, 1.81 to 8.42, ≥8.42 5.1. Meglitinides Subclass 1.87 (2.56) <0.33, 0.33 to 1.72, ≥1.72 2.07 (3.82) <0.23, 0.23 to 1.48, ≥1.48 5.1.1. Repaglinide Individual 1.88 (2.56) <0.33, 0.33 to 1.73, ≥1.73 2.08 (3.83) <0.23, 0.23 to 1.48, ≥1.48 5.2. Sulfonylureas Subclass 4.29 (4.25) <1.48, 1.48 to 5.01, ≥5.01 8.36 (10.75) <1.82, 1.82 to 8.43, ≥8.43 5.2.1. Gliclazide Individual 2.84 (3.13) <0.82, 0.82 to 3.12, ≥3.12 7.89 (10.92) <1.75, 1.75 to 7.26, ≥7.26 5.2.2. Glyburide Individual 3.86 (3.98) <1.15, 1.15 to 4.52, ≥4.52 6.41 (8.45) <1.14, 1.14 to 6.34, ≥6.34 6. Thiazolidinediones Class 2.52 (2.64) <0.74, 0.74 to 2.92, ≥2.92 2.50 (2.95) <0.60, 0.60 to 2.68, ≥2.68 6.1. Pioglitazone Individual 2.37 (2.59) <0.63, 0.63 to 2.66, ≥2.66 2.42 (2.91) <0.55, 0.55 to 2.55, ≥2.55 6.2. Rosiglitazone Individual 2.12 (2.24) <0.57, 0.57 to 2.43, ≥2.43 2.06 (2.50) <0.49, 0.49 to 2.16, ≥2.16 7. Insulins and analogues Class 3.75 (4.17) <1.00, 1.00 to 4.22, ≥4.22 6.52 (8.87) <1.37, 1.37 to 6.67, ≥6.67 7.1. Basal insulins Subclass 3.26 (3.61) <0.90, 0.90 to 3.68, ≥3.68 5.64 (7.50) <1.23, 1.23 to 5.67, ≥5.67 7.2. Bolus insulins Subclass 2.39 (3.06) <0.42, 0.42 to 2.46, ≥2.46 3.90 (5.96) <0.62, 0.62 to 3.59, ≥3.59 AGIs: Alpha-glucosidase inhibitors. DPP-4 inhibitors: Dipeptidyl peptidase 4 inhibitors. GLP-1 receptor agonists: Glucagon-like peptide 1 receptor agonists. SGLT-2 inhibitors: Sodium-glucose cotransporter 2 inhibitors. SD: Standard deviation. Duration is expressed in years, and dose is expressed in 1-year-equivalent doses. 53 Table 4-4. Site and morphology codes for cancer types and subtypes Cancer and subtypes Site code Morphology code Breast cancer C500-C509 Exclude 9050-9055, 9140, 9590-9992, 80102, 80502, 80522, 80702, 81402, 82012, 82302, 82612, 85002, 85012, 85032, 85042, 85072, 85092, 85192, 85202, 85222, 85232 Ductal C500-C509 85003, 85013, 80223, 81413, 82013 Lobular C500-C509 85203 Colorectal cancer C180-C189, C199, C209, C260 Exclude 9050-9055, 9140, 9590-9992 Colon C180-C189, C260 Exclude 9050-9055, 9140, 9590-9992 Proximal colon C180-185 Exclude 9050-9055, 9140, 9590-9992 Distal colon C186, C187 Exclude 9050-9055, 9140, 9590-9992 Rectum C199, C209 Exclude 9050-9055, 9140, 9590-9992 Pancreatic cancer C250-C259 Exclude 9050-9055, 9140, 9590-9992 Adenocarcinoma C250-C253, C257-C259 Exclude 9050-9055, 9140, 9590-9992, 8150, 8151, 8153, 8155, 8240, and 8246 4.5 Potential confounders The selection of confounders for models was guided by a priori knowledge derived from the literature review presented in Chapter 2. Several baseline demographic and geographic measures were included in all analyses: age, birth cohort (1896-1940, 1941-1950, 1951-1957, 1958-1964, and 1965-1980), sex at birth, neighbourhood income quintile at study entry, and health authority at study entry (Interior, Fraser, Vancouver Coastal, Vancouver Island, or Northern) (Table 4-5). Health authority was included because it is possible that the characteristics encapsulated by the health authority, such as population size, demographics, and healthcare infrastructure, may influence the occurrence or diagnosis of diabetes (hence exposure to diabetes medication) and/or cancer. 54 Table 4-5. Definition of potential confounders in adjusted models Confounder Description Collection time Data source Variable type Age Calendar year minus birthyear At each year BC Vital Statistics Agency Continuous; unit: years Birth cohort Categorized birthyear At birth BC Vital Statistics Agency Categorical: 1896-1940, 1941-1950, 1951-1957, 1958-1964, and 1965-1980 Sex Biological sex At birth BC Vital Statistics Agency Binary: male/female Health authority Health authority of the individual’s residence At study entry Consolidation file, MSP registry Categorical: Interior, Fraser (reference), Vancouver Coastal, Vancouver Island, and Northern Neighbourhood income quintile Neighbourhood income per person (equivalent to household income adjusted for household size) At study entry Consolidation file, Census geodata Categorical: quintile 1, quintile 2, quintile 3, quintile 4, and quintile 5 (reference) BC: British Columbia MSP: Medical Services Plan PopData: Population Data BC 4.6 Statistical analysis For each categorical exposure parameterization (binary, categorized cumulative duration and categorized cumulative dose), crude incidence rates of cancers with 95% confidence intervals were calculated based on the Poisson distribution using SAS (version 9.4; SAS Institute, Inc., Cary, NC). Missing data for covariates were handled using single imputation with predictive mean matching 212. Birth year, sex at birth, exposure to various diabetes medications during follow-up, diagnosis of incident cancer were included as auxiliary variables in the imputation model. 55 4.6.1 Primary analysis Time-varying Cox proportional hazards models with age as the underlying time axis were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for each study outcome. Each diabetes medication of interest was treated as a time-varying variable. Separate time-varying Cox models were implemented to provide risk estimates for each of the five exposure parameterizations. Throughout the study period, the exposure to the medication is not fixed. Instead, it changes over time, with individuals beginning, discontinuing, or altering their medication at various points. A 1-year washout period was implemented to exclude prevalent users of any diabetes medication 206. A 1-year lag period 207 was applied to exclude users who started a new diabetes medication within one year prior to the endpoint to attenuate protopathic bias 213 and reflect cancer latency 207. The following models were specified: (1) a crude model and (2) a model adjusted for sex at birth (if colorectal or pancreatic cancer), birth cohort, health authority, and neighbourhood income quintile (fully adjusted model). Analyses were conducted with SAS (version 9.4; SAS Institute, Inc., Cary, NC). A two-sided P value less than 0.05 was deemed to indicate statistical significance. 4.6.2 Sensitivity analyses 4.6.2.1 Additional adjustment for other diabetes medications When metformin is insufficient to reach glycemic targets or the patient exhibits symptomatic hyperglycemia, a second-line medication is added or substituted 74. The selection of the second- 56 line medication is based on the patient’s health conditions and other factors, such as the mode of administration and potential side effects 74. Therefore, accounting for concomitant medications (co-medication) in the models allows for the adjustment of the individual’s health status and diabetes severity. For this reason, the models were further adjusted to account for the time-varying use of other diabetes medications during the follow-up period 214. For each medication, a list of other mutually exclusive diabetes medications was identified. For example, when repaglinide was the primary exposure under consideration, metformin, incretin-based medicines, SGLT-2 inhibitors, acarbose, sulfonylureas, thiazolidinediones, and insulins and analogues during the study period were separately included as covariates in models. This approach was applied to continuous and categorized cumulative duration and dose respectively. 4.6.2.2 Washout and lag periods To evaluate whether there was an impact of the pre-defined medication washout period and lag time window, the primary analysis was repeated with 0-year and 2-year washout and lag periods. The sensitivity analysis consisted of five models, each of them was derived from a fully adjusted model and differed only in terms of their respective washout and lag periods: Model 1, with a 1-year washout and a 1-year lag period (i.e., the primary analysis); Model 2, with a 1-year washout and a 0-year lag period; Model 3, with a 1-year washout and a 2-year lag period; Model 4, with a 0-year washout and a 1-year lag period; and Model 5, with a 2-year washout and a 1-year lag period. Models 2 and 4 served as methodological reference points, assisting in understanding the impact of omitting considerations of time-related biases. In contrast, Models 3 and 5 were used to evaluate the impact of extending the lag and washout periods, respectively, in comparison to 57 Model 1's 1-year durations. The comparison across these models allowed for a thorough examination of the influence of different time-related bias mitigation strategies on the study associations 206,207. 4.6.2.3 BCGP analysis Within the main cohort, a subset (n = 26,703) were part of the BCGP study, and thus had self-reported data on various additional sociodemographic, physical measures, and lifestyle factors. The demographic information for participants from the BCGP study is summarized in Table 4-6. The BCGP analysis was used to assess the effect of adjustment for additional factors for the significant associations identified in the primary analysis. In the BCGP analysis, additional sociodemographic and lifestyle-related factors 120,132,134,214–219 from the baseline BCGP study questionnaire that were identified as potential confounders (Table 4-7) from prior literature were included in the adjusted models to supplement the primary analysis: race/ethnicity (white vs non-white) 215, marital status (married or living in common-law vs single, divorced or widowed) 132, highest education obtained (high school or less, trade/technical/vocational training, bachelor’s degree, and postgraduate degree) 216, household income (<$50,000, $50,000-74,999, $75,000-99,999, $100,000-149,999 and > $150,000) 214, number of live births in women (nulliparous, one child, two, and > two children) 120, high waist to hip ratio (<0.86 vs ≥0.86 for females and <1 or ≥1 for males) 216,218, BMI (under or normal weight (<25 kg/m2), overweight (25.0-29.9 kg/m2), or obese (≥30 kg/m2) 134,216, physical activity (<600 Metabolic Equivalent Minute [MET] minutes per week vs ≥600 MET-minutes per week) 217,219, fruit and vegetable consumption (<five servings per day vs ≥five servings per day) 134,217, alcohol consumption frequency (never, 58 up to three times per month, up to five times per week, and nearly daily) 216, and smoking status (never, former, or current smokers) 134,216. Table 4-6. Baseline characteristics at cohort entry of participants from the BCGP study Total Characteristic N = 26,703, n (%) Incident breast cancer 1,174 (6.4) Incident colorectal cancer 377 (1.4) Incident pancreatic cancer 52 (0.2) Age (years)a 35-39 9,894 (37.1) 40-44 4,938 (18.5) 45-49 5,650 (21.2) 50-54 4,824 (18.1) 55-59 1,018 (3.8) 60-64 313 (1.2) 65-69 66 (0.2) 70-100 Mean±SD 43.4±7.1 (0.0) Birth cohortb 1896-1940 162 (0.6) 1941-1950 9,983 (37.4) 1951-1957 7,010 (26.3) 1958-1964 5,259 (19.7) 1965-1980 4,289 (16.1) Sexb Female 18,308 (68.6) Male 8,395 (31.4) Health authoritya Interior 3,545 (13.3) Fraser 7,456 (27.9) Vancouver Coastal 7,896 (29.6) Vancouver Island 5,367 (20.1) Northern 2,037 (7.6) Missing 402 (1.5) Neighbourhood income quintilea Quintile 1 3,296 (12.3) Quintile 2 4,001 (15.0) Quintile 3 4,976 (18.6) Quintile 4 6,251 (23.4) Quintile 5 7,524 (28.2) Missing 655 (2.5) Race/ethnicity Non-white 2,731 (10.2) White 23,972 (89.8) Marital status Single, divorced, or widowed 6,414 (24.0) Married or living in common-law 20,289 (76.0) Highest education obtained High school or less 5,145 (19.3) 59 Total Characteristic N = 26,703, n (%) Trade/technical/vocational training 10,173 (38.1) Bachelor’s degree 6,737 (25.2) Postgraduate degree 4,648 (17.4) Household income <$50,000 5,926 (22.2) $50,000-74,999 5,695 (21.3) $75,000-99,999 4,922 (18.4) $100,000-149,999 5,862 (22.0) >$150,000 4,298 (16.1) Number of live births in women Nulliparous 1,042 (5.7) One child 3,343 (18.3) Two children 9,271 (50.6) >Two children 4,652 (25.4) High waist to hip ratio <0.86 for females and <1 for males 16,929 (63.4) ≥0.86 for females and ≥1 for males 9,774 (36.6) Body mass index Underweight or normal weight (<25 kg/m2) 12,193 (45.7) Overweight (25.0-29.9 kg/m2) 9,549 (35.8) Obese (≥30 kg/m2) 4,961 (18.6) Lack of physical activity ≥600 METs-minutes/week 18,705 (70.1) <600 METs-minutes/week 7,998 (30.0) Low fruit and vegetable consumption ≥5 servings of fruits and vegetables/day 15,476 (58.0) <5 servings of fruits and vegetables/day 11,227 (42.0) Alcohol consumption frequency Never 2,624 (9.8) Up to 3 times/month 8,358 (31.3) Up to 5 times/month 11,819 (44.3) Nearly daily 3,902 (14.6) Smoking status Never smokers 14,373 (53.8) Former smokers 10,950 (41.0) Current smokers 1,380 (5.2) a: Measured at study entry. b: Measured at birth. BCGP: British Columbia Generations Project. MET: Metabolic Equivalent of Task. 60 Table 4-7. Definition of additional confounders in BCGP analysis Confounder Description Collection time Data source Variable type Race/ethnicity At study entry Social demographics characteristics Binary: non-white vs white Marital status At study entry Social demographics characteristics Categorical: single, divorced, or widowed vs married or living in common-law Highest education obtained Highest level of education completed At study entry BCGP, Social demographics characteristics Categorical: high school or less, trade/technical/vocational training (reference), bachelor’s degree, and postgraduate degree Household income Average yearly household income before taxes, including salaries, pensions, and allowances At study entry BCGP, Social demographics characteristics Categorical: <$50,000, $50,000-74,999, $75,000-99,999, $100,000-149,999 and >$150,000 (reference) Number of live births in women Female participant’s total live births At study entry BCGP, Health status Categorical: nulliparous, one child, two (reference), and >two children High waist to hip ratio Consolidated waist and hip circumference measures (taken or self-reported), prioritizing taken measurements. At study entry BCGP, Physical measurements Binary: ≥0.86 vs <0.86 for females or ≥1 vs <1 for males BMI Body weight (in kilogram) divided by body height (in meter) squared. BMI = (body weight) / (Standing body height) ^2. Consolidated taken (using Tanita bioelectrical impedance device for body weight and/or Seca stadiometer for body height) and/or self-reported BMI, prioritizing taken measurements. At study entry BCGP, Physical measurements Categorical: under or normal weight (<25 kg/m2), overweight (25.0-29.9 kg/m2), or obese (≥30 kg/m2) Lack of physical activity Total of vigorous and moderate MET‐minutes/week = (8.0 * vigorous‐intensity activity minutes * vigorous‐intensity activity days) + (4.0 * moderate‐intensity activity minutes * moderate‐intensity activity days) At study entry BCGP, Physical activity Binary: ≥600 MET minutes per week vs <600 MET minutes per week 61 Confounder Description Collection time Data source Variable type Low fruit and vegetable consumption The average daily consumption of fruit (excluding juice) and/or vegetable (approximately 125 millilitres) At study entry BCGP, Lifestyle Binary: ≥5 servings per day vs <5 servings per day Alcohol consumption frequency Frequency of alcohol consumption during the past 12 months At study entry BCGP, Lifestyle Categorical: never, up to three times per month, up to five times per week (reference), and nearly daily Smoking status Cigarette smoking status. A participant is considered a past smoker if he/she does not smoke currently but has ever smoked 100 cigarettes or more during his/her lifetime At study entry BCGP, Lifestyle Categorical: never (reference), former, or current smokers BC: British Columbia. BCGP: British Columbia Generations Project. BMI: Body mass index. MET: Metabolic Equivalent of Task. MSP: Medical Services Plan. PopData: Population Data BC. 62 4.6.2.4 Active comparator analysis Confounding by indication may occur if the indication of the medication is associated with the risk of outcome 220. Diabetes is a risk factor for certain types of cancer, for instance, colorectal cancer 152. Mitigating confounding by indication allows for a clearer understanding of the true effect of diabetes medications on cancer risk, independent of the confounding effect of diabetes itself. For this purpose, an active comparator, new-user analysis was conducted to estimate the effects of a type of diabetes medication (i.e., a class, a subclass, or an individual medication) in comparison to alternative medications on study cancer incidence 221. Alternative medications were chosen based on associations with cancer risk. To focus on relevant comparisons with potential clinical implications, only medications with significant associations in the primary analysis and sensitivity analyses were analyzed. Glyburide, GLP-1 receptor agonists, and pioglitazone were selected as active comparators for breast, colorectal, and pancreatic cancers, respectively, because they did not have a significant association with cancer risks in the primary and sensitivity analyses. Only individuals who began monotherapy with one of the identified diabetes medications were included in the analysis. The exposure to the identified medication was recorded as a dichotomous variable (yes/no). In addition to the endpoints in the main analyses (any cancer diagnosis, death, censoring, or the year 2019), follow-up was further censored for termination of initial medication, transition to, or augmentation with another identified medication. Individuals were censored upon stopping the initial medication to address the issue of medication discontinuation and minimize exposure misclassification. 63 4.6.3 Cancer subtype analysis Several secondary analyses were conducted. Associations between diabetes medications and morphological subtypes of breast and pancreatic cancer were explored: ductal (morphology code: 85003, 85013, 80223, 81413, 82013) versus lobular breast cancer (85203) 222 and pancreatic adenocarcinoma (site code: C250-C253, C257-C259 and morphology code: excluding 9050-9055, 9140, 9590-9992, 8150, 8151, 8153, 8155, 8240, and 8246) 223. Colorectal cancer was further explored by location: colon (site code: C180-C189, C260), proximal colon (C180-185), distal colon (C186, C187), and rectum (C199, C209) 224. 64 Chapter 5: Diabetes medications and risk of breast cancer: a population-based cohort study 5.1 Chapter overview Purpose: Some diabetes medications show inverse associations with breast cancer risk, but prior studies were prone to methodological limitations. This study investigated associations between different classes, subclasses, individual diabetes medications and breast cancer risk. Methods: In a cohort of females aged ≥35 years living in British Columbia (1996-2019), diabetes medication prescription was defined as ever/never, cumulative duration, and cumulative dose (years receiving the defined daily dose). Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between new diabetes medication use (time-varying with a 1-year lag) and breast cancer incidence, adjusting for demographics. For a subset of participants in the British Columbia Generations Project (BCGP), additional factors were adjusted. The impact of confounding by indication was evaluated using an active comparator analysis. Results: In a cohort of 1,599,418 females (26,916,960 person-years), 53,584 had incident breast cancer. Every 1-year increase in cumulative metformin dose was associated with a 2% greater risk (HR=1.02, 95%CI=1.01-1.02). Low (HR=0.44, 95%CI=0.27-0.72) and medium (HR=0.54, 95%CI=0.35-0.84) SGLT-2 inhibitor cumulative doses were related to lower risks than never use. Insulins, especially bolus insulins, was linked to a 2% higher risk (HR=1.02, 95%CI=1.01- 65 1.03) for each 1-year increase in dose. Associations for SGLT-2 inhibitors and insulins were consistent in the BCGP subset. Although not significant, SGLT-2 inhibitors (HR=0.28, 95%CI=0.05-1.56) showed a lower risk than glyburide, the comparator. Conclusion: SGLT-2 inhibitors were associated with a lower breast cancer risk, highlighting the need to assess the long-term health implications of frequently prescribed medications. 5.2 Introduction In 2021, about 28,000 new breast cancer cases, the most common cancer in women, were diagnosed in Canada 95. Around 90% of people with diabetes have type 2, the most common type 10. Diabetes affected approximately 537 million adults worldwide and 3 million Canadian adults in 2021 10. Diabetes has been linked to a higher risk of breast cancer 225. Certain diabetes medications may also be linked to breast cancer. Some studies have reported an inverse association between certain diabetes medications, such as metformin 226,227, while others have not observed such a link 228. The heterogeneity in the literature on diabetes medications and breast cancer may be attributable to methodological limitations, such as inconsistent variable adjustment for demographic and clinical factors, lack of consideration of cancer latency, and confounding by indication. In addition, the tendency of previous studies to group medications together, disregarding individual or subclass distinctions based on mechanism of action, has hindered a comprehensive understanding of how diabetes medications may affect breast cancer risk. Therefore, it is 66 necessary to investigate the associations between distinct classes, subclasses, individual diabetes medications and breast cancer risk to understand these connections and their potential implications. The present study examined the associations between new diabetes medication use and breast cancer incidence in a large female cohort in British Columbia (BC). 5.3 Methods 5.3.1 Data sources Population Data BC (PopData) provides access to longitudinal, individual-level administrative data, including demographic, prescription (excluding in-hospital medications and over-the-counter medications), cancer diagnosis, and mortality data for all BC residents, implementing linkage procedures and unique identifiers for each individual in the public health insurance program 200. Moreover, a subset of the British Columbia Generations Project (BCGP) data 205, a longitudinal cohort study, was linked with PopData datasets to supplement additional sociodemographic and lifestyle factors. 5.3.2 Study population Our cohort consisted of female individuals aged 35 to 100 registered with the Medical Services Plan between January 1, 1996, and December 31, 2019. We excluded individuals who had a cancer diagnosis before study entry, were registered with MSP for less than five consecutive years, had fewer than five years of follow-up data, were prescribed diabetes medications in the 67 first year of follow-up 221, or initiated new diabetes medications in the final year of follow-up 207. The cohort was followed from the year of entry until the first incidence of any cancer (excluding non-melanoma skin cancer), death, loss to follow-up, or December 31, 2019. 5.3.3 Exposure assessment Seven different medication classes, six subclasses, and seven individual medications were examined in the study. Each medication was parameterized by five definitions 229: binary (ever versus never use), continuous cumulative duration, continuous cumulative dose, categorized cumulative duration, and categorized cumulative dose. The cumulative duration was determined by converting the total number of medication supply days into years. The cumulative dose was computed using the World Health Organization’s defined daily dose 211, which standardizes different medication strengths. Individuals were considered unexposed until they recorded their first prescription, at which point they transitioned to exposed, allowing us to examine real-world scenarios such as switching between medications during the follow-up period and concurrent exposure to multiple medications. 5.3.4 Outcome assessment Using BC Cancer Registry, which captures approximately 95% of all cancer occurrences in BC 203, our study focused on incident breast cancer (site code: C500-C509; morphology code: exclude 9050-9055, 9140, 9590-9992, 80102, 80502, 80522, 80702, 81402, 82012, 82302, 82612, 85002, 85012, 85032, 85042, 85072, 85092, 85192, 85202, 85222, 85232), and ductal (morphology code: 85003, 85013, 80223, 81413, 82013) and lobular histology subtypes 68 (morphology code: 85203) 222 using ICD-O-3 (International Classification of Diseases in Oncology, Third Edition). 5.3.5 Potential confounders Based on the literature review presented in Chapter 3, confounding variables, namely age, birth cohort, neighbourhood income quintile, and health authority, were chosen as confounders. 5.3.6 Statistical analysis Using the Poisson distribution, crude breast cancer incidence rates and the corresponding 95% confidence intervals (CIs) were calculated for each categorical exposure parameterization (binary and categorized cumulative duration and dose). Single imputation of missing covariate data was performed using predictive mean matching 212, with birth year, exposure to diabetes medications, and incident cancer diagnosis as auxiliary variables in the imputation model. 5.3.6.1 Primary analysis To calculate breast cancer hazard ratios (HRs) and 95%CIs, time-varying Cox proportional hazards models were used, with age as the time axis and each diabetes medication as a dynamic factor. Separate models provided risk estimates for each parameterization of exposure, accounting for the non-static nature of medication exposure over time. The implementation of 1-year washout 221 and lag periods 207 assisted in the exclusion of prevalent medication users and the adjustment for cancer latency, respectively. Using SAS (version 9.4; SAS Institute, Inc., Cary, NC), models were first adjusted for age and additionally adjusted for birth cohort, health 69 authority, and neighbourhood income quintile, with a two-sided significance level of less than 0.05. 5.3.6.2 Sensitivity analyses 5.3.6.2.1 Additional adjustment for other diabetes medications When metformin is insufficient to achieve glycemic targets, or there is the presence of symptomatic hyperglycemia, it is necessary to implement a second-line medication, determined based on the patient’s health conditions along with additional factors 74. The models were adjusted for the time-varying use of other diabetes medications throughout the follow-up period to account for an individual’s health status and diabetes severity 214. 5.3.6.2.2 Washout and lag periods The impact of the predetermined medication washout and lag periods were evaluated by repeating the primary analysis with 0-year and 2-year intervals. 5.3.6.2.3 BCGP analysis Self-reported sociodemographic, physical, and lifestyle factors from a subset of the BCGP cohort were used to assess the influence of various potential confounders 120,132,134,214–219 on significant associations from the primary analysis. 70 5.3.6.2.4 Active comparator analysis A new-user active comparator analysis 221 was conducted to reduce confounding by indication 220, focusing on diabetes medications with significant associations in the primary and other sensitivity analyses, using glyburide as the active comparator. Individuals initiating monotherapy with one of these identified medications were included in the study, and exposure was recorded as a dichotomous variable. In addition to the endpoints in the primary analysis, the follow-up was also censored for discontinuation of the initial medication or transition to another identified medication. This strategy intended to minimize exposure misclassification by censoring individuals upon discontinuing the initial medication. 5.3.6.3 Breast cancer subtype analysis Secondary analyses were conducted to investigate the associations between diabetes medications and ductal and lobular breast cancer subtypes 222. 5.4 Results In the breast cancer analysis, a cohort of 1,599,418 females were followed for a mean of 16.8 (SD = 6.7) years, with a total of 26,916,960 person-years of follow-up, see Figure 5-1. During this study period, 53,584 female individuals were diagnosed with breast cancer—a crude incidence rate of 199.1 (95%CI=197.4-200.8) per 100,000 person-years. Among breast cancer cases, the median time between cohort entry and the incident diagnosis was 13 years (IQR [interquartile range]: 9-18 years). 71 Figure 5-1. Flowchart of study cohort 72 Table 5-1 summarizes the distribution of baseline demographic and use of diabetes medications stratified by breast cancer case status. Breast cancer cases were older than non-cases at baseline. Biguanides and incretin-based medicines were the most prescribed diabetes medication at the class level (prescription rates 5.8% and 1.1%, respectively), while AGIs were the least prescribed (0.1%). Table 5-1. Baseline characteristics at cohort entry of the overall cohort and stratified by incident breast cancer case status at cohort entry Total Cases Non-cases Characteristic N = 1,599,418, n (%) N = 53,584, n (%) N = 1,545,834, n (%) Age (years)a 35-39 713,769 (44.6) 13,547 (25.3) 700,222 (45.3) 40-44 195,900 (12.2) 7,540 (14.1) 188,360 (12.2) 45-49 162,573 (10.2) 7,707 (14.4) 154,866 (10.0) 50-54 122,284 (7.6) 6,886 (12.9) 115,398 (7.5) 55-59 97,539 (6.1) 5,424 (10.1) 92,115 (6.0) 60-64 82,389 (5.2) 4,302 (8.0) 78,087 (5.1) 65-69 71,185 (4.5) 3,426 (6.4) 67,759 (4.4) 70-100 153,779 (9.6) 4,752 (8.9) 149,027 (9.6) Mean±SD 46.2±13.2 50.1±12.5 46.7±13.9 Calendar yeara 1996 840,085 (52.5) 41,032 (76.6) 799,053 (51.7) 1997-1999 134,624 (8.4) 4,190 (7.8) 130,434 (8.4) 2000-2002 116,570 (7.3) 2,902 (5.4) 113,668 (7.4) 2003-2005 121,998 (7.6) 2,343 (4.4) 119,655 (7.7) 2006-2008 121,715 (7.6) 1,631 (3.0) 120,084 (7.8) 2009-2011 113,732 (7.1) 982 (1.8) 112,750 (7.3) 2012-2015 150,694 (9.4) 504 (0.9) 150,190 (9.7) Birth cohortb 1896-1940 342,979 (21.4) 15,736 (29.4) 327,243 (21.2) 1941-1950 252,283 (15.8) 14,306 (26.7) 237,977 (15.4) 1951-1957 245,574 (15.4) 10,166 (19.0) 235,408 (15.2) 1958-1964 271,892 (17.0) 7,978 (14.9) 263,914 (17.1) 1965-1980 486,690 (30.4) 5,398 (10.1) 481,292 (31.1) Sexb Female 1,599,418 (100.0) 53,584 (100.0) 1,545,834 (100.0) Male Health authoritya Interior 255,029 (15.9) 8,833 (16.5) 246,196 (15.9) Fraser 513,312 (32.1) 16,743 (31.2) 496,569 (32.1) Vancouver Coastal 440,337 (27.5) 14,478 (27.0) 425,859 (27.5) Vancouver Island 269,218 (16.8) 9,757 (18.2) 259,461 (16.8) Northern 92,533 (5.8) 2,958 (5.5) 89,575 (5.8) Missing 28,989 (1.8) 815 (1.5) 28,174 (1.8) Neighbourhood income quintilea Quintile 1 324,418 (20.3) 9,900 (18.5) 314,518 (20.3) Quintile 2 313,637 (19.6) 9,901 (18.5) 303,736 (19.6) Quintile 3 306,037 (19.1) 10,186 (19.0) 295,851 (19.1) Quintile 4 304,507 (19.0) 10,812 (20.2) 293,695 (19.0) Quintile 5 298,196 (18.6) 11,258 (21.0) 286,938 (18.6) Missing 52,623 (3.3) 1,527 (2.8) 51,096 (3.3) Diabetes medicationc 1. Biguanides (i.e., metformin) 73 Total Cases Non-cases Characteristic N = 1,599,418, n (%) N = 53,584, n (%) N = 1,545,834, n (%) Non-users 1,505,930 (94.2) 50,695 (94.6) 1,455,235 (94.1) Users 93,488 (5.8) 2,889 (5.4) 90,599 (5.9) 2. Incretin-based medicines Non-users 1,581,443 (98.9) 53,289 (99.4) 1,528,154 (98.9) Users 17,975 (1.1) 295 (0.6) 17,680 (1.1) 2.1. DPP-4 inhibitors Non-users 1,586,963 (99.2) 53,352 (99.6) 1,533,611 (99.2) Users 12,455 (0.8) 232 (0.4) 12,223 (0.8) 2.1.1. Linagliptin Non-users 1,592,871 (99.6) 53,506 (99.9) 1,539,365 (99.6) Users 6,547 (0.4) 78 (0.1) 6,469 (0.4) 2.1.2. Sitagliptin Non-users 1,592,154 (99.5) 53,416 (99.7) 1,538,738 (99.5) Users 7,264 (0.5) 168 (0.3) 7,096 (0.5) 2.2. GLP-1 receptor agonists Non-users 1,591,447 (99.5) 53,484 (99.8) 1,537,963 (99.5) Users 7,971 (0.5) 100 (0.2) 7,871 (0.5) 3. SGLT-2 inhibitors Non-users 1,590,818 (99.5) 53,509 (99.9) 1,537,309 (99.4) Users 8,600 (0.5) 75 (0.1) 8,525 (0.6) 4. AGIs (i.e., acarbose) Non-users 1,597,430 (99.9) 53,529 (99.9) 1,543,901 (99.9) Users 1,988 (0.1) 55 (0.1) 1,933 (0.1) 5. Insulin secretagogues Non-users 1,561,388 (97.6) 52,414 (97.8) 1,508,974 (97.6) Users 38,030 (2.4) 1,170 (2.2) 36,860 (2.4) 5.1. Meglitinides Non-users 1,597,720 (99.9) 53,518 (99.9) 1,544,202 (99.9) Users 1,698 (0.1) 66 (0.1) 1,632 (0.1) 5.1.1. Repaglinide Non-users 1,597,746 (99.9) 53,518 (99.9) 1,544,228 (99.9) Users 1,672 (0.1) 66 (0.1) 1,606 (0.1) 5.2. Sulfonylureas Non-users 1,561,773 (97.6) 52,431 (97.8) 1,509,342 (97.6) Users 37,645 (2.4) 1,153 (2.2) 36,492 (2.4) 5.2.1. Gliclazide Non-users 1,577,231 (98.6) 53,057 (99.0) 1,524,174 (98.6) Users 22,187 (1.4) 527 (1.0) 21,660 (1.4) 5.2.2. Glyburide Non-users 1,573,553 (98.4) 52,734 (98.4) 1,520,819 (98.4) Users 25,865 (1.6) 850 (1.6) 25,015 (1.6) 6. Thiazolidinediones Non-users 1,591,967 (99.5) 53,289 (99.4) 1,538,678 (99.5) Users 7,451 (0.5) 295 (0.6) 7,156 (0.5) 6.1. Pioglitazone Non-users 1,595,632 (99.8) 53,445 (99.7) 1,542,187 (99.8) Users 3,786 (0.2) 139 (0.3) 3,647 (0.2) 6.2. Rosiglitazone Non-users 1,594,716 (99.7) 53,391 (99.6) 1,541,325 (99.7) Users 4,702 (0.3) 193 (0.4) 4,509 (0.3) 7. Insulins and analogues Non-users 1,581,215 (98.9) 53,186 (99.3) 1,528,029 (98.8) Users 18,203 (1.1) 398 (0.7) 17,805 (1.2) 7.1. Basal insulins Non-users 1,581,946 (98.9) 53,201 (99.3) 1,528,745 (98.9) Users 17,472 (1.1) 383 (0.7) 17,089 (1.1) 7.2. Bolus insulins Non-users 1,590,417 (99.4) 53,388 (99.6) 1,537,029 (99.4) Users 9,001 (0.6) 196 (0.4) 8,805 (0.6) a: Measured at study entry. b: Measured at birth. c: Measured during follow-up. SD: Standard deviation. AGIs: Alpha-glucosidase inhibitors. 74 DPP-4 inhibitors: Dipeptidyl peptidase 4 inhibitors. GLP-1 receptor agonists: Glucagon-like peptide 1 receptor agonists. SGLT-2 inhibitors: Sodium-glucose cotransporter 2 inhibitors. 5.4.1 Findings from the primary analysis Supplementary Table B-1 shows the primary analysis results for each diabetes medication class, subclass and individual medication with breast cancer risk. Effects estimates are presented in sequentially adjusted models, with Model 1 adjusted for age and Model 2 additionally adjusted for birth cohort, health authority, and neighbourhood income quintile. Statistically significant findings from Model 2 are summarized below and in Table 5-2. Table 5-2. Associations between select diabetes medications and the risk of breast cancer Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 25,974,019 50,695 195.2 (193.5-196.9) 1.00 1.00 Ever use 942,941 2,889 310.6 (297.6-324.2) 1.14 (1.09-1.19)* 1.09 (1.04-1.14)* Cumulative duration Low 363,231 876 241.2 (225.7-257.7) 0.97 (0.91-1.04) 0.93 (0.87-0.99)* Medium 323,170 1,090 337.3 (317.8-357.9) 1.24 (1.17-1.32)* 1.19 (1.12-1.26)* High 256,540 923 359.8 (337.3-383.8) 1.22 (1.14-1.30)* 1.14 (1.07-1.21)* Continuous 1.02 (1.02-1.03)* 1.02 (1.01-1.02)* Cumulative dose Low 383,543 947 246.9 (231.7-263.1) 0.98 (0.92-1.04) 0.94 (0.88-1.00)* Medium 327,502 1,146 349.9 (330.2-370.8) 1.28 (1.21-1.36)* 1.22 (1.15-1.30)* High 231,896 796 343.3 (320.2-368.0) 1.18 (1.10-1.27)* 1.10 (1.02-1.18)* Continuous 1.03 (1.02-1.03)* 1.02 (1.01-1.02)* 3. SGLT-2 inhibitors Never 26,879,533 53,509 199.1 (197.4-200.8) 1.00 1.00 Ever use 37,427 75 189.0 (142.4-250.8) 0.72 (0.54-0.95)* 0.64 (0.48-0.85)* Cumulative duration Low 12,099 15 124.0 (74.7-205.6) 0.47 (0.28-0.78)* 0.42 (0.25-0.70)* Medium 12,583 21 166.9 (108.8-256.0) 0.63 (0.41-0.97)* 0.57 (0.37-0.87)* High 12,745 39 306.0 (223.6-418.8) 1.12 (0.82-1.53) 1.00 (0.73-1.37) Continuous 1.01 (0.91-1.13) 0.97 (0.86-1.08) Cumulative dose Low 12,132 16 131.9 (80.8-215.3) 0.50 (0.31-0.82)* 0.44 (0.27-0.72)* Medium 12,532 20 159.6 (103.0-247.4) 0.61 (0.39-0.94)* 0.54 (0.35-0.84)* High 12,763 39 305.6 (223.3-418.2) 1.13 (0.83-1.55) 1.01 (0.74-1.38) Continuous 1.03 (0.94-1.12) 0.99 (0.91-1.08) 5. Insulin secretagogues Never 26,526,445 52,414 197.6 (195.9-199.3) 1.00 1.00 Ever use 390,515 1,170 308.1 (286.6-331.3) 1.11 (1.03-1.19)* 1.08 (1.00-1.16) Cumulative duration Low 157,864 389 246.4 (223.1-272.2) 0.92 (0.83-1.02) 0.90 (0.82-1.00)* Medium 132,423 427 322.5 (293.3-354.5) 1.16 (1.05-1.27)* 1.11 (1.01-1.22)* High 100,228 354 353.2 (318.3-392.0) 1.18 (1.07-1.31)* 1.12 (1.01-1.24)* Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.02)* Cumulative dose 75 Exposure Person-years Events Incidence rate Model 1 Model 2 Low 164,182 404 246.1 (223.2-271.3) 0.91 (0.82-1.00)* 0.89 (0.81-0.98)* Medium 131,919 458 347.2 (316.8-380.5) 1.24 (1.13-1.36)* 1.19 (1.09-1.31)* High 94,414 308 326.2 (291.8-364.8) 1.11 (1.00-1.25) 1.04 (0.93-1.16) Continuous 1.01 (1.00-1.01) 1.00 (1.00-1.01) 5.2. Sulfonylureas Never 26,532,030 52,431 197.6 (195.9-199.3) 1.00 1.00 Ever use 384,930 1,153 303.9 (282.3-327.2) 1.09 (1.01-1.18)* 1.06 (0.98-1.14) Cumulative duration Low 157,130 386 245.7 (222.3-271.4) 0.92 (0.83-1.01) 0.90 (0.81-0.99)* Medium 129,438 421 325.3 (295.6-357.9) 1.17 (1.06-1.28)* 1.12 (1.02-1.23)* High 98,362 346 351.8 (316.6-390.9) 1.18 (1.06-1.31)* 1.11 (1.00-1.24) Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.02)* Cumulative dose Low 161,924 393 242.7 (219.9-267.9) 0.89 (0.81-0.99)* 0.88 (0.80-0.97)* Medium 129,793 457 352.1 (321.3-385.9) 1.26 (1.15-1.38)* 1.21 (1.10-1.33)* High 93,213 303 325.1 (290.4-363.8) 1.11 (0.99-1.24) 1.04 (0.93-1.16) Continuous 1.01 (1.00-1.01) 1.00 (1.00-1.01) 5.2.1. Gliclazide Never 26,747,400 53,057 198.4 (196.7-200.1) 1.00 1.00 Ever use 169,560 527 307.7 (276.3-342.6) 1.10 (0.98-1.22) 1.02 (0.92-1.14) Cumulative duration Low 56,423 154 272.9 (233.1-319.6) 1.00 (0.86-1.17) 0.94 (0.81-1.11) Medium 57,402 157 273.5 (233.9-319.8) 0.98 (0.84-1.15) 0.92 (0.79-1.07) High 55,735 216 387.5 (339.2-442.8) 1.32 (1.15-1.50)* 1.22 (1.06-1.39)* Continuous 1.03 (1.01-1.05)* 1.02 (1.00-1.04)* Cumulative dose Low 59,361 146 246.0 (209.1-289.3) 0.90 (0.76-1.06) 0.85 (0.72-1.00)* Medium 57,663 201 348.6 (303.6-400.3) 1.24 (1.08-1.43)* 1.16 (1.01-1.33)* High 52,536 180 342.6 (296.1-396.5) 1.17 (1.01-1.36)* 1.08 (0.94-1.26) Continuous 1.01 (1.00-1.01) 1.00 (1.00-1.01) 7. Insulins and analogues Never 26,763,779 53,186 198.7 (197.0-200.4) 1.00 1.00 Ever use 153,181 398 279.2 (248.3-313.9) 1.07 (0.95-1.20) 0.99 (0.88-1.12) Cumulative duration Low 79,227 160 202.0 (173.0-235.8) 0.97 (0.83-1.14) 0.90 (0.77-1.06) Medium 48,672 138 283.5 (240.0-335.0) 1.05 (0.89-1.24) 0.98 (0.83-1.15) High 25,282 100 395.5 (325.1-481.2) 1.38 (1.13-1.67)* 1.25 (1.03-1.53)* Continuous 1.04 (1.02-1.07)* 1.03 (1.01-1.05)* Cumulative dose Low 80,901 163 201.5 (172.8-234.9) 0.96 (0.82-1.12) 0.89 (0.76-1.04) Medium 46,657 133 285.1 (240.5-337.9) 1.06 (0.89-1.25) 0.98 (0.83-1.16) High 25,623 102 398.1 (327.9-483.3) 1.40 (1.16-1.70)* 1.28 (1.06-1.56)* Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 7.1. Basal insulins Never 26,770,645 53,201 198.7 (197.0-200.4) 1.00 1.00 Ever use 146,315 383 280.8 (248.8-316.9) 1.08 (0.96-1.22) 1.00 (0.89-1.13) Cumulative duration Low 74,490 152 204.1 (174.1-239.2) 0.98 (0.83-1.15) 0.91 (0.77-1.06) Medium 47,092 133 282.4 (238.3-334.7) 1.05 (0.88-1.24) 0.97 (0.82-1.15) High 24,733 98 396.2 (325.1-483.0) 1.37 (1.13-1.68)* 1.26 (1.03-1.53)* Continuous 1.05 (1.02-1.08)* 1.03 (1.01-1.06)* Cumulative dose Low 75,643 151 199.6 (170.2-234.1) 0.95 (0.81-1.11) 0.88 (0.75-1.03) Medium 45,900 132 287.6 (242.5-341.1) 1.07 (0.90-1.26) 0.99 (0.83-1.17) High 24,772 100 403.7 (331.8-491.1) 1.42 (1.17-1.73)* 1.30 (1.07-1.58)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.04)* 7.2. Bolus insulins Never 26,844,167 53,388 198.9 (197.2-200.6) 1.00 1.00 Ever use 72,793 196 343.4 (288.4-408.9) 1.41 (1.18-1.68)* 1.30 (1.10-1.55)* Cumulative duration Low 41,607 80 192.3 (154.4-239.4) 1.02 (0.82-1.26) 0.93 (0.75-1.16) Medium 21,239 79 372.0 (298.3-463.7) 1.48 (1.19-1.84)* 1.36 (1.09-1.70)* High 9,947 37 372.0 (269.5-513.4) 1.34 (0.97-1.85) 1.22 (0.88-1.68) Continuous 1.09 (1.04-1.15)* 1.07 (1.02-1.13)* Cumulative dose 76 Exposure Person-years Events Incidence rate Model 1 Model 2 Low 43,110 86 199.5 (161.5-246.4) 1.04 (0.84-1.29) 0.96 (0.78-1.18) Medium 19,439 64 329.2 (257.7-420.6) 1.30 (1.01-1.66)* 1.20 (0.94-1.53) High 10,244 46 449.0 (336.3-599.5) 1.66 (1.24-2.21)* 1.50 (1.12-2.00)* Continuous 1.03 (1.01-1.06)* 1.03 (1.01-1.05)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income quintile. This table summarized the associations between select diabetes medications and breast cancer. The full results for all diabetes medications assessed can be found in Supplementary Table B-1. * denotes p<0.05. 5.4.1.1 Biguanides (i.e., metformin) – Class Compared with never use, ever use of metformin was significantly associated with a 9% increase in the risk of incident breast cancer (HR=1.09, 95%CI=1.04-1.14). Continuous cumulative duration (HR=1.02, 95%CI=1.01-1.02) and dose of metformin use (HR=1.02, 95%CI=1.01-1.02) were significantly associated with breast cancer risk: every 1-year increase in duration or dose was associated with a 2% higher risk of breast cancer. Significant associations were also evident with the categorical analysis of cumulative duration and dose of metformin use, with low duration (HR=0.93, 95%CI=0.87-0.99) and dose categories (HR=0.94, 95%CI=0.88-1.00) associated with 7% and 6% lower risks, respectively. Medium duration (HR=1.19, 95%CI=1.12-1.26) and dose categories (HR=1.22, 95%CI=1.15-1.30) were associated with 19% and 22% higher risks, respectively, and high duration (HR=1.14, 95%CI=1.07-1.21) and dose categories (HR=1.10, 95%CI=1.02-1.18) were associated with 14% and 10% higher risks, respectively. 5.4.1.2 SGLT-2 inhibitors – Class Relative to never use, ever use of SGLT-2 inhibitors was significantly associated with a lower risk of incident breast cancer (HR=0.64, 95%CI=0.48-0.85). Significant associations were apparent in the categorized cumulative duration and dose analysis for SGLT-2 inhibitors: low 77 (HR=0.42, 95%CI=0.25-0.70) and medium duration (HR=0.57, 95%CI=0.37-0.87) were associated with 58% and 43% lower risks, respectively, and low (HR=0.44, 95%CI=0.27-0.72) and medium dose (HR=0.54, 95%CI=0.35-0.84) were associated with 56% and 46% lower risks of breast cancer, respectively, in comparison with never use. No associations were observed for high cumulative duration or dose. 5.4.1.3 Insulin secretagogues – Class No association with breast cancer risk was observed for ever use of insulin secretagogues compared with never use. Every 1-year increase in duration was associated with a 1% higher risk of breast cancer (HR=1.01, 95%CI=1.00-1.02). Low cumulative duration category (HR=0.90, 95%CI=0.82-1.00) was associated with a lower risk of breast cancer, but the medium (HR=1.11, 95%CI=1.01-1.22) and high cumulative duration categories (HR=1.12, 95%CI=1.01-1.24) were associated with higher risks of breast cancer compared to never use of insulin secretagogues. In the categorized cumulative dose analysis for insulin secretagogues, a significant relationship was observed, with the low dose (HR=0.89, 95%CI=0.81-0.98) and medium dose (HR=1.19, 95%CI=1.09-1.31) associated with 11% lower and 19% higher risks of breast cancer relative to never use. 5.4.1.4 Sulfonylureas – Subclass A significant relationship was observed in the continuous cumulative duration analysis for sulfonylureas (HR=1.01, 95%CI=1.00-1.02). Significant relationships were also observed in the categorized cumulative duration analysis with low (HR=0.90, 95%CI=0.81-0.99) and medium 78 duration categories (HR=1.12, 95%CI=1.02-1.23) associated with lower and higher risks of breast cancer, respectively, in comparison with never use. Likewise, significant relationships in categorized cumulative dose analysis were detected with low (HR=0.88, 95%CI=0.80-0.97) and medium doses (HR=1.21, 95%CI=1.10-1.33), respectively. 5.4.1.5 Gliclazide – Individual The continuous cumulative duration of gliclazide, an individual medication of the sulfonylureas subclass, demonstrated a significant relationship with the risk of breast cancer: every 1-year increase related to a 2% higher risk (HR=1.02, 95%CI=1.00-1.04). A significant association was also found in the categorized cumulative duration analysis, with the high duration associated with a higher risk (HR=1.22, 95%CI=1.06-1.39). Significant associations were detected in the low (HR=0.85, 95%CI=0.72-1.00) and medium cumulative dose categories (HR=1.16, 95%CI=1.01-1.33) in comparison to never use. 5.4.1.6 Insulins and analogues – Class The use of insulins and analogues showed significant relationships in continuous cumulative duration and dose analyses: every 1-year increase in cumulative duration was associated with a 3% increase in breast cancer risk (HR=1.03, 95%CI=1.01-1.05) while every 1-year increase in cumulative dose was associated with a 2% increase in breast cancer risk (HR=1.02, 95%CI=1.01-1.03). Significant relationships were also observed in high cumulative duration (HR=1.25, 95%CI=1.03-1.53) and high cumulative dose categories (HR=1.28, 95%CI=1.06-1.56). 79 5.4.1.7 Basal insulins – Subclass Associations with breast cancer risk were similar between insulin and analogues and the basal insulin subclass. Significant relationships were observed for basal insulin use in continuous cumulative duration (HR=1.03, 95%CI=1.01-1.06) and dose analyses (HR=1.02, 95%CI=1.01-1.04). Significant relationships were also observed in high cumulative duration (HR=1.26, 95%CI=1.03-1.53) and dose categories (HR=1.30, 95%CI=1.07-1.58). 5.4.1.8 Bolus insulins – Subclass Associations in the bolus insulin subclass differed slightly relative to associations with the class of insulin and analogues medications. Compared to never use, ever use of bolus insulins was significantly associated with a higher risk of breast cancer (HR=1.30, 95%CI=1.10-1.55). Continuous cumulative duration (HR=1.07, 95%CI=1.02-1.13) and dose analyses (HR=1.03, 95%CI=1.01-1.05) for bolus insulins showed significant relationships with breast cancer risks. Significant relationships were also observed in medium cumulative duration (HR=1.36, 95%CI=1.09-1.70) and high dose categories (HR=1.50, 95%CI=1.12-2.00). 5.4.2 Findings from sensitivity analyses 5.4.2.1 Additional adjustment for other diabetes medications In Supplementary Table B-2, all associations are presented, regardless of statistical significance. Table 5-3 shows the medications with statistically significant findings from the primary analysis. After adjusting for other diabetes medications, the use of metformin and 80 insulin class (and specifically the bolus insulin subclass) were consistently associated with higher risks of breast cancer. In contrast, the use of SGLT-2 inhibitors was consistently associated with a lower risk. On the other hand, the positive relationships between insulin secretagogues (and sulfonylurea subclass and individual medication gliclazide) and basal insulins with breast cancer risk observed in the primary analysis were all attenuated to null. Table 5-3. Associations between select diabetes medications and the risk of breast cancer with adjustment for other diabetes medications Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 25,974,019 50,695 195.2 (193.5-196.9) 1.00 1.00 Ever use 942,941 2,889 310.6 (297.6-324.2) 1.09 (1.04-1.14)* 1.11 (1.05-1.16)* Cumulative duration Low 363,231 876 241.2 (225.7-257.7) 0.93 (0.87-0.99)* 0.96 (0.90-1.03) Medium 323,170 1,090 337.3 (317.8-357.9) 1.19 (1.12-1.26)* 1.24 (1.16-1.33)* High 256,540 923 359.8 (337.3-383.8) 1.14 (1.07-1.21)* 1.21 (1.12-1.31)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.03)* Cumulative dose Low 383,543 947 246.9 (231.7-263.1) 0.94 (0.88-1.00)* 0.97 (0.90-1.03) Medium 327,502 1,146 349.9 (330.2-370.8) 1.22 (1.15-1.30)* 1.28 (1.20-1.36)* High 231,896 796 343.3 (320.2-368.0) 1.10 (1.02-1.18)* 1.19 (1.08-1.30)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.03)* 3. SGLT-2 inhibitors Never 26,879,533 53,509 199.1 (197.4-200.8) 1.00 1.00 Ever use 37,427 75 189.0 (142.4-250.8) 0.64 (0.48-0.85)* 0.63 (0.47-0.85)* Cumulative duration Low 12,099 15 124.0 (74.7-205.6) 0.42 (0.25-0.70)* 0.40 (0.24-0.67)* Medium 12,583 21 166.9 (108.8-256.0) 0.57 (0.37-0.87)* 0.53 (0.34-0.82)* High 12,745 39 306.0 (223.6-418.8) 1.00 (0.73-1.37) 0.91 (0.65-1.26) Continuous 0.97 (0.86-1.08) 0.94 (0.84-1.06) Cumulative dose Low 12,132 16 131.9 (80.8-215.3) 0.44 (0.27-0.72)* 0.42 (0.26-0.70)* Medium 12,532 20 159.6 (103.0-247.4) 0.54 (0.35-0.84)* 0.51 (0.33-0.79)* High 12,763 39 305.6 (223.3-418.2) 1.01 (0.74-1.38) 0.94 (0.68-1.31) Continuous 0.99 (0.91-1.08) 0.98 (0.89-1.07) 5. Insulin secretagogues Never 26,526,445 52,414 197.6 (195.9-199.3) 1.00 1.00 Ever use 390,515 1,170 308.1 (286.6-331.3) 1.08 (1.00-1.16) 1.05 (0.97-1.14) Cumulative duration Low 157,864 389 246.4 (223.1-272.2) 0.90 (0.82-1.00)* 0.85 (0.76-0.94)* Medium 132,423 427 322.5 (293.3-354.5) 1.11 (1.01-1.22)* 1.02 (0.91-1.13) High 100,228 354 353.2 (318.3-392.0) 1.12 (1.01-1.24)* 1.03 (0.91-1.18) Continuous 1.01 (1.00-1.02)* 1.00 (0.98-1.01) Cumulative dose Low 164,182 404 246.1 (223.2-271.3) 0.89 (0.81-0.98)* 0.82 (0.74-0.92)* Medium 131,919 458 347.2 (316.8-380.5) 1.19 (1.09-1.31)* 1.08 (0.97-1.21) High 94,414 308 326.2 (291.8-364.8) 1.04 (0.93-1.16) 0.98 (0.85-1.13) Continuous 1.00 (1.00-1.01) 1.00 (0.99-1.00) 5.2. Sulfonylureas Never 26,532,030 52,431 197.6 (195.9-199.3) 1.00 1.00 Ever use 384,930 1,153 303.9 (282.3-327.2) 1.06 (0.98-1.14) 1.03 (0.95-1.12) Cumulative duration Low 157,130 386 245.7 (222.3-271.4) 0.90 (0.81-0.99)* 0.84 (0.75-0.94)* 81 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 129,438 421 325.3 (295.6-357.9) 1.12 (1.02-1.23)* 1.02 (0.92-1.14) High 98,362 346 351.8 (316.6-390.9) 1.11 (1.00-1.24) 1.03 (0.91-1.17) Continuous 1.01 (1.00-1.02)* 1.00 (0.98-1.01) Cumulative dose Low 161,924 393 242.7 (219.9-267.9) 0.88 (0.80-0.97)* 0.81 (0.73-0.90)* Medium 129,793 457 352.1 (321.3-385.9) 1.21 (1.10-1.33)* 1.10 (0.98-1.22) High 93,213 303 325.1 (290.4-363.8) 1.04 (0.93-1.16) 0.98 (0.85-1.12) Continuous 1.00 (1.00-1.01) 1.00 (0.99-1.00) 5.2.1. Gliclazide Never 26,747,400 53,057 198.4 (196.7-200.1) 1.00 1.00 Ever use 169,560 527 307.7 (276.3-342.6) 1.02 (0.92-1.14) 1.01 (0.90-1.14) Cumulative duration Low 56,423 154 272.9 (233.1-319.6) 0.94 (0.81-1.11) 0.92 (0.78-1.09) Medium 57,402 157 273.5 (233.9-319.8) 0.92 (0.79-1.07) 0.88 (0.75-1.04) High 55,735 216 387.5 (339.2-442.8) 1.22 (1.06-1.39)* 1.20 (1.03-1.39)* Continuous 1.02 (1.00-1.04)* 1.01 (0.99-1.03) Cumulative dose Low 59,361 146 246.0 (209.1-289.3) 0.85 (0.72-1.00)* 0.82 (0.69-0.97)* Medium 57,663 201 348.6 (303.6-400.3) 1.16 (1.01-1.33)* 1.11 (0.96-1.29) High 52,536 180 342.6 (296.1-396.5) 1.08 (0.94-1.26) 1.08 (0.92-1.27) Continuous 1.00 (1.00-1.01) 1.00 (0.99-1.01) 7. Insulins and analogues Never 26,763,779 53,186 198.7 (197.0-200.4) 1.00 1.00 Ever use 153,181 398 279.2 (248.3-313.9) 0.99 (0.88-1.12) 0.98 (0.87-1.11) Cumulative duration Low 79,227 160 202.0 (173.0-235.8) 0.90 (0.77-1.06) 0.88 (0.75-1.04) Medium 48,672 138 283.5 (240.0-335.0) 0.98 (0.83-1.15) 0.95 (0.79-1.13) High 25,282 100 395.5 (325.1-481.2) 1.25 (1.03-1.53)* 1.24 (1.01-1.53)* Continuous 1.03 (1.01-1.05)* 1.02 (0.99-1.04) Cumulative dose Low 80,901 163 201.5 (172.8-234.9) 0.89 (0.76-1.04) 0.87 (0.74-1.02) Medium 46,657 133 285.1 (240.5-337.9) 0.98 (0.83-1.16) 0.95 (0.79-1.13) High 25,623 102 398.1 (327.9-483.3) 1.28 (1.06-1.56)* 1.26 (1.02-1.54)* Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.03)* 7.1. Basal insulins Never 26,770,645 53,201 198.7 (197.0-200.4) 1.00 1.00 Ever use 146,315 383 280.8 (248.8-316.9) 1.00 (0.89-1.13) 0.84 (0.71-0.98)* Cumulative duration Low 74,490 152 204.1 (174.1-239.2) 0.91 (0.77-1.06) 0.85 (0.71-1.02) Medium 47,092 133 282.4 (238.3-334.7) 0.97 (0.82-1.15) 0.83 (0.68-1.02) High 24,733 98 396.2 (325.1-483.0) 1.26 (1.03-1.53)* 1.05 (0.81-1.37) Continuous 1.03 (1.01-1.06)* 1.00 (0.97-1.04) Cumulative dose Low 75,643 151 199.6 (170.2-234.1) 0.88 (0.75-1.03) 0.83 (0.69-0.99)* Medium 45,900 132 287.6 (242.5-341.1) 0.99 (0.83-1.17) 0.87 (0.70-1.07) High 24,772 100 403.7 (331.8-491.1) 1.30 (1.07-1.58)* 1.07 (0.82-1.39) Continuous 1.02 (1.01-1.04)* 1.02 (1.00-1.03) 7.2. Bolus insulins Never 26,844,167 53,388 198.9 (197.2-200.6) 1.00 1.00 Ever use 72,793 196 343.4 (288.4-408.9) 1.30 (1.10-1.55)* 1.52 (1.22-1.91)* Cumulative duration Low 41,607 80 192.3 (154.4-239.4) 0.93 (0.75-1.16) 1.04 (0.81-1.34) Medium 21,239 79 372.0 (298.3-463.7) 1.36 (1.09-1.70)* 1.50 (1.15-1.97)* High 9,947 37 372.0 (269.5-513.4) 1.22 (0.88-1.68) 1.23 (0.84-1.81) Continuous 1.07 (1.02-1.13)* 1.05 (0.98-1.13) Cumulative dose Low 43,110 86 199.5 (161.5-246.4) 0.96 (0.78-1.18) 1.07 (0.84-1.36) Medium 19,439 64 329.2 (257.7-420.6) 1.20 (0.94-1.53) 1.27 (0.95-1.70) High 10,244 46 449.0 (336.3-599.5) 1.50 (1.12-2.00)* 1.47 (1.03-2.10)* Continuous 1.03 (1.01-1.05)* 1.01 (0.98-1.04) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, birth cohort, health authority, and neighbourhood income quintile. Model 2 further adjusted for other mutually exclusive diabetes medications. 82 This table summarized the associations between select diabetes medications and breast cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table B-2. * denotes p<0.05. 5.4.2.2 Washout and lag periods All associations for the sensitivity analysis adjusting for varying lag and washout periods are included in Supplementary Table B-3. Table 5-4 presents analyses for the medications that were statistically significant in the primary analysis. Associations between metformin and breast cancer risk were consistent across different combinations of washout and lag periods. Risk estimates of SGLT-2 inhibitors, gliclazide (a sulfonylurea in insulin secretagogues), and both basal and bolus insulins in Model 2 (1-year washout and 0-year lag periods) differ from those in the primary analysis Model 1 (1-year washout and 1-year lag periods); however, risk estimates were generally consistent between Model 1 and Models 3-5, suggesting a lag period of at least 1-year is required to obtain robust estimates for these medications. Table 5-4. Associations between select diabetes medications and the risk of breast cancer with variation in washout and lag periods Exposure Model 1 Model 2 Model 3 Model 4 Model 5 1. Biguanides (i.e., metformin) Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.09 (1.04-1.14)* 1.23 (1.18-1.27)* 1.08 (1.03-1.13)* 1.03 (0.99-1.07) 1.09 (1.05-1.15)* Cumulative duration Low 0.93 (0.87-0.99)* 1.28 (1.21-1.35)* 0.91 (0.84-0.97)* 0.85 (0.80-0.90)* 0.94 (0.88-1.01) Medium 1.19 (1.12-1.26)* 1.20 (1.13-1.26)* 1.11 (1.04-1.18)* 1.10 (1.04-1.16)* 1.18 (1.11-1.26)* High 1.14 (1.07-1.21)* 1.11 (1.05-1.18)* 1.16 (1.08-1.24)* 1.10 (1.05-1.16)* 1.15 (1.08-1.24)* Continuous 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 1.02 (1.01-1.02)* Cumulative dose Low 0.94 (0.88-1.00)* 1.27 (1.21-1.34)* 0.88 (0.82-0.94)* 0.86 (0.81-0.92)* 0.95 (0.89-1.01) Medium 1.22 (1.15-1.30)* 1.20 (1.14-1.27)* 1.19 (1.12-1.26)* 1.12 (1.06-1.18)* 1.22 (1.15-1.30)* High 1.10 (1.02-1.18)* 1.10 (1.03-1.17)* 1.11 (1.03-1.19)* 1.08 (1.02-1.14)* 1.11 (1.04-1.20)* Continuous 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 1.02 (1.01-1.03)* 1.01 (1.00-1.01)* 1.02 (1.01-1.03)* 3. SGLT-2 inhibitors Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.64 (0.48-0.85)* 1.03 (0.86-1.24) 0.53 (0.37-0.75)* 0.69 (0.55-0.87)* 0.65 (0.48-0.87)* Cumulative duration Low 0.42 (0.25-0.70)* 0.89 (0.67-1.17) 0.37 (0.20-0.69)* 0.47 (0.31-0.71)* 0.42 (0.25-0.71)* Medium 0.57 (0.37-0.87)* 0.96 (0.73-1.26) 0.50 (0.29-0.84)* 0.58 (0.41-0.84)* 0.58 (0.38-0.90)* High 1.00 (0.73-1.37) 1.20 (0.92-1.55) 0.72 (0.48-1.08) 0.96 (0.73-1.26) 0.99 (0.71-1.37) Continuous 0.97 (0.86-1.08) 1.05 (0.96-1.14) 0.87 (0.76-1.00)* 0.95 (0.86-1.04) 0.97 (0.87-1.09) Cumulative dose 83 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Low 0.44 (0.27-0.72)* 0.93 (0.71-1.22) 0.41 (0.23-0.74)* 0.55 (0.38-0.80)* 0.45 (0.27-0.74)* Medium 0.54 (0.35-0.84)* 0.91 (0.69-1.21) 0.46 (0.27-0.80)* 0.56 (0.39-0.81)* 0.55 (0.35-0.86)* High 1.01 (0.74-1.38) 1.20 (0.92-1.55) 0.71 (0.47-1.07) 0.92 (0.70-1.22) 1.00 (0.72-1.39) Continuous 0.99 (0.91-1.08) 1.04 (0.97-1.12) 0.91 (0.81-1.02) 0.97 (0.90-1.05) 0.99 (0.91-1.09) 5. Insulin secretagogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.08 (1.00-1.16) 1.16 (1.09-1.24)* 1.09 (1.00-1.17)* 0.92 (0.87-0.98)* 1.09 (1.01-1.18)* Cumulative duration Low 0.90 (0.82-1.00)* 1.11 (1.02-1.20)* 0.90 (0.81-1.00)* 0.81 (0.74-0.88)* 0.88 (0.79-0.98)* Medium 1.11 (1.01-1.22)* 1.14 (1.05-1.24)* 1.06 (0.95-1.17) 0.91 (0.85-0.99)* 1.12 (1.01-1.24)* High 1.12 (1.01-1.24)* 1.10 (1.00-1.22)* 1.11 (0.99-1.24) 1.05 (0.98-1.13) 1.16 (1.04-1.30)* Continuous 1.01 (1.00-1.02)* 1.01 (1.00-1.02)* 1.01 (1.00-1.02) 1.00 (0.99-1.01) 1.02 (1.01-1.03)* Cumulative dose Low 0.89 (0.81-0.98)* 1.09 (1.01-1.18)* 0.88 (0.80-0.98)* 0.82 (0.76-0.90)* 0.87 (0.79-0.97)* Medium 1.19 (1.09-1.31)* 1.19 (1.09-1.30)* 1.17 (1.06-1.29)* 0.98 (0.91-1.05) 1.20 (1.09-1.32)* High 1.04 (0.93-1.16) 1.07 (0.96-1.18) 1.01 (0.89-1.13) 0.98 (0.92-1.06) 1.08 (0.96-1.22) Continuous 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 1.00 (1.00-1.01) 5.2. Sulfonylureas Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.06 (0.98-1.14) 1.15 (1.08-1.23)* 1.07 (0.99-1.16) 0.91 (0.86-0.97)* 1.08 (1.00-1.17) Cumulative duration Low 0.90 (0.81-0.99)* 1.10 (1.01-1.19)* 0.89 (0.80-0.99)* 0.81 (0.74-0.88)* 0.88 (0.79-0.98)* Medium 1.12 (1.02-1.23)* 1.15 (1.06-1.25)* 1.07 (0.97-1.19) 0.92 (0.85-0.99)* 1.13 (1.02-1.25)* High 1.11 (1.00-1.24) 1.10 (1.00-1.21) 1.10 (0.98-1.23) 1.05 (0.98-1.12) 1.15 (1.03-1.29)* Continuous 1.01 (1.00-1.02)* 1.01 (1.00-1.02)* 1.01 (1.00-1.02) 1.00 (0.99-1.01) 1.02 (1.00-1.03)* Cumulative dose Low 0.88 (0.80-0.97)* 1.08 (0.99-1.17) 0.86 (0.78-0.96)* 0.82 (0.75-0.89)* 0.86 (0.77-0.96)* Medium 1.21 (1.10-1.33)* 1.20 (1.11-1.31)* 1.18 (1.07-1.31)* 0.98 (0.91-1.06) 1.22 (1.10-1.34)* High 1.04 (0.93-1.16) 1.07 (0.96-1.18) 1.00 (0.89-1.13) 0.98 (0.91-1.05) 1.08 (0.95-1.22) Continuous 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 1.00 (1.00-1.01) 5.2.1. Gliclazide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.02 (0.92-1.14) 1.12 (1.02-1.22)* 1.04 (0.93-1.17) 0.91 (0.83-1.00)* 1.03 (0.92-1.16) Cumulative duration Low 0.94 (0.81-1.11) 1.11 (0.98-1.27) 0.98 (0.83-1.16) 0.92 (0.81-1.04) 0.96 (0.82-1.13) Medium 0.92 (0.79-1.07) 1.04 (0.91-1.19) 0.84 (0.70-1.00)* 0.86 (0.76-0.98)* 0.93 (0.79-1.09) High 1.22 (1.06-1.39)* 1.19 (1.05-1.35)* 1.19 (1.04-1.38)* 1.03 (0.92-1.15) 1.25 (1.09-1.44)* Continuous 1.02 (1.00-1.04)* 1.02 (1.01-1.04)* 1.01 (0.99-1.04) 1.00 (0.98-1.01) 1.03 (1.01-1.05)* Cumulative dose Low 0.85 (0.72-1.00)* 1.05 (0.92-1.19) 0.87 (0.73-1.04) 0.86 (0.75-0.97)* 0.86 (0.72-1.01) Medium 1.16 (1.01-1.33)* 1.21 (1.07-1.37)* 1.14 (0.98-1.32) 0.99 (0.88-1.11) 1.18 (1.02-1.36)* High 1.08 (0.94-1.26) 1.09 (0.96-1.24) 1.02 (0.87-1.19) 0.96 (0.86-1.08) 1.11 (0.95-1.30) Continuous 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 (0.99-1.01) 1.00 (0.99-1.00) 1.01 (1.00-1.01) 7. Insulins and analogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.99 (0.88-1.12) 1.20 (1.09-1.33)* 0.93 (0.82-1.06) 0.98 (0.91-1.05) 1.01 (0.89-1.14) Cumulative duration Low 0.90 (0.77-1.06) 1.20 (1.06-1.35)* 0.89 (0.76-1.05) 0.83 (0.73-0.94)* 0.93 (0.79-1.10) Medium 0.98 (0.83-1.15) 1.09 (0.94-1.27) 0.83 (0.69-1.00) 0.89 (0.80-1.00) 1.01 (0.85-1.21) High 1.25 (1.03-1.53)* 1.21 (1.00-1.46) 1.21 (0.98-1.49) 1.17 (1.07-1.29)* 1.18 (0.95-1.48) Continuous 1.03 (1.01-1.05)* 1.03 (1.01-1.05)* 1.02 (0.99-1.05) 1.01 (1.00-1.02)* 1.03 (1.00-1.06) Cumulative dose Low 0.89 (0.76-1.04) 1.19 (1.05-1.34)* 0.86 (0.73-1.02) 0.84 (0.75-0.95)* 0.91 (0.78-1.07) Medium 0.98 (0.83-1.16) 1.10 (0.95-1.28) 0.84 (0.69-1.02) 0.86 (0.77-0.96)* 1.03 (0.87-1.23) High 1.28 (1.06-1.56)* 1.21 (1.00-1.46) 1.25 (1.02-1.53)* 1.19 (1.09-1.31)* 1.19 (0.96-1.49) Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 1.01 (1.00-1.03)* 1.01 (1.00-1.01)* 1.02 (1.00-1.03)* 7.1. Basal insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.00 (0.89-1.13) 1.21 (1.09-1.34)* 0.94 (0.83-1.08) 0.99 (0.92-1.06) 1.02 (0.89-1.16) Cumulative duration Low 0.91 (0.77-1.06) 1.20 (1.06-1.36)* 0.88 (0.75-1.05) 0.84 (0.74-0.95)* 0.92 (0.78-1.10) Medium 0.97 (0.82-1.15) 1.08 (0.93-1.26) 0.84 (0.70-1.02) 0.86 (0.77-0.97)* 1.01 (0.85-1.21) High 1.26 (1.03-1.53)* 1.20 (0.99-1.45) 1.21 (0.98-1.49) 1.19 (1.09-1.31)* 1.19 (0.95-1.49) Continuous 1.03 (1.01-1.06)* 1.03 (1.01-1.06)* 1.02 (0.99-1.05) 1.02 (1.01-1.03)* 1.03 (1.00-1.06) Cumulative dose 84 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Low 0.88 (0.75-1.03) 1.15 (1.01-1.30)* 0.84 (0.71-1.00) 0.83 (0.73-0.94)* 0.90 (0.76-1.06) Medium 0.99 (0.83-1.17) 1.12 (0.96-1.31) 0.86 (0.71-1.04) 0.86 (0.77-0.96)* 1.04 (0.87-1.24) High 1.30 (1.07-1.58)* 1.24 (1.03-1.50)* 1.27 (1.04-1.56)* 1.20 (1.09-1.32)* 1.22 (0.98-1.53) Continuous 1.02 (1.01-1.04)* 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 1.01 (1.01-1.02)* 1.02 (1.01-1.04)* 7.2. Bolus insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.30 (1.10-1.55)* 1.42 (1.22-1.66)* 1.20 (0.99-1.45) 1.14 (1.03-1.25)* 1.31 (1.08-1.58)* Cumulative duration Low 0.93 (0.75-1.16) 1.14 (0.95-1.37) 0.84 (0.66-1.07) 0.97 (0.84-1.13) 0.91 (0.71-1.17) Medium 1.36 (1.09-1.70)* 1.36 (1.10-1.68)* 1.23 (0.97-1.57) 1.07 (0.93-1.23) 1.34 (1.05-1.70)* High 1.22 (0.88-1.68) 1.16 (0.85-1.59) 1.15 (0.82-1.61) 1.18 (1.04-1.35)* 1.13 (0.78-1.63) Continuous 1.07 (1.02-1.13)* 1.07 (1.01-1.12)* 1.05 (0.99-1.11) 1.02 (1.00-1.04)* 1.06 (1.00-1.13)* Cumulative dose Low 0.96 (0.78-1.18) 1.13 (0.95-1.35) 0.85 (0.67-1.08) 0.96 (0.83-1.10) 0.95 (0.75-1.20) Medium 1.20 (0.94-1.53) 1.24 (0.98-1.56) 1.07 (0.82-1.40) 1.06 (0.92-1.22) 1.17 (0.90-1.53) High 1.50 (1.12-2.00)* 1.44 (1.09-1.90)* 1.44 (1.07-1.95)* 1.22 (1.07-1.39)* 1.39 (1.00-1.94)* Continuous 1.03 (1.01-1.05)* 1.03 (1.01-1.05)* 1.02 (1.00-1.05) 1.01 (1.00-1.02)* 1.03 (1.00-1.06) Model 1 adjusted for age, birth cohort, health authority, and neighbourhood income with 1-year washout and 1-year lag periods in the primary analysis. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income with 1-year washout and 0-year lag periods. Model 3 adjusted for age, birth cohort, health authority, and neighbourhood income with 1-year washout and 2-year lag periods. Model 4 adjusted for age, birth cohort, health authority, and neighbourhood income with 0-year washout and 1-year lag periods. Model 5 adjusted for age, birth cohort, health authority, and neighbourhood income with 2-year washout and 1-year lag periods. This table summarized the associations between select diabetes medications and breast cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table B-3. * denotes p<0.05. 5.4.2.3 BCGP analysis Supplementary Table B-4 shows all associations in the BCGP analysis, irrespective of their statistical significance. There were too few events to estimate associations with acarbose, meglitinides (and repaglinide), thiazolidinediones (and pioglitazone and rosiglitazone) and linagliptin. Medications that showed statistically significant findings from the primary analysis are presented in Table 5-5. Although not statistically significant, the use of SGLT-2 inhibitors remained inversely associated with the risk of breast cancer after adjusting for sociodemographic and lifestyle-related factors in the BCGP subset. Insulin secretagogues as a class, sulfonylureas as a subclass, and gliclazide as an individual medication all showed consistent significant positive relationships with breast cancer risk. The association with breast cancer risk for insulin class and the basal insulin subclass indicated a positive association, similar to the results from the primary analysis. However, the association of bolus insulins was inconsistent with those from the 85 primary analysis; the direction of effect estimates shifted between Model 1 and Model 2 before adjusting for additional sociodemographic and lifestyle-related factors in the BCGP subpopulation. Lastly, the association with breast cancer for metformin was inconclusive. 86 Table 5-5. Associations between select diabetes medications and the risk of breast cancer among people in the BCGP Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 1. Biguanides (i.e., metformin) Never 369,350 1,158 313.5 (296.0-332.1) 1.00 1.00 1.00 Ever use 4,755 16 336.5 (206.1-549.3) 1.09 (1.04-1.14)* 0.82 (0.50-1.35) 0.75 (0.45-1.23) Cumulative duration - continuous 1.02 (1.01-1.02)* 1.01 (0.94-1.07) 1.00 (0.93-1.06) Cumulative dose - continuous 1.02 (1.01-1.02)* 1.01 (0.93-1.09) 0.99 (0.92-1.08) 3. SGLT-2 inhibitors Never 373,830 1,173 313.8 (296.3-332.3) 1.00 1.00 1.00 Ever use 275 Suppressed 363.6 (51.2-2581.6) 0.64 (0.48-0.85)* 0.94 (0.13-6.70) 0.88 (0.12-6.24) Cumulative duration - continuous 0.97 (0.86-1.08) 0.90 (0.33-2.47) 0.88 (0.32-2.42) Cumulative dose - continuous 0.99 (0.91-1.08) 0.80 (0.28-2.32) 0.78 (0.27-2.30) 5. Insulin secretagogues Never 372,854 1,170 313.8 (296.3-332.3) 1.00 1.00 1.00 Ever use 1,251 Suppressed 319.7 (120.0-851.9) 1.08 (1.00-1.16) 0.78 (0.29-2.07) 0.70 (0.26-1.89) Cumulative duration - continuous 1.01 (1.00-1.02)* 1.07 (0.98-1.16) 1.05 (0.97-1.15) Cumulative dose - continuous 1.00 (1.00-1.01) 1.04 (1.01-1.06)* 1.03 (1.01-1.06)* 5.2. Sulfonylureas Never 372,886 1,170 313.8 (296.3-332.3) 1.00 1.00 1.00 Ever use 1,219 Suppressed 328.1 (123.2-874.3) 1.06 (0.98-1.14) 0.80 (0.30-2.12) 0.72 (0.27-1.93) Cumulative duration - continuous 1.01 (1.00-1.02)* 1.07 (0.98-1.17) 1.06 (0.97-1.16) Cumulative dose - continuous 1.00 (1.00-1.01) 1.04 (1.02-1.06)* 1.04 (1.01-1.06)* 5.2.1. Gliclazide Never 373,384 1,171 313.6 (296.2-332.1) 1.00 1.00 1.00 Ever use 721 Suppressed 416.1 (134.2-1290.1) 1.02 (0.92-1.14) 1.00 (0.32-3.11) 0.90 (0.29-2.80) Cumulative duration - continuous 1.02 (1.00-1.04)* 1.11 (1.01-1.22)* 1.09 (1.00-1.20) Cumulative dose - continuous 1.00 (1.00-1.01) 1.04 (1.02-1.07)* 1.04 (1.01-1.06)* 7. Insulins and analogues Never 373,247 1,171 313.7 (296.3-332.2) 1.00 1.00 1.00 Ever use 858 Suppressed 349.7 (112.8-1084.1) 0.99 (0.88-1.12) 0.88 (0.28-2.73) 0.81 (0.26-2.52) Cumulative duration - continuous 1.03 (1.01-1.05)* 1.00 (0.79-1.27) 0.99 (0.77-1.26) Cumulative dose - continuous 1.02 (1.01-1.03)* 1.02 (0.92-1.14) 1.02 (0.91-1.13) 7.1. Basal insulins Never 373,296 1,171 313.7 (296.2-332.2) 1.00 1.00 1.00 Ever use 809 Suppressed 370.8 (119.6-1149.8) 1.00 (0.89-1.13) 0.92 (0.30-2.87) 0.85 (0.27-2.65) Cumulative duration - continuous 1.03 (1.01-1.06)* 1.01 (0.76-1.35) 0.99 (0.74-1.33) Cumulative dose - continuous 1.02 (1.01-1.04)* 1.04 (0.92-1.17) 1.03 (0.91-1.16) 7.2. Bolus insulins Never 373,717 1,171 313.3 (295.9-331.8) 1.00 1.00 1.00 Ever use 388 Suppressed 773.2 (249.4-2397.4) 1.30 (1.10-1.55)* 2.06 (0.66-6.39) 1.90 (0.61-5.91) Cumulative duration - continuous 1.07 (1.02-1.13)* 0.92 (0.48-1.77) 0.90 (0.46-1.76) Cumulative dose - continuous 1.03 (1.01-1.05)* 0.90 (0.55-1.49) 0.89 (0.53-1.49) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, birth cohort, health authority, and neighbourhood income quintile in the primary analysis using Population Data BC. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income quintile in the BCGP subset. 87 Model 3 further adjusted for sociodemographic and lifestyle-related factors: race/ethnicity, marital status, physical activity, education, individual-level income, reproductive history, fruit and vegetable consumption, alcohol consumption, smoking status, waist to hip ratio, and body mass index using the BCGP subset. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table summarized the associations between select diabetes medications and breast cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table B-4. * denotes p<0.05. 88 5.4.2.4 Active comparator analysis The evaluation of the association for bolus insulins was not possible due to the limited number of events (Table 5-6). Compared to glyburide, metformin (HR=0.86, 95%CI=0.67-1.10), SGLT2 inhibitors (HR=0.28, 95%CI=0.05-1.56), gliclazide (HR=0.61, 95%CI=0.35-1.07), and basal insulins (HR=0.58, 95%CI=0.31-1.09) were associated with lower risks of breast cancer; however, none of these associations were statistically significant. Table 5-6. Associations between diabetes medication and breast cancer, an active comparator analysis among new users of medication Exposure definition Person-years Events Incidence rate Model 1 Model 2 5.2.2. Glyburide 20,008 70 349.9 (276.8-442.2) 1.00 1.00 1. Biguanides (i.e., metformin) 409,526 1,315 321.1 (304.2-338.9) 0.94 (0.74-1.20) 0.86 (0.67-1.10) 5.2.2. Glyburide 20,008 70 349.9 (276.8-442.2) 1.00 1.00 3. SGLT2 inhibitors 664 Suppressed 301.2 (75.3-1204.4) 1.00 (0.24-4.16) 0.28 (0.05-1.56) 5.2.2. Glyburide 20,008 70 349.9 (276.8-442.2) 1.00 1.00 5.2.1. Gliclazide 6,717 19 282.9 (180.4-443.5) 0.78 (0.47-1.31) 0.61 (0.35-1.07) 5.2.2. Glyburide 20,008 70 349.9 (276.8-442.2) 1.00 1.00 7.1. Basal insulins 7,554 16 211.8 (129.8-345.7) 0.79 (0.45-1.37) 0.58 (0.31-1.09) Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. 5.4.3 Findings from cancer subtype analysis Supplementary Table B-5 displays all associations with ductal breast cancer, regardless of their statistical significance. Medications that showed statistically significant findings from the primary analysis are presented in Table 5-7 for ductal breast cancers. Lobular breast cancer was also evaluated (Supplementary Table B-6); however, due to the limited number of cases, the results for lobular breast cancer are not reported. The effects of metformin, SGLT-2 inhibitors, insulin secretagogues as well as sulfonylurea subclass and individual medication gliclazide, and insulins and basal and bolus insulins with the risk of ductal breast cancer were consistent with those for overall breast cancer risk. 89 Table 5-7. Associations between select diabetes medications and the risk of breast cancer morphological subtype: ductal Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 25,974,019 33,684 129.7 (128.3-131.1) 1.00 1.00 Ever use 942,941 1,965 210.7 (200.0-221.9) 1.17 (1.11-1.24)* 1.11 (1.05-1.17)* Cumulative duration Low 363,231 605 166.6 (153.8-180.4) 1.01 (0.94-1.10) 0.97 (0.89-1.05) Medium 323,170 726 224.6 (208.9-241.6) 1.26 (1.17-1.36)* 1.19 (1.11-1.28)* High 256,540 634 247.1 (228.6-267.1) 1.28 (1.19-1.39)* 1.18 (1.09-1.27)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* Cumulative dose Low 383,543 645 168.2 (155.7-181.7) 1.01 (0.93-1.09) 0.96 (0.89-1.04) Medium 327,502 763 233.0 (217.0-250.1) 1.30 (1.21-1.40)* 1.23 (1.14-1.32)* High 231,896 557 240.2 (221.1-261.0) 1.26 (1.16-1.37)* 1.16 (1.06-1.26)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* 3. SGLT-2 inhibitors Never 26,879,533 35,599 132.4 (131.1-133.8) 1.00 1.00 Ever use 37,427 50 126.0 (89.1-178.2) 0.72 (0.51-1.02) 0.63 (0.45-0.89)* Cumulative duration Low 12,099 Suppressed 41.3 (17.2-99.3) 0.24 (0.10-0.57)* 0.21 (0.09-0.50)* Medium 12,583 18 143.1 (90.1-227.1) 0.82 (0.51-1.30) 0.72 (0.45-1.14) High 12,745 27 211.8 (145.3-308.9) 1.17 (0.80-1.70) 1.01 (0.69-1.48) Continuous 1.03 (0.91-1.18) 0.97 (0.85-1.11) Cumulative dose Low 12,132 Suppressed 57.7 (27.5-121.0) 0.33 (0.16-0.69)* 0.29 (0.14-0.60)* Medium 12,532 16 127.7 (78.2-208.4) 0.72 (0.44-1.18) 0.63 (0.39-1.03) High 12,763 27 211.5 (145.1-308.5) 1.18 (0.81-1.72) 1.02 (0.70-1.49) Continuous 1.04 (0.94-1.16) 1.00 (0.89-1.11) 5. Insulin secretagogues Never 26,526,445 34,818 131.3 (129.9-132.6) 1.00 1.00 Ever use 390,515 831 213.9 (196.0-233.4) 1.17 (1.07-1.27)* 1.13 (1.03-1.23)* Cumulative duration Low 157,864 283 179.3 (159.6-201.4) 1.02 (0.91-1.14) 0.99 (0.88-1.12) Medium 132,423 294 222.0 (198.0-248.9) 1.21 (1.08-1.36)* 1.16 (1.03-1.30)* High 100,228 254 253.4 (224.1-286.6) 1.30 (1.15-1.47)* 1.21 (1.07-1.37)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* Cumulative dose Low 164,182 292 177.9 (158.6-199.5) 1.00 (0.89-1.12) 0.98 (0.87-1.10) Medium 131,919 310 235.0 (210.2-262.7) 1.28 (1.15-1.43)* 1.22 (1.09-1.37)* High 94,414 229 242.5 (213.1-276.1) 1.26 (1.11-1.44)* 1.17 (1.02-1.33)* Continuous 1.01 (1.00-1.02)* 1.01 (1.00-1.01) 5.2. Sulfonylureas Never 26,532,030 34,831 131.3 (129.9-132.7) 1.00 1.00 Ever use 384,930 818 210.0 (192.1-229.5) 1.15 (1.05-1.25)* 1.11 (1.01-1.21)* Cumulative duration Low 157,130 281 178.8 (159.1-201.0) 1.01 (0.90-1.14) 0.99 (0.88-1.11) Medium 129,438 288 222.5 (198.2-249.7) 1.21 (1.08-1.36)* 1.16 (1.03-1.30)* High 98,362 249 253.1 (223.6-286.6) 1.30 (1.15-1.47)* 1.21 (1.07-1.37)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* Cumulative dose Low 161,924 284 175.4 (156.1-197.0) 0.98 (0.87-1.10) 0.96 (0.86-1.08) Medium 129,793 307 236.5 (211.5-264.5) 1.29 (1.15-1.44)* 1.23 (1.10-1.37)* High 93,213 227 243.5 (213.8-277.4) 1.27 (1.11-1.45)* 1.17 (1.03-1.33)* Continuous 1.01 (1.00-1.02)* 1.01 (1.00-1.01) 5.2.1. Gliclazide Never 26,747,400 35,272 131.9 (130.5-133.3) 1.00 1.00 Ever use 169,560 377 216.8 (190.8-246.5) 1.17 (1.03-1.33)* 1.08 (0.95-1.23) Cumulative duration Low 56,423 108 191.4 (158.5-231.1) 1.07 (0.88-1.29) 0.99 (0.82-1.20) Medium 57,402 113 196.9 (163.7-236.7) 1.07 (0.89-1.29) 0.99 (0.83-1.19) High 55,735 156 279.9 (239.2-327.5) 1.45 (1.24-1.70)* 1.32 (1.13-1.55)* Continuous 1.05 (1.03-1.08)* 1.04 (1.02-1.06)* Cumulative dose Low 59,361 107 180.3 (149.1-217.9) 1.00 (0.83-1.21) 0.93 (0.77-1.13) 90 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 57,663 136 235.9 (199.4-279.0) 1.28 (1.08-1.51)* 1.18 (1.00-1.40) High 52,536 134 255.1 (215.3-302.1) 1.33 (1.12-1.58)* 1.21 (1.02-1.44)* Continuous 1.01 (1.01-1.02)* 1.01 (1.00-1.02)* 7. Insulins and analogues Never 26,763,779 35,356 132.1 (130.7-133.5) 1.00 1.00 Ever use 153,181 293 211.1 (184.5-241.6) 1.22 (1.07-1.40)* 1.12 (0.98-1.28) Cumulative duration Low 79,227 115 145.2 (120.9-174.3) 1.05 (0.88-1.26) 0.96 (0.80-1.16) Medium 48,672 96 197.2 (161.5-240.9) 1.11 (0.91-1.35) 1.01 (0.83-1.24) High 25,282 82 324.3 (261.2-402.7) 1.71 (1.38-2.12)* 1.53 (1.23-1.90)* Continuous 1.07 (1.04-1.10)* 1.05 (1.03-1.08)* Cumulative dose Low 80,901 116 143.4 (119.5-172.0) 1.03 (0.86-1.23) 0.94 (0.78-1.13) Medium 46,657 94 201.5 (164.6-246.6) 1.13 (0.92-1.38) 1.03 (0.85-1.27) High 25,623 83 323.9 (261.2-401.7) 1.73 (1.39-2.14)* 1.56 (1.26-1.93)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 7.1. Basal insulins Never 26,770,645 35,364 132.1 (130.7-133.5) 1.00 1.00 Ever use 146,315 285 213.5 (185.9-245.3) 1.24 (1.08-1.42)* 1.13 (0.99-1.30) Cumulative duration Low 74,490 112 150.4 (124.9-180.9) 1.08 (0.90-1.30) 0.99 (0.82-1.19) Medium 47,092 94 199.6 (163.1-244.3) 1.12 (0.92-1.37) 1.03 (0.84-1.26) High 24,733 79 319.4 (256.2-398.2) 1.68 (1.35-2.09)* 1.51 (1.21-1.88)* Continuous 1.08 (1.05-1.11)* 1.06 (1.03-1.09)* Cumulative dose Low 75,643 111 146.7 (121.8-176.7) 1.04 (0.87-1.26) 0.96 (0.79-1.15) Medium 45,900 91 198.3 (161.4-243.5) 1.11 (0.91-1.37) 1.02 (0.83-1.25) High 24,772 83 335.1 (270.2-415.5) 1.78 (1.44-2.21)* 1.60 (1.29-1.99)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.05)* 7.2. Bolus insulins Never 26,844,167 35,499 132.2 (130.9-133.6) 1.00 1.00 Ever use 72,793 150 272.5 (224.0-331.5) 1.68 (1.38-2.05)* 1.54 (1.27-1.88)* Cumulative duration Low 41,607 57 137.0 (105.7-177.6) 1.08 (0.83-1.40) 0.98 (0.76-1.28) Medium 21,239 61 287.2 (223.5-369.1) 1.72 (1.34-2.21)* 1.57 (1.22-2.01)* High 9,947 32 321.7 (227.5-454.9) 1.75 (1.24-2.47)* 1.57 (1.11-2.22)* Continuous 1.13 (1.07-1.19)* 1.10 (1.04-1.17)* Cumulative dose Low 43,110 63 146.1 (114.2-187.1) 1.14 (0.89-1.46) 1.04 (0.81-1.33) Medium 19,439 49 252.1 (190.5-333.5) 1.50 (1.13-1.98)* 1.36 (1.03-1.80)* High 10,244 38 370.9 (269.9-509.8) 2.05 (1.49-2.81)* 1.83 (1.33-2.51)* Continuous 1.04 (1.02-1.07)* 1.04 (1.02-1.06)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table summarized the associations between select diabetes medications and ductal breast cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table B-5. * denotes p<0.05. 5.5 Discussion 5.5.1 Key findings SGLT-2 inhibitors were significantly associated with a reduced overall breast cancer risk, even when accounting for other diabetes medications, additional sociodemographic and lifestyle factors, and potential confounding by indication; this inverse link extended to ductal breast 91 cancer risk. However, metformin, insulins, and bolus insulins were associated with higher breast cancer risks, with the effects of sociodemographic and lifestyle factors on these associations remaining indeterminate and the positive association for metformin being potentially confounded by diabetes. 5.5.2 Comparison with other studies Contrary to past systematic reviews based on data from clinical trials 230,231, this study showed an inverse relationship between SGLT-2 inhibitors and breast cancer risk, particularly for low and medium duration and dose. A review of clinical trials found a non-significant positive association between SGLT-2 inhibitors and total cancer mortality 230. Randomized controlled trials (RCTs) revealed non-significant increases in breast cancer risk associated with SGLT-2 inhibitors compared to a placebo or other diabetes medications 231. Variations in the types of SGLT-2 inhibitors included and outcomes (breast cancer diagnosis versus mortality) could contribute to these discrepancies 230. Inherent limitations of clinical trials, such as stringent inclusion criteria and brief follow-up, may also contribute to the discrepancies between the results of the present study and those of previous RCTs 230,231. These limitations may hinder RCTs’ generalizability, possibly leading to incompatible findings in broader real-world populations. SGLT-2 inhibitors reduces blood glucose and insulin production by inhibiting glucose reabsorption 232. Their potential protective effect against breast cancer could arise from their influence on cancer cells’ energy metabolism and demonstrated anti-proliferative effects 233–235. As SGLT-2 inhibitors are relatively new, additional research is needed. 92 5.5.3 Strengths and limitations The study has multiple strengths. First, we obtained accurate data on diabetes medication prescriptions and breast cancer diagnoses using administrative health data, thus reducing recall and misclassification biases. Second, the study analyzed a sizable female cohort to comprehensively understand the associations between a spectrum of diabetes medications, from commonly to less frequently prescribed and breast cancer risk. Third, the implementation of a washout period reduced biases associated with prevalent users 221. Forth, a lag period was incorporated to reduce the possibility of protopathic 213 and detection biases 236. Fifth, we defined exposures in a time-varying manner to help reduce the immortal time bias 237. Lastly, the study’s use of various exposure definitions (dichotomous, continuous, and categorized) allowed for a comprehensive evaluation of the potential effects of diabetes medications on breast cancer risk. This study has several limitations. First, misclassification bias is possible due to the inability to measure medication adherence 238. However, the misclassification was likely non-differential, which would attenuate the effect estimates rather than bias them. Second, due to the implementation of multiple exclusion criteria, the study population might not accurately represent the broader BC population, thereby limiting the generalizability of the results. Thirdly, evolving diabetes and cancer screening practices might affect exposure to diabetes medication and cancer incidence, subsequently influencing the results. Lastly, missing demographic data and their single imputation may introduce potential biases in the validity of the relationships among variables 212. 93 5.6 Conclusion This study investigated the complex links between numerous diabetes medications and breast cancer risk. It emphasizes the necessity for a nuanced understanding of diabetes medications’ potential health risks. We primarily observed null associations, indicating possible safety regarding most diabetes medications. However, significant inverse relationships were noted for SGLT-2 inhibitors at low and medium cumulative duration and dose. Validation of these findings in larger-scale studies in different demographic settings could enhance our understanding of these relationships, improving public health and care for individuals with diabetes. 94 Chapter 6: Diabetes medications and risk of colorectal cancer: a population-based cohort study 6.1 Chapter overview Purpose: The association between diabetes medications on colorectal cancer risk is uncertain. This study aimed to clarify associations between various classes, subclasses and individual diabetes medications and colorectal cancer risk. Methods: In a cohort of British Columbians aged ≥35 (1996-2019), diabetes medication prescription was parameterized as ever/never use, duration, and cumulative dose. Time-varying Cox proportional hazards models determined hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between new diabetes medication use (1-year lag) and colorectal cancer incidence, adjusting for demographics. Additional factors were adjusted for a British Columbia Generations Project (BCGP) subset. Active comparator analysis assessed the influence of confounding by indication. Results: The cohort included 3,118,538 people (~52 million person-years), with 42,809 diagnosed with colorectal cancer. Each 1-year increase in cumulative dose of metformin (HR=1.04, 95%CI=1.04-1.05) and insulin secretagogues, including gliclazide and glyburide in the sulfonylurea subclass (HR=1.02, 95%CI=1.01-1.02), were associated with 4% and 2% increased risk, respectively. The association for metformin was consistent after adjusting for additional sociodemographic and lifestyle factors in the BCGP subset. Although not significant, 95 metformin (HR=1.33, 95%CI=0.55-3.22), gliclazide (HR=2.36, 95%CI=0.73-7.62), and glyburide (HR=2.57, 95%CI=0.67-9.87) showed higher risks compared to GLP-1 receptor agonists in the active comparator analysis. Conclusion: Metformin and insulin secretagogues were linked to increased colorectal cancer risk, emphasizing the potential importance of evaluating the long-term health implications of commonly prescribed medications. 6.2 Introduction Diabetes, a prevalent metabolic disorder that affected 11.9% of Canadian adults in 2021 10, has been linked to an increased risk of numerous complications, such as cardiovascular disease, kidney failure, and blindness 15. The risk of colorectal cancer has been observed to be elevated among individuals with diabetes 152. However, the effect of different diabetes medications on the risk of colorectal cancer is still unknown, and understanding these associations is crucial for expanding our understanding of the potential implications. Previous studies examining the association between diabetes medications and the risk of colorectal cancer have yielded inconclusive results. Some studies have reported associations between specific diabetes medications and the risk of colorectal cancer, such as an inverse association for metformin 239 and acarbose 240, whereas others have found no such connections 241. The literature’s heterogeneity may be attributable to distinct research settings and methodological limitations, such as confounding by indication, inconsistent adjustment for 96 confounders, and lack of a latency period. By aggregating various diabetes medications and disregarding subclass and individual medications, previous research may have obscured the effect on the risk of colorectal cancer. In light of these discrepancies and the potential methodological flaws of previous studies, additional research is necessary to clarify the associations between various classes, subclasses, and individual diabetes medications and the risk of colorectal cancer. In the current study, we examined the associations between new diabetes medication use and the incidence of colorectal cancer in a large cohort in British Columbia (BC). 6.3 Methods 6.3.1 Data sources Population Data BC (PopData), an extensive database of longitudinal, individual-level data for all BC residents, was used for this study 200. Personal Health Numbers are linked to demographic, prescription medication, cancer diagnosis, and mortality data 200. The dataset has been supplemented with a subset of the British Columbia Generations Project (BCGP), a cohort study of British Columbia residents aged 35 to 69 years old who self-reported additional sociodemographic and lifestyle information 205. 6.3.2 Study populations The study assembled a cohort of BC residents aged 35-100 enrolled in the Medical Services Plan (MSP) between January 1, 1996, and December 31, 2019. Exclusion criteria included a cancer 97 diagnosis (excluding non-melanoma skin cancer) before study entry, fewer than five consecutive years on the MSP registry, follow-up under five years, prevalent diabetes medication use 221, or initiating a new diabetes medication within one year before the endpoint 207. All individuals were followed from the time they entered the cohort until their first cancer diagnosis (excluding non-melanoma skin cancer), death, loss of follow-up, or December 31, 2019, whichever came first. 6.3.3 Exposure assessment The study analyzed seven medication classes, six subclasses, and seven individual medications; each identified medication was structured according to five definitions 229: ever versus never use, cumulative duration and dose, and categorized cumulative duration and dose (low, medium, or high versus never). Each person was considered unexposed until they received their first prescription, at which point they were declared exposed. The cumulative dose was calculated using the World Health Organization’s defined daily dose to standardize the potencies of various medications 211. The approach provided a comprehensive representation of real-world scenarios, including the concurrent use of multiple medications and transitions between medications throughout the observation period. 6.3.4 Outcome assessment The BC Cancer Registry, which documents about 95% of all cancer cases in BC 203, was used to identify incident colorectal cancer (site code: C180-C189, C199, C209, C260; morphology code: exclude 9050-9055, 9140, 9590-9992) and its location subtypes, namely colon (C180-C189, C260), proximal colon (C180-185), distal colon (C186, C187), and rectum (C199, C209) 224, 98 within the study population according to ICD-O-3 (International Classification of Diseases in Oncology, Third Edition). 6.3.5 Potential confounders Confounder selection in the study relied on a priori knowledge from the literature review in Chapter 3, including factors like age, birth cohort, sex at birth, income quintile of neighbourhood, and health authority. 6.3.6 Statistical analysis Using the Poisson distribution, colorectal cancer incidence rates and their 95% confidence intervals (CIs) were calculated for each category of exposure parameterization (ever vs never use and categorized cumulative duration and dose). To address missing information in covariates, a single imputation using predictive mean matching 212 was employed, with auxiliary variables including birth year, sex at birth, diabetes medication exposure, and cancer incidence incorporated into the imputation model. 6.3.6.1 Primary analysis Hazard ratios (HRs) and corresponding 95% CIs for colorectal cancer were estimated using time-varying Cox proportional hazards models with age as the time axis and diabetes medications as time-varying factors. Due to the fluctuating nature of medication exposure, separate models accounted for each exposure parameterization, while 1-year washout 221 and lag periods 207 were incorporated to exclude prevalent medication users and account for cancer latency, respectively. 99 The models were crudely adjusted for age and subsequently for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile using SAS (version 9.4; SAS Institute, Inc., Cary, NC), with statistical significance denoted by a two-sided P value less than 0.05. 6.3.6.2 Sensitivity analyses 6.3.6.2.1 Additional adjustment for other diabetes medications When metformin is insufficient to achieve glycemic targets or in cases of symptomatic hyperglycemia, a second-line medication is required, with the selection dependent on the patient’s health profile and other considerations such as ease of administration 74. Time-varying use of other diabetes medications during follow-up was additionally adjusted in the models to model changing health status and severity of diabetes 214. 6.3.6.2.2 Washout and lag periods The primary analysis was re-evaluated using 0-year and 2-year washout and lag periods to determine the effect of the initially defined medication washout period and lag time window. 6.3.6.2.3 BCGP analysis In the subset of participants in the BCGP study, further adjustment for additional sociodemographic and lifestyle measures 120,132,134,214–219 was employed to examine the influence on the key associations found in the primary analysis. 100 6.3.6.2.4 Active comparator analysis An active comparator new-user analysis 221 was conducted to assess possible confounding by indication 220. Analyses focused on diabetes medications identified as significant in the primary and other sensitivity analyses. GLP-1 receptor agonists were the active comparator due to their lack of association with colorectal cancer risk. Exposure was recorded as a dichotomous variable for individuals who initiated monotherapy with one of the identified medications. In addition to endpoints described in the primary analysis, follow-up was further censored for cessation or modification of initial medication, thus minimizing exposure misclassification. 6.3.6.3 Colorectal cancer subtype analysis The exploration of colorectal cancer was extended to its location subtypes, including colon (proximal and distal) and rectal cancer 224. 6.4 Results A cohort of 3,118,538 people (Figure 5-1) was followed for a mean of 16.7 (SD = 6.7) years, yielding 52,088,644 person-years. During the follow-up period, 42,809 people were diagnosed with colorectal cancer; crude incidence rate 82.2 (95%CI=81.4-83.0) per 100,000 person-years. Among cases, the median (and IQR) time between cohort entry and diagnosis of colorectal cancer was 14 years (9 to 19 years). Table 6-1 shows the distribution of baseline demographics and use of diabetes medications by colorectal case status. At cohort entry, cases were older than non-cases. The proportion of males was higher in cases than among non-cases. At the class level, 101 biguanides and incretin-based medicines were the most commonly prescribed diabetes medication (prescription rates 6.6% and 1.2%), whereas AGIs was the least (0.1%). Table 6-1. Baseline characteristics at cohort entry of the overall cohort and stratified by incident colorectal cancer case status at cohort entry Total Cases Non-cases Characteristic N = 3,118,538, n (%) N = 42,809, n (%) N = 3,075,729, n (%) Age (years)a 35-39 1,411,812 (45.3) 5,141 (12.0) 1,406,671 (45.7) 40-44 389,893 (12.5) 3,956 (9.2) 385,937 (12.5) 45-49 331,161 (10.6) 5,041 (11.8) 326,120 (10.6) 50-54 247,063 (7.9) 5,353 (12.5) 241,710 (7.9) 55-59 192,779 (6.2) 5,275 (12.3) 187,504 (6.1) 60-64 160,924 (5.2) 5,241 (12.2) 155,683 (5.1) 65-69 136,083 (4.4) 5,107 (11.9) 130,976 (4.3) 70-100 248,823 (8.0) 7,695 (18.0) 241,128 (7.8) Mean±SD 46.2±13.2 56.5±13.0 46.1±13.1 Calendar yeara 1996 1,604,354 (51.4) 36,791 (85.9) 1,567,563 (51.0) 1997-1999 273,249 (8.8) 2,166 (5.1) 271,083 (8.8) 2000-2002 235,319 (7.5) 1,392 (3.3) 233,927 (7.6) 2003-2005 243,377 (7.8) 1,083 (2.5) 242,294 (7.9) 2006-2008 240,857 (7.7) 769 (1.8) 240,088 (7.8) 2009-2011 223,425 (7.2) 399 (0.9) 223,026 (7.3) 2012-2015 297,957 (9.6) 209 (0.5) 297,748 (9.7) Birth cohortb 1896-1940 617,377 (19.8) 21,628 (50.5) 595,749 (19.4) 1941-1950 506,643 (16.2) 10,626 (24.8) 496,017 (16.1) 1951-1957 487,886 (15.6) 5,477 (12.8) 482,409 (15.7) 1958-1964 543,217 (17.4) 3,400 (7.9) 539,817 (17.6) 1965-1980 963,415 (30.9) 1,678 (3.9) 961,737 (31.3) Sexb Female 1,599,418 (51.3) 19,940 (46.6) 1,579,478 (51.4) Male 1,519,120 (48.7) 22,869 (53.4) 1,496,251 (48.6) Health authoritya Interior 494,698 (15.9) 7,828 (18.3) 486,870 (15.8) Fraser 991,476 (31.8) 13,044 (30.5) 978,432 (31.8) Vancouver Coastal 853,983 (27.4) 10,319 (24.1) 843,664 (27.4) Vancouver Island 511,764 (16.4) 8,389 (19.6) 503,375 (16.4) Northern 189,820 (6.1) 2,600 (6.1) 187,220 (6.1) Missing 76,797 (2.5) 629 (1.5) 76,168 (2.5) Neighbourhood income quintilea Quintile 1 632,793 (20.3) 8,324 (19.4) 624,469 (20.3) Quintile 2 606,382 (19.4) 8,092 (18.9) 598,290 (19.5) Quintile 3 591,755 (19.0) 8,096 (18.9) 583,659 (19.0) Quintile 4 587,599 (18.8) 8,481 (19.8) 579,118 (18.8) Quintile 5 571,889 (18.3) 8,546 (20.0) 563,343 (18.3) Missing 128,120 (4.1) 1,270 (3.0) 126,850 (4.1) Diabetes medicationc 1. Biguanides (i.e., metformin) Non-users 2,913,581 (93.4) 39,259 (91.7) 2,874,322 (93.5) Users 204,957 (6.6) 3,550 (8.3) 201,407 (6.5) 2. Incretin-based medicines Non-users 3,079,804 (98.8) 42,469 (99.2) 3,037,335 (98.8) Users 38,734 (1.2) 340 (0.8) 38,394 (1.2) 2.1. DPP-4 inhibitors Non-users 3,088,342 (99.0) 42,517 (99.3) 3,045,825 (99.0) Users 30,196 (1.0) 292 (0.7) 29,904 (1.0) 2.1.1. Linagliptin 102 Total Cases Non-cases Characteristic N = 3,118,538, n (%) N = 42,809, n (%) N = 3,075,729, n (%) Non-users 3,103,627 (99.5) 42,713 (99.8) 3,060,914 (99.5) Users 14,911 (0.5) 96 (0.2) 14,815 (0.5) 2.1.2. Sitagliptin Non-users 3,100,549 (99.4) 42,603 (99.5) 3,057,946 (99.4) Users 17,989 (0.6) 206 (0.5) 17,783 (0.6) 2.2. GLP-1 receptor agonists Non-users 3,104,469 (99.5) 42,726 (99.8) 3,061,743 (99.5) Users 14,069 (0.5) 83 (0.2) 13,986 (0.5) 3. SGLT-2 inhibitors Non-users 3,097,235 (99.3) 42,717 (99.8) 3,054,518 (99.3) Users 21,303 (0.7) 92 (0.2) 21,211 (0.7) 4. AGIs (i.e., acarbose) Non-users 3,114,407 (99.9) 42,742 (99.8) 3,071,665 (99.9) Users 4,131 (0.1) 67 (0.2) 4,064 (0.1) 5. Insulin secretagogues Non-users 3,027,943 (97.1) 41,019 (95.8) 2,986,924 (97.1) Users 90,595 (2.9) 1,790 (4.2) 88,805 (2.9) 5.1. Meglitinides Non-users 3,114,915 (99.9) 42,732 (99.8) 3,072,183 (99.9) Users 3,623 (0.1) 77 (0.2) 3,546 (0.1) 5.1.1. Repaglinide Non-users 3,114,965 (99.9) 42,734 (99.8) 3,072,231 (99.9) Users 3,573 (0.1) 75 (0.2) 3,498 (0.1) 5.2. Sulfonylureas Non-users 3,028,815 (97.1) 41,033 (95.9) 2,987,782 (97.1) Users 89,723 (2.9) 1,776 (4.1) 87,947 (2.9) 5.2.1. Gliclazide Non-users 3,066,066 (98.3) 42,011 (98.1) 3,024,055 (98.3) Users 52,472 (1.7) 798 (1.9) 51,674 (1.7) 5.2.2. Glyburide Non-users 3,057,803 (98.1) 41,454 (96.8) 3,016,349 (98.1) Users 60,735 (1.9) 1,355 (3.2) 59,380 (1.9) 6. Thiazolidinediones Non-users 3,100,990 (99.4) 42,418 (99.1) 3,058,572 (99.4) Users 17,548 (0.6) 391 (0.9) 17,157 (0.6) 6.1. Pioglitazone Non-users 3,109,560 (99.7) 42,639 (99.6) 3,066,921 (99.7) Users 8,978 (0.3) 170 (0.4) 8,808 (0.3) 6.2. Rosiglitazone Non-users 3,107,467 (99.6) 42,536 (99.4) 3,064,931 (99.6) Users 11,071 (0.4) 273 (0.6) 10,798 (0.4) 7. Insulins and analogues Non-users 3,079,862 (98.8) 42,325 (98.9) 3,037,537 (98.8) Users 38,676 (1.2) 484 (1.1) 38,192 (1.2) 7.1. Basal insulins Non-users 3,081,238 (98.8) 42,336 (98.9) 3,038,902 (98.8) Users 37,300 (1.2) 473 (1.1) 36,827 (1.2) 7.2. Bolus insulins Non-users 3,100,018 (99.4) 42,600 (99.5) 3,057,418 (99.4) Users 18,520 (0.6) 209 (0.5) 18,311 (0.6) a: Measured at study entry. b: Measured at birth. c: Measured during follow-up. SD: Standard deviation. AGIs: Alpha-glucosidase inhibitors. DPP-4 inhibitors: Dipeptidyl peptidase 4 inhibitors. GLP-1 receptor agonists: Glucagon-like peptide 1 receptor agonists. SGLT-2 inhibitors: Sodium-glucose cotransporter 2 inhibitors. 103 6.4.1 Findings from the primary analysis The findings from the primary analysis for each diabetes medication class, subclass, and individual medication are summarized in Supplementary Table C-1. Age is adjusted in Model 1, while sex at birth, birth cohort, health authority, and neighbourhood income quintile are further adjusted in Model 2. Statistically significant results from Model 2 are presented in Table 6-2 and summarized below. Table 6-2. Associations between select diabetes medications and the risk of colorectal cancer Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 39,259 78.4 (77.6-79.2) 1.00 1.00 Ever use 2,021,426 3,550 176.4 (169.8-183.2) 1.29 (1.24-1.34)* 1.21 (1.17-1.26)* Cumulative duration Low 736,609 807 109.6 (102.3-117.4) 0.93 (0.87-1.00)* 0.89 (0.83-0.95)* Medium 720,912 1,321 183.2 (173.6-193.4) 1.36 (1.29-1.43)* 1.28 (1.21-1.35)* High 563,905 1,422 252.2 (239.4-265.6) 1.49 (1.41-1.57)* 1.41 (1.33-1.48)* Continuous 1.04 (1.04-1.05)* 1.04 (1.03-1.04)* Cumulative dose Low 761,186 897 117.8 (110.4-125.8) 0.95 (0.89-1.02) 0.91 (0.86-0.98)* Medium 720,432 1,307 181.4 (171.8-191.5) 1.31 (1.24-1.38)* 1.24 (1.17-1.31)* High 539,808 1,346 249.3 (236.4-263.0) 1.58 (1.50-1.67)* 1.47 (1.39-1.56)* Continuous 1.05 (1.05-1.06)* 1.04 (1.04-1.05)* 5. Insulin secretagogues Never 51,176,005 41,019 80.2 (79.4-80.9) 1.00 1.00 Ever use 912,639 1,790 197.8 (186.6-209.7) 1.41 (1.33-1.50)* 1.33 (1.25-1.41)* Cumulative duration Low 360,923 506 140.2 (128.5-153.0) 1.07 (0.98-1.17) 1.03 (0.94-1.12) Medium 315,845 638 202.0 (186.9-218.3) 1.44 (1.33-1.56)* 1.35 (1.25-1.46)* High 235,871 646 273.9 (253.6-295.8) 1.59 (1.47-1.71)* 1.49 (1.38-1.61)* Continuous 1.05 (1.04-1.06)* 1.05 (1.04-1.05)* Cumulative dose Low 372,575 572 153.5 (141.4-166.6) 1.12 (1.03-1.22)* 1.08 (0.99-1.17) Medium 314,231 655 208.4 (193.1-225.0) 1.45 (1.34-1.56)* 1.36 (1.26-1.47)* High 225,833 563 249.3 (229.5-270.8) 1.57 (1.44-1.70)* 1.46 (1.34-1.59)* Continuous 1.02 (1.02-1.02)* 1.02 (1.01-1.02)* 5.2. Sulfonylureas Never 51,188,413 41,033 80.2 (79.4-80.9) 1.00 1.00 Ever use 900,231 1,776 198.5 (187.2-210.5) 1.41 (1.33-1.50)* 1.33 (1.26-1.41)* Cumulative duration Low 359,009 517 144.0 (132.1-157.0) 1.10 (1.01-1.20)* 1.05 (0.97-1.15) Medium 309,407 624 201.7 (186.5-218.1) 1.44 (1.33-1.55)* 1.35 (1.24-1.46)* High 231,815 635 273.9 (253.4-296.1) 1.58 (1.47-1.71)* 1.49 (1.38-1.61)* Continuous 1.05 (1.04-1.06)* 1.05 (1.04-1.05)* Cumulative dose Low 367,838 575 156.3 (144.0-169.6) 1.14 (1.05-1.24)* 1.09 (1.01-1.19)* Medium 309,412 644 208.1 (192.7-224.8) 1.45 (1.34-1.56)* 1.36 (1.25-1.46)* High 222,981 557 249.8 (229.9-271.4) 1.57 (1.44-1.70)* 1.46 (1.35-1.59)* Continuous 1.02 (1.02-1.02)* 1.02 (1.01-1.02)* 5.2.1. Gliclazide Never 51,695,028 42,011 81.3 (80.5-82.0) 1.00 1.00 Ever use 393,616 798 207.0 (190.2-225.4) 1.43 (1.31-1.55)* 1.32 (1.22-1.44)* 104 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative duration Low 126,908 224 176.5 (154.8-201.2) 1.31 (1.15-1.49)* 1.23 (1.08-1.40)* Medium 136,638 250 183.0 (161.6-207.1) 1.29 (1.14-1.46)* 1.20 (1.06-1.35)* High 130,070 324 249.1 (223.4-277.8) 1.51 (1.35-1.68)* 1.42 (1.27-1.58)* Continuous 1.06 (1.05-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 133,699 232 173.5 (152.6-197.4) 1.25 (1.10-1.42)* 1.18 (1.04-1.34)* Medium 136,394 267 195.8 (173.6-220.7) 1.34 (1.19-1.52)* 1.25 (1.11-1.41)* High 123,523 299 242.1 (216.1-271.1) 1.52 (1.36-1.71)* 1.43 (1.28-1.60)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 5.2.2. Glyburide Never 51,418,210 41,454 80.6 (79.8-81.4) 1.00 1.00 Ever use 670,434 1,355 192.7 (177.9-208.7) 1.40 (1.29-1.52)* 1.34 (1.24-1.45)* Cumulative duration Low 283,215 462 163.1 (148.9-178.7) 1.19 (1.09-1.31)* 1.15 (1.05-1.26)* Medium 224,722 438 194.9 (177.5-214.0) 1.37 (1.25-1.51)* 1.30 (1.18-1.43)* High 162,497 455 280.0 (255.4-307.0) 1.61 (1.47-1.77)* 1.51 (1.38-1.66)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* Cumulative dose Low 296,014 499 168.6 (154.4-184.0) 1.18 (1.08-1.29)* 1.14 (1.05-1.25)* Medium 230,574 499 216.4 (198.2-236.3) 1.48 (1.35-1.61)* 1.40 (1.28-1.53)* High 143,846 357 248.2 (223.7-275.3) 1.55 (1.40-1.72)* 1.45 (1.31-1.61)* Continuous 1.03 (1.02-1.03)* 1.02 (1.02-1.03)* 6. Thiazolidinediones Never 51,871,508 42,418 81.8 (81.0-82.6) 1.00 1.00 Ever use 217,136 391 141.3 (116.4-171.5) 1.27 (1.05-1.55)* 1.21 (0.99-1.46) Cumulative duration Low 76,357 113 148.0 (123.1-178.0) 1.17 (0.97-1.40) 1.10 (0.92-1.33) Medium 72,351 125 172.8 (145.0-205.9) 1.35 (1.13-1.61)* 1.27 (1.06-1.51)* High 68,428 153 223.6 (190.8-262.0) 1.55 (1.33-1.82)* 1.42 (1.22-1.67)* Continuous 1.07 (1.05-1.10)* 1.06 (1.03-1.08)* Cumulative dose Low 75,982 112 147.4 (122.5-177.4) 1.15 (0.95-1.38) 1.09 (0.90-1.31) Medium 74,257 134 180.5 (152.3-213.7) 1.40 (1.18-1.66)* 1.31 (1.11-1.56)* High 66,897 145 216.8 (184.2-255.1) 1.53 (1.30-1.80)* 1.40 (1.19-1.65)* Continuous 1.07 (1.04-1.09)* 1.05 (1.03-1.08)* 6.2. Rosiglitazone Never 51,946,176 42,536 81.9 (81.1-82.7) 1.00 1.00 Ever use 142,468 273 121.8 (91.2-162.6) 1.18 (0.89-1.58) 1.14 (0.85-1.52) Cumulative duration Low 49,170 80 162.7 (130.7-202.6) 1.26 (1.01-1.57)* 1.20 (0.96-1.49) Medium 48,028 87 181.1 (146.8-223.5) 1.41 (1.14-1.74)* 1.33 (1.08-1.64)* High 45,270 106 234.2 (193.6-283.3) 1.68 (1.39-2.03)* 1.54 (1.28-1.87)* Continuous 1.10 (1.07-1.14)* 1.09 (1.05-1.12)* Cumulative dose Low 49,567 82 165.4 (133.2-205.4) 1.28 (1.03-1.59)* 1.21 (0.98-1.51) Medium 49,349 90 182.4 (148.3-224.2) 1.41 (1.14-1.73)* 1.32 (1.08-1.63)* High 43,552 101 231.9 (190.8-281.8) 1.68 (1.38-2.04)* 1.54 (1.27-1.87)* Continuous 1.10 (1.07-1.14)* 1.08 (1.05-1.12)* 7. Insulins and analogues Never 51,772,245 42,325 81.8 (81.0-82.5) 1.00 1.00 Ever use 316,399 484 168.0 (152.1-185.6) 1.33 (1.20-1.47)* 1.21 (1.10-1.34)* Cumulative duration Low 143,015 129 90.2 (75.9-107.2) 0.90 (0.76-1.07) 0.84 (0.70-1.00)* Medium 113,499 216 190.3 (166.5-217.5) 1.45 (1.27-1.66)* 1.33 (1.16-1.52)* High 59,885 139 232.1 (196.6-274.1) 1.61 (1.37-1.91)* 1.50 (1.27-1.77)* Continuous 1.07 (1.05-1.09)* 1.05 (1.03-1.08)* Cumulative dose Low 146,186 137 93.7 (79.3-110.8) 0.91 (0.77-1.08) 0.85 (0.72-1.00) Medium 108,141 202 186.8 (162.7-214.4) 1.42 (1.24-1.64)* 1.30 (1.14-1.50)* High 62,072 145 233.6 (198.5-274.9) 1.70 (1.44-2.00)* 1.54 (1.31-1.82)* Continuous 1.03 (1.02-1.04)* 1.02 (1.02-1.03)* 7.1. Basal insulins Never 51,784,863 42,336 81.8 (81.0-82.5) 1.00 1.00 Ever use 303,781 473 169.2 (152.7-187.4) 1.34 (1.21-1.49)* 1.23 (1.11-1.36)* 105 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative duration Low 135,289 135 99.8 (84.3-118.1) 1.00 (0.84-1.18) 0.93 (0.78-1.10) Medium 109,417 205 187.4 (163.4-214.8) 1.44 (1.26-1.65)* 1.32 (1.15-1.51)* High 59,075 133 225.1 (189.9-266.8) 1.56 (1.31-1.85)* 1.44 (1.21-1.71)* Continuous 1.08 (1.05-1.10)* 1.06 (1.04-1.09)* Cumulative dose Low 136,909 135 98.6 (83.3-116.7) 0.96 (0.81-1.14) 0.90 (0.76-1.06) Medium 106,571 195 183.0 (159.0-210.5) 1.40 (1.22-1.61)* 1.28 (1.12-1.48)* High 60,301 143 237.1 (201.3-279.4) 1.71 (1.45-2.02)* 1.56 (1.32-1.84)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 7.2. Bolus insulins Never 51,947,122 42,600 82.0 (81.2-82.8) 1.00 1.00 Ever use 141,522 209 169.7 (144.0-199.9) 1.52 (1.29-1.79)* 1.38 (1.17-1.62)* Cumulative duration Low 68,567 73 106.5 (84.6-133.9) 1.16 (0.92-1.46) 1.08 (0.86-1.36) Medium 48,161 76 157.8 (126.0-197.6) 1.38 (1.10-1.73)* 1.25 (1.00-1.57) High 24,794 60 242.0 (187.9-311.7) 1.93 (1.50-2.48)* 1.75 (1.36-2.25)* Continuous 1.10 (1.05-1.15)* 1.08 (1.03-1.13)* Cumulative dose Low 71,251 78 109.5 (87.7-136.7) 1.17 (0.94-1.46) 1.09 (0.87-1.36) Medium 44,054 71 161.2 (127.7-203.4) 1.40 (1.11-1.77)* 1.27 (1.01-1.61)* High 26,217 60 228.9 (177.7-294.8) 1.89 (1.47-2.44)* 1.70 (1.32-2.19)* Continuous 1.04 (1.03-1.06)* 1.04 (1.02-1.06)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. This table summarized the associations between select diabetes medications and colorectal cancer. The full results for all diabetes medications assessed can be found in Supplementary Table C-1. * denotes p<0.05. 6.4.1.1 Biguanides (i.e., metformin) – Class Compared with never use, ever use of metformin was significantly associated with a 21% increase in the risk of colorectal cancer (HR=1.21, 95%CI=1.17-1.26). Significant relationships were found for both continuous cumulative duration (HR=1.04, 95%CI=1.03-1.04) and dose analyses (HR=1.04, 95%CI=1.04-1.05) for metformin. Significant relationships were also detected in the categorized cumulative duration and dose analyses. The low duration (HR=0.89, 95%CI=0.83-0.95) and dose categories (HR=0.91, 95%CI=0.86-0.98) were associated with 11% and 9% decreased risks of colorectal cancer relative to never use. Medium duration (HR=1.28, 95%CI=1.21-1.35) and dose categories (HR=1.24, 95%CI=1.17-1.31) were associated with 28% and 24% higher risks, respectively, and high duration (HR=1.41, 95%CI=1.33-1.48) and dose 106 categories (HR=1.47, 95%CI=1.39-1.56) were associated with 41% and 47% higher risks, respectively. These associations indicate potential duration- and dose-responses. 6.4.1.2 Insulin secretagogues – Class Relative to never use, ever use of insulin secretagogues was significantly related to an increased risk of colorectal cancer (HR=1.33, 95%CI=1.25-1.41). Significant associations were observed between continuous cumulative duration (HR=1.05, 95%CI=1.04-1.05) and dose of insulin secretagogues (HR=1.02, 95%CI=1.01-1.02) with colorectal cancer risk. Significant associations were observed in categorized cumulative duration and dose analyses for insulin secretagogues. The medium duration (HR=1.35, 95%CI=1.25-1.46) and dose categories (HR=1.36, 95%CI=1.26-1.47) were associated with 35% and 36% increases in colorectal cancer risk. In contrast, the high duration (HR=1.49, 95%CI=1.38-1.61) and dose categories (HR=1.46, 95%CI=1.34-1.59) were linked to 49% and 46% higher risks, respectively. These results indicate duration- and dose-responses between insulin secretagogues and colorectal cancer risk. 6.4.1.3 Sulfonylureas – Subclass Sulfonylureas, a subclass of insulin secretagogues, were found to have comparable associations with incident colorectal cancer risk; ever use of sulfonylureas was significantly associated with a higher risk of colorectal cancer compared to never use (HR=1.33, 95%CI=1.26-1.41). The continuous cumulative duration (HR=1.05, 95%CI=1.04-1.05) and dose analyses (HR=1.02, 95%CI=1.01-1.02) for sulfonylureas indicate significant relationships. Significant associations were also detected in the categorized cumulative duration and dose analyses. Relative to never 107 use, the medium (HR=1.35, 95%CI=1.24-1.46) and high duration categories (HR=1.49, 95%CI=1.38-1.61) of sulfonylurea use were associated with 35% and 49% increases in colorectal cancer risk. The low (HR=1.09, 95%CI=1.01-1.19), medium (HR=1.36, 95%CI=1.25-1.46), and high dose categories (HR=1.46, 95%CI=1.35-1.59) were linked to 9%, 36%, and 46% higher risks compared to never use of sulfonylureas. There was evidence for duration- and dose-responses. 6.4.1.4 Gliclazide – Individual Gliclazide, a medication in the sulfonylurea subclass, had similar relationships with colorectal cancer risk as the sulfonylurea subclass and insulin secretagogue class medications. Ever use of gliclazide was significantly associated with an increase in the risk of colorectal cancer compared to never use (HR=1.32, 95%CI=1.22-1.44). Significant relationships were found in both continuous and categorized cumulative duration and dose analyses for gliclazide. Every 1-year increase in duration (HR=1.05, 95%CI=1.04-1.07) or dose (HR=1.02, 95%CI=1.01-1.02) was linked to a 5% or 2% higher risk of colorectal cancer. The low (HR=1.23, 95%CI=1.08-1.40), medium (HR=1.20, 95%CI=1.06-1.35), and high duration categories (HR=1.42, 95%CI=1.27-1.58) of gliclazide use were linked with increased colorectal cancer risks of 23%, 20%, and 42%, respectively, compared to never use. The low (HR=1.18, 95%CI=1.04-1.34), medium (HR=1.25, 95%CI=1.11-1.41), and high dose categories (HR=1.43, 95%CI=1.28-1.60) were associated with 18%, 25%, and 43% increased risk, suggesting a dose-response relationship. 108 6.4.1.5 Glyburide – Individual Glyburide, another medication in the sulfonylurea subclass, also had similar associations with colorectal cancer risk as found for the subclass and class medications. Compared to never use, ever use of glyburide was significantly related to an elevated risk of colorectal cancer (HR=1.34, 95%CI=1.24-1.45). Both continuous and categorized cumulative duration and dose analyses for glyburide revealed significant relationships; each 1-year increase in duration (HR=1.05, 95%CI=1.04-1.06) or dose (HR=1.02, 95%CI=1.02-1.03) was associated with a 5% or 2% increased colorectal cancer risk, respectively. In comparison to never use, the low (HR=1.15, 95%CI=1.05-1.26), medium (HR=1.30, 95%CI=1.18-1.43), and high duration categories (HR=1.51, 95%CI=1.38-1.66) of glyburide use were associated with 15%, 30%, and 51% increases in colorectal cancer risk, indicating a duration-response. The low (HR=1.14, 95%CI=1.05-1.25), medium (HR=1.40, 95%CI=1.28-1.53), and high dose categories (HR=1.45, 95%CI=1.31-1.61) were related to 14%, 40%, and 45% higher risk. 6.4.1.6 Thiazolidinediones – Class In the analyses of continuous cumulative duration and dose, thiazolidinediones demonstrated significant relationships with risks of colorectal cancer; every 1-year increase in cumulative duration (HR=1.06, 95%CI=1.03-1.08) and dose (HR=1.05, 95%CI=1.03-1.08) were associated with 6% and 5% higher risks. Significant relationships were also found for categorized cumulative duration and dose analyses for thiazolidinediones. The medium duration (HR=1.27, 95%CI=1.06-1.51) and dose categories (HR=1.31, 95%CI=1.11-1.56) were related to 27% and 31% increases in colorectal cancer risk, and high duration (HR=1.42, 95%CI=1.22-1.67) and 109 dose categories (HR=1.40, 95%CI=1.19-1.65) were associated with 42% and 40% increases in colorectal cancer risk. There was evidence for duration- and dose-responses with colorectal cancer risk in thiazolidinediones. 6.4.1.7 Rosiglitazone – Individual The associations with colorectal cancer risk for rosiglitazone were similar to those in the medication class thiazolidinediones. Rosiglitazone use showed significant relationships with risk of colorectal cancer in continuous cumulative duration (HR=1.09, 95%CI=1.05-1.12) and dose analyses (HR=1.08, 95%CI=1.05-1.12). Significant relationships for categorized cumulative duration and dose of rosiglitazone use were detected as well: the medium duration (HR=1.33, 95%CI=1.08-1.64) and dose categories (HR=1.32, 95%CI=1.08-1.63) were related to a 33% and 32% higher risk of colorectal cancer, and the high duration (HR=1.54, 95%CI=1.28-1.87) and dose categories (HR=1.54, 95%CI=1.27-1.87) were both associated with 54% higher risks relative to never use. These results indicated duration- and dose-responses between rosiglitazone and colorectal cancer risk. 6.4.1.8 Insulins and analogues – Class Ever use of insulins and analogues was linked to a higher risk of developing colorectal cancer compared to never use (HR=1.21, 95%CI=1.10-1.34). Significant relationships were detected for continuous cumulative duration and dose analyses: duration (HR=1.05, 95%CI=1.03-1.08) and dose (HR=1.02, 95%CI=1.02-1.03). The categorized cumulative duration and dose of insulins and analogues also showed significant associations, with the low duration category (HR=0.84, 110 95%CI=0.70-1.00) linked to a 16% decreased risk. In comparison to never use, medium duration (HR=1.33, 95%CI=1.16-1.52) and dose categories (HR=1.30, 95%CI=1.14-1.50) were associated with 33% and 30% higher risks, and high duration (HR=1.50, 95%CI=1.27-1.77) and dose categories (HR=1.54, 95%CI=1.31-1.82) were related to 50% and 54% higher risks of colorectal cancer. These findings indicated possible duration- and dose-responses in the risk of colorectal cancer. 6.4.1.9 Basal insulins – Subclass Similar associations with colorectal cancer risk were seen in the basal insulin subclass as the insulin and analogues class. Ever use of basal insulins was associated with an increased risk of colorectal cancer compared to never use (HR=1.23, 95%CI=1.11-1.36). Both continuous and categorized cumulative duration and dose analyses for basal insulin use showed significant relationships. Each 1-year increase in cumulative duration (HR=1.06, 95%CI=1.04-1.09) or dose (HR=1.03, 95%CI=1.02-1.04) was related to a 6% or 3% increase in the risk of colorectal cancer. Compared to never use, the risk of colorectal cancer was 32% or 28% higher for the medium cumulative duration (HR=1.32, 95%CI=1.15-1.51) or dose category (HR=1.28, 95%CI=1.12-1.48) and 44% or 56% higher for the high cumulative duration (HR=1.44, 95%CI=1.21-1.71) or dose category (HR=1.56, 95%CI=1.32-1.84). There was evidence for duration- and dose-responses in colorectal cancer risk for basal insulin. 111 6.4.1.10 Bolus insulins – Subclass Similar to the basal insulin subclass, associations with colorectal cancer in the subclass of bolus insulins were associated with an increased risk of colorectal cancer. Ever use of bolus insulins was significantly related to an elevated risk of colorectal cancer (HR=1.38, 95%CI=1.17-1.62). There were significant associations between continuous cumulative duration (HR=1.08, 95%CI=1.03-1.13), dose of bolus insulins (HR=1.04, 95%CI=1.02-1.06) and colorectal cancer risk. The medium dose category (HR=1.27, 95%CI=1.01-1.61), and high duration (HR=1.75, 95%CI=1.36-2.25) or high dose category (HR=1.70, 95%CI=1.32-2.19) showed significant associations as well. Duration- and dose-responses were suggested by these results. 6.4.2 Findings from sensitivity analyses 6.4.2.1 Additional adjustment for other diabetes medications Supplementary Table C-2 includes all associations further adjusting for other diabetes medications, irrespective of statistical significance. Table 6-3 presents the diabetes medications for which the primary analysis showed statistically significant results. Metformin and the class of insulin secretagogues (as well as gliclazide and glyburide in the subclass of sulfonylureas) were consistently associated with increased risks of colorectal cancer after adjusting for the use of other diabetes medications. Compared to significant results in the primary analysis, the associations between the class of thiazolidinediones (and individual medication rosiglitazone), the class of insulins and analogues (and basal and bolus insulin subclass) and colorectal cancer risk were all diminished to null. 112 Table 6-3. Associations between select diabetes medications and the risk of colorectal cancer with adjustment for other diabetes medications Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 39,259 78.4 (77.6-79.2) 1.00 1.00 Ever use 2,021,426 3,550 176.4 (169.8-183.2) 1.21 (1.17-1.26)* 1.17 (1.11-1.22)* Cumulative duration Low 736,609 807 109.6 (102.3-117.4) 0.89 (0.83-0.95)* 0.89 (0.83-0.96)* Medium 720,912 1,321 183.2 (173.6-193.4) 1.28 (1.21-1.35)* 1.26 (1.19-1.34)* High 563,905 1,422 252.2 (239.4-265.6) 1.41 (1.33-1.48)* 1.35 (1.26-1.45)* Continuous 1.04 (1.03-1.04)* 1.03 (1.03-1.04)* Cumulative dose Low 761,186 897 117.8 (110.4-125.8) 0.91 (0.86-0.98)* 0.92 (0.86-0.98)* Medium 720,432 1,307 181.4 (171.8-191.5) 1.24 (1.17-1.31)* 1.24 (1.17-1.32)* High 539,808 1,346 249.3 (236.4-263.0) 1.47 (1.39-1.56)* 1.47 (1.36-1.58)* Continuous 1.04 (1.04-1.05)* 1.04 (1.04-1.05)* 5. Insulin secretagogues Never 51,176,005 41,019 80.2 (79.4-80.9) 1.00 1.00 Ever use 912,639 1,790 197.8 (186.6-209.7) 1.33 (1.25-1.41)* 1.24 (1.15-1.33)* Cumulative duration Low 360,923 506 140.2 (128.5-153.0) 1.03 (0.94-1.12) 0.96 (0.87-1.05) Medium 315,845 638 202.0 (186.9-218.3) 1.35 (1.25-1.46)* 1.20 (1.10-1.31)* High 235,871 646 273.9 (253.6-295.8) 1.49 (1.38-1.61)* 1.31 (1.19-1.45)* Continuous 1.05 (1.04-1.05)* 1.02 (1.01-1.03)* Cumulative dose Low 372,575 572 153.5 (141.4-166.6) 1.08 (0.99-1.17) 0.97 (0.89-1.06) Medium 314,231 655 208.4 (193.1-225.0) 1.36 (1.26-1.47)* 1.16 (1.06-1.27)* High 225,833 563 249.3 (229.5-270.8) 1.46 (1.34-1.59)* 1.25 (1.12-1.40)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.01)* 5.2. Sulfonylureas Never 51,188,413 41,033 80.2 (79.4-80.9) 1.00 1.00 Ever use 900,231 1,776 198.5 (187.2-210.5) 1.33 (1.26-1.41)* 1.24 (1.16-1.33)* Cumulative duration Low 359,009 517 144.0 (132.1-157.0) 1.05 (0.97-1.15) 0.98 (0.89-1.08) Medium 309,407 624 201.7 (186.5-218.1) 1.35 (1.24-1.46)* 1.20 (1.09-1.31)* High 231,815 635 273.9 (253.4-296.1) 1.49 (1.38-1.61)* 1.31 (1.19-1.45)* Continuous 1.05 (1.04-1.05)* 1.02 (1.01-1.03)* Cumulative dose Low 367,838 575 156.3 (144.0-169.6) 1.09 (1.01-1.19)* 0.99 (0.90-1.08) Medium 309,412 644 208.1 (192.7-224.8) 1.36 (1.25-1.46)* 1.16 (1.06-1.27)* High 222,981 557 249.8 (229.9-271.4) 1.46 (1.35-1.59)* 1.26 (1.13-1.40)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.01)* 5.2.1. Gliclazide Never 51,695,028 42,011 81.3 (80.5-82.0) 1.00 1.00 Ever use 393,616 798 207.0 (190.2-225.4) 1.32 (1.22-1.44)* 1.24 (1.13-1.36)* Cumulative duration Low 126,908 224 176.5 (154.8-201.2) 1.23 (1.08-1.40)* 1.07 (0.93-1.23) Medium 136,638 250 183.0 (161.6-207.1) 1.20 (1.06-1.35)* 1.02 (0.90-1.17) High 130,070 324 249.1 (223.4-277.8) 1.42 (1.27-1.58)* 1.22 (1.08-1.38)* Continuous 1.05 (1.04-1.07)* 1.02 (1.01-1.04)* Cumulative dose Low 133,699 232 173.5 (152.6-197.4) 1.18 (1.04-1.34)* 1.01 (0.88-1.16) Medium 136,394 267 195.8 (173.6-220.7) 1.25 (1.11-1.41)* 1.05 (0.92-1.19) High 123,523 299 242.1 (216.1-271.1) 1.43 (1.28-1.60)* 1.20 (1.06-1.37)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.01) 5.2.2. Glyburide Never 51,418,210 41,454 80.6 (79.8-81.4) 1.00 1.00 Ever use 670,434 1,355 192.7 (177.9-208.7) 1.34 (1.24-1.45)* 1.21 (1.11-1.32)* Cumulative duration Low 283,215 462 163.1 (148.9-178.7) 1.15 (1.05-1.26)* 1.02 (0.93-1.13) Medium 224,722 438 194.9 (177.5-214.0) 1.30 (1.18-1.43)* 1.12 (1.01-1.24)* High 162,497 455 280.0 (255.4-307.0) 1.51 (1.38-1.66)* 1.27 (1.14-1.42)* Continuous 1.05 (1.04-1.06)* 1.02 (1.01-1.03)* Cumulative dose Low 296,014 499 168.6 (154.4-184.0) 1.14 (1.05-1.25)* 0.99 (0.90-1.09) 113 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 230,574 499 216.4 (198.2-236.3) 1.40 (1.28-1.53)* 1.17 (1.06-1.29)* High 143,846 357 248.2 (223.7-275.3) 1.45 (1.31-1.61)* 1.18 (1.04-1.33)* Continuous 1.02 (1.02-1.03)* 1.01 (1.00-1.01) 6. Thiazolidinediones Never 51,871,508 42,418 81.8 (81.0-82.6) 1.00 1.00 Ever use 217,136 391 141.3 (116.4-171.5) 1.21 (0.99-1.46) 0.99 (0.81-1.21) Cumulative duration Low 76,357 113 148.0 (123.1-178.0) 1.10 (0.92-1.33) 0.88 (0.73-1.06) Medium 72,351 125 172.8 (145.0-205.9) 1.27 (1.06-1.51)* 0.97 (0.81-1.17) High 68,428 153 223.6 (190.8-262.0) 1.42 (1.22-1.67)* 1.10 (0.93-1.30) Continuous 1.06 (1.03-1.08)* 1.01 (0.98-1.03) Cumulative dose Low 75,982 112 147.4 (122.5-177.4) 1.09 (0.90-1.31) 0.85 (0.71-1.03) Medium 74,257 134 180.5 (152.3-213.7) 1.31 (1.11-1.56)* 0.99 (0.83-1.19) High 66,897 145 216.8 (184.2-255.1) 1.40 (1.19-1.65)* 1.06 (0.89-1.26) Continuous 1.05 (1.03-1.08)* 1.00 (0.98-1.03) 6.2. Rosiglitazone Never 51,946,176 42,536 81.9 (81.1-82.7) 1.00 1.00 Ever use 142,468 273 121.8 (91.2-162.6) 1.14 (0.85-1.52) 0.92 (0.69-1.23) Cumulative duration Low 49,170 80 162.7 (130.7-202.6) 1.20 (0.96-1.49) 0.97 (0.77-1.21) Medium 48,028 87 181.1 (146.8-223.5) 1.33 (1.08-1.64)* 1.05 (0.84-1.30) High 45,270 106 234.2 (193.6-283.3) 1.54 (1.28-1.87)* 1.22 (1.00-1.48) Continuous 1.09 (1.05-1.12)* 1.03 (0.99-1.07) Cumulative dose Low 49,567 82 165.4 (133.2-205.4) 1.21 (0.98-1.51) 0.97 (0.78-1.22) Medium 49,349 90 182.4 (148.3-224.2) 1.32 (1.08-1.63)* 1.03 (0.83-1.27) High 43,552 101 231.9 (190.8-281.8) 1.54 (1.27-1.87)* 1.19 (0.97-1.46) Continuous 1.08 (1.05-1.12)* 1.03 (0.99-1.06) 7. Insulins and analogues Never 51,772,245 42,325 81.8 (81.0-82.5) 1.00 1.00 Ever use 316,399 484 168.0 (152.1-185.6) 1.21 (1.10-1.34)* 1.11 (1.00-1.23) Cumulative duration Low 143,015 129 90.2 (75.9-107.2) 0.84 (0.70-1.00)* 0.70 (0.59-0.84)* Medium 113,499 216 190.3 (166.5-217.5) 1.33 (1.16-1.52)* 1.04 (0.90-1.20) High 59,885 139 232.1 (196.6-274.1) 1.50 (1.27-1.77)* 1.19 (0.99-1.41) Continuous 1.05 (1.03-1.08)* 1.01 (0.99-1.03) Cumulative dose Low 146,186 137 93.7 (79.3-110.8) 0.85 (0.72-1.00) 0.70 (0.59-0.83)* Medium 108,141 202 186.8 (162.7-214.4) 1.30 (1.14-1.50)* 0.99 (0.86-1.15) High 62,072 145 233.6 (198.5-274.9) 1.54 (1.31-1.82)* 1.18 (0.99-1.41) Continuous 1.02 (1.02-1.03)* 1.01 (1.00-1.02) 7.1. Basal insulins Never 51,784,863 42,336 81.8 (81.0-82.5) 1.00 1.00 Ever use 303,781 473 169.2 (152.7-187.4) 1.23 (1.11-1.36)* 1.03 (0.91-1.18) Cumulative duration Low 135,289 135 99.8 (84.3-118.1) 0.93 (0.78-1.10) 0.77 (0.64-0.93)* Medium 109,417 205 187.4 (163.4-214.8) 1.32 (1.15-1.51)* 1.00 (0.85-1.18) High 59,075 133 225.1 (189.9-266.8) 1.44 (1.21-1.71)* 1.01 (0.81-1.26) Continuous 1.06 (1.04-1.09)* 1.00 (0.97-1.04) Cumulative dose Low 136,909 135 98.6 (83.3-116.7) 0.90 (0.76-1.06) 0.74 (0.61-0.88)* Medium 106,571 195 183.0 (159.0-210.5) 1.28 (1.12-1.48)* 0.96 (0.81-1.14) High 60,301 143 237.1 (201.3-279.4) 1.56 (1.32-1.84)* 1.11 (0.89-1.37) Continuous 1.03 (1.02-1.04)* 1.00 (0.99-1.02) 7.2. Bolus insulins Never 51,947,122 42,600 82.0 (81.2-82.8) 1.00 1.00 Ever use 141,522 209 169.7 (144.0-199.9) 1.38 (1.17-1.62)* 1.26 (1.03-1.55)* Cumulative duration Low 68,567 73 106.5 (84.6-133.9) 1.08 (0.86-1.36) 0.99 (0.77-1.28) Medium 48,161 76 157.8 (126.0-197.6) 1.25 (1.00-1.57) 1.04 (0.80-1.34) High 24,794 60 242.0 (187.9-311.7) 1.75 (1.36-2.25)* 1.45 (1.07-1.97)* Continuous 1.08 (1.03-1.13)* 1.02 (0.96-1.09) Cumulative dose Low 71,251 78 109.5 (87.7-136.7) 1.09 (0.87-1.36) 1.00 (0.78-1.27) 114 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 44,054 71 161.2 (127.7-203.4) 1.27 (1.01-1.61)* 1.03 (0.79-1.34) High 26,217 60 228.9 (177.7-294.8) 1.70 (1.32-2.19)* 1.27 (0.94-1.72) Continuous 1.04 (1.02-1.06)* 1.02 (1.00-1.05) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Model 2 further adjusted for other mutually exclusive diabetes medications. This table summarized the associations between select diabetes medications and colorectal cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table C-2. * denotes p<0.05. 6.4.2.2 Washout and lag periods Further analyses adjusting for different lag and washout periods are shown in Supplementary Table C-3, irrespective of statistical significance. Associations for the statistically significant diabetes medications in the primary analysis are presented in Table 6-4. Associations between the select medications and colorectal cancer were consistent across different washout and lag periods. Overall, results from Models 3 (1-year washout and 2-year lag periods) and 5 (2-year washout and 1-year lag periods) resemble those in the primary analysis Model 1 (1-year washout and 1-year lag periods). On the other hand, results from Models 2 (1-year washout and 0-year lag periods) and 4 (0-year washout and 1-year lag periods) slightly deviated from those found in Model 1 in insulin secretagogues as well as gliclazide and glyburide in the subclass of sulfonylureas, and thiazolidinediones. Table 6-4. Associations between select diabetes medications and the risk of colorectal cancer with variation in washout and lag periods Exposure Model 1 Model 2 Model 3 Model 4 Model 5 1. Biguanides (i.e., metformin) Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.21 (1.17-1.26)* 1.36 (1.31-1.41)* 1.20 (1.15-1.25)* 1.20 (1.16-1.24)* 1.21 (1.16-1.26)* Cumulative duration Low 0.89 (0.83-0.95)* 1.36 (1.29-1.43)* 0.86 (0.80-0.93)* 0.85 (0.79-0.90)* 0.89 (0.83-0.96)* Medium 1.28 (1.21-1.35)* 1.30 (1.24-1.37)* 1.20 (1.13-1.27)* 1.23 (1.17-1.28)* 1.28 (1.21-1.36)* High 1.41 (1.33-1.48)* 1.37 (1.31-1.44)* 1.41 (1.33-1.49)* 1.40 (1.34-1.46)* 1.40 (1.32-1.48)* Continuous 1.04 (1.03-1.04)* 1.03 (1.03-1.04)* 1.04 (1.03-1.04)* 1.03 (1.03-1.03)* 1.04 (1.03-1.04)* Cumulative dose Low 0.91 (0.86-0.98)* 1.36 (1.30-1.43)* 0.85 (0.79-0.91)* 0.88 (0.83-0.93)* 0.91 (0.85-0.98)* Medium 1.24 (1.17-1.31)* 1.25 (1.19-1.31)* 1.20 (1.13-1.27)* 1.19 (1.13-1.24)* 1.24 (1.17-1.31)* High 1.47 (1.39-1.56)* 1.43 (1.36-1.50)* 1.48 (1.40-1.57)* 1.43 (1.37-1.49)* 1.47 (1.39-1.56)* Continuous 1.04 (1.04-1.05)* 1.04 (1.03-1.05)* 1.04 (1.04-1.05)* 1.03 (1.03-1.04)* 1.04 (1.04-1.05)* 115 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 5. Insulin secretagogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.33 (1.25-1.41)* 1.45 (1.38-1.53)* 1.35 (1.27-1.44)* 1.19 (1.14-1.25)* 1.33 (1.25-1.42)* Cumulative duration Low 1.03 (0.94-1.12) 1.38 (1.29-1.48)* 1.04 (0.95-1.14) 0.91 (0.84-0.98)* 1.02 (0.93-1.12) Medium 1.35 (1.25-1.46)* 1.38 (1.28-1.48)* 1.29 (1.18-1.40)* 1.20 (1.13-1.28)* 1.34 (1.23-1.45)* High 1.49 (1.38-1.61)* 1.45 (1.35-1.56)* 1.46 (1.35-1.59)* 1.39 (1.32-1.46)* 1.50 (1.38-1.64)* Continuous 1.05 (1.04-1.05)* 1.04 (1.04-1.05)* 1.04 (1.03-1.05)* 1.03 (1.02-1.03)* 1.05 (1.04-1.06)* Cumulative dose Low 1.08 (0.99-1.17) 1.40 (1.31-1.49)* 1.06 (0.98-1.16) 0.96 (0.90-1.04) 1.06 (0.97-1.16) Medium 1.36 (1.26-1.47)* 1.38 (1.29-1.48)* 1.33 (1.22-1.44)* 1.23 (1.16-1.30)* 1.35 (1.24-1.46)* High 1.46 (1.34-1.59)* 1.42 (1.32-1.54)* 1.43 (1.31-1.57)* 1.35 (1.28-1.42)* 1.47 (1.34-1.61)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 1.01 (1.01-1.01)* 1.02 (1.01-1.02)* 5.2. Sulfonylureas Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.33 (1.26-1.41)* 1.45 (1.38-1.53)* 1.36 (1.28-1.45)* 1.19 (1.14-1.25)* 1.33 (1.25-1.42)* Cumulative duration Low 1.05 (0.97-1.15) 1.40 (1.31-1.50)* 1.07 (0.97-1.17) 0.93 (0.86-1.00)* 1.04 (0.95-1.15) Medium 1.35 (1.24-1.46)* 1.37 (1.27-1.47)* 1.28 (1.18-1.40)* 1.20 (1.13-1.27)* 1.33 (1.22-1.45)* High 1.49 (1.38-1.61)* 1.45 (1.34-1.56)* 1.47 (1.35-1.59)* 1.39 (1.32-1.46)* 1.50 (1.38-1.64)* Continuous 1.05 (1.04-1.05)* 1.04 (1.04-1.05)* 1.04 (1.04-1.05)* 1.03 (1.02-1.03)* 1.05 (1.04-1.06)* Cumulative dose Low 1.09 (1.01-1.19)* 1.41 (1.32-1.51)* 1.08 (0.99-1.18) 0.97 (0.90-1.04) 1.08 (0.99-1.18) Medium 1.36 (1.25-1.46)* 1.37 (1.28-1.48)* 1.32 (1.22-1.44)* 1.23 (1.16-1.30)* 1.34 (1.24-1.46)* High 1.46 (1.35-1.59)* 1.43 (1.32-1.54)* 1.44 (1.32-1.57)* 1.35 (1.28-1.42)* 1.47 (1.34-1.61)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 1.01 (1.01-1.01)* 1.02 (1.01-1.02)* 5.2.1. Gliclazide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.32 (1.22-1.44)* 1.46 (1.36-1.56)* 1.35 (1.23-1.48)* 1.22 (1.14-1.31)* 1.34 (1.22-1.46)* Cumulative duration Low 1.23 (1.08-1.40)* 1.58 (1.42-1.75)* 1.25 (1.09-1.44)* 1.21 (1.10-1.34)* 1.26 (1.10-1.44)* Medium 1.20 (1.06-1.35)* 1.33 (1.19-1.48)* 1.12 (0.97-1.28) 1.12 (1.02-1.24)* 1.21 (1.06-1.38)* High 1.42 (1.27-1.58)* 1.34 (1.21-1.48)* 1.41 (1.26-1.58)* 1.28 (1.17-1.39)* 1.42 (1.26-1.59)* Continuous 1.05 (1.04-1.07)* 1.05 (1.04-1.07)* 1.05 (1.03-1.07)* 1.03 (1.02-1.04)* 1.05 (1.04-1.07)* Cumulative dose Low 1.18 (1.04-1.34)* 1.55 (1.41-1.72)* 1.19 (1.04-1.37)* 1.19 (1.07-1.31)* 1.21 (1.06-1.38)* Medium 1.25 (1.11-1.41)* 1.31 (1.17-1.45)* 1.19 (1.05-1.36)* 1.18 (1.08-1.30)* 1.25 (1.10-1.42)* High 1.43 (1.28-1.60)* 1.37 (1.23-1.52)* 1.40 (1.24-1.59)* 1.24 (1.14-1.36)* 1.44 (1.27-1.62)* Continuous 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 1.02 (1.01-1.02)* 1.01 (1.01-1.01)* 1.01 (1.01-1.02)* 5.2.2. Glyburide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.34 (1.24-1.45)* 1.44 (1.34-1.55)* 1.37 (1.26-1.49)* 1.19 (1.12-1.26)* 1.33 (1.22-1.45)* Cumulative duration Low 1.15 (1.05-1.26)* 1.37 (1.27-1.48)* 1.14 (1.03-1.25)* 1.00 (0.92-1.08) 1.13 (1.02-1.24)* Medium 1.30 (1.18-1.43)* 1.34 (1.23-1.46)* 1.23 (1.11-1.36)* 1.16 (1.08-1.24)* 1.30 (1.17-1.44)* High 1.51 (1.38-1.66)* 1.48 (1.36-1.61)* 1.49 (1.35-1.64)* 1.39 (1.32-1.47)* 1.53 (1.38-1.70)* Continuous 1.05 (1.04-1.06)* 1.05 (1.04-1.06)* 1.05 (1.04-1.06)* 1.03 (1.03-1.04)* 1.05 (1.04-1.06)* Cumulative dose Low 1.14 (1.05-1.25)* 1.35 (1.26-1.46)* 1.11 (1.01-1.22)* 1.03 (0.96-1.11) 1.12 (1.02-1.23)* Medium 1.40 (1.28-1.53)* 1.41 (1.30-1.53)* 1.36 (1.24-1.49)* 1.23 (1.15-1.31)* 1.39 (1.27-1.53)* High 1.45 (1.31-1.61)* 1.42 (1.29-1.57)* 1.43 (1.28-1.60)* 1.33 (1.25-1.41)* 1.47 (1.31-1.65)* Continuous 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 1.01 (1.01-1.02)* 1.03 (1.02-1.03)* 6. Thiazolidinediones Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.21 (0.99-1.46) 1.36 (1.15-1.60)* 1.27 (1.04-1.55)* 1.26 (1.11-1.44)* 1.24 (1.01-1.53)* Cumulative duration Low 1.10 (0.92-1.33) 1.29 (1.10-1.51)* 1.09 (0.89-1.32) 1.14 (1.01-1.30)* 1.13 (0.93-1.38) Medium 1.27 (1.06-1.51)* 1.31 (1.12-1.54)* 1.20 (0.99-1.45) 1.30 (1.16-1.47)* 1.27 (1.05-1.53)* High 1.42 (1.22-1.67)* 1.33 (1.14-1.54)* 1.45 (1.23-1.71)* 1.40 (1.26-1.56)* 1.45 (1.22-1.72)* Continuous 1.06 (1.03-1.08)* 1.05 (1.03-1.07)* 1.06 (1.03-1.09)* 1.05 (1.04-1.07)* 1.06 (1.03-1.09)* Cumulative dose Low 1.09 (0.90-1.31) 1.26 (1.08-1.48)* 1.08 (0.89-1.31) 1.16 (1.02-1.32)* 1.10 (0.90-1.34) Medium 1.31 (1.11-1.56)* 1.36 (1.17-1.59)* 1.23 (1.02-1.48)* 1.29 (1.14-1.45)* 1.37 (1.14-1.64)* High 1.40 (1.19-1.65)* 1.31 (1.12-1.52)* 1.44 (1.21-1.70)* 1.40 (1.26-1.56)* 1.39 (1.16-1.66)* Continuous 1.05 (1.03-1.08)* 1.05 (1.02-1.07)* 1.05 (1.03-1.08)* 1.05 (1.03-1.06)* 1.05 (1.03-1.08)* 116 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 6.2. Rosiglitazone Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.14 (0.85-1.52) 1.34 (1.05-1.70)* 1.18 (0.87-1.59) 1.13 (0.94-1.37) 1.19 (0.87-1.62) Cumulative duration Low 1.20 (0.96-1.49) 1.43 (1.19-1.73)* 1.23 (0.98-1.54) 1.25 (1.08-1.45)* 1.22 (0.97-1.55) Medium 1.33 (1.08-1.64)* 1.30 (1.07-1.58)* 1.26 (1.00-1.58)* 1.21 (1.04-1.40)* 1.34 (1.06-1.68)* High 1.54 (1.28-1.87)* 1.40 (1.17-1.68)* 1.52 (1.25-1.86)* 1.47 (1.29-1.67)* 1.59 (1.29-1.95)* Continuous 1.09 (1.05-1.12)* 1.07 (1.04-1.11)* 1.08 (1.05-1.12)* 1.07 (1.05-1.10)* 1.09 (1.05-1.13)* Cumulative dose Low 1.21 (0.98-1.51) 1.44 (1.19-1.73)* 1.23 (0.99-1.55) 1.24 (1.07-1.44)* 1.23 (0.98-1.55) Medium 1.32 (1.08-1.63)* 1.33 (1.10-1.60)* 1.23 (0.98-1.54) 1.20 (1.03-1.39)* 1.36 (1.09-1.69)* High 1.54 (1.27-1.87)* 1.38 (1.14-1.67)* 1.55 (1.26-1.90)* 1.49 (1.31-1.69)* 1.57 (1.27-1.95)* Continuous 1.08 (1.05-1.12)* 1.07 (1.04-1.10)* 1.08 (1.05-1.12)* 1.07 (1.04-1.09)* 1.09 (1.05-1.13)* 7. Insulins and analogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.21 (1.10-1.34)* 1.64 (1.51-1.77)* 1.14 (1.02-1.27)* 1.18 (1.12-1.26)* 1.18 (1.06-1.32)* Cumulative duration Low 0.84 (0.70-1.00)* 1.79 (1.61-1.99)* 0.78 (0.64-0.95)* 0.65 (0.57-0.75)* 0.79 (0.66-0.96)* Medium 1.33 (1.16-1.52)* 1.35 (1.19-1.53)* 1.19 (1.03-1.38)* 1.16 (1.06-1.27)* 1.29 (1.11-1.49)* High 1.50 (1.27-1.77)* 1.45 (1.23-1.70)* 1.43 (1.20-1.70)* 1.43 (1.32-1.54)* 1.55 (1.29-1.85)* Continuous 1.05 (1.03-1.08)* 1.06 (1.04-1.07)* 1.04 (1.02-1.07)* 1.03 (1.02-1.04)* 1.06 (1.04-1.08)* Cumulative dose Low 0.85 (0.72-1.00) 1.72 (1.54-1.91)* 0.79 (0.66-0.95)* 0.68 (0.59-0.78)* 0.81 (0.67-0.97)* Medium 1.30 (1.14-1.50)* 1.38 (1.21-1.56)* 1.13 (0.97-1.32) 1.16 (1.05-1.27)* 1.26 (1.08-1.46)* High 1.54 (1.31-1.82)* 1.50 (1.28-1.76)* 1.53 (1.29-1.81)* 1.42 (1.31-1.53)* 1.61 (1.35-1.92)* Continuous 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 1.02 (1.01-1.03)* 1.01 (1.01-1.01)* 1.03 (1.02-1.04)* 7.1. Basal insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.23 (1.11-1.36)* 1.63 (1.50-1.77)* 1.16 (1.04-1.30)* 1.19 (1.12-1.26)* 1.19 (1.07-1.33)* Cumulative duration Low 0.93 (0.78-1.10) 1.82 (1.63-2.03)* 0.81 (0.67-0.98)* 0.73 (0.63-0.83)* 0.87 (0.72-1.05) Medium 1.32 (1.15-1.51)* 1.35 (1.19-1.54)* 1.21 (1.04-1.41)* 1.14 (1.04-1.25)* 1.29 (1.11-1.49)* High 1.44 (1.21-1.71)* 1.38 (1.17-1.63)* 1.39 (1.16-1.66)* 1.42 (1.31-1.53)* 1.47 (1.22-1.77)* Continuous 1.06 (1.04-1.09)* 1.06 (1.04-1.09)* 1.05 (1.03-1.08)* 1.04 (1.03-1.05)* 1.07 (1.04-1.10)* Cumulative dose Low 0.90 (0.76-1.06) 1.74 (1.56-1.94)* 0.81 (0.67-0.98)* 0.74 (0.64-0.85)* 0.84 (0.70-1.01) Medium 1.28 (1.12-1.48)* 1.34 (1.18-1.53)* 1.14 (0.98-1.34) 1.11 (1.01-1.22)* 1.25 (1.07-1.46)* High 1.56 (1.32-1.84)* 1.51 (1.29-1.77)* 1.52 (1.28-1.80)* 1.44 (1.33-1.55)* 1.61 (1.34-1.92)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 1.02 (1.02-1.02)* 1.03 (1.02-1.04)* 7.2. Bolus insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.38 (1.17-1.62)* 1.72 (1.50-1.97)* 1.27 (1.07-1.52)* 1.26 (1.16-1.38)* 1.30 (1.08-1.56)* Cumulative duration Low 1.08 (0.86-1.36) 1.68 (1.42-1.99)* 1.00 (0.78-1.29) 1.12 (0.97-1.30) 1.01 (0.78-1.30) Medium 1.25 (1.00-1.57) 1.36 (1.11-1.66)* 1.12 (0.87-1.43) 1.23 (1.08-1.40)* 1.21 (0.95-1.55) High 1.75 (1.36-2.25)* 1.63 (1.28-2.09)* 1.65 (1.27-2.16)* 1.32 (1.17-1.48)* 1.80 (1.36-2.37)* Continuous 1.08 (1.03-1.13)* 1.08 (1.03-1.13)* 1.07 (1.02-1.12)* 1.04 (1.02-1.05)* 1.08 (1.02-1.14)* Cumulative dose Low 1.09 (0.87-1.36) 1.66 (1.41-1.96)* 1.00 (0.78-1.27) 1.15 (1.00-1.32) 1.04 (0.82-1.33) Medium 1.27 (1.01-1.61)* 1.38 (1.12-1.71)* 1.09 (0.84-1.42) 1.17 (1.03-1.34)* 1.24 (0.96-1.60) High 1.70 (1.32-2.19)* 1.59 (1.24-2.03)* 1.69 (1.30-2.19)* 1.36 (1.21-1.53)* 1.67 (1.26-2.22)* Continuous 1.04 (1.02-1.06)* 1.04 (1.02-1.05)* 1.04 (1.02-1.06)* 1.02 (1.01-1.03)* 1.04 (1.02-1.06)* Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 1-year lag periods in the primary analysis. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 0-year lag periods. Model 3 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 2-year lag periods. Model 4 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 0-year washout and 1-year lag periods. Model 5 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 2-year washout and 1-year lag periods. This table summarized the associations between select diabetes medications and colorectal cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table C-3. * denotes p<0.05. 117 6.4.2.3 BCGP analysis All associations in the BCGP analysis, regardless of statistical significance, are presented in Supplementary Table C-4. There were too few incident colorectal cancer cases to examine associations with linagliptin, acarbose, rosiglitazone and the binary exposure definition of thiazolidinediones. Table 6-5 displays the medications for which the primary analysis showed statistically significant findings. After adjusting for sociodemographic and lifestyle factors in the BCGP subset (Model 3), although not statistically significant, the use of metformin, the class of insulin secretagogues, and the class of thiazolidinediones were associated with higher risks of colorectal cancer, which aligns with the direction of risk estimates from the primary analysis (Model 1). Findings for associations between the subclass of sulfonylureas (and gliclazide) were not consistent across exposure definitions. Additionally, the associations in Models 2 and 3 between glyburide, basal insulins, bolus insulins and insulins as a class of medications were inconsistent with findings from the primary analysis (Model 1); this suggested that the differences were attributable to not only the additional sociodemographic and lifestyle factors but also the variation in sample demographics. 118 Table 6-5. Associations between select diabetes medications and the risk of colorectal cancer among people in the BCGP Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 1. Biguanides (i.e., metformin) Never 537,721 364 67.7 (61.1-75.0) 1.00 1.00 1.00 Ever use 8,443 13 154.0 (89.4-265.2) 1.21 (1.17-1.26)* 1.31 (0.75-2.29) 1.20 (0.68-2.12) Cumulative duration - trend 1.04 (1.03-1.04)* 1.04 (0.97-1.11) 1.03 (0.96-1.11) Cumulative dose - trend 1.04 (1.04-1.05)* 1.02 (0.94-1.12) 1.01 (0.92-1.11) 5. Insulin secretagogues Never 543,809 372 68.4 (61.8-75.7) 1.00 1.00 1.00 Ever use 2,355 Suppressed 212.3 (88.4-510.1) 1.33 (1.25-1.41)* 1.73 (0.71-4.18) 1.63 (0.67-3.97) Cumulative duration - trend 1.05 (1.04-1.05)* 1.07 (0.95-1.20) 1.06 (0.94-1.19) Cumulative dose - trend 1.02 (1.01-1.02)* 1.00 (0.94-1.07) 1.00 (0.93-1.07) 5.2. Sulfonylureas Never 543,866 373 68.6 (62.0-75.9) 1.00 1.00 1.00 Ever use 2,298 Suppressed 174.1 (65.3-463.8) 1.33 (1.26-1.41)* 1.41 (0.52-3.78) 1.32 (0.49-3.57) Cumulative duration - trend 1.05 (1.04-1.05)* 1.02 (0.87-1.19) 1.01 (0.86-1.18) Cumulative dose - trend 1.02 (1.01-1.02)* 1.00 (0.93-1.08) 0.99 (0.92-1.07) 5.2.1. Gliclazide Never 544,845 374 68.6 (62.0-76.0) 1.00 1.00 1.00 Ever use 1,319 Suppressed 227.4 (73.4-705.2) 1.32 (1.22-1.44)* 1.80 (0.58-5.61) 1.67 (0.53-5.25) Cumulative duration - trend 1.05 (1.04-1.07)* 1.05 (0.85-1.30) 1.04 (0.84-1.29) Cumulative dose - trend 1.02 (1.01-1.02)* 1.00 (0.91-1.10) 0.99 (0.90-1.09) 5.2.2. Glyburide Never 545,144 376 69.0 (62.3-76.3) 1.00 1.00 1.00 Ever use 1,020 Suppressed 98.0 (13.8-696.0) 1.34 (1.24-1.45)* 0.81 (0.11-5.75) 0.76 (0.11-5.45) Cumulative duration - trend 1.05 (1.04-1.06)* 0.99 (0.77-1.28) 0.98 (0.76-1.26) Cumulative dose - trend 1.02 (1.02-1.03)* 1.00 (0.87-1.15) 0.99 (0.87-1.14) 6. Thiazolidinediones Never 545,633 375 68.7 (62.1-76.0) 1.00 1.00 1.00 Ever use 531 Suppressed 376.6 (94.2-1506.0) 1.21 (0.99-1.46) Not shown Not shown Cumulative duration - trend 1.06 (1.03-1.08)* 1.10 (0.88-1.37) 1.09 (0.87-1.36) Cumulative dose - trend 1.05 (1.03-1.08)* 1.07 (0.86-1.33) 1.06 (0.86-1.31) 7. Insulins and analogues Never 544,673 376 69.0 (62.4-76.4) 1.00 1.00 1.00 Ever use 1,491 Suppressed 67.1 (9.4-476.1) 1.21 (1.10-1.34)* 0.55 (0.08-3.91) 0.50 (0.07-3.60) Cumulative duration - trend 1.05 (1.03-1.08)* 0.97 (0.66-1.41) 0.95 (0.65-1.39) Cumulative dose - trend 1.02 (1.02-1.03)* 0.97 (0.77-1.22) 0.96 (0.76-1.21) 7.1. Basal insulins Never 544,761 376 69.0 (62.4-76.4) 1.00 1.00 1.00 Ever use 1,403 Suppressed 71.3 (10.0-506.0) 1.23 (1.11-1.36)* 0.58 (0.08-4.11) 0.53 (0.07-3.78) Cumulative duration - trend 1.06 (1.04-1.09)* 0.99 (0.65-1.50) 0.97 (0.63-1.47) Cumulative dose - trend 1.03 (1.02-1.04)* 0.98 (0.77-1.25) 0.97 (0.75-1.24) 7.2. Bolus insulins Never 545,495 376 68.9 (62.3-76.3) 1.00 1.00 1.00 Ever use 669 Suppressed 149.5 (21.1-1061.2) 1.38 (1.17-1.62)* 1.32 (0.19-9.40) 1.23 (0.17-8.79) Cumulative duration - trend 1.08 (1.03-1.13)* 0.87 (0.31-2.45) 0.85 (0.30-2.44) 119 Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 Cumulative dose - trend 1.04 (1.02-1.06)* 0.91 (0.48-1.71) 0.90 (0.47-1.71) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile in the primary analysis using Population Data BC. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile in the BCGP subset. Model 3 further adjusted for sociodemographic and lifestyle-related factors: race/ethnicity, marital status, physical activity, education, individual-level income, fruit and vegetable consumption, alcohol consumption, smoking status, waist to hip ratio, and body mass index using the BCGP subset. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. Effect estimates denoted as “Not shown” have been omitted due to low number of events, which may result in unreliable estimates. This table summarized the associations between select diabetes medications and colorectal cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table C-4. * denotes p<0.05. 120 6.4.2.4 Active comparator analysis Metformin (HR=1.33, 95%CI=0.55-3.22), gliclazide (HR=2.36, 95%CI=0.73-7.62), glyburide (HR=2.57, 95%CI=0.67-9.87), rosiglitazone (HR=2.17, 95%CI=0.09-51.91), basal insulins (HR=1.06, 95%CI=0.31-3.62), and bolus insulins (HR=1.49, 95%CI=0.24-9.28) were associated with higher risks of colorectal cancer in comparison with GLP-1 receptor agonists. The findings for rosiglitazone might be unreliable because of the limited number of cases observed. Nevertheless, none of these associations were statistically significant (Table 6-6). Table 6-6. Associations between diabetes medication and colorectal cancer, an active comparator analysis among new users of medication Exposure definition Person-years Events Incidence rate Model 1 Model 2 2.2. GLP-1 receptor agonists 8,244 Suppressed 60.7 (25.2-145.7) 1.00 1.00 1. Biguanides (i.e., metformin) 863,377 1,493 172.9 (164.4-181.9) 1.39 (0.58-3.36) 1.33 (0.55-3.22) 2.2. GLP-1 receptor agonists 8,244 Suppressed 60.7 (25.2-145.7) 1.00 1.00 5.2.1. Gliclazide 14,398 40 277.8 (203.8-378.7) 1.81 (0.64-5.09) 2.36 (0.73-7.62) 2.2. GLP-1 receptor agonists 8,244 Suppressed 60.7 (25.2-145.7) 1.00 1.00 5.2.2. Glyburide 47,526 104 218.8 (180.6-265.2) 1.46 (0.57-3.74) 2.57 (0.67-9.87) 2.2. GLP-1 receptor agonists 8,244 Suppressed 60.7 (25.2-145.7) 1.00 1.00 6.2. Rosiglitazone 3,149 Suppressed 254.0 (127.0-508.0) 1.58 (0.45-5.61) 2.17 (0.09-51.91) 2.2. GLP-1 receptor agonists 8,244 Suppressed 60.7 (25.2-145.7) 1.00 1.00 7.1. Basal insulins 15,080 20 132.6 (85.6-205.6) 1.34 (0.47-3.86) 1.06 (0.31-3.62) 2.2. GLP-1 receptor agonists 8,244 Suppressed 60.7 (25.2-145.7) 1.00 1.00 7.2. Bolus insulins 2,304 Suppressed 130.2 (42.0-403.7) 2.52 (0.60-10.62) 1.49 (0.24-9.28) Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. * denotes p<0.05. 6.4.3 Findings from cancer subtype analysis Only diabetes medications that showed statistically significant findings from the primary analysis are explored for subtypes of colorectal cancer. Supplementary Table C-5 includes all associations with colon cancer risk, regardless of their statistical significance level. Medications that were significantly associated with the risk of overall colorectal cancer were also consistently associated with colon cancer risk (Table 6-7). 121 Table 6-7. Associations between select diabetes medications and the risk of colorectal cancer location subtype: colon Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 24,715 49.4 (48.8-50.0) 1.00 1.00 Ever use 2,021,426 2,367 116.9 (111.6-122.4) 1.33 (1.27-1.39)* 1.27 (1.21-1.33)* Cumulative duration Low 736,609 531 72.1 (66.2-78.5) 0.96 (0.88-1.04) 0.92 (0.85-1.01) Medium 720,912 877 121.7 (113.9-130.0) 1.40 (1.31-1.50)* 1.33 (1.25-1.43)* High 563,905 959 170.1 (159.6-181.2) 1.52 (1.43-1.63)* 1.45 (1.36-1.55)* Continuous 1.05 (1.04-1.05)* 1.04 (1.03-1.05)* Cumulative dose Low 761,186 595 78.2 (72.1-84.7) 0.98 (0.90-1.06) 0.95 (0.88-1.03) Medium 720,432 875 121.5 (113.7-129.8) 1.35 (1.26-1.44)* 1.29 (1.21-1.38)* High 539,808 897 166.2 (155.6-177.4) 1.61 (1.51-1.73)* 1.52 (1.43-1.63)* Continuous 1.06 (1.05-1.06)* 1.05 (1.04-1.06)* 5. Insulin secretagogues Never 51,176,005 25,895 50.6 (50.0-51.2) 1.00 1.00 Ever use 912,639 1,187 131.8 (122.7-141.6) 1.45 (1.35-1.56)* 1.39 (1.29-1.50)* Cumulative duration Low 360,923 325 90.0 (80.8-100.4) 1.07 (0.96-1.19) 1.03 (0.93-1.15) Medium 315,845 414 131.1 (119.0-144.3) 1.44 (1.31-1.59)* 1.38 (1.25-1.52)* High 235,871 448 189.9 (173.1-208.4) 1.66 (1.51-1.82)* 1.58 (1.44-1.74)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* Cumulative dose Low 372,575 376 100.9 (91.2-111.7) 1.13 (1.02-1.25)* 1.10 (1.00-1.22) Medium 314,231 424 134.9 (122.7-148.4) 1.44 (1.31-1.59)* 1.37 (1.25-1.51)* High 225,833 387 171.4 (155.1-189.3) 1.64 (1.49-1.82)* 1.56 (1.41-1.72)* Continuous 1.02 (1.02-1.03)* 1.02 (1.01-1.02)* 5.2. Sulfonylureas Never 51,188,413 25,904 50.6 (50.0-51.2) 1.00 1.00 Ever use 900,231 1,178 132.2 (123.0-142.0) 1.45 (1.35-1.56)* 1.39 (1.29-1.50)* Cumulative duration Low 359,009 334 93.0 (83.6-103.6) 1.10 (0.99-1.22) 1.06 (0.96-1.19) Medium 309,407 405 130.9 (118.7-144.3) 1.44 (1.31-1.59)* 1.37 (1.24-1.51)* High 231,815 439 189.4 (172.5-207.9) 1.65 (1.50-1.82)* 1.58 (1.43-1.73)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* Cumulative dose Low 367,838 381 103.6 (93.7-114.5) 1.16 (1.05-1.28)* 1.13 (1.02-1.25)* Medium 309,412 416 134.4 (122.1-148.0) 1.44 (1.30-1.58)* 1.37 (1.24-1.51)* High 222,981 381 170.9 (154.5-188.9) 1.64 (1.48-1.81)* 1.55 (1.40-1.72)* Continuous 1.02 (1.02-1.03)* 1.02 (1.01-1.02)* 5.2.1. Gliclazide Never 51,695,028 26,546 51.4 (50.7-52.0) 1.00 1.00 Ever use 393,616 536 136.7 (123.2-151.8) 1.45 (1.30-1.61)* 1.36 (1.23-1.51)* Cumulative duration Low 126,908 154 121.3 (103.6-142.1) 1.39 (1.19-1.63)* 1.32 (1.13-1.55)* Medium 136,638 163 119.3 (102.3-139.1) 1.30 (1.11-1.51)* 1.22 (1.05-1.42)* High 130,070 219 168.4 (147.5-192.2) 1.55 (1.35-1.77)* 1.47 (1.29-1.68)* Continuous 1.07 (1.05-1.09)* 1.06 (1.04-1.08)* Cumulative dose Low 133,699 156 116.7 (99.7-136.5) 1.30 (1.11-1.52)* 1.23 (1.05-1.44)* Medium 136,394 177 129.8 (112.0-150.4) 1.37 (1.18-1.59)* 1.29 (1.11-1.49)* High 123,523 203 164.3 (143.2-188.6) 1.58 (1.38-1.81)* 1.49 (1.30-1.71)* Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.02)* 5.2.2. Glyburide Never 51,418,210 26,180 50.9 (50.3-51.5) 1.00 1.00 Ever use 670,434 902 129.7 (117.7-143.0) 1.47 (1.33-1.62)* 1.42 (1.29-1.57)* Cumulative duration Low 283,215 302 106.6 (95.3-119.4) 1.20 (1.07-1.34)* 1.17 (1.04-1.31)* Medium 224,722 289 128.6 (114.6-144.3) 1.40 (1.25-1.57)* 1.35 (1.20-1.51)* High 162,497 311 191.4 (171.3-213.9) 1.66 (1.49-1.86)* 1.58 (1.42-1.77)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.07)* Cumulative dose Low 296,014 327 110.5 (99.1-123.1) 1.19 (1.07-1.32)* 1.16 (1.04-1.29)* 122 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 230,574 331 143.6 (128.9-159.9) 1.50 (1.35-1.68)* 1.44 (1.30-1.61)* High 143,846 244 169.6 (149.6-192.3) 1.62 (1.43-1.84)* 1.54 (1.36-1.75)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.03)* 6. Thiazolidinediones Never 51,871,508 26,830 51.7 (51.1-52.3) 1.00 1.00 Ever use 217,136 252 80.3 (62.1-103.9) 1.16 (0.90-1.51) 1.11 (0.86-1.44) Cumulative duration Low 76,357 87 113.9 (92.3-140.6) 1.41 (1.14-1.74)* 1.35 (1.09-1.66)* Medium 72,351 77 106.4 (85.1-133.1) 1.31 (1.05-1.64)* 1.24 (0.99-1.55) High 68,428 88 128.6 (104.4-158.5) 1.39 (1.13-1.71)* 1.29 (1.05-1.59)* Continuous 1.06 (1.02-1.09)* 1.04 (1.01-1.08)* Cumulative dose Low 75,982 86 113.2 (91.6-139.8) 1.38 (1.12-1.71)* 1.32 (1.07-1.63)* Medium 74,257 86 115.8 (93.8-143.1) 1.41 (1.14-1.75)* 1.34 (1.08-1.66)* High 66,897 80 119.6 (96.1-148.9) 1.32 (1.06-1.64)* 1.22 (0.98-1.52) Continuous 1.06 (1.02-1.09)* 1.04 (1.01-1.08)* 6.2. Rosiglitazone Never 51,946,176 26,903 51.8 (51.2-52.4) 1.00 1.00 Ever use 142,468 179 76.8 (53.4-110.5) 1.21 (0.84-1.74) 1.17 (0.82-1.69) Cumulative duration Low 49,170 55 111.9 (85.9-145.7) 1.36 (1.05-1.77)* 1.30 (1.00-1.70) Medium 48,028 62 129.1 (100.6-165.6) 1.58 (1.23-2.03)* 1.51 (1.18-1.94)* High 45,270 62 137.0 (106.8-175.7) 1.54 (1.20-1.98)* 1.44 (1.12-1.85)* Continuous 1.10 (1.05-1.15)* 1.08 (1.04-1.13)* Cumulative dose Low 49,567 58 117.0 (90.5-151.4) 1.42 (1.10-1.84)* 1.36 (1.05-1.76)* Medium 49,349 60 121.6 (94.4-156.6) 1.47 (1.14-1.90)* 1.40 (1.09-1.81)* High 43,552 61 140.1 (109.0-180.0) 1.59 (1.24-2.05)* 1.49 (1.16-1.91)* Continuous 1.10 (1.06-1.14)* 1.09 (1.04-1.13)* 7. Insulins and analogues Never 51,772,245 26,771 51.7 (51.1-52.3) 1.00 1.00 Ever use 316,399 311 109.6 (96.9-123.9) 1.36 (1.20-1.54)* 1.26 (1.11-1.43)* Cumulative duration Low 143,015 80 55.9 (44.9-69.6) 0.89 (0.71-1.10) 0.83 (0.67-1.03) Medium 113,499 136 119.8 (101.3-141.8) 1.43 (1.21-1.70)* 1.33 (1.12-1.57)* High 59,885 95 158.6 (129.7-194.0) 1.72 (1.41-2.11)* 1.61 (1.31-1.96)* Continuous 1.08 (1.05-1.10)* 1.07 (1.04-1.09)* Cumulative dose Low 146,186 86 58.8 (47.6-72.7) 0.90 (0.73-1.11) 0.85 (0.68-1.05) Medium 108,141 125 115.6 (97.0-137.7) 1.38 (1.16-1.64)* 1.28 (1.07-1.53)* High 62,072 100 161.1 (132.4-196.0) 1.84 (1.51-2.24)* 1.70 (1.40-2.07)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 7.1. Basal insulins Never 51,784,863 26,778 51.7 (51.1-52.3) 1.00 1.00 Ever use 303,781 304 112.0 (98.8-127.0) 1.40 (1.23-1.59)* 1.30 (1.14-1.47)* Cumulative duration Low 135,289 85 62.8 (50.8-77.7) 1.00 (0.81-1.23) 0.93 (0.75-1.15) Medium 109,417 125 114.2 (95.9-136.1) 1.38 (1.16-1.64)* 1.28 (1.07-1.52)* High 59,075 94 159.1 (130.0-194.8) 1.72 (1.40-2.11)* 1.60 (1.31-1.96)* Continuous 1.09 (1.06-1.12)* 1.08 (1.05-1.11)* Cumulative dose Low 136,909 86 62.8 (50.8-77.6) 0.97 (0.78-1.20) 0.91 (0.74-1.12) Medium 106,571 118 110.7 (92.4-132.6) 1.33 (1.11-1.59)* 1.23 (1.03-1.48)* High 60,301 100 165.8 (136.3-201.7) 1.89 (1.55-2.30)* 1.74 (1.43-2.12)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.05)* 7.2. Bolus insulins Never 51,947,122 26,941 51.9 (51.2-52.5) 1.00 1.00 Ever use 141,522 141 116.3 (95.4-141.7) 1.65 (1.36-2.02)* 1.52 (1.25-1.86)* Cumulative duration Low 68,567 43 62.7 (46.5-84.6) 1.08 (0.80-1.45) 1.01 (0.75-1.36) Medium 48,161 59 122.5 (94.9-158.1) 1.71 (1.32-2.20)* 1.57 (1.21-2.02)* High 24,794 39 157.3 (114.9-215.3) 2.00 (1.46-2.74)* 1.84 (1.34-2.52)* Continuous 1.12 (1.06-1.19)* 1.11 (1.05-1.17)* Cumulative dose Low 71,251 47 66.0 (49.6-87.8) 1.11 (0.83-1.47) 1.04 (0.78-1.38) 123 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 44,054 53 120.3 (91.9-157.5) 1.67 (1.27-2.18)* 1.53 (1.17-2.01)* High 26,217 41 156.4 (115.1-212.4) 2.08 (1.53-2.83)* 1.89 (1.39-2.57)* Continuous 1.05 (1.03-1.07)* 1.05 (1.03-1.07)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. This table summarized the associations between select diabetes medications and colon cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table C-5. * denotes p<0.05. All associations with the risk of proximal colon cancer, including those that are not statistically significant, can be found in Supplementary Table C-6. Statistically significant results from the proximal colon cancer analysis are presented in Table 6-8. Medications that were significantly associated with overall colorectal cancer risk were also associated with proximal colon cancer risk. Table 6-8. Associations between select diabetes medications and the risk of colorectal cancer location subtype: proximal colon Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 13,770 27.5 (27.0-28.0) 1.00 1.00 Ever use 2,021,426 1,368 67.5 (63.5-71.8) 1.35 (1.27-1.44)* 1.31 (1.23-1.40)* Cumulative duration Low 736,609 297 40.3 (36.0-45.2) 0.95 (0.85-1.07) 0.93 (0.83-1.04) Medium 720,912 500 69.4 (63.5-75.7) 1.41 (1.29-1.54)* 1.37 (1.25-1.49)* High 563,905 571 101.3 (93.3-109.9) 1.57 (1.44-1.71)* 1.51 (1.39-1.64)* Continuous 1.05 (1.04-1.06)* 1.04 (1.04-1.05)* Cumulative dose Low 761,186 330 43.4 (38.9-48.3) 0.96 (0.86-1.07) 0.94 (0.84-1.05) Medium 720,432 501 69.5 (63.7-75.9) 1.36 (1.24-1.48)* 1.32 (1.21-1.44)* High 539,808 537 99.5 (91.4-108.3) 1.68 (1.55-1.84)* 1.61 (1.48-1.76)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* 5. Insulin secretagogues Never 51,176,005 14,443 28.2 (27.8-28.7) 1.00 1.00 Ever use 912,639 695 76.9 (70.0-84.4) 1.49 (1.35-1.63)* 1.45 (1.32-1.60)* Cumulative duration Low 360,923 177 49.0 (42.3-56.8) 1.02 (0.88-1.19) 1.01 (0.87-1.17) Medium 315,845 239 75.7 (66.7-85.9) 1.47 (1.29-1.67)* 1.43 (1.25-1.62)* High 235,871 279 118.3 (105.2-133.0) 1.78 (1.58-2.01)* 1.73 (1.54-1.95)* Continuous 1.06 (1.05-1.08)* 1.06 (1.05-1.07)* Cumulative dose Low 372,575 217 58.2 (51.0-66.5) 1.15 (1.00-1.31)* 1.14 (0.99-1.30) Medium 314,231 240 76.4 (67.3-86.7) 1.43 (1.26-1.62)* 1.39 (1.22-1.58)* High 225,833 238 105.4 (92.8-119.7) 1.76 (1.55-2.00)* 1.70 (1.49-1.93)* Continuous 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 5.2. Sulfonylureas Never 51,188,413 14,448 28.2 (27.8-28.7) 1.00 1.00 Ever use 900,231 690 77.1 (70.1-84.7) 1.49 (1.35-1.64)* 1.46 (1.32-1.60)* Cumulative duration 124 Exposure Person-years Events Incidence rate Model 1 Model 2 Low 359,009 183 51.0 (44.1-58.9) 1.06 (0.92-1.23) 1.05 (0.91-1.21) Medium 309,407 233 75.3 (66.2-85.6) 1.46 (1.28-1.66)* 1.42 (1.24-1.61)* High 231,815 274 118.2 (105.0-133.1) 1.78 (1.58-2.01)* 1.73 (1.53-1.95)* Continuous 1.06 (1.05-1.08)* 1.06 (1.05-1.07)* Cumulative dose Low 367,838 221 60.1 (52.7-68.5) 1.18 (1.03-1.35)* 1.17 (1.02-1.34)* Medium 309,412 234 75.6 (66.5-86.0) 1.42 (1.24-1.61)* 1.37 (1.21-1.56)* High 222,981 235 105.4 (92.7-119.8) 1.76 (1.55-2.00)* 1.70 (1.49-1.93)* Continuous 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 5.2.1. Gliclazide Never 51,695,028 14,823 28.7 (28.2-29.1) 1.00 1.00 Ever use 393,616 315 76.9 (66.9-88.4) 1.43 (1.24-1.64)* 1.36 (1.18-1.57)* Cumulative duration Low 126,908 97 76.4 (62.6-93.3) 1.54 (1.26-1.88)* 1.48 (1.21-1.81)* Medium 136,638 91 66.6 (54.2-81.8) 1.27 (1.04-1.56)* 1.21 (0.99-1.49) High 130,070 127 97.6 (82.1-116.2) 1.56 (1.31-1.85)* 1.49 (1.25-1.78)* Continuous 1.07 (1.05-1.10)* 1.06 (1.04-1.09)* Cumulative dose Low 133,699 99 74.0 (60.8-90.2) 1.44 (1.18-1.76)* 1.39 (1.14-1.70)* Medium 136,394 95 69.7 (57.0-85.2) 1.29 (1.05-1.58)* 1.23 (1.00-1.50)* High 123,523 121 98.0 (82.0-117.1) 1.64 (1.37-1.96)* 1.57 (1.31-1.88)* Continuous 1.02 (1.02-1.03)* 1.02 (1.01-1.03)* 5.2.2. Glyburide Never 51,418,210 14,598 28.4 (27.9-28.9) 1.00 1.00 Ever use 670,434 540 76.7 (67.6-87.1) 1.52 (1.34-1.73)* 1.52 (1.34-1.73)* Cumulative duration Low 283,215 167 59.0 (50.7-68.6) 1.16 (1.00-1.35) 1.16 (0.99-1.35) Medium 224,722 178 79.2 (68.4-91.7) 1.52 (1.31-1.76)* 1.49 (1.29-1.73)* High 162,497 195 120.0 (104.3-138.1) 1.80 (1.56-2.07)* 1.75 (1.52-2.02)* Continuous 1.07 (1.05-1.08)* 1.07 (1.05-1.08)* Cumulative dose Low 296,014 187 63.2 (54.7-72.9) 1.19 (1.03-1.37)* 1.18 (1.02-1.36)* Medium 230,574 204 88.5 (77.1-101.5) 1.62 (1.41-1.86)* 1.59 (1.39-1.83)* High 143,846 149 103.6 (88.2-121.6) 1.73 (1.47-2.03)* 1.68 (1.43-1.97)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 6. Thiazolidinediones Never 51,871,508 14,982 28.9 (28.4-29.3) 1.00 1.00 Ever use 217,136 156 40.2 (27.9-57.8) 1.06 (0.73-1.52) 1.04 (0.72-1.50) Cumulative duration Low 76,357 54 70.7 (54.2-92.3) 1.56 (1.19-2.04)* 1.52 (1.16-1.98)* Medium 72,351 49 67.7 (51.2-89.6) 1.49 (1.12-1.97)* 1.43 (1.08-1.90)* High 68,428 53 77.5 (59.2-101.4) 1.48 (1.13-1.94)* 1.40 (1.07-1.83)* Continuous 1.08 (1.03-1.12)* 1.06 (1.02-1.11)* Cumulative dose Low 75,982 51 67.1 (51.0-88.3) 1.45 (1.11-1.91)* 1.41 (1.07-1.86)* Medium 74,257 57 76.8 (59.2-99.5) 1.67 (1.29-2.16)* 1.60 (1.24-2.08)* High 66,897 48 71.8 (54.1-95.2) 1.41 (1.06-1.87)* 1.32 (1.00-1.76) Continuous 1.07 (1.03-1.11)* 1.06 (1.02-1.10)* 6.2. Rosiglitazone Never 51,946,176 15,024 28.9 (28.5-29.4) 1.00 1.00 Ever use 142,468 114 42.4 (26.0-69.1) 1.22 (0.75-1.99) 1.22 (0.75-2.00) Cumulative duration Low 49,170 36 73.2 (52.8-101.5) 1.59 (1.14-2.20)* 1.54 (1.11-2.13)* Medium 48,028 39 81.2 (59.3-111.1) 1.78 (1.30-2.43)* 1.71 (1.25-2.34)* High 45,270 39 86.1 (62.9-117.9) 1.73 (1.26-2.36)* 1.63 (1.19-2.23)* Continuous 1.12 (1.06-1.18)* 1.10 (1.05-1.17)* Cumulative dose Low 49,567 39 78.7 (57.5-107.7) 1.70 (1.24-2.33)* 1.65 (1.20-2.25)* Medium 49,349 40 81.1 (59.5-110.5) 1.75 (1.29-2.39)* 1.69 (1.24-2.30)* High 43,552 35 80.4 (57.7-111.9) 1.63 (1.17-2.27)* 1.54 (1.10-2.14)* Continuous 1.11 (1.06-1.17)* 1.10 (1.05-1.16)* 7. Insulins and analogues Never 51,772,245 14,952 28.9 (28.4-29.3) 1.00 1.00 Ever use 316,399 186 67.6 (57.8-79.0) 1.50 (1.28-1.75)* 1.39 (1.19-1.63)* Cumulative duration 125 Exposure Person-years Events Incidence rate Model 1 Model 2 Low 143,015 48 33.6 (25.3-44.5) 0.95 (0.72-1.26) 0.89 (0.67-1.19) Medium 113,499 82 72.2 (58.2-89.7) 1.54 (1.24-1.91)* 1.43 (1.15-1.78)* High 59,885 56 93.5 (72.0-121.5) 1.81 (1.39-2.35)* 1.67 (1.28-2.17)* Continuous 1.09 (1.06-1.12)* 1.08 (1.04-1.11)* Cumulative dose Low 146,186 51 34.9 (26.5-45.9) 0.95 (0.72-1.25) 0.90 (0.68-1.18) Medium 108,141 77 71.2 (57.0-89.0) 1.51 (1.21-1.89)* 1.40 (1.12-1.76)* High 62,072 58 93.4 (72.2-120.9) 1.91 (1.48-2.47)* 1.75 (1.35-2.27)* Continuous 1.03 (1.02-1.05)* 1.03 (1.02-1.04)* 7.1. Basal insulins Never 51,784,863 14,955 28.9 (28.4-29.3) 1.00 1.00 Ever use 303,781 183 69.1 (58.9-81.1) 1.54 (1.31-1.81)* 1.44 (1.22-1.69)* Cumulative duration Low 135,289 52 38.4 (29.3-50.4) 1.09 (0.83-1.43) 1.03 (0.78-1.35) Medium 109,417 77 70.4 (56.3-88.0) 1.51 (1.21-1.89)* 1.40 (1.12-1.76)* High 59,075 54 91.4 (70.0-119.4) 1.75 (1.34-2.29)* 1.62 (1.24-2.12)* Continuous 1.11 (1.07-1.14)* 1.09 (1.06-1.13)* Cumulative dose Low 136,909 51 37.3 (28.3-49.0) 1.03 (0.78-1.35) 0.97 (0.73-1.27) Medium 106,571 72 67.6 (53.6-85.1) 1.44 (1.14-1.82)* 1.34 (1.06-1.69)* High 60,301 60 99.5 (77.3-128.1) 2.02 (1.57-2.61)* 1.86 (1.44-2.40)* Continuous 1.04 (1.03-1.05)* 1.04 (1.02-1.05)* 7.2. Bolus insulins Never 51,947,122 15,063 29.0 (28.5-29.5) 1.00 1.00 Ever use 141,522 75 58.1 (43.9-76.9) 1.50 (1.13-1.98)* 1.37 (1.04-1.82)* Cumulative duration Low 68,567 21 30.6 (20.0-47.0) 0.94 (0.61-1.44) 0.88 (0.57-1.35) Medium 48,161 31 64.4 (45.3-91.5) 1.61 (1.14-2.30)* 1.48 (1.04-2.11)* High 24,794 23 92.8 (61.6-139.6) 2.13 (1.42-3.21)* 1.94 (1.29-2.92)* Continuous 1.12 (1.04-1.21)* 1.10 (1.02-1.19)* Cumulative dose Low 71,251 25 35.1 (23.7-51.9) 1.05 (0.71-1.55) 0.99 (0.67-1.46) Medium 44,054 29 65.8 (45.7-94.7) 1.64 (1.14-2.36)* 1.51 (1.05-2.17)* High 26,217 21 80.1 (52.2-122.9) 1.93 (1.26-2.97)* 1.74 (1.14-2.68)* Continuous 1.05 (1.03-1.07)* 1.05 (1.02-1.07)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table summarized the associations between select diabetes medications and proximal colon cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table C-6. * denotes p<0.05. Table 6-9 shows the similarity in risk estimates between medications associated with overall colorectal cancer risk and those associated with the risk of distal colon cancer, except for the class of thiazolidinediones. Supplementary Table C-7 presents all associations with distal colon cancer risk, regardless of statistical significance. 126 Table 6-9. Associations between select diabetes medications and the risk of colorectal cancer location subtype: distal colon Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 9,490 19.0 (18.6-19.3) 1.00 1.00 Ever use 2,021,426 881 44.8 (41.6-48.3) 1.36 (1.25-1.47)* 1.26 (1.16-1.36)* Cumulative duration Low 736,609 205 27.8 (24.3-31.9) 0.98 (0.85-1.12) 0.92 (0.80-1.06) Medium 720,912 333 46.2 (41.5-51.4) 1.42 (1.27-1.58)* 1.31 (1.18-1.46)* High 563,905 343 60.8 (54.7-67.6) 1.52 (1.36-1.69)* 1.41 (1.27-1.57)* Continuous 1.05 (1.04-1.06)* 1.04 (1.03-1.05)* Cumulative dose Low 761,186 230 30.2 (26.6-34.4) 1.01 (0.89-1.16) 0.96 (0.84-1.10) Medium 720,432 330 45.8 (41.1-51.0) 1.38 (1.23-1.54)* 1.28 (1.15-1.43)* High 539,808 321 59.5 (53.3-66.3) 1.57 (1.41-1.76)* 1.44 (1.29-1.62)* Continuous 1.05 (1.04-1.07)* 1.04 (1.03-1.06)* 5. Insulin secretagogues Never 51,176,005 9,951 19.4 (19.1-19.8) 1.00 1.00 Ever use 912,639 420 49.2 (43.8-55.3) 1.45 (1.28-1.63)* 1.34 (1.19-1.51)* Cumulative duration Low 360,923 127 35.2 (29.6-41.9) 1.12 (0.94-1.33) 1.05 (0.88-1.25) Medium 315,845 149 47.2 (40.2-55.4) 1.39 (1.18-1.63)* 1.28 (1.09-1.51)* High 235,871 144 61.1 (51.9-71.9) 1.49 (1.26-1.75)* 1.37 (1.16-1.62)* Continuous 1.04 (1.03-1.06)* 1.04 (1.02-1.05)* Cumulative dose Low 372,575 137 36.8 (31.1-43.5) 1.12 (0.95-1.32) 1.06 (0.89-1.25) Medium 314,231 155 49.3 (42.1-57.7) 1.42 (1.21-1.67)* 1.31 (1.12-1.54)* High 225,833 128 56.7 (47.7-67.4) 1.48 (1.24-1.76)* 1.36 (1.14-1.62)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.02)* 5.2. Sulfonylureas Never 51,188,413 9,954 19.4 (19.1-19.8) 1.00 1.00 Ever use 900,231 417 49.4 (43.9-55.6) 1.45 (1.29-1.64)* 1.34 (1.19-1.51)* Cumulative duration Low 359,009 130 36.2 (30.5-43.0) 1.15 (0.96-1.36) 1.08 (0.91-1.28) Medium 309,407 146 47.2 (40.1-55.5) 1.39 (1.18-1.63)* 1.28 (1.09-1.51)* High 231,815 141 60.8 (51.6-71.7) 1.48 (1.25-1.75)* 1.37 (1.16-1.61)* Continuous 1.05 (1.03-1.06)* 1.04 (1.02-1.05)* Cumulative dose Low 367,838 138 37.5 (31.8-44.3) 1.14 (0.96-1.35) 1.08 (0.91-1.27) Medium 309,412 153 49.4 (42.2-57.9) 1.43 (1.22-1.67)* 1.31 (1.12-1.54)* High 222,981 126 56.5 (47.5-67.3) 1.47 (1.24-1.76)* 1.35 (1.13-1.61)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.02)* 5.2.1. Gliclazide Never 51,695,028 10,179 19.7 (19.3-20.1) 1.00 1.00 Ever use 393,616 192 54.0 (45.7-63.8) 1.54 (1.30-1.82)* 1.40 (1.19-1.66)* Cumulative duration Low 126,908 54 42.6 (32.6-55.6) 1.30 (1.00-1.70) 1.20 (0.92-1.57) Medium 136,638 59 43.2 (33.5-55.7) 1.26 (0.98-1.63) 1.15 (0.89-1.48) High 130,070 79 60.7 (48.7-75.7) 1.54 (1.24-1.93)* 1.43 (1.14-1.78)* Continuous 1.06 (1.03-1.09)* 1.05 (1.02-1.08)* Cumulative dose Low 133,699 52 38.9 (29.6-51.0) 1.17 (0.89-1.53) 1.08 (0.82-1.42) Medium 136,394 67 49.1 (38.7-62.4) 1.40 (1.10-1.78)* 1.28 (1.01-1.63)* High 123,523 73 59.1 (47.0-74.3) 1.55 (1.23-1.95)* 1.43 (1.13-1.80)* Continuous 1.01 (1.00-1.03)* 1.01 (1.00-1.02) 5.2.2. Glyburide Never 51,418,210 10,065 19.6 (19.2-20.0) 1.00 1.00 Ever use 670,434 306 47.5 (40.5-55.8) 1.42 (1.21-1.67)* 1.33 (1.13-1.57)* Cumulative duration Low 283,215 114 40.3 (33.5-48.4) 1.22 (1.01-1.47)* 1.16 (0.96-1.39) Medium 224,722 93 41.4 (33.8-50.7) 1.20 (0.98-1.48) 1.12 (0.91-1.38) High 162,497 99 60.9 (50.0-74.2) 1.48 (1.21-1.80)* 1.36 (1.12-1.66)* Continuous 1.05 (1.03-1.07)* 1.04 (1.02-1.06)* Cumulative dose Low 296,014 117 39.5 (33.0-47.4) 1.16 (0.96-1.39) 1.10 (0.92-1.32) 127 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 230,574 108 46.8 (38.8-56.6) 1.33 (1.10-1.61)* 1.24 (1.02-1.49)* High 143,846 81 56.3 (45.3-70.0) 1.47 (1.18-1.82)* 1.34 (1.08-1.67)* Continuous 1.02 (1.01-1.03)* 1.02 (1.00-1.03)* 6.2. Rosiglitazone Never 51,946,176 10,310 19.8 (19.5-20.2) 1.00 1.00 Ever use 142,468 61 31.8 (18.0-55.9) 1.23 (0.70-2.17) 1.16 (0.66-2.04) Cumulative duration Low 49,170 17 34.6 (21.5-55.6) 1.09 (0.68-1.76) 1.02 (0.63-1.64) Medium 48,028 21 43.7 (28.5-67.1) 1.39 (0.90-2.12) 1.28 (0.84-1.97) High 45,270 23 50.8 (33.8-76.5) 1.49 (0.99-2.23) 1.34 (0.89-2.02) Continuous 1.10 (1.02-1.17)* 1.08 (1.00-1.15)* Cumulative dose Low 49,567 17 34.3 (21.3-55.2) 1.08 (0.67-1.74) 1.01 (0.63-1.63) Medium 49,349 19 38.5 (24.6-60.4) 1.21 (0.77-1.89) 1.12 (0.71-1.75) High 43,552 25 57.4 (38.8-85.0) 1.69 (1.14-2.50)* 1.52 (1.03-2.25)* Continuous 1.10 (1.03-1.17)* 1.08 (1.01-1.15)* 7. Insulins and analogues Never 51,772,245 10,267 19.8 (19.5-20.2) 1.00 1.00 Ever use 316,399 104 35.9 (29.0-44.6) 1.15 (0.93-1.43) 1.05 (0.85-1.31) Cumulative duration Low 143,015 25 17.5 (11.8-25.9) 0.72 (0.48-1.06) 0.66 (0.45-0.98)* Medium 113,499 46 40.5 (30.4-54.1) 1.27 (0.95-1.69) 1.15 (0.86-1.54) High 59,885 33 55.1 (39.2-77.5) 1.57 (1.12-2.21)* 1.44 (1.03-2.03)* Continuous 1.06 (1.02-1.10)* 1.05 (1.00-1.09)* Cumulative dose Low 146,186 29 19.8 (13.8-28.5) 0.79 (0.55-1.14) 0.73 (0.51-1.06) Medium 108,141 41 37.9 (27.9-51.5) 1.18 (0.87-1.61) 1.08 (0.79-1.46) High 62,072 34 54.8 (39.1-76.7) 1.61 (1.15-2.25)* 1.47 (1.05-2.06)* Continuous 1.03 (1.01-1.04)* 1.02 (1.01-1.04)* 7.1. Basal insulins Never 51,784,863 10,269 19.8 (19.5-20.2) 1.00 1.00 Ever use 303,781 102 36.9 (29.6-45.9) 1.19 (0.95-1.48) 1.08 (0.87-1.35) Cumulative duration Low 135,289 28 20.7 (14.3-30.0) 0.85 (0.58-1.23) 0.78 (0.54-1.13) Medium 109,417 40 36.6 (26.8-49.8) 1.15 (0.84-1.57) 1.04 (0.76-1.42) High 59,075 34 57.6 (41.1-80.5) 1.62 (1.16-2.27)* 1.49 (1.06-2.08)* Continuous 1.07 (1.02-1.12)* 1.05 (1.00-1.10)* Cumulative dose Low 136,909 30 21.9 (15.3-31.3) 0.88 (0.61-1.25) 0.81 (0.57-1.16) Medium 106,571 41 38.5 (28.3-52.2) 1.20 (0.89-1.63) 1.10 (0.81-1.49) High 60,301 31 51.4 (36.2-73.1) 1.51 (1.06-2.14)* 1.37 (0.96-1.94) Continuous 1.03 (1.01-1.05)* 1.03 (1.01-1.05)* 7.2. Bolus insulins Never 51,947,122 10,314 19.9 (19.5-20.2) 1.00 1.00 Ever use 141,522 57 51.0 (37.8-68.8) 1.84 (1.36-2.48)* 1.67 (1.24-2.25)* Cumulative duration Low 68,567 16 23.3 (14.3-38.1) 1.05 (0.64-1.72) 0.98 (0.60-1.60) Medium 48,161 25 51.9 (35.1-76.8) 1.83 (1.24-2.71)* 1.66 (1.12-2.46)* High 24,794 16 64.5 (39.5-105.3) 2.07 (1.27-3.37)* 1.88 (1.15-3.07)* Continuous 1.14 (1.05-1.23)* 1.12 (1.03-1.22)* Cumulative dose Low 71,251 17 23.9 (14.8-38.4) 1.05 (0.66-1.70) 0.98 (0.61-1.58) Medium 44,054 21 47.7 (31.1-73.1) 1.67 (1.09-2.57)* 1.52 (0.99-2.34) High 26,217 19 72.5 (46.2-113.6) 2.41 (1.54-3.77)* 2.16 (1.38-3.39)* Continuous 1.05 (1.03-1.08)* 1.05 (1.02-1.08)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. This table summarized the associations between select diabetes medications and distal colon cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table C-7. * denotes p<0.05. 128 Similarly, all medications found significantly related to overall colorectal cancer were also significantly associated with the risk of rectal cancer (Table 6-10), except for the subclass of bolus insulins. All associations with rectal cancer risk, regardless of their statistical significance, are listed in Supplementary Table C-8. Table 6-10. Associations between select diabetes medications and the risk of colorectal cancer location subtype: rectum Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 13,125 26.2 (25.8-26.7) 1.00 1.00 Ever use 2,021,426 1,101 55.5 (51.9-59.4) 1.25 (1.17-1.34)* 1.15 (1.07-1.23)* Cumulative duration Low 736,609 252 34.2 (30.2-38.7) 0.89 (0.78-1.00) 0.83 (0.74-0.94)* Medium 720,912 416 57.7 (52.4-63.5) 1.32 (1.19-1.45)* 1.21 (1.09-1.33)* High 563,905 433 76.8 (69.9-84.4) 1.46 (1.32-1.60)* 1.35 (1.23-1.49)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.04)* Cumulative dose Low 761,186 273 35.9 (31.9-40.4) 0.89 (0.79-1.01) 0.85 (0.75-0.95)* Medium 720,432 406 56.4 (51.1-62.1) 1.26 (1.14-1.40)* 1.17 (1.06-1.29)* High 539,808 422 78.2 (71.1-86.0) 1.56 (1.41-1.72)* 1.42 (1.29-1.56)* Continuous 1.05 (1.04-1.06)* 1.04 (1.03-1.05)* 5. Insulin secretagogues Never 51,176,005 13,661 26.7 (26.3-27.1) 1.00 1.00 Ever use 912,639 565 61.8 (55.7-68.6) 1.36 (1.23-1.52)* 1.25 (1.12-1.38)* Cumulative duration Low 360,923 171 47.4 (40.8-55.0) 1.12 (0.97-1.31) 1.05 (0.90-1.22) Medium 315,845 212 67.1 (58.7-76.8) 1.48 (1.29-1.70)* 1.35 (1.18-1.55)* High 235,871 182 77.2 (66.7-89.2) 1.44 (1.24-1.67)* 1.32 (1.14-1.53)* Continuous 1.05 (1.03-1.06)* 1.04 (1.02-1.05)* Cumulative dose Low 372,575 186 49.9 (43.2-57.6) 1.14 (0.99-1.32) 1.07 (0.92-1.23) Medium 314,231 216 68.7 (60.2-78.5) 1.49 (1.31-1.71)* 1.36 (1.19-1.56)* High 225,833 163 72.2 (61.9-84.2) 1.43 (1.23-1.67)* 1.30 (1.12-1.52)* Continuous 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 5.2. Sulfonylureas Never 51,188,413 13,666 26.7 (26.3-27.1) 1.00 1.00 Ever use 900,231 560 62.1 (55.9-68.9) 1.37 (1.23-1.52)* 1.25 (1.12-1.39)* Cumulative duration Low 359,009 173 48.2 (41.5-55.9) 1.14 (0.98-1.33) 1.06 (0.91-1.23) Medium 309,407 207 66.9 (58.4-76.7) 1.48 (1.29-1.69)* 1.34 (1.17-1.54)* High 231,815 180 77.6 (67.1-89.9) 1.45 (1.25-1.68)* 1.33 (1.15-1.54)* Continuous 1.05 (1.03-1.06)* 1.04 (1.02-1.05)* Cumulative dose Low 367,838 184 50.0 (43.3-57.8) 1.14 (0.99-1.32) 1.07 (0.92-1.23) Medium 309,412 213 68.8 (60.2-78.7) 1.50 (1.31-1.71)* 1.36 (1.19-1.56)* High 222,981 163 73.1 (62.7-85.2) 1.45 (1.24-1.69)* 1.32 (1.13-1.54)* Continuous 1.02 (1.01-1.03)* 1.01 (1.01-1.02)* 5.2.1. Gliclazide Never 51,695,028 13,977 27.0 (26.6-27.5) 1.00 1.00 Ever use 393,616 249 66.8 (57.5-77.6) 1.44 (1.24-1.67)* 1.31 (1.12-1.52)* Cumulative duration Low 126,908 67 52.8 (41.6-67.1) 1.21 (0.95-1.54) 1.12 (0.88-1.42) Medium 136,638 79 57.8 (46.4-72.1) 1.27 (1.02-1.58)* 1.15 (0.92-1.43) High 130,070 103 79.2 (65.3-96.1) 1.53 (1.26-1.86)* 1.42 (1.17-1.72)* Continuous 1.07 (1.04-1.09)* 1.05 (1.03-1.08)* 129 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 133,699 74 55.3 (44.1-69.5) 1.25 (0.99-1.57) 1.15 (0.91-1.44) Medium 136,394 84 61.6 (49.7-76.3) 1.32 (1.07-1.64)* 1.20 (0.97-1.49) High 123,523 91 73.7 (60.0-90.5) 1.47 (1.20-1.80)* 1.35 (1.10-1.66)* Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.02)* 5.2.2. Glyburide Never 51,418,210 13,806 26.9 (26.4-27.3) 1.00 1.00 Ever use 670,434 420 57.8 (49.9-66.9) 1.29 (1.12-1.50)* 1.19 (1.03-1.38)* Cumulative duration Low 283,215 153 54.0 (46.1-63.3) 1.23 (1.05-1.44)* 1.16 (0.99-1.36) Medium 224,722 136 60.5 (51.2-71.6) 1.33 (1.12-1.57)* 1.21 (1.02-1.44)* High 162,497 131 80.6 (67.9-95.7) 1.50 (1.27-1.79)* 1.36 (1.15-1.62)* Continuous 1.05 (1.03-1.07)* 1.03 (1.02-1.05)* Cumulative dose Low 296,014 163 55.1 (47.2-64.2) 1.22 (1.04-1.42)* 1.15 (0.98-1.34) Medium 230,574 156 67.7 (57.8-79.2) 1.45 (1.24-1.70)* 1.33 (1.13-1.56)* High 143,846 101 70.2 (57.8-85.3) 1.39 (1.14-1.69)* 1.25 (1.03-1.52)* Continuous 1.02 (1.01-1.04)* 1.02 (1.01-1.03)* 6. Thiazolidinediones Never 51,871,508 14,096 27.2 (26.7-27.6) 1.00 1.00 Ever use 217,136 130 54.0 (39.5-73.9) 1.43 (1.04-1.95)* 1.30 (0.95-1.78) Cumulative duration Low 76,357 26 34.1 (23.2-50.0) 0.81 (0.55-1.19) 0.75 (0.51-1.11) Medium 72,351 42 58.1 (42.9-78.6) 1.36 (1.01-1.84)* 1.25 (0.92-1.69) High 68,428 62 90.6 (70.6-116.2) 1.91 (1.49-2.45)* 1.71 (1.33-2.19)* Continuous 1.10 (1.06-1.14)* 1.08 (1.04-1.12)* Cumulative dose Low 75,982 26 34.2 (23.3-50.3) 0.81 (0.55-1.19) 0.75 (0.51-1.11) Medium 74,257 44 59.3 (44.1-79.6) 1.38 (1.03-1.86)* 1.27 (0.95-1.71) High 66,897 60 89.7 (69.6-115.5) 1.91 (1.48-2.46)* 1.70 (1.32-2.19)* Continuous 1.09 (1.05-1.13)* 1.07 (1.03-1.11)* 6.2. Rosiglitazone Never 51,946,176 14,138 27.2 (26.8-27.7) 1.00 1.00 Ever use 142,468 88 34.4 (20.0-59.3) 0.97 (0.56-1.66) 0.89 (0.52-1.54) Cumulative duration Low 49,170 25 50.8 (34.4-75.2) 1.19 (0.81-1.77) 1.11 (0.75-1.64) Medium 48,028 23 47.9 (31.8-72.1) 1.12 (0.75-1.69) 1.03 (0.69-1.56) High 45,270 40 88.4 (64.8-120.5) 1.91 (1.40-2.61)* 1.71 (1.26-2.34)* Continuous 1.11 (1.05-1.18)* 1.09 (1.03-1.16)* Cumulative dose Low 49,567 24 48.4 (32.5-72.2) 1.14 (0.76-1.70) 1.06 (0.71-1.58) Medium 49,349 27 54.7 (37.5-79.8) 1.27 (0.87-1.85) 1.17 (0.80-1.71) High 43,552 37 85.0 (61.6-117.3) 1.85 (1.34-2.56)* 1.65 (1.20-2.28)* Continuous 1.10 (1.04-1.16)* 1.08 (1.02-1.14)* 7. Insulins and analogues Never 51,772,245 14,071 27.2 (26.7-27.6) 1.00 1.00 Ever use 316,399 155 53.3 (44.6-63.6) 1.27 (1.06-1.52)* 1.13 (0.95-1.36) Cumulative duration Low 143,015 43 30.1 (22.3-40.5) 0.90 (0.67-1.22) 0.82 (0.61-1.11) Medium 113,499 70 61.7 (48.8-78.0) 1.43 (1.13-1.81)* 1.28 (1.01-1.62)* High 59,885 42 70.1 (51.8-94.9) 1.49 (1.10-2.01)* 1.36 (1.00-1.83)* Continuous 1.05 (1.01-1.09)* 1.03 (1.00-1.07) Cumulative dose Low 146,186 45 30.8 (23.0-41.2) 0.91 (0.68-1.21) 0.83 (0.62-1.11) Medium 108,141 66 61.0 (47.9-77.7) 1.42 (1.11-1.80)* 1.27 (1.00-1.62) High 62,072 44 70.9 (52.8-95.3) 1.55 (1.16-2.09)* 1.39 (1.03-1.87)* Continuous 1.02 (1.01-1.04)* 1.02 (1.00-1.03) 7.1. Basal insulins Never 51,784,863 14,074 27.2 (26.7-27.6) 1.00 1.00 Ever use 303,781 152 53.0 (44.2-63.6) 1.27 (1.05-1.52)* 1.13 (0.94-1.36) Cumulative duration Low 135,289 44 32.5 (24.2-43.7) 0.98 (0.73-1.31) 0.89 (0.66-1.19) Medium 109,417 71 64.9 (51.4-81.9) 1.52 (1.20-1.92)* 1.35 (1.07-1.71)* High 59,075 37 62.6 (45.4-86.4) 1.32 (0.95-1.82) 1.20 (0.87-1.65) Continuous 1.05 (1.01-1.10)* 1.03 (0.99-1.08) 130 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 136,909 43 31.4 (23.3-42.3) 0.92 (0.69-1.25) 0.85 (0.63-1.14) Medium 106,571 67 62.9 (49.5-79.9) 1.46 (1.15-1.86)* 1.31 (1.03-1.67)* High 60,301 42 69.7 (51.5-94.2) 1.52 (1.12-2.05)* 1.36 (1.00-1.84)* Continuous 1.02 (1.00-1.04)* 1.02 (0.99-1.04) Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. This table summarized the associations between select diabetes medications and rectal cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table C-8. * denotes p<0.05. 6.5 Discussion 6.5.1 Key findings Metformin and insulin secretagogues, particularly gliclazide and glyburide, were associated with greater colorectal cancer risks, even after adjusting for other diabetes medications, additional sociodemographic and lifestyle factors, and the potential confounding by diabetes. These positive associations were consistently observed across all anatomic location subtypes, including proximal and distal colon cancer and rectal cancer. 6.5.2 Comparison with other studies Contrary to previous studies that reported inverse association for metformin 239, our study persistently observed an increased colorectal cancer risk across all location subtypes, even after adjusting for other diabetes medications. Bradley et al.’s cohort study found long-term metformin use to be linked to lower colorectal cancer risk in men with diabetes, adjusting for demographic, lifestyle, and health-related variables 239. However, other research, such as Bodmer et al.’s nested case-control study, aligns with our findings, indicating a significant increase in colorectal cancer risk with substantial metformin use in people with diabetes 241. The difference 131 between our results and previous studies might be due to differences in demographics, study design, methodology or confounder adjustment. This study observed a significant association between insulin secretagogues and increased colorectal cancer risk. While Bodmer et al. found no significant link in sulfonylureas 241, our findings are consistent with Lee et al.’s 242 and Shin et al.’s studies 243; both reported significant increases in colorectal cancer risk with sulfonylurea use. However, Shin et al. observed a potential, albeit non-significant, decrease in colorectal cancer risk with gliclazide use 243. The number of studies examining glyburide is limited, with the exception of a study by Tuccori et al. study 244. However, Tuccori et al.’s study compared glyburide to other second-generation sulfonylureas, making it inapplicable to compare their findings with those of the current research directly. 6.5.3 Strengths and limitations Our study has multiple strengths. It leveraged administrative health data, mitigating biases common in self-reported medication and cancer data. The study benefited from a large cohort of individuals aged 35 or older who were followed for up to 24 years, allowing for the examination of various links between diabetes medications and colorectal cancer. Exposures of interest were evaluated in a time-varying fashion, minimizing the risk of immortal time bias 237. Prevalent user bias was attenuated by implementing a washout period 221. We included a lag period to mitigate potential protopathic 213 and detection biases 236. Finally, the use of various exposure 132 parameterizations improves the comprehensiveness of our understanding of the associations between diabetes medications and colorectal cancer risk. We acknowledge several limitations in this study. The inability of prescription data to explicitly assess medication adherence could result in misclassification bias in exposure 238. Nevertheless, the bias is likely non-differential and thus expected to attenuate, not bias, the effect estimates. The selectivity of the cohort and the application of specific exclusion criteria might limit the generalizability of the findings to the broader population in BC. Shifts in diabetes and cancer screening practices during the study period might impact the exposure to diabetes medication and cancer detection rates, respectively. 6.6 Conclusion The study examined the relationships between numerous diabetes medications, spanning frequently to less commonly prescribed medications, and the incidence of colorectal cancer. While many medications appeared to show no associations, significant positive relationships were observed with metformin, insulin secretagogue subclass, gliclazide, and glyburide. The study also revealed several associations specific to medication subclasses or individual medications, highlighting the need for future studies to study medications granularly, rather than as a collective. The findings suggest that there may be potential long-term health risks of certain diabetes medications which could warrant consideration with respect to prescribing practices, particularly for populations at high risk of colorectal cancer. Further research in populations with different demographics are needed to validate findings. 133 Chapter 7: Diabetes medications and risk of pancreatic cancer: a population-based cohort study 7.1 Chapter overview Purpose: There is limited evidence on the relationship between diabetes medications and pancreatic cancer despite evidence diabetes may increase the risk of pancreatic cancer. This study aimed to examine associations between different classes, subclasses, individual diabetes medications and pancreatic cancer risk. Methods: In a cohort of British Columbians aged ≥35 (1996-2019), prescriptions for diabetes medications were categorized by ever/never use, duration, and cumulative dose. Adjusting for demographic factors, time-varying Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between new diabetes medication use (1-year lag) and pancreatic cancer incidence. For a subset of the British Columbia Generations Project (BCGP), additional factors were adjusted. The influence of confounding by indication was evaluated using active comparator analysis. Results: The cohort comprised 3,118,538 people (52,088,644 person-years), 7,540 of whom were diagnosed with pancreatic cancer. Insulin secretagogue class, and glyburide in the sulfonylurea subclass, were associated with 2% risk increases (HR=1.02, 95%CI=1.02-1.03) for each 1-year increase in dose. For every 1-year increase in dose, insulins and both basal bolus insulins, were linked to a 4% higher risk (HR=1.04, 95%CI=1.03-1.05). All of the associations except 134 glyburide were consistent after adjusting for additional sociodemographic and lifestyle factors in the BCGP subset. Although not significant, basal insulins (HR=1.49, 95%CI=0.33-6.63) showed a higher risk compared to pioglitazone in the active comparator analysis. Conclusion: Basal insulins may be associated with higher pancreatic cancer risk, suggesting the need for confirmatory studies, particularly given the dearth of known risk factors for pancreatic cancer. 7.2 Introduction In 2021, 10.1% and 17.6% of Canadians aged 50-64 and 65 and older had been diagnosed with diabetes 245. In Canada, diabetes is the seventh leading cause of death 14 and is linked to various health conditions, including cardiovascular disease, and complications such as kidney failure, and blindness 15. There is also some evidence that people with diabetes may have a higher risk of pancreatic cancer 163. Previous studies examining the relationship between various diabetes medications and pancreatic cancer risk have shown inconclusive results, with some studies reporting associations between insulin, sulfonylureas, and higher risks of pancreatic cancer 246. In contrast, incretin-based medicines show no such links compared to sulfonylureas 247. A complete understanding of the relationships between various diabetes medications and pancreatic cancer risk is limited by methodological limitations within the existing literature. These limitations range from confounding by indication to inconsistent adjustment of confounders and a lack of consideration 135 for cancer latency. Moreover, the existing literature has yet to fully explore whether the associations identified were specific to a medication class, subclass, or individual medications. Therefore, additional research is required to elucidate the associations between various classes, subclasses, individual diabetes medications and pancreatic cancer risk. In the present study, we investigated the associations between new diabetes medication use and pancreatic cancer incidence in a large cohort from British Columbia (BC). 7.3 Methods 7.3.1 Data sources This research used databases on longitudinal individual-level data of BC residents housed within Population Data BC (PopData). Demographics, prescription medications, cancer diagnoses, and mortality records were linked through Personal Health Numbers 200. Additional linkage with a subset of the British Columbia Generations Project (BCGP), involving approximately 30,000 BC residents, was conducted to supplement information on additional sociodemographic and lifestyle factors 205. 7.3.2 Study populations The study cohort comprised BC residents aged 35-100 who were registered with Medical Services Plan (MSP) between 1996-2019, with exclusion criteria: pre-existing cancer diagnosis (except non-melanoma skin cancer), short MSP registry history, and fewer than five years of follow-up data, the prevalent use of diabetes 221, and people who started a new diabetes 136 medication within one year before the endpoint 207. Prescription data was sourced from PharmaNet beginning in 1996, and the latest cancer outcome data were obtained from the BC Cancer Registry up until the end of 2019. Participants were followed from cohort entry until the occurrence of any cancer (excluding non-melanoma skin cancer), death, loss to follow-up, or until December 31, 2019, whichever occurred first. 7.3.3 Exposure assessment Exposures of interest included seven distinct medication classes, six subclasses, and seven individual medications; each was parameterized through five methods 229: ever/never, continuous cumulative duration and dose, and categorized cumulative duration and dose. The cumulative duration was calculated by converting the total days of medication supplied into years, while the cumulative dose was computed using the World Health Organization’s defined daily dose to standardize varying medication potencies 211. This approach allowed for the analysis of real-world scenarios, including concurrent exposure to multiple medications and medication transitions during the follow-up period. 7.3.4 Outcome assessment According to ICD-O-3 (International Classification of Diseases in Oncology, Third Edition), incident pancreatic cancer (site code: C250-C259; morphology code: exclude 9050-9055, 9140, 9590-9992) and adenocarcinoma histology subtype (site code: C250-C253, C257-C259; morphology code: exclude 9050-9055, 9140, 9590-9992, 8150, 8151, 8153, 8155, 8240, and 137 8246) 223 were determined in the source population through the BC Cancer Registry, which captures about 95% of cancer cases in BC 203. 7.3.5 Potential confounders Models accounted for confounders selected based on previous literature, considering basic demographic and geographic variables such as age, birth cohort, sex at birth, neighbourhood income quintile, and health authority. 7.3.6 Statistical analysis Crude incidence rates of pancreatic cancer and corresponding 95% confidence intervals (CIs) were estimated for each categorical exposure parameterization (ever/never, categorized cumulative duration and dose) based on the Poisson distribution. Missing data in covariates were addressed using predictive mean matching for single imputation 212, incorporating birth year, sex at birth, exposure to diabetes medications, and incident cancer diagnosis as auxiliary variables in the imputation model. 7.3.6.1 Primary analysis Time-varying Cox proportional hazards models were used with age as the underlying time axis facilitated the estimation of hazard ratios (HRs) and 95% CIs for pancreatic cancer. Each diabetes medication was treated as a time-dependent variable. Separate models were developed for each exposure parameterization, incorporating 1-year washout 221 and lag periods 207 to exclude prevalent users and address cancer latency, respectively. Two sets of models were 138 developed using SAS (version 9.4; SAS Institute, Inc., Cary, NC): crudely adjusted for age alone and fully adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Statistical significance was identified by a two-sided P value less than 0.05. 7.3.6.2 Sensitivity analyses 7.3.6.2.1 Additional adjustment for other diabetes medications When symptomatic hyperglycemia occurs or metformin fails to achieve glycemic targets or is present, a second-line medication is introduced based on the patient’s health status and other factors 74. Recognizing the implications of concurrent medication use on an individual’s health and diabetes severity, the models were adjusted to reflect the time-varying use of other diabetes medications during follow-up 214. 7.3.6.2.2 Washout and lag periods The effect of the pre-determined medication washout period and lag time span was assessed by iterating the primary analysis with 0-year and 2-year washout and lag periods. 7.3.6.2.3 BCGP analysis The subset of participants in the BCGP, which included self-reported sociodemographic and lifestyle data, was examined to determine the effect of additional adjustment on significant associations identified in the primary analysis 120,132,134,214–219. 139 7.3.6.2.4 Active comparator analysis To address confounding by indication 220, an active comparator new-user analysis 221 was performed, focusing on diabetes medications with significant associations in the primary and sensitivity analyses. Pioglitazone served as an active comparator because of its null association with pancreatic cancer risk. The analysis involved individuals starting monotherapy with one of the identified medications. Exposure was recorded as a dichotomous variable. Follow-up was further censored for termination of initial medication or transition to another identified medication, in addition to the endpoints detailed in the primary analysis, thereby minimizing exposure misclassification. 7.3.6.3 Pancreatic cancer subtype analysis An analysis was conducted on the relationship between diabetes medications and morphological subtypes of pancreatic cancer, focusing on pancreatic adenocarcinoma 223. 7.4 Results For pancreatic cancer, the cohort consisted of 3,118,538 people followed for a mean of 16.7 (SD = 6.7) years, totaling 52,088,644 person-years of follow-up, see Figure 5-1. During the study period, 7,540 cases of pancreatic cancer were diagnosed, resulting in a crude incidence rate of 14.5 (95%CI=14.2-14.8) per 100,000 person-years. The median between cohort entry and incident diagnosis of pancreatic cancer among cases was 15 years (IQR: 10-20 years). Table 7-1 summarizes the distribution of baseline demographics and use of diabetes medications stratified by pancreatic case status. People in the cohort who did not develop pancreatic cancer were 140 younger than pancreatic cancer cases at cohort entry. At a prescription rate of 0.1%, AGIs was the least prescribed diabetes medication at the class level, while biguanides (6.6%) and incretin-based medicines (1.2%) were the most prescribed. Table 7-1. Baseline characteristics at cohort entry of the overall cohort and stratified by incident pancreatic cancer case status at cohort entry Total Cases Non-cases Characteristic N = 3,118,538, n (%) N = 7,540, n (%) N = 3,110,998, n (%) Age (years)a 35-39 1,411,812 (45.3) 716 (9.5) 1,411,096 (45.4) 40-44 389,893 (12.5) 579 (7.7) 389,314 (12.5) 45-49 331,161 (10.6) 875 (11.6) 330,286 (10.6) 50-54 247,063 (7.9) 947 (12.6) 246,116 (7.9) 55-59 192,779 (6.2) 915 (12.1) 191,864 (6.2) 60-64 160,924 (5.2) 913 (12.1) 160,011 (5.1) 65-69 136,083 (4.4) 1,008 (13.4) 135,075 (4.3) 70-100 248,823 (8.0) 1,587 (21.0) 247,236 (7.9) Mean±SD 46.2±13.2 58.0±13.0 46.2±13.2 Calendar yeara 1996 1,604,354 (51.4) 6,591 (87.4) 1,597,763 (51.4) 1997-1999 273,249 (8.8) 354 (4.7) 272,895 (8.8) 2000-2002 235,319 (7.5) 194 (2.6) 235,125 (7.6) 2003-2005 243,377 (7.8) 181 (2.4) 243,196 (7.8) 2006-2008 240,857 (7.7) 123 (1.6) 240,734 (7.7) 2009-2011 223,425 (7.2) 59 (0.8) 223,366 (7.2) 2012-2015 297,957 (9.6) 38 (0.5) 297,919 (9.6) Birth cohortb 1896-1940 617,377 (19.8) 4,093 (54.3) 613,284 (19.7) 1941-1950 506,643 (16.2) 1,911 (25.3) 504,732 (16.2) 1951-1957 487,886 (15.6) 858 (11.4) 487,028 (15.7) 1958-1964 543,217 (17.4) 491 (6.5) 542,726 (17.4) 1965-1980 963,415 (30.9) 187 (2.5) 963,228 (31.0) Sexb Female 1,599,418 (51.3) 3,874 (51.4) 1,595,544 (51.3) Male 1,519,120 (48.7) 3,666 (48.6) 1,515,454 (48.7) Health authoritya Interior 494,698 (15.9) 1,353 (17.9) 493,345 (15.9) Fraser 991,476 (31.8) 2,274 (30.2) 989,202 (31.8) Vancouver Coastal 853,983 (27.4) 1,874 (24.9) 852,109 (27.4) Vancouver Island 511,764 (16.4) 1,474 (19.5) 510,290 (16.4) Northern 189,820 (6.1) 480 (6.4) 189,340 (6.1) Missing 76,797 (2.5) 85 (1.1) 76,712 (2.5) Neighbourhood income quintilea Quintile 1 632,793 (20.3) 1,493 (19.8) 631,300 (20.3) Quintile 2 606,382 (19.4) 1,471 (19.5) 604,911 (19.4) Quintile 3 591,755 (19.0) 1,384 (18.4) 590,371 (19.0) Quintile 4 587,599 (18.8) 1,438 (19.1) 586,161 (18.8) Quintile 5 571,889 (18.3) 1,545 (20.5) 570,344 (18.3) Missing 128,120 (4.1) 209 (2.8) 127,911 (4.1) Diabetes medicationc 1. Biguanides (i.e., metformin) Non-users 2,913,581 (93.4) 6,828 (90.6) 2,906,753 (93.4) Users 204,957 (6.6) 712 (9.4) 204,245 (6.6) 2. Incretin-based medicines Non-users 3,079,804 (98.8) 7,452 (98.8) 3,072,352 (98.8) Users 38,734 (1.2) 88 (1.2) 38,646 (1.2) 2.1. DPP-4 inhibitors 141 Total Cases Non-cases Characteristic N = 3,118,538, n (%) N = 7,540, n (%) N = 3,110,998, n (%) Non-users 3,088,342 (99.0) 7,467 (99.0) 3,080,875 (99.0) Users 30,196 (1.0) 73 (1.0) 30,123 (1.0) 2.1.1. Linagliptin Non-users 3,103,627 (99.5) 7,515 (99.7) 3,096,112 (99.5) Users 14,911 (0.5) 25 (0.3) 14,886 (0.5) 2.1.2. Sitagliptin Non-users 3,100,549 (99.4) 7,491 (99.4) 3,093,058 (99.4) Users 17,989 (0.6) 49 (0.6) 17,940 (0.6) 2.2. GLP-1 receptor agonists Non-users 3,104,469 (99.5) 7,522 (99.8) 3,096,947 (99.5) Users 14,069 (0.5) 18 (0.2) 14,051 (0.5) 3. SGLT-2 inhibitors Non-users 3,097,235 (99.3) 7,507 (99.6) 3,089,728 (99.3) Users 21,303 (0.7) 33 (0.4) 21,270 (0.7) 4. AGIs (i.e., acarbose) Non-users 3,114,407 (99.9) 7,519 (99.7) 3,106,888 (99.9) Users 4,131 (0.1) 21 (0.3) 4,110 (0.1) 5. Insulin secretagogues Non-users 3,027,943 (97.1) 7,161 (95.0) 3,020,782 (97.1) Users 90,595 (2.9) 379 (5.0) 90,216 (2.9) 5.1. Meglitinides Non-users 3,114,915 (99.9) 7,518 (99.7) 3,107,397 (99.9) Users 3,623 (0.1) 22 (0.3) 3,601 (0.1) 5.1.1. Repaglinide Non-users 3,114,965 (99.9) 7,518 (99.7) 3,107,447 (99.9) Users 3,573 (0.1) 22 (0.3) 3,551 (0.1) 5.2. Sulfonylureas Non-users 3,028,815 (97.1) 7,165 (95.0) 3,021,650 (97.1) Users 89,723 (2.9) 375 (5.0) 89,348 (2.9) 5.2.1. Gliclazide Non-users 3,066,066 (98.3) 7,365 (97.7) 3,058,701 (98.3) Users 52,472 (1.7) 175 (2.3) 52,297 (1.7) 5.2.2. Glyburide Non-users 3,057,803 (98.1) 7,250 (96.2) 3,050,553 (98.1) Users 60,735 (1.9) 290 (3.8) 60,445 (1.9) 6. Thiazolidinediones Non-users 3,100,990 (99.4) 7,448 (98.8) 3,093,542 (99.4) Users 17,548 (0.6) 92 (1.2) 17,456 (0.6) 6.1. Pioglitazone Non-users 3,109,560 (99.7) 7,503 (99.5) 3,102,057 (99.7) Users 8,978 (0.3) 37 (0.5) 8,941 (0.3) 6.2. Rosiglitazone Non-users 3,107,467 (99.6) 7,478 (99.2) 3,099,989 (99.6) Users 11,071 (0.4) 62 (0.8) 11,009 (0.4) 7. Insulins and analogues Non-users 3,079,862 (98.8) 7,342 (97.4) 3,072,520 (98.8) Users 38,676 (1.2) 198 (2.6) 38,478 (1.2) 7.1. Basal insulins Non-users 3,081,238 (98.8) 7,350 (97.5) 3,073,888 (98.8) Users 37,300 (1.2) 190 (2.5) 37,110 (1.2) 7.2. Bolus insulins Non-users 3,100,018 (99.4) 7,435 (98.6) 3,092,583 (99.4) Users 18,520 (0.6) 105 (1.4) 18,415 (0.6) a: Measured at study entry. b: Measured at birth. c: Measured during follow-up. SD: Standard deviation. AGIs: Alpha-glucosidase inhibitors. DPP-4 inhibitors: Dipeptidyl peptidase 4 inhibitors. GLP-1 receptor agonists: Glucagon-like peptide 1 receptor agonists. SGLT-2 inhibitors: Sodium-glucose cotransporter 2 inhibitors. 142 7.4.1 Findings from the primary analysis Supplementary Table D-1 summarizes the findings from the primary analysis for each diabetes medication class, subclass, and individual medication, regardless of statistical significance. Model 1 adjusts for age, while Model 2 further adjusts for sex at birth, birth cohort, health authority, and neighbourhood income quintile. Table 7-2 presents the medications with statistically significant results for Model 2. Table 7-2. Associations between select diabetes medications and the risk of pancreatic cancer Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 6,828 13.6 (13.3-14.0) 1.00 1.00 Ever use 2,021,426 712 33.8 (31.0-36.8) 1.38 (1.26-1.51)* 1.29 (1.18-1.41)* Cumulative duration Low 736,609 188 25.5 (22.1-29.4) 1.22 (1.06-1.41)* 1.17 (1.02-1.36)* Medium 720,912 284 39.4 (35.1-44.3) 1.63 (1.45-1.84)* 1.54 (1.36-1.73)* High 563,905 240 42.6 (37.5-48.3) 1.36 (1.20-1.55)* 1.24 (1.09-1.41)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.04)* Cumulative dose Low 761,186 195 25.6 (22.3-29.5) 1.16 (1.00-1.33)* 1.11 (0.97-1.28) Medium 720,432 268 37.2 (33.0-41.9) 1.48 (1.31-1.68)* 1.40 (1.24-1.58)* High 539,808 249 46.1 (40.7-52.2) 1.61 (1.42-1.82)* 1.45 (1.28-1.65)* Continuous 1.06 (1.04-1.07)* 1.04 (1.03-1.06)* 2. Incretin-based medicines Never 51,846,234 7,452 14.4 (14.1-14.7) 1.00 1.00 Ever use 242,410 88 26.4 (19.7-35.4) 1.24 (0.92-1.66) 1.08 (0.81-1.45) Cumulative duration Low 76,647 30 39.1 (27.4-56.0) 2.00 (1.40-2.86)* 1.77 (1.24-2.54)* Medium 82,123 20 24.4 (15.7-37.7) 1.18 (0.76-1.84) 1.04 (0.67-1.61) High 83,640 38 45.4 (33.1-62.4) 1.83 (1.33-2.52)* 1.58 (1.15-2.18)* Continuous 1.12 (1.05-1.19)* 1.08 (1.02-1.15)* Cumulative dose Low 79,230 34 42.9 (30.7-60.1) 2.36 (1.69-3.30)* 2.07 (1.48-2.90)* Medium 80,356 20 24.9 (16.1-38.6) 1.17 (0.75-1.81) 1.03 (0.66-1.59) High 82,824 34 41.1 (29.3-57.5) 1.62 (1.15-2.26)* 1.40 (1.00-1.96) Continuous 1.13 (1.05-1.20)* 1.09 (1.02-1.17)* 2.1. DPP-4 inhibitors Never 51,896,422 7,467 14.4 (14.1-14.7) 1.00 1.00 Ever use 192,222 73 30.1 (22.0-41.2) 1.29 (0.94-1.76) 1.13 (0.82-1.55) Cumulative duration Low 63,002 25 39.7 (26.8-58.7) 1.80 (1.22-2.67)* 1.60 (1.08-2.37)* Medium 63,244 18 28.5 (17.9-45.2) 1.27 (0.80-2.02) 1.11 (0.70-1.77) High 65,976 30 45.5 (31.8-65.0) 1.73 (1.21-2.47)* 1.50 (1.04-2.14)* Continuous 1.12 (1.05-1.20)* 1.09 (1.02-1.17)* Cumulative dose Low 64,188 25 38.9 (26.3-57.6) 1.76 (1.19-2.61)* 1.56 (1.05-2.31)* Medium 61,937 16 25.8 (15.8-42.2) 1.15 (0.71-1.88) 1.01 (0.62-1.65) High 66,097 32 48.4 (34.2-68.5) 1.85 (1.31-2.62)* 1.60 (1.13-2.27)* Continuous 1.13 (1.05-1.20)* 1.09 (1.02-1.17)* 2.1.2. Sitagliptin Never 51,955,454 7,491 14.4 (14.1-14.7) 1.00 1.00 Ever use 133,190 49 25.9 (16.1-41.6) 1.25 (0.78-2.02) 1.11 (0.69-1.78) 143 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative duration Low 42,249 14 33.1 (19.6-56.0) 1.51 (0.89-2.54) 1.34 (0.79-2.26) Medium 47,499 11 23.2 (12.8-41.8) 1.06 (0.59-1.92) 0.93 (0.52-1.69) High 43,442 24 55.2 (37.0-82.4) 2.21 (1.48-3.30)* 1.91 (1.28-2.85)* Continuous 1.17 (1.07-1.26)* 1.13 (1.04-1.23)* Cumulative dose Low 43,259 14 32.4 (19.2-54.6) 1.46 (0.87-2.47) 1.30 (0.77-2.20) Medium 45,625 10 21.9 (11.8-40.7) 1.00 (0.54-1.87) 0.88 (0.47-1.64) High 44,306 25 56.4 (38.1-83.5) 2.29 (1.55-3.38)* 1.97 (1.33-2.92)* Continuous 1.17 (1.08-1.27)* 1.13 (1.04-1.23)* 5. Insulin secretagogues Never 51,176,005 7,161 14.0 (13.7-14.3) 1.00 1.00 Ever use 912,639 379 38.3 (33.6-43.8) 1.51 (1.32-1.73)* 1.43 (1.25-1.64)* Cumulative duration Low 360,923 116 32.1 (26.8-38.6) 1.37 (1.14-1.64)* 1.32 (1.10-1.59)* Medium 315,845 139 44.0 (37.3-52.0) 1.74 (1.47-2.06)* 1.64 (1.39-1.94)* High 235,871 124 52.6 (44.1-62.7) 1.64 (1.37-1.96)* 1.51 (1.26-1.80)* Continuous 1.06 (1.05-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 372,575 126 33.8 (28.4-40.3) 1.36 (1.14-1.62)* 1.32 (1.11-1.58)* Medium 314,231 127 40.4 (34.0-48.1) 1.55 (1.30-1.84)* 1.45 (1.22-1.73)* High 225,833 126 55.8 (46.9-66.4) 1.92 (1.61-2.29)* 1.74 (1.46-2.08)* Continuous 1.03 (1.02-1.04)* 1.02 (1.02-1.03)* 5.2. Sulfonylureas Never 51,188,413 7,165 14.0 (13.7-14.3) 1.00 1.00 Ever use 900,231 375 38.3 (33.5-43.8) 1.51 (1.32-1.73)* 1.43 (1.25-1.64)* Cumulative duration Low 359,009 119 33.1 (27.7-39.7) 1.41 (1.17-1.68)* 1.36 (1.13-1.63)* Medium 309,407 133 43.0 (36.3-50.9) 1.70 (1.43-2.02)* 1.60 (1.35-1.90)* High 231,815 123 53.1 (44.5-63.3) 1.65 (1.38-1.97)* 1.52 (1.27-1.82)* Continuous 1.06 (1.05-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 367,838 127 34.5 (29.0-41.1) 1.39 (1.16-1.65)* 1.35 (1.13-1.61)* Medium 309,412 125 40.4 (33.9-48.1) 1.55 (1.29-1.84)* 1.45 (1.22-1.73)* High 222,981 123 55.2 (46.2-65.8) 1.89 (1.58-2.26)* 1.72 (1.44-2.06)* Continuous 1.03 (1.02-1.03)* 1.02 (1.02-1.03)* 5.2.1. Gliclazide Never 51,695,028 7,365 14.2 (13.9-14.6) 1.00 1.00 Ever use 393,616 175 39.2 (32.3-47.7) 1.48 (1.21-1.80)* 1.35 (1.11-1.64)* Cumulative duration Low 126,908 56 44.1 (34.0-57.3) 1.81 (1.39-2.35)* 1.68 (1.29-2.18)* Medium 136,638 52 38.1 (29.0-49.9) 1.48 (1.13-1.94)* 1.35 (1.03-1.77)* High 130,070 67 51.5 (40.5-65.4) 1.68 (1.32-2.14)* 1.51 (1.19-1.93)* Continuous 1.07 (1.04-1.11)* 1.06 (1.02-1.09)* Cumulative dose Low 133,699 54 40.4 (30.9-52.7) 1.60 (1.23-2.10)* 1.49 (1.14-1.95)* Medium 136,394 58 42.5 (32.9-55.0) 1.60 (1.24-2.07)* 1.46 (1.13-1.89)* High 123,523 63 51.0 (39.8-65.3) 1.75 (1.36-2.24)* 1.57 (1.22-2.01)* Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 5.2.2. Glyburide Never 51,418,210 7,250 14.1 (13.8-14.4) 1.00 1.00 Ever use 670,434 290 37.9 (31.6-45.4) 1.53 (1.28-1.84)* 1.50 (1.25-1.80)* Cumulative duration Low 283,215 91 32.1 (26.2-39.5) 1.29 (1.05-1.59)* 1.25 (1.02-1.54)* Medium 224,722 113 50.3 (41.8-60.5) 1.96 (1.63-2.36)* 1.88 (1.56-2.27)* High 162,497 86 52.9 (42.8-65.4) 1.64 (1.32-2.03)* 1.53 (1.23-1.89)* Continuous 1.07 (1.05-1.09)* 1.06 (1.04-1.08)* Cumulative dose Low 296,014 100 33.8 (27.8-41.1) 1.30 (1.07-1.58)* 1.26 (1.04-1.54)* Medium 230,574 108 46.8 (38.8-56.6) 1.75 (1.45-2.12)* 1.68 (1.39-2.03)* High 143,846 82 57.0 (45.9-70.8) 1.95 (1.57-2.43)* 1.81 (1.45-2.25)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.05)* 6. Thiazolidinediones Never 51,871,508 7,448 14.4 (14.0-14.7) 1.00 1.00 Ever use 217,136 92 18.0 (10.5-31.0) 0.94 (0.55-1.62) 0.94 (0.54-1.62) 144 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative duration Low 76,357 26 34.1 (23.2-50.0) 1.51 (1.03-2.23)* 1.43 (0.97-2.10) Medium 72,351 29 40.1 (27.9-57.7) 1.78 (1.23-2.56)* 1.67 (1.16-2.41)* High 68,428 37 54.1 (39.2-74.6) 2.09 (1.52-2.89)* 1.90 (1.38-2.63)* Continuous 1.12 (1.07-1.17)* 1.10 (1.05-1.15)* Cumulative dose Low 75,982 25 32.9 (22.2-48.7) 1.44 (0.97-2.13) 1.36 (0.92-2.02) Medium 74,257 36 48.5 (35.0-67.2) 2.13 (1.53-2.95)* 2.00 (1.44-2.78)* High 66,897 31 46.3 (32.6-65.9) 1.83 (1.29-2.61)* 1.66 (1.17-2.37)* Continuous 1.11 (1.06-1.16)* 1.09 (1.04-1.14)* 6.2. Rosiglitazone Never 51,946,176 7,478 14.4 (14.1-14.7) 1.00 1.00 Ever use 142,468 62 18.5 (8.8-38.9) 1.06 (0.50-2.22) 1.08 (0.52-2.27) Cumulative duration Low 49,170 17 34.6 (21.5-55.6) 1.51 (0.94-2.43) 1.43 (0.89-2.30) Medium 48,028 21 43.7 (28.5-67.1) 1.93 (1.26-2.96)* 1.81 (1.18-2.78)* High 45,270 24 53.0 (35.5-79.1) 2.14 (1.44-3.20)* 1.96 (1.31-2.92)* Continuous 1.15 (1.08-1.23)* 1.13 (1.06-1.21)* Cumulative dose Low 49,567 17 34.3 (21.3-55.2) 1.50 (0.93-2.41) 1.41 (0.88-2.27) Medium 49,349 23 46.6 (31.0-70.1) 2.03 (1.35-3.06)* 1.91 (1.27-2.88)* High 43,552 22 50.5 (33.3-76.7) 2.06 (1.36-3.13)* 1.88 (1.24-2.86)* Continuous 1.15 (1.08-1.22)* 1.13 (1.06-1.20)* 7. Insulins and analogues Never 51,772,245 7,342 14.2 (13.9-14.5) 1.00 1.00 Ever use 316,399 198 70.2 (60.1-81.8) 3.17 (2.71-3.70)* 2.84 (2.43-3.32)* Cumulative duration Low 143,015 71 49.6 (39.3-62.6) 2.87 (2.27-3.63)* 2.66 (2.11-3.36)* Medium 113,499 89 78.4 (63.7-96.5) 3.41 (2.77-4.21)* 3.06 (2.48-3.78)* High 59,885 38 63.5 (46.2-87.2) 2.51 (1.83-3.45)* 2.18 (1.58-3.00)* Continuous 1.16 (1.13-1.20)* 1.14 (1.11-1.18)* Cumulative dose Low 146,186 75 51.3 (40.9-64.3) 2.87 (2.28-3.60)* 2.65 (2.11-3.33)* Medium 108,141 88 81.4 (66.0-100.3) 3.53 (2.87-4.36)* 3.18 (2.57-3.92)* High 62,072 35 56.4 (40.5-78.5) 2.35 (1.69-3.28)* 2.04 (1.46-2.85)* Continuous 1.05 (1.04-1.06)* 1.04 (1.03-1.05)* 7.1. Basal insulins Never 51,784,863 7,350 14.2 (13.9-14.5) 1.00 1.00 Ever use 303,781 190 71.4 (61.0-83.6) 3.24 (2.77-3.80)* 2.91 (2.48-3.41)* Cumulative duration Low 135,289 67 49.5 (39.0-62.9) 2.87 (2.26-3.65)* 2.66 (2.09-3.38)* Medium 109,417 83 75.9 (61.2-94.1) 3.33 (2.68-4.13)* 2.98 (2.40-3.71)* High 59,075 40 67.7 (49.7-92.3) 2.66 (1.95-3.63)* 2.31 (1.69-3.16)* Continuous 1.18 (1.14-1.23)* 1.16 (1.12-1.20)* Cumulative dose Low 136,909 71 51.9 (41.1-65.4) 2.92 (2.31-3.69)* 2.69 (2.13-3.40)* Medium 106,571 82 76.9 (62.0-95.5) 3.36 (2.70-4.17)* 3.01 (2.42-3.75)* High 60,301 37 61.4 (44.5-84.7) 2.54 (1.84-3.51)* 2.21 (1.60-3.05)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* 7.2. Bolus insulins Never 51,947,122 7,435 14.3 (14.0-14.6) 1.00 1.00 Ever use 141,522 105 86.6 (68.9-108.9) 4.47 (3.55-5.62)* 3.97 (3.15-5.01)* Cumulative duration Low 68,567 53 77.3 (59.1-101.2) 4.82 (3.68-6.31)* 4.44 (3.39-5.82)* Medium 48,161 31 64.4 (45.3-91.5) 3.25 (2.29-4.63)* 2.89 (2.03-4.11)* High 24,794 21 84.7 (55.2-129.9) 3.91 (2.55-6.00)* 3.37 (2.19-5.17)* Continuous 1.26 (1.19-1.34)* 1.24 (1.17-1.32)* Cumulative dose Low 71,251 53 74.4 (56.8-97.4) 4.52 (3.45-5.92)* 4.16 (3.17-5.45)* Medium 44,054 29 65.8 (45.7-94.7) 3.31 (2.30-4.76)* 2.94 (2.04-4.24)* High 26,217 23 87.7 (58.3-132.0) 4.25 (2.82-6.40)* 3.64 (2.42-5.49)* Continuous 1.07 (1.04-1.09)* 1.06 (1.04-1.09)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. 145 This table summarized the associations between select diabetes medications and pancreatic cancer. The full results for all diabetes medications assessed can be found in Supplementary Table D-1. * denotes p<0.05. 7.4.1.1 Biguanides (i.e., metformin) – Class Ever use of metformin was significantly associated with a higher risk of pancreatic cancer (HR=1.29, 95%CI=1.18-1.41) compared to never use. Significant relationships with pancreatic cancer risk were present for the continuous cumulative duration (HR=1.03, 95%CI=1.02-1.04) and dose analyses (HR=1.04, 95%CI=1.03-1.06) for metformin. Significant relations were also detected for the categorized cumulative duration and dose analyses for metformin. The low (HR=1.17, 95%CI=1.02-1.36), medium (HR=1.54, 95%CI=1.36-1.73), and high duration categories (HR=1.24, 95%CI=1.09-1.41) of metformin use were associated with 17%, 54%, and 24% higher risks of pancreatic cancer compared to never use. The medium (HR=1.40, 95%CI=1.24-1.58) and high dose categories (HR=1.45, 95%CI=1.28-1.65) were related to 40% and 45% higher risk of pancreatic cancer. 7.4.1.2 Incretin-based medicines – Class Significant relationships with pancreatic cancer risk were detected for the continuous cumulative duration (HR=1.08, 95%CI=1.02-1.15) and dose analyses for incretin-based medicine use (HR=1.09, 95%CI=1.02-1.17). Significant relationships were observed in low duration (HR=1.77, 95%CI=1.24-2.54) and low dose (HR=2.07, 95%CI=1.48-2.90), and high duration categories (HR=1.58, 95%CI=1.15-2.18). 146 7.4.1.3 DPP-4 inhibitors – Subclass Similar relationships with pancreatic cancer risk were found among DPP-4 inhibitors — a subclass of incretin-based medicines. The continuous cumulative duration and dose analyses for DPP-4 inhibitors showed significant associations with pancreatic cancer risk: every 1-year increase in the cumulative duration (HR=1.09, 95%CI=1.02-1.17) or 1-year increase in the cumulative dose (HR=1.09, 95%CI=1.02-1.17) was associated with a 9% increase in pancreatic cancer risk. Significant relationships were observed in the categorized cumulative duration and dose analyses for DPP-4 inhibitor use. Compared to never use of DPP-4 inhibitors, low (HR=1.60, 95%CI=1.08-2.37) and high duration categories (HR=1.50, 95%CI=1.04-2.14) were related to 60% and 50% higher risks of pancreatic cancer, while low (HR=1.56, 95%CI=1.05-2.31) and high dose categories (HR=1.60, 95%CI=1.13-2.27) were associated with 56% and 60% greater risks. 7.4.1.4 Sitagliptin – Individual Risk estimates for sitagliptin, a medication in the DPP-4 inhibitor subclass, resemble those in the incretin-based medicine class and DPP-4 inhibitor subclass. Continuous cumulative duration and dose of sitagliptin demonstrated significant relationships with pancreatic cancer risk: each 1-year increase in the cumulative duration (HR=1.13, 95%CI=1.04-1.23) or cumulative dose (HR=1.13, 95%CI=1.04-1.23) was associated with a 13% increase in pancreatic cancer risk. Significant relationships were observed for the categorized cumulative duration and dose analyses. The high cumulative duration (HR=1.91, 95%CI=1.28-2.85) and dose (HR=1.97, 95%CI=1.33-2.92) were 147 associated with 91% and 97% greater risks of pancreatic cancer relative to never use, suggesting possible duration- and dose-responses. 7.4.1.5 Insulin secretagogues – Class Compared to never use, ever use of insulin secretagogues was significantly associated with an increased risk of pancreatic cancer (HR=1.43, 95%CI=1.25-1.64). Significant associations existed in continuous cumulative duration (HR=1.05, 95%CI=1.04-1.07) and dose analyses (HR=1.02, 95%CI=1.02-1.03) for insulin secretagogues. In addition, significant relationships were observed in the categorized cumulative duration and dose analyses. The low (HR=1.32, 95%CI=1.10-1.59), medium (HR=1.64, 95%CI=1.39-1.94), and high duration categories (HR=1.51, 95%CI=1.26-1.80) of insulin secretagogue use were related to increased pancreatic cancer risks of 32%, 64%, and 51% compared to never use. The low (HR=1.32, 95%CI=1.11-1.58), medium (HR=1.45, 95%CI=1.22-1.73), and high dose categories (HR=1.74, 95%CI=1.46-2.08) were associated with risk increases of 32%, 45%, and 74%, respectively. Results from the categorized dose analysis indicated a dose-response between insulin secretagogues and pancreatic cancer risk. 7.4.1.6 Sulfonylureas – Subclass Sulfonylureas exhibit similar relationships with the risk of pancreatic cancer as insulin secretagogues. Relative to never use, ever use of sulfonylureas was significantly associated with a greater risk of pancreatic cancer (HR=1.43, 95%CI=1.25-1.64). Continuous cumulative duration (HR=1.05, 95%CI=1.04-1.07) and dose analyses for sulfonylurea use (HR=1.02, 148 95%CI=1.02-1.03) demonstrated significant relationships. In comparison to those who never used sulfonylureas, the risks of developing pancreatic cancer were higher by 36%, 60%, and 50% for the low (HR=1.36, 95%CI=1.13-1.63), moderate (HR=1.60, 95%CI=1.35-1.90), and high duration categories (HR=1.52, 95%CI=1.27-1.82), respectively. Risks were 35%, 45%, and 72% higher for low (HR=1.35, 95%CI=1.13-1.61), medium (HR=1.45, 95%CI=1.22-1.73), and high dose categories (HR=1.72, 95%CI=1.44-2.06) of sulfonylureas. There was evidence for a dose-response in pancreatic cancer risk. 7.4.1.7 Gliclazide – Individual Similar associations with pancreatic cancer risk were observed for gliclazide, a member of the sulfonylurea subclass. Ever use of gliclazide was significantly related to a higher risk of developing pancreatic cancer compared to never use (HR=1.35, 95%CI=1.11-1.64). Significant associations were found for the continuous cumulative duration (HR=1.06, 95%CI=1.02-1.09) and dose analyses (HR=1.02, 95%CI=1.01-1.03). With low (HR=1.68, 95%CI=1.29-2.18), medium (HR=1.35, 95%CI=1.03-1.77), and high cumulative duration categories (HR=1.51, 95%CI=1.19-1.93) of gliclazide, pancreatic cancer risks increased by 68%, 35%, and 51% in comparison to never use. The low (HR=1.49, 95%CI=1.14-1.95), medium (HR=1.46, 95%CI=1.13-1.89), and high cumulative dose categories (HR=1.57, 95%CI=1.22-2.01) were related to risk increases of 49%, 46%, and 57%, respectively. 149 7.4.1.8 Glyburide – Individual Glyburide, another medication in the sulfonylurea subclass, had risk of pancreatic cancer comparable to that of the other medications in its subclass and class of insulin secretagogues. Ever use of glyburide was associated with a greater risk of pancreatic cancer than never use (HR=1.50, 95%CI=1.25-1.80). Significant associations with pancreatic cancer risk were found in the continuous cumulative duration (HR=1.06, 95%CI=1.04-1.08) and dose analyses (HR=1.03, 95%CI=1.02-1.05). With low (HR=1.25, 95%CI=1.02-1.54), medium (HR=1.88, 95%CI=1.56-2.27), and high cumulative duration categories (HR=1.53, 95%CI=1.23-1.89), the risks of developing pancreatic cancer increased by 25%, 88%, and 53%, in comparison to never use of glyburide use. The risks increased by 26% with the low dose (HR=1.26, 95%CI=1.04-1.54), 68% with the medium dose (HR=1.68, 95%CI=1.39-2.03), and 81% with the high dose (HR=1.81, 95%CI=1.45-2.25), indicating a dose-response relationship. 7.4.1.9 Thiazolidinediones – Class Use of thiazolidinediones showed significant relationships with pancreatic cancer risk: each 1-year increase in cumulative duration (HR=1.10, 95%CI=1.05-1.15) or cumulative dose (HR=1.09, 95%CI=1.04-1.14) was related to a 10% or 9% increase in pancreatic cancer risk. Significant associations were also detected for the categorized cumulative duration and dose analyses for thiazolidinedione. The risks were higher compared to never use for medium (HR=1.67, 95%CI=1.16-2.41) or high duration category (HR=1.90, 95%CI=1.38-2.63) and medium (HR=2.00, 95%CI=1.44-2.78) or high dose category (HR=1.66, 95%CI=1.17-2.37). These results suggested a duration-response relationship. 150 7.4.1.10 Rosiglitazone – Individual Rosiglitazone’s relationships with pancreatic cancer risk were comparable to those for its medication class, thiazolidinediones. For continuous cumulative duration (HR=1.13, 95%CI=1.06-1.21) and dose analyses (HR=1.13, 95%CI=1.06-1.20) for rosiglitazone use, significant associations were observed with the risk of pancreatic cancer. Significant relations were also found in the categorized cumulative duration and dose analyses for rosiglitazone. The medium duration (HR=1.67, 95%CI=1.16-2.41) or dose category (HR=1.91, 95%CI=1.27-2.88) was linked to an 81% or 91% greater risk of pancreatic cancer, and the high duration (HR=1.96, 95%CI=1.31-2.92) or dose category (HR=1.88, 95%CI=1.24-2.86) was associated with a 96% or 88% higher risk compared to never use. This indicates a duration-response relationship between rosiglitazone and pancreatic cancer risk. 7.4.1.11 Insulins and analogues – Class Ever use of insulins and analogues had a greater risk of pancreatic cancer compared to never use (HR=2.84, 95%CI=2.43-3.32). Continuous cumulative duration (HR=1.14, 95%CI=1.11-1.18) and dose analyses (HR=1.04, 95%CI=1.03-1.05) showed significant associations. Significant relationships were also found in the categorized cumulative duration and dose analyses for insulins and analogues. The use of insulins and analogues for low (HR=2.66, 95%CI=2.11-3.36), medium (HR=3.06, 95%CI=2.48-3.78), and high cumulative duration categories (HR=2.18, 95%CI=1.58-3.00) were related to higher risks of pancreatic cancer. Besides, greater pancreatic cancer risks were observed in low (HR=2.65, 95%CI=2.11-3.33), medium (HR=3.18, 151 95%CI=2.57-3.92), and high dose categories (HR=2.04, 95%CI=1.46-2.85) compared to never use. 7.4.1.12 Basal insulins – Subclass The basal insulin subclass showed similar relationships with pancreatic cancer risk as the insulin and analogues class. When compared to people who never used basal insulins, there was a higher risk of pancreatic cancer in ever users (HR=2.91, 95%CI=2.48-3.41). Significant relationships were found in continuous cumulative duration and dose analyses. Every 1-year increase in cumulative duration (HR=1.16, 95%CI=1.12-1.20) and dose (HR=1.05, 95%CI=1.04-1.06) were associated with greater risk of pancreatic cancer. Greater pancreatic cancer risks were observed in low (HR=2.66, 95%CI=2.09-3.38), medium (HR=2.98, 95%CI=2.40-3.71), and high duration categories of basal insulins (HR=2.31, 95%CI=1.69-3.16) compared to never use. The use of basal insulins for low (HR=2.69, 95%CI=2.13-3.40), medium (HR=3.01, 95%CI=2.42-3.75), and high cumulative duration categories (HR=2.21, 95%CI=1.60-3.05) were related to higher risks of pancreatic cancer. 7.4.1.13 Bolus insulins – Subclass The subclass of bolus insulins had stronger relationships with pancreatic cancer than the basal insulin subclass. Bolus insulin ever users had a greater risk of pancreatic cancer than those who had never used bolus insulins (HR=3.97, 95%CI=3.15-5.01). Continuous cumulative duration and dose revealed significant associations: every 1-year increase in cumulative duration (HR=1.24, 95%CI=1.17-1.32) or dose (HR=1.06, 95%CI=1.04-1.09) was associated with a 24% 152 or 6% increased risk. Significant relations were identified with pancreatic cancer risk. Significant associations were also evident in the categorical analysis of cumulative duration and dose of bolus insulin. Low (HR=4.44, 95%CI=3.39-5.82), medium (HR=2.89, 95%CI=2.03-4.11), and higher duration categories (HR=3.37, 95%CI=2.19-5.17) were associated with higher risks of pancreatic cancer. Moreover, elevated risks of pancreatic cancer were observed in low (HR=4.16, 95%CI=3.17-5.45), medium (HR=2.94, 95%CI=2.04-4.24), and higher dose categories (HR=3.64, 95%CI=2.42-5.49) of bolus insulin. 7.4.2 Findings from sensitivity analyses 7.4.2.1 Additional adjustment for other diabetes medications Risk estimates for which the primary analysis showed statistically significant results were further adjusted for the use of other diabetes medications (Table 7-3). The classes of insulin secretagogues, the sulfonylurea subclass and glyburide, insulins and analogues, including both basal and bolus insulin subclasses, were consistently related to higher risks of pancreatic cancer after adjusting for other diabetes medications. However, relationships between metformin, the class of incretin-based medicines, the subclass of DPP-4 inhibitors, sitagliptin, gliclazide, thiazolidinediones and rosiglitazone, with pancreatic cancer were all attenuated to the null in comparison to significant results in the primary analysis. Supplementary Table D-2 includes all associations, regardless of their level of statistical significance. Table 7-3. Associations between select diabetes medications and the risk of pancreatic cancer with adjustment for other diabetes medications Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 6,828 13.6 (13.3-14.0) 1.00 1.00 Ever use 2,021,426 712 33.8 (31.0-36.8) 1.29 (1.18-1.41)* 1.11 (0.99-1.23) Cumulative duration Low 736,609 188 25.5 (22.1-29.4) 1.17 (1.02-1.36)* 1.05 (0.90-1.22) 153 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 720,912 284 39.4 (35.1-44.3) 1.54 (1.36-1.73)* 1.32 (1.15-1.51)* High 563,905 240 42.6 (37.5-48.3) 1.24 (1.09-1.41)* 0.91 (0.77-1.09) Continuous 1.03 (1.02-1.04)* 1.01 (0.99-1.02) Cumulative dose Low 761,186 195 25.6 (22.3-29.5) 1.11 (0.97-1.28) 1.02 (0.88-1.18) Medium 720,432 268 37.2 (33.0-41.9) 1.40 (1.24-1.58)* 1.24 (1.08-1.42)* High 539,808 249 46.1 (40.7-52.2) 1.45 (1.28-1.65)* 1.08 (0.90-1.29) Continuous 1.04 (1.03-1.06)* 1.02 (1.00-1.04) 2. Incretin-based medicines Never 51,846,234 7,452 14.4 (14.1-14.7) 1.00 1.00 Ever use 242,410 88 26.4 (19.7-35.4) 1.08 (0.81-1.45) 0.67 (0.49-0.91)* Cumulative duration Low 76,647 30 39.1 (27.4-56.0) 1.77 (1.24-2.54)* 1.11 (0.77-1.62) Medium 82,123 20 24.4 (15.7-37.7) 1.04 (0.67-1.61) 0.64 (0.40-1.01) High 83,640 38 45.4 (33.1-62.4) 1.58 (1.15-2.18)* 0.97 (0.67-1.39) Continuous 1.08 (1.02-1.15)* 0.97 (0.90-1.04) Cumulative dose Low 79,230 34 42.9 (30.7-60.1) 2.07 (1.48-2.90)* 1.24 (0.87-1.77) Medium 80,356 20 24.9 (16.1-38.6) 1.03 (0.66-1.59) 0.60 (0.38-0.96)* High 82,824 34 41.1 (29.3-57.5) 1.40 (1.00-1.96) 0.81 (0.55-1.18) Continuous 1.09 (1.02-1.17)* 0.98 (0.91-1.07) 2.1. DPP-4 inhibitors Never 51,896,422 7,467 14.4 (14.1-14.7) 1.00 1.00 Ever use 192,222 73 30.1 (22.0-41.2) 1.13 (0.82-1.55) 0.73 (0.52-1.01) Cumulative duration Low 63,002 25 39.7 (26.8-58.7) 1.60 (1.08-2.37)* 0.99 (0.66-1.49) Medium 63,244 18 28.5 (17.9-45.2) 1.11 (0.70-1.77) 0.69 (0.43-1.12) High 65,976 30 45.5 (31.8-65.0) 1.50 (1.04-2.14)* 0.94 (0.64-1.40) Continuous 1.09 (1.02-1.17)* 0.99 (0.91-1.07) Cumulative dose Low 64,188 25 38.9 (26.3-57.6) 1.56 (1.05-2.31)* 0.95 (0.63-1.43) Medium 61,937 16 25.8 (15.8-42.2) 1.01 (0.62-1.65) 0.62 (0.37-1.02) High 66,097 32 48.4 (34.2-68.5) 1.60 (1.13-2.27)* 0.93 (0.64-1.38) Continuous 1.09 (1.02-1.17)* 0.98 (0.91-1.07) 2.1.2. Sitagliptin Never 51,955,454 7,491 14.4 (14.1-14.7) 1.00 1.00 Ever use 133,190 49 25.9 (16.1-41.6) 1.11 (0.69-1.78) 0.77 (0.48-1.26) Cumulative duration Low 42,249 14 33.1 (19.6-56.0) 1.34 (0.79-2.26) 0.83 (0.48-1.41) Medium 47,499 11 23.2 (12.8-41.8) 0.93 (0.52-1.69) 0.59 (0.32-1.08) High 43,442 24 55.2 (37.0-82.4) 1.91 (1.28-2.85)* 1.28 (0.83-1.98) Continuous 1.13 (1.04-1.23)* 1.03 (0.94-1.13) Cumulative dose Low 43,259 14 32.4 (19.2-54.6) 1.30 (0.77-2.20) 0.79 (0.46-1.35) Medium 45,625 10 21.9 (11.8-40.7) 0.88 (0.47-1.64) 0.54 (0.29-1.02) High 44,306 25 56.4 (38.1-83.5) 1.97 (1.33-2.92)* 1.23 (0.81-1.89) Continuous 1.13 (1.04-1.23)* 1.03 (0.93-1.13) 5. Insulin secretagogues Never 51,176,005 7,161 14.0 (13.7-14.3) 1.00 1.00 Ever use 912,639 379 38.3 (33.6-43.8) 1.43 (1.25-1.64)* 1.20 (1.03-1.40)* Cumulative duration Low 360,923 116 32.1 (26.8-38.6) 1.32 (1.10-1.59)* 1.04 (0.85-1.27) Medium 315,845 139 44.0 (37.3-52.0) 1.64 (1.39-1.94)* 1.18 (0.96-1.44) High 235,871 124 52.6 (44.1-62.7) 1.51 (1.26-1.80)* 1.05 (0.83-1.32) Continuous 1.05 (1.04-1.07)* 1.03 (1.01-1.05)* Cumulative dose Low 372,575 126 33.8 (28.4-40.3) 1.32 (1.11-1.58)* 1.06 (0.87-1.29) Medium 314,231 127 40.4 (34.0-48.1) 1.45 (1.22-1.73)* 1.05 (0.85-1.29) High 225,833 126 55.8 (46.9-66.4) 1.74 (1.46-2.08)* 1.09 (0.86-1.39) Continuous 1.02 (1.02-1.03)* 1.01 (1.00-1.02)* 5.2. Sulfonylureas Never 51,188,413 7,165 14.0 (13.7-14.3) 1.00 1.00 Ever use 900,231 375 38.3 (33.5-43.8) 1.43 (1.25-1.64)* 1.20 (1.02-1.40)* Cumulative duration Low 359,009 119 33.1 (27.7-39.7) 1.36 (1.13-1.63)* 1.06 (0.87-1.30) 154 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 309,407 133 43.0 (36.3-50.9) 1.60 (1.35-1.90)* 1.15 (0.93-1.40) High 231,815 123 53.1 (44.5-63.3) 1.52 (1.27-1.82)* 1.06 (0.84-1.34) Continuous 1.05 (1.04-1.07)* 1.03 (1.01-1.05)* Cumulative dose Low 367,838 127 34.5 (29.0-41.1) 1.35 (1.13-1.61)* 1.08 (0.89-1.31) Medium 309,412 125 40.4 (33.9-48.1) 1.45 (1.22-1.73)* 1.05 (0.85-1.29) High 222,981 123 55.2 (46.2-65.8) 1.72 (1.44-2.06)* 1.07 (0.84-1.37) Continuous 1.02 (1.02-1.03)* 1.01 (1.00-1.02)* 5.2.1. Gliclazide Never 51,695,028 7,365 14.2 (13.9-14.6) 1.00 1.00 Ever use 393,616 175 39.2 (32.3-47.7) 1.35 (1.11-1.64)* 1.09 (0.88-1.35) Cumulative duration Low 126,908 56 44.1 (34.0-57.3) 1.68 (1.29-2.18)* 1.14 (0.86-1.51) Medium 136,638 52 38.1 (29.0-49.9) 1.35 (1.03-1.77)* 0.92 (0.69-1.23) High 130,070 67 51.5 (40.5-65.4) 1.51 (1.19-1.93)* 1.05 (0.80-1.38) Continuous 1.06 (1.02-1.09)* 1.02 (0.98-1.06) Cumulative dose Low 133,699 54 40.4 (30.9-52.7) 1.49 (1.14-1.95)* 1.04 (0.78-1.38) Medium 136,394 58 42.5 (32.9-55.0) 1.46 (1.13-1.89)* 1.01 (0.77-1.34) High 123,523 63 51.0 (39.8-65.3) 1.57 (1.22-2.01)* 0.99 (0.75-1.32) Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.02) 5.2.2. Glyburide Never 51,418,210 7,250 14.1 (13.8-14.4) 1.00 1.00 Ever use 670,434 290 37.9 (31.6-45.4) 1.50 (1.25-1.80)* 1.28 (1.05-1.56)* Cumulative duration Low 283,215 91 32.1 (26.2-39.5) 1.25 (1.02-1.54)* 0.96 (0.77-1.20) Medium 224,722 113 50.3 (41.8-60.5) 1.88 (1.56-2.27)* 1.32 (1.07-1.63)* High 162,497 86 52.9 (42.8-65.4) 1.53 (1.23-1.89)* 1.07 (0.84-1.37) Continuous 1.06 (1.04-1.08)* 1.03 (1.01-1.06)* Cumulative dose Low 296,014 100 33.8 (27.8-41.1) 1.26 (1.04-1.54)* 0.99 (0.79-1.22) Medium 230,574 108 46.8 (38.8-56.6) 1.68 (1.39-2.03)* 1.19 (0.96-1.48) High 143,846 82 57.0 (45.9-70.8) 1.81 (1.45-2.25)* 1.13 (0.87-1.47) Continuous 1.03 (1.02-1.05)* 1.02 (1.00-1.03)* 6. Thiazolidinediones Never 51,871,508 7,448 14.4 (14.0-14.7) 1.00 1.00 Ever use 217,136 92 18.0 (10.5-31.0) 0.94 (0.54-1.62) 0.73 (0.42-1.27) Cumulative duration Low 76,357 26 34.1 (23.2-50.0) 1.43 (0.97-2.10) 0.86 (0.57-1.28) Medium 72,351 29 40.1 (27.9-57.7) 1.67 (1.16-2.41)* 1.01 (0.69-1.48) High 68,428 37 54.1 (39.2-74.6) 1.90 (1.38-2.63)* 1.28 (0.91-1.82) Continuous 1.10 (1.05-1.15)* 1.04 (0.98-1.09) Cumulative dose Low 75,982 25 32.9 (22.2-48.7) 1.36 (0.92-2.02) 0.82 (0.55-1.24) Medium 74,257 36 48.5 (35.0-67.2) 2.00 (1.44-2.78)* 1.20 (0.85-1.70) High 66,897 31 46.3 (32.6-65.9) 1.66 (1.17-2.37)* 1.04 (0.72-1.52) Continuous 1.09 (1.04-1.14)* 1.03 (0.97-1.08) 6.2. Rosiglitazone Never 51,946,176 7,478 14.4 (14.1-14.7) 1.00 1.00 Ever use 142,468 62 18.5 (8.8-38.9) 1.08 (0.52-2.27) 0.85 (0.40-1.80) Cumulative duration Low 49,170 17 34.6 (21.5-55.6) 1.43 (0.89-2.30) 0.87 (0.53-1.42) Medium 48,028 21 43.7 (28.5-67.1) 1.81 (1.18-2.78)* 1.12 (0.72-1.75) High 45,270 24 53.0 (35.5-79.1) 1.96 (1.31-2.92)* 1.31 (0.86-1.99) Continuous 1.13 (1.06-1.21)* 1.05 (0.97-1.14) Cumulative dose Low 49,567 17 34.3 (21.3-55.2) 1.41 (0.88-2.27) 0.86 (0.53-1.41) Medium 49,349 23 46.6 (31.0-70.1) 1.91 (1.27-2.88)* 1.18 (0.77-1.81) High 43,552 22 50.5 (33.3-76.7) 1.88 (1.24-2.86)* 1.17 (0.76-1.81) Continuous 1.13 (1.06-1.20)* 1.05 (0.98-1.13) 7. Insulins and analogues Never 51,772,245 7,342 14.2 (13.9-14.5) 1.00 1.00 Ever use 316,399 198 70.2 (60.1-81.8) 2.84 (2.43-3.32)* 2.67 (2.25-3.16)* Cumulative duration Low 143,015 71 49.6 (39.3-62.6) 2.66 (2.11-3.36)* 2.43 (1.90-3.12)* 155 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 113,499 89 78.4 (63.7-96.5) 3.06 (2.48-3.78)* 2.84 (2.24-3.61)* High 59,885 38 63.5 (46.2-87.2) 2.18 (1.58-3.00)* 2.03 (1.44-2.87)* Continuous 1.14 (1.11-1.18)* 1.11 (1.07-1.15)* Cumulative dose Low 146,186 75 51.3 (40.9-64.3) 2.65 (2.11-3.33)* 2.42 (1.90-3.09)* Medium 108,141 88 81.4 (66.0-100.3) 3.18 (2.57-3.92)* 2.83 (2.22-3.61)* High 62,072 35 56.4 (40.5-78.5) 2.04 (1.46-2.85)* 1.78 (1.24-2.55)* Continuous 1.04 (1.03-1.05)* 1.04 (1.02-1.05)* 7.1. Basal insulins Never 51,784,863 7,350 14.2 (13.9-14.5) 1.00 1.00 Ever use 303,781 190 71.4 (61.0-83.6) 2.91 (2.48-3.41)* 2.13 (1.70-2.67)* Cumulative duration Low 135,289 67 49.5 (39.0-62.9) 2.66 (2.09-3.38)* 1.87 (1.40-2.48)* Medium 109,417 83 75.9 (61.2-94.1) 2.98 (2.40-3.71)* 2.08 (1.56-2.78)* High 59,075 40 67.7 (49.7-92.3) 2.31 (1.69-3.16)* 1.44 (0.95-2.19) Continuous 1.16 (1.12-1.20)* 1.09 (1.03-1.15)* Cumulative dose Low 136,909 71 51.9 (41.1-65.4) 2.69 (2.13-3.40)* 1.91 (1.45-2.53)* Medium 106,571 82 76.9 (62.0-95.5) 3.01 (2.42-3.75)* 1.95 (1.45-2.63)* High 60,301 37 61.4 (44.5-84.7) 2.21 (1.60-3.05)* 1.19 (0.77-1.84) Continuous 1.05 (1.04-1.06)* 1.04 (1.02-1.06)* 7.2. Bolus insulins Never 51,947,122 7,435 14.3 (14.0-14.6) 1.00 1.00 Ever use 141,522 105 86.6 (68.9-108.9) 3.97 (3.15-5.01)* 1.86 (1.36-2.53)* Cumulative duration Low 68,567 53 77.3 (59.1-101.2) 4.44 (3.39-5.82)* 2.31 (1.66-3.21)* Medium 48,161 31 64.4 (45.3-91.5) 2.89 (2.03-4.11)* 1.44 (0.95-2.18) High 24,794 21 84.7 (55.2-129.9) 3.37 (2.19-5.17)* 1.94 (1.15-3.28)* Continuous 1.24 (1.17-1.32)* 1.09 (1.00-1.20) Cumulative dose Low 71,251 53 74.4 (56.8-97.4) 4.16 (3.17-5.45)* 2.20 (1.58-3.05)* Medium 44,054 29 65.8 (45.7-94.7) 2.94 (2.04-4.24)* 1.54 (1.00-2.37) High 26,217 23 87.7 (58.3-132.0) 3.64 (2.42-5.49)* 2.27 (1.36-3.79)* Continuous 1.06 (1.04-1.09)* 1.02 (0.98-1.06) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Model 2 further adjusted for other mutually exclusive diabetes medications. This table summarized the associations between select diabetes medications and pancreatic cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table D-2. * denotes p<0.05. 7.4.2.2 Washout and lag periods Table 7-4 displays additional analyses for varied lag and washout durations for the medications that were statistically significant in the primary analysis. All associations are displayed in Supplementary Table D-3, regardless of their statistical significance. Relationships between these medications and the risk of pancreatic cancer were consistent across various combinations of lag and washout durations. Generally, the results of Models 3, 4, and 5 closely mirror those of Model 1 used in the primary analysis, but Model 2 results differed. For example, ever use of 156 thiazolidinediones was related to an increase in pancreatic cancer risk compared to never use (HR=2.91, 95%CI=2.25-3.76). Low duration (HR=3.31, 95%CI=2.67-4.12) and low dose (HR=3.28, 95%CI=2.64-4.07) were associated with higher risks in comparison to never use in Model 2. A similar phenomenon was also observed for rosiglitazone and the insulin and analogues class (and both subclasses). Similar associations were not found in other models. Table 7-4. Associations between select diabetes medications and the risk of pancreatic cancer with variation in washout and lag periods Exposure Model 1 Model 2 Model 3 Model 4 Model 5 1. Biguanides (i.e., metformin) Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.29 (1.18-1.41)* 3.11 (2.94-3.29)* 1.15 (1.04-1.27)* 1.19 (1.10-1.29)* 1.31 (1.20-1.44)* Cumulative duration Low 1.17 (1.02-1.36)* 5.11 (4.78-5.46)* 1.02 (0.87-1.20) 1.09 (0.96-1.24) 1.20 (1.04-1.39)* Medium 1.54 (1.36-1.73)* 2.34 (2.14-2.56)* 1.25 (1.09-1.43)* 1.43 (1.29-1.58)* 1.55 (1.37-1.75)* High 1.24 (1.09-1.41)* 1.79 (1.62-1.98)* 1.17 (1.02-1.34)* 1.27 (1.15-1.41)* 1.24 (1.08-1.42)* Continuous 1.03 (1.02-1.04)* 1.07 (1.06-1.07)* 1.02 (1.01-1.04)* 1.03 (1.02-1.04)* 1.03 (1.02-1.05)* Cumulative dose Low 1.11 (0.97-1.28) 4.55 (4.25-4.87)* 0.93 (0.79-1.10) 1.04 (0.91-1.19) 1.14 (0.98-1.31) Medium 1.40 (1.24-1.58)* 2.40 (2.20-2.62)* 1.18 (1.03-1.36)* 1.33 (1.19-1.48)* 1.42 (1.25-1.61)* High 1.45 (1.28-1.65)* 2.06 (1.87-2.28)* 1.34 (1.17-1.54)* 1.40 (1.27-1.55)* 1.46 (1.27-1.67)* Continuous 1.04 (1.03-1.06)* 1.08 (1.07-1.09)* 1.03 (1.02-1.05)* 1.04 (1.03-1.05)* 1.05 (1.03-1.06)* 2. Incretin-based medicines Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.08 (0.81-1.45) 2.73 (2.36-3.17)* 1.08 (0.78-1.50) 0.97 (0.75-1.25) 1.10 (0.81-1.49) Cumulative duration Low 1.77 (1.24-2.54)* 4.29 (3.57-5.16)* 1.69 (1.12-2.55)* 1.59 (1.16-2.18)* 1.72 (1.18-2.52)* Medium 1.04 (0.67-1.61) 2.56 (2.04-3.21)* 0.72 (0.40-1.30) 1.04 (0.72-1.50) 1.07 (0.68-1.67) High 1.58 (1.15-2.18)* 2.27 (1.81-2.85)* 1.31 (0.89-1.91) 1.42 (1.08-1.88)* 1.55 (1.11-2.18)* Continuous 1.08 (1.02-1.15)* 1.20 (1.15-1.24)* 1.04 (0.97-1.12) 1.07 (1.01-1.13)* 1.08 (1.02-1.16)* Cumulative dose Low 2.07 (1.48-2.90)* 4.17 (3.44-5.05)* 1.87 (1.26-2.76)* 1.78 (1.31-2.41)* 1.97 (1.38-2.82)* Medium 1.03 (0.66-1.59) 2.62 (2.10-3.27)* 0.83 (0.48-1.44) 1.03 (0.71-1.48) 1.06 (0.67-1.66) High 1.40 (1.00-1.96) 2.40 (1.93-2.99)* 1.12 (0.74-1.69) 1.32 (1.00-1.76) 1.40 (0.98-1.99) Continuous 1.09 (1.02-1.17)* 1.22 (1.17-1.27)* 1.04 (0.96-1.13) 1.08 (1.02-1.14)* 1.09 (1.02-1.17)* 2.1. DPP-4 inhibitors Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.13 (0.82-1.55) 2.99 (2.56-3.49)* 1.13 (0.79-1.60) 1.02 (0.77-1.34) 1.14 (0.82-1.58) Cumulative duration Low 1.60 (1.08-2.37)* 4.23 (3.49-5.12)* 1.50 (0.96-2.36) 1.40 (0.99-1.98) 1.60 (1.06-2.40)* Medium 1.11 (0.70-1.77) 2.69 (2.11-3.42)* 0.71 (0.37-1.36) 1.10 (0.75-1.62) 1.14 (0.71-1.84) High 1.50 (1.04-2.14)* 2.27 (1.77-2.90)* 1.28 (0.84-1.95) 1.43 (1.06-1.93)* 1.48 (1.01-2.16)* Continuous 1.09 (1.02-1.17)* 1.21 (1.17-1.26)* 1.04 (0.96-1.13) 1.08 (1.02-1.14)* 1.09 (1.02-1.17)* Cumulative dose Low 1.56 (1.05-2.31)* 4.16 (3.43-5.03)* 1.47 (0.94-2.30) 1.37 (0.97-1.94) 1.56 (1.04-2.35)* Medium 1.01 (0.62-1.65) 2.63 (2.05-3.37)* 0.72 (0.37-1.38) 1.04 (0.70-1.56) 1.03 (0.62-1.71) High 1.60 (1.13-2.27)* 2.34 (1.84-2.99)* 1.29 (0.85-1.96) 1.50 (1.12-2.02)* 1.59 (1.10-2.29)* Continuous 1.09 (1.02-1.17)* 1.22 (1.17-1.27)* 1.04 (0.96-1.13) 1.08 (1.02-1.14)* 1.09 (1.02-1.17)* 2.1.2. Sitagliptin Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.11 (0.69-1.78) 2.70 (2.11-3.46)* 1.09 (0.65-1.84) 0.98 (0.65-1.49) 1.06 (0.64-1.76) Cumulative duration Low 1.34 (0.79-2.26) 2.56 (1.87-3.51)* 1.33 (0.76-2.35) 1.27 (0.82-1.97) 1.36 (0.79-2.34) 157 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 0.93 (0.52-1.69) 2.11 (1.52-2.93)* 0.69 (0.33-1.45) 1.14 (0.73-1.77) 0.93 (0.50-1.73) High 1.91 (1.28-2.85)* 2.61 (1.96-3.48)* 1.57 (0.97-2.52) 1.69 (1.19-2.39)* 1.85 (1.20-2.83)* Continuous 1.13 (1.04-1.23)* 1.23 (1.16-1.29)* 1.07 (0.97-1.19) 1.12 (1.04-1.20)* 1.13 (1.03-1.23)* Cumulative dose Low 1.30 (0.77-2.20) 2.47 (1.80-3.39)* 1.30 (0.74-2.29) 1.23 (0.79-1.91) 1.32 (0.77-2.27) Medium 0.88 (0.47-1.64) 2.14 (1.54-2.99)* 0.61 (0.28-1.37) 1.13 (0.72-1.77) 0.87 (0.45-1.67) High 1.97 (1.33-2.92)* 2.64 (1.99-3.51)* 1.64 (1.03-2.61)* 1.72 (1.22-2.42)* 1.91 (1.26-2.91)* Continuous 1.13 (1.04-1.23)* 1.23 (1.16-1.30)* 1.07 (0.97-1.19) 1.12 (1.04-1.20)* 1.13 (1.04-1.24)* 5. Insulin secretagogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.43 (1.25-1.64)* 4.10 (3.82-4.41)* 1.21 (1.04-1.42)* 1.09 (0.98-1.22) 1.48 (1.28-1.70)* Cumulative duration Low 1.32 (1.10-1.59)* 5.86 (5.41-6.33)* 1.14 (0.92-1.40) 1.14 (0.97-1.34) 1.38 (1.14-1.66)* Medium 1.64 (1.39-1.94)* 2.49 (2.20-2.81)* 1.24 (1.01-1.52)* 1.40 (1.22-1.60)* 1.69 (1.42-2.02)* High 1.51 (1.26-1.80)* 1.91 (1.66-2.20)* 1.39 (1.14-1.69)* 1.37 (1.22-1.54)* 1.48 (1.21-1.80)* Continuous 1.05 (1.04-1.07)* 1.08 (1.07-1.10)* 1.04 (1.02-1.06)* 1.03 (1.02-1.04)* 1.06 (1.04-1.08)* Cumulative dose Low 1.32 (1.11-1.58)* 5.18 (4.78-5.61)* 1.04 (0.85-1.29) 1.10 (0.94-1.29) 1.36 (1.13-1.63)* Medium 1.45 (1.22-1.73)* 2.68 (2.39-3.01)* 1.20 (0.98-1.47) 1.26 (1.10-1.45)* 1.53 (1.27-1.83)* High 1.74 (1.46-2.08)* 2.23 (1.94-2.56)* 1.60 (1.31-1.94)* 1.52 (1.35-1.71)* 1.72 (1.41-2.09)* Continuous 1.02 (1.02-1.03)* 1.03 (1.03-1.04)* 1.02 (1.01-1.03)* 1.02 (1.01-1.02)* 1.03 (1.02-1.03)* 5.2. Sulfonylureas Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.43 (1.25-1.64)* 4.13 (3.84-4.43)* 1.21 (1.03-1.41)* 1.10 (0.98-1.23) 1.48 (1.29-1.71)* Cumulative duration Low 1.36 (1.13-1.63)* 5.87 (5.43-6.35)* 1.18 (0.96-1.45) 1.15 (0.98-1.35) 1.41 (1.16-1.70)* Medium 1.60 (1.35-1.90)* 2.44 (2.16-2.77)* 1.18 (0.96-1.46) 1.38 (1.20-1.58)* 1.63 (1.36-1.95)* High 1.52 (1.27-1.82)* 1.92 (1.66-2.21)* 1.40 (1.15-1.70)* 1.38 (1.22-1.55)* 1.51 (1.24-1.84)* Continuous 1.05 (1.04-1.07)* 1.08 (1.07-1.10)* 1.04 (1.02-1.06)* 1.03 (1.02-1.04)* 1.06 (1.04-1.08)* Cumulative dose Low 1.35 (1.13-1.61)* 5.22 (4.81-5.66)* 1.07 (0.87-1.31) 1.10 (0.94-1.29) 1.37 (1.14-1.65)* Medium 1.45 (1.22-1.73)* 2.68 (2.39-3.01)* 1.19 (0.97-1.46) 1.27 (1.10-1.46)* 1.50 (1.25-1.81)* High 1.72 (1.44-2.06)* 2.20 (1.91-2.53)* 1.57 (1.29-1.91)* 1.51 (1.35-1.70)* 1.73 (1.43-2.11)* Continuous 1.02 (1.02-1.03)* 1.03 (1.03-1.04)* 1.02 (1.01-1.03)* 1.02 (1.01-1.02)* 1.03 (1.02-1.03)* 5.2.1. Gliclazide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.35 (1.11-1.64)* 3.75 (3.39-4.14)* 1.18 (0.94-1.48) 1.15 (0.97-1.36) 1.40 (1.15-1.72)* Cumulative duration Low 1.68 (1.29-2.18)* 5.78 (5.13-6.52)* 1.56 (1.16-2.09)* 1.49 (1.21-1.84)* 1.75 (1.34-2.29)* Medium 1.35 (1.03-1.77)* 2.95 (2.52-3.45)* 0.83 (0.57-1.21) 1.33 (1.08-1.64)* 1.33 (1.00-1.77) High 1.51 (1.19-1.93)* 1.85 (1.54-2.24)* 1.49 (1.15-1.92)* 1.38 (1.15-1.67)* 1.51 (1.17-1.95)* Continuous 1.06 (1.02-1.09)* 1.11 (1.09-1.13)* 1.04 (1.01-1.08)* 1.05 (1.02-1.07)* 1.06 (1.02-1.10)* Cumulative dose Low 1.49 (1.14-1.95)* 5.39 (4.78-6.07)* 1.35 (0.99-1.82) 1.36 (1.09-1.69)* 1.54 (1.17-2.03)* Medium 1.46 (1.13-1.89)* 2.88 (2.46-3.37)* 1.05 (0.75-1.45) 1.38 (1.13-1.69)* 1.45 (1.11-1.91)* High 1.57 (1.22-2.01)* 1.99 (1.65-2.40)* 1.48 (1.13-1.95)* 1.45 (1.20-1.75)* 1.56 (1.20-2.03)* Continuous 1.02 (1.01-1.03)* 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* 1.01 (1.01-1.02)* 1.02 (1.01-1.03)* 5.2.2. Glyburide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.50 (1.25-1.80)* 4.27 (3.89-4.69)* 1.25 (1.01-1.55)* 1.06 (0.92-1.23) 1.55 (1.28-1.89)* Cumulative duration Low 1.25 (1.02-1.54)* 4.47 (4.05-4.93)* 1.11 (0.88-1.40) 1.03 (0.86-1.23) 1.31 (1.05-1.62)* Medium 1.88 (1.56-2.27)* 2.66 (2.32-3.06)* 1.45 (1.16-1.81)* 1.45 (1.25-1.68)* 1.92 (1.57-2.34)* High 1.53 (1.23-1.89)* 1.80 (1.52-2.14)* 1.36 (1.07-1.72)* 1.40 (1.23-1.60)* 1.52 (1.20-1.93)* Continuous 1.06 (1.04-1.08)* 1.09 (1.07-1.10)* 1.04 (1.02-1.07)* 1.04 (1.02-1.05)* 1.07 (1.04-1.09)* Cumulative dose Low 1.26 (1.04-1.54)* 4.10 (3.72-4.52)* 1.06 (0.84-1.33) 1.06 (0.89-1.27) 1.28 (1.04-1.58)* Medium 1.68 (1.39-2.03)* 2.58 (2.25-2.95)* 1.42 (1.14-1.76)* 1.32 (1.14-1.54)* 1.74 (1.42-2.13)* High 1.81 (1.45-2.25)* 2.12 (1.78-2.53)* 1.53 (1.19-1.96)* 1.49 (1.31-1.70)* 1.85 (1.45-2.37)* Continuous 1.03 (1.02-1.05)* 1.04 (1.04-1.05)* 1.03 (1.01-1.04)* 1.02 (1.01-1.03)* 1.04 (1.03-1.05)* 6. Thiazolidinediones Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.94 (0.54-1.62) 2.91 (2.25-3.76)* 0.74 (0.38-1.41) 0.86 (0.59-1.26) 1.12 (0.65-1.92) Cumulative duration Low 1.43 (0.97-2.10) 3.31 (2.67-4.12)* 1.16 (0.74-1.82) 1.43 (1.09-1.86)* 1.59 (1.08-2.36)* 158 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 1.67 (1.16-2.41)* 2.13 (1.62-2.81)* 1.34 (0.87-2.06) 1.29 (0.97-1.71) 1.84 (1.26-2.68)* High 1.90 (1.38-2.63)* 2.42 (1.90-3.08)* 1.50 (1.02-2.20)* 1.79 (1.43-2.24)* 2.05 (1.45-2.88)* Continuous 1.10 (1.05-1.15)* 1.14 (1.10-1.18)* 1.06 (1.00-1.12) 1.08 (1.05-1.12)* 1.12 (1.06-1.17)* Cumulative dose Low 1.36 (0.92-2.02) 3.28 (2.64-4.07)* 1.02 (0.64-1.65) 1.38 (1.05-1.82)* 1.51 (1.01-2.25)* Medium 2.00 (1.44-2.78)* 2.38 (1.84-3.07)* 1.67 (1.15-2.44)* 1.57 (1.22-2.02)* 2.15 (1.53-3.03)* High 1.66 (1.17-2.37)* 2.22 (1.71-2.87)* 1.31 (0.86-2.00) 1.59 (1.25-2.01)* 1.83 (1.26-2.65)* Continuous 1.09 (1.04-1.14)* 1.12 (1.09-1.16)* 1.06 (1.00-1.12) 1.07 (1.04-1.10)* 1.10 (1.05-1.16)* 6.2. Rosiglitazone Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.08 (0.52-2.27) 3.40 (2.39-4.84)* 0.69 (0.26-1.85) 0.94 (0.57-1.56) 1.30 (0.62-2.73) Cumulative duration Low 1.43 (0.89-2.30) 3.14 (2.39-4.14)* 1.21 (0.70-2.09) 1.42 (1.03-1.96)* 1.67 (1.04-2.69)* Medium 1.81 (1.18-2.78)* 2.19 (1.57-3.05)* 1.53 (0.94-2.51) 1.53 (1.12-2.09)* 2.15 (1.40-3.30)* High 1.96 (1.31-2.92)* 2.44 (1.80-3.31)* 1.80 (1.16-2.79)* 1.68 (1.27-2.23)* 2.20 (1.45-3.34)* Continuous 1.13 (1.06-1.21)* 1.18 (1.13-1.24)* 1.11 (1.03-1.20)* 1.10 (1.05-1.16)* 1.16 (1.08-1.24)* Cumulative dose Low 1.41 (0.88-2.27) 3.05 (2.31-4.03)* 1.20 (0.69-2.06) 1.34 (0.96-1.87) 1.65 (1.03-2.66)* Medium 1.91 (1.27-2.88)* 2.28 (1.66-3.14)* 1.57 (0.98-2.53) 1.55 (1.14-2.11)* 2.24 (1.49-3.37)* High 1.88 (1.24-2.86)* 2.45 (1.79-3.34)* 1.79 (1.14-2.81)* 1.74 (1.32-2.30)* 2.13 (1.37-3.30)* Continuous 1.13 (1.06-1.20)* 1.17 (1.12-1.22)* 1.12 (1.04-1.20)* 1.10 (1.05-1.14)* 1.15 (1.08-1.22)* 7. Insulins and analogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 2.84 (2.43-3.32)* 11.00 (10.21-11.84)* 2.48 (2.08-2.96)* 2.18 (1.96-2.42)* 2.87 (2.43-3.40)* Cumulative duration Low 2.66 (2.11-3.36)* 18.37 (16.97-19.88)* 2.01 (1.50-2.68)* 1.83 (1.49-2.25)* 2.83 (2.22-3.59)* Medium 3.06 (2.48-3.78)* 3.57 (2.99-4.26)* 2.72 (2.15-3.44)* 2.30 (1.97-2.69)* 2.98 (2.37-3.73)* High 2.18 (1.58-3.00)* 2.20 (1.64-2.94)* 2.25 (1.63-3.12)* 2.09 (1.79-2.43)* 2.31 (1.64-3.25)* Continuous 1.14 (1.11-1.18)* 1.16 (1.13-1.19)* 1.14 (1.10-1.17)* 1.08 (1.06-1.09)* 1.15 (1.11-1.19)* Cumulative dose Low 2.65 (2.11-3.33)* 17.76 (16.42-19.20)* 2.13 (1.62-2.80)* 1.83 (1.50-2.25)* 2.85 (2.26-3.60)* Medium 3.18 (2.57-3.92)* 3.34 (2.77-4.03)* 2.77 (2.19-3.50)* 2.29 (1.96-2.67)* 3.13 (2.50-3.93)* High 2.04 (1.46-2.85)* 1.99 (1.47-2.71)* 2.04 (1.45-2.88)* 2.11 (1.81-2.46)* 2.00 (1.38-2.90)* Continuous 1.04 (1.03-1.05)* 1.05 (1.04-1.05)* 1.04 (1.03-1.05)* 1.01 (1.01-1.01)* 1.04 (1.03-1.06)* 7.1. Basal insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 2.91 (2.48-3.41)* 10.85 (10.05-11.72)* 2.53 (2.11-3.03)* 2.20 (1.97-2.45)* 2.92 (2.46-3.47)* Cumulative duration Low 2.66 (2.09-3.38)* 18.06 (16.64-19.61)* 1.97 (1.46-2.66)* 1.83 (1.48-2.26)* 2.82 (2.20-3.61)* Medium 2.98 (2.40-3.71)* 3.58 (2.99-4.28)* 2.78 (2.19-3.52)* 2.30 (1.97-2.69)* 2.99 (2.37-3.77)* High 2.31 (1.69-3.16)* 2.24 (1.68-2.98)* 2.33 (1.70-3.21)* 2.10 (1.80-2.44)* 2.25 (1.59-3.18)* Continuous 1.16 (1.12-1.20)* 1.19 (1.15-1.22)* 1.16 (1.11-1.20)* 1.08 (1.07-1.10)* 1.17 (1.13-1.22)* Cumulative dose Low 2.69 (2.13-3.40)* 17.67 (16.30-19.16)* 2.10 (1.57-2.79)* 1.85 (1.50-2.28)* 2.85 (2.24-3.63)* Medium 3.01 (2.42-3.75)* 3.20 (2.64-3.88)* 2.75 (2.16-3.49)* 2.23 (1.91-2.62)* 2.98 (2.35-3.76)* High 2.21 (1.60-3.05)* 2.17 (1.61-2.92)* 2.22 (1.59-3.10)* 2.15 (1.85-2.50)* 2.19 (1.53-3.14)* Continuous 1.05 (1.04-1.06)* 1.05 (1.04-1.06)* 1.05 (1.04-1.06)* 1.04 (1.03-1.04)* 1.05 (1.04-1.07)* 7.2. Bolus insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 3.97 (3.15-5.01)* 13.73 (12.31-15.33)* 3.67 (2.85-4.72)* 2.71 (2.35-3.13)* 4.08 (3.19-5.23)* Cumulative duration Low 4.44 (3.39-5.82)* 17.43 (15.49-19.61)* 3.69 (2.69-5.05)* 3.28 (2.68-4.02)* 5.00 (3.80-6.56)* Medium 2.89 (2.03-4.11)* 4.61 (3.60-5.91)* 2.64 (1.80-3.88)* 1.97 (1.55-2.51)* 3.04 (2.10-4.40)* High 3.37 (2.19-5.17)* 3.13 (2.11-4.64)* 3.58 (2.33-5.50)* 2.38 (1.93-2.94)* 2.95 (1.78-4.91)* Continuous 1.24 (1.17-1.32)* 1.26 (1.20-1.32)* 1.24 (1.17-1.32)* 1.11 (1.08-1.14)* 1.24 (1.16-1.33)* Cumulative dose Low 4.16 (3.17-5.45)* 17.14 (15.28-19.24)* 3.38 (2.45-4.65)* 3.19 (2.62-3.90)* 4.69 (3.57-6.16)* Medium 2.94 (2.04-4.24)* 3.79 (2.85-5.05)* 2.85 (1.94-4.19)* 1.87 (1.46-2.40)* 3.20 (2.19-4.67)* High 3.64 (2.42-5.49)* 3.21 (2.18-4.71)* 3.69 (2.43-5.61)* 2.49 (2.02-3.07)* 3.12 (1.91-5.09)* Continuous 1.06 (1.04-1.09)* 1.07 (1.05-1.09)* 1.06 (1.04-1.09)* 1.04 (1.03-1.05)* 1.06 (1.04-1.09)* Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 1-year lag periods in the primary analysis. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 0-year lag periods. Model 3 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 2-year lag periods. Model 4 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 0-year washout and 1-year lag periods. 159 Model 5 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 2-year washout and 1-year lag periods. This table summarized the associations between select diabetes medications and pancreatic cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table D-3. * denotes p<0.05. 7.4.2.3 BCGP analysis Risk estimates for statistically significant results in the primary analysis are shown in Table 7-5 with additional adjustment for potential confounders captured in the BCGP. All associations, regardless of statistical significance, are shown in Supplementary Table D-4. The limited number of incident pancreatic cancers precluded the evaluation of associations with linagliptin, GLP-1 receptor agonists, meglitinides (and repaglinide), glyburide, rosiglitazone and the binary exposure definitions except for metformin. Metformin, incretin-based medicines, DPP-4 inhibitors, sitagliptin, insulin secretagogues, sulfonylureas and gliclazide remained significantly associated with greater risks of pancreatic cancer after adjusting for sociodemographic and lifestyle variables in the BCGP subset. Although not statistically significant, thiazolidinedione, insulin classes, both basal and bolus insulin subclasses were associated with higher risks of pancreatic cancer, similar to findings from the primary analysis. 160 Table 7-5. Associations between select diabetes medications and the risk of pancreatic cancer among people in the BCGP Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 1. Biguanides (i.e., metformin) Never 537,721 48 8.9 (6.7-11.8) 1.00 1.00 1.00 Ever use 8,443 Suppressed 47.4 (17.8-126.2) 1.29 (1.18-1.41)* 2.37 (0.85-6.64) 2.90 (0.99-8.48) Cumulative duration - trend 1.03 (1.02-1.04)* 1.11 (1.00-1.22)* 1.13 (1.02-1.25)* Cumulative dose - trend 1.04 (1.03-1.06)* 1.14 (1.03-1.26)* 1.16 (1.05-1.29)* 2. Incretin-based medicines Never 544,775 51 9.4 (7.1-12.3) 1.00 1.00 1.00 Ever use 1,389 Suppressed 72.0 (10.1-511.1) 1.08 (0.81-1.45) Not shown Not shown Cumulative duration - trend 1.08 (1.02-1.15)* 1.44 (1.09-1.88)* 1.55 (1.18-2.05)* Cumulative dose - trend 1.09 (1.02-1.17)* 1.52 (1.16-1.99)* 1.65 (1.26-2.17)* 2.1. DPP-4 inhibitors Never 545,345 51 9.4 (7.1-12.3) 1.00 1.00 1.00 Ever use 819 Suppressed 122.1 (17.2-866.8) 1.13 (0.82-1.55) Not shown Not shown Cumulative duration - trend 1.09 (1.02-1.17)* 1.53 (1.17-1.99)* 1.66 (1.26-2.18)* Cumulative dose - trend 1.09 (1.02-1.17)* 1.53 (1.17-2.00)* 1.66 (1.27-2.18)* 2.1.2. Sitagliptin Never 545,712 51 9.3 (7.1-12.3) 1.00 1.00 1.00 Ever use 452 Suppressed 221.2 (31.2-1570.6) 1.11 (0.69-1.78) Not shown Not shown Cumulative duration - trend 1.13 (1.04-1.23)* 1.59 (1.14-2.20)* 1.67 (1.21-2.30)* Cumulative dose - trend 1.13 (1.04-1.23)* 1.59 (1.15-2.20)* 1.67 (1.21-2.30)* 5. Insulin secretagogues Never 543,809 50 9.2 (7.0-12.1) 1.00 1.00 1.00 Ever use 2,355 Suppressed 84.9 (21.2-339.6) 1.43 (1.25-1.64)* Not shown Not shown Cumulative duration - trend 1.05 (1.04-1.07)* 1.17 (1.03-1.33)* 1.20 (1.05-1.37)* Cumulative dose - trend 1.02 (1.02-1.03)* 1.07 (1.03-1.11)* 1.08 (1.04-1.13)* 5.2. Sulfonylureas Never 543,866 50 9.2 (7.0-12.1) 1.00 1.00 1.00 Ever use 2,298 Suppressed 87.0 (21.8-348.0) 1.43 (1.25-1.64)* Not shown Not shown Cumulative duration - trend 1.05 (1.04-1.07)* 1.17 (1.04-1.33)* 1.20 (1.05-1.37)* Cumulative dose - trend 1.02 (1.02-1.03)* 1.07 (1.03-1.11)* 1.08 (1.04-1.13)* 5.2.1. Gliclazide Never 544,845 51 9.4 (7.1-12.3) 1.00 1.00 1.00 Ever use 1,319 Suppressed 75.8 (10.7-538.2) 1.35 (1.11-1.64)* Not shown Not shown Cumulative duration - trend 1.06 (1.02-1.09)* 1.21 (1.06-1.38)* 1.29 (1.10-1.51)* Cumulative dose - trend 1.02 (1.01-1.03)* 1.07 (1.03-1.11)* 1.09 (1.05-1.14)* 6. Thiazolidinediones Never 545,633 51 9.3 (7.1-12.3) 1.00 1.00 1.00 Ever use 531 Suppressed 188.3 (26.5-1337.0) 0.94 (0.54-1.62) Not shown Not shown Cumulative duration - trend 1.10 (1.05-1.15)* 1.22 (0.93-1.61) 1.28 (0.96-1.69) Cumulative dose - trend 1.09 (1.04-1.14)* 1.13 (0.81-1.57) 1.18 (0.83-1.67) 7. Insulins and analogues Never 544,673 50 9.2 (7.0-12.1) 1.00 1.00 1.00 Ever use 1,491 Suppressed 134.1 (33.5-536.4) 2.84 (2.43-3.32)* Not shown Not shown Cumulative duration - trend 1.14 (1.11-1.18)* 1.14 (0.77-1.69) 1.19 (0.80-1.77) 161 Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 Cumulative dose - trend 1.04 (1.03-1.05)* 1.04 (0.80-1.35) 1.07 (0.82-1.38) 7.1. Basal insulins Never 544,761 50 9.2 (7.0-12.1) 1.00 1.00 1.00 Ever use 1,403 Suppressed 142.6 (35.7-570.0) 2.91 (2.48-3.41)* Not shown Not shown Cumulative duration - trend 1.16 (1.12-1.20)* 1.20 (0.76-1.90) 1.27 (0.79-2.02) Cumulative dose - trend 1.05 (1.04-1.06)* 1.06 (0.79-1.42) 1.08 (0.81-1.45) 7.2. Bolus insulins Never 545,495 50 9.2 (6.9-12.1) 1.00 1.00 1.00 Ever use 669 Suppressed 299.0 (74.8-1195.4) 3.97 (3.15-5.01)* Not shown Not shown Cumulative duration - trend 1.24 (1.17-1.32)* 1.19 (0.40-3.51) 1.29 (0.44-3.79) Cumulative dose - trend 1.06 (1.04-1.09)* 1.06 (0.57-1.97) 1.11 (0.60-2.06) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile in the primary analysis using Population Data BC. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile in the BCGP subset. Model 3 further adjusted for sociodemographic and lifestyle-related factors: race/ethnicity, marital status, physical activity, education, individual-level income, fruit and vegetable consumption, alcohol consumption, smoking status, waist to hip ratio, and body mass index using the BCGP subset. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. Effect estimates denoted as “Not shown” have been omitted due to low number of events, which may result in unreliable estimates. This table summarized the associations between select diabetes medications and pancreatic cancer. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table D-4. * denotes p<0.05. 162 7.4.2.4 Active comparator analysis There were too few pancreatic cancers to evaluate associations for sitagliptin and bolus insulins (Table 7-6). Compared to pioglitazone, metformin (HR=0.33, 95%CI=0.08-1.31), gliclazide (HR=0.43, 95%CI=0.07-2.66), and glyburide (HR=0.33, 95%CI=0.07-1.46) were associated with lower risks of pancreatic cancer, but basal insulins (HR=1.49, 95%CI=0.33-6.63) was related to a higher risk; however, none of the associations was statistically significant. Table 7-6. Associations between diabetes medication and pancreatic cancer, an active comparator analysis among new users of medication Exposure definition Person-years Events Incidence rate Model 1 Model 2 6.1. Pioglitazone 2,764 Suppressed 72.4 (18.1-289.3) 1.00 1.00 1. Biguanides (i.e., metformin) 863,377 269 31.2 (27.6-35.1) 0.35 (0.09-1.41) 0.33 (0.08-1.31) 6.1. Pioglitazone 2,764 Suppressed 72.4 (18.1-289.3) 1.00 1.00 5.2.1. Gliclazide 14,398 Suppressed 55.6 (27.8-111.1) 0.54 (0.11-2.72) 0.43 (0.07-2.66) 6.1. Pioglitazone 2,764 Suppressed 72.4 (18.1-289.3) 1.00 1.00 5.2.2. Glyburide 47,526 20 42.1 (27.1-65.2) 0.37 (0.09-1.63) 0.33 (0.07-1.46) 6.1. Pioglitazone 2,764 Suppressed 72.4 (18.1-289.3) 1.00 1.00 7.1. Basal insulins 15,080 19 126.0 (80.4-197.5) 1.85 (0.43-7.96) 1.49 (0.33-6.63) Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. * denotes p<0.05. 7.4.3 Findings from cancer subtype analysis Table 7-7 summarizes the medications that demonstrated statistically significant findings in the primary analysis for pancreatic adenocarcinoma. The risk of pancreatic adenocarcinoma was found to be significantly associated with the same medications as in the analysis of overall pancreatic cancer risk. In Supplementary Table D-5, all associations are listed, regardless of whether they are statistically significant. 163 Table 7-7. Associations between select diabetes medications and the risk of pancreatic cancer morphological subtype: adenocarcinoma Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 6,525 13.0 (12.7-13.4) 1.00 1.00 Ever use 2,021,426 669 31.3 (28.6-34.2) 1.32 (1.20-1.45)* 1.24 (1.13-1.36)* Cumulative duration Low 736,609 175 23.8 (20.5-27.6) 1.18 (1.02-1.38)* 1.14 (0.98-1.33) Medium 720,912 268 37.2 (33.0-41.9) 1.60 (1.41-1.80)* 1.51 (1.34-1.71)* High 563,905 226 40.1 (35.2-45.7) 1.32 (1.16-1.51)* 1.22 (1.06-1.39)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.04)* Cumulative dose Low 761,186 184 24.2 (20.9-27.9) 1.13 (0.98-1.31) 1.09 (0.94-1.27) Medium 720,432 254 35.3 (31.2-39.9) 1.46 (1.29-1.65)* 1.38 (1.22-1.57)* High 539,808 231 42.8 (37.6-48.7) 1.54 (1.35-1.76)* 1.41 (1.23-1.61)* Continuous 1.05 (1.04-1.07)* 1.04 (1.03-1.06)* 2. Incretin-based medicines Never 51,846,234 7,114 13.7 (13.4-14.0) 1.00 1.00 Ever use 242,410 80 24.1 (17.7-32.7) 1.18 (0.87-1.60) 1.05 (0.77-1.42) Cumulative duration Low 76,647 25 32.6 (22.0-48.3) 1.75 (1.18-2.58)* 1.57 (1.06-2.32)* Medium 82,123 19 23.1 (14.8-36.3) 1.18 (0.75-1.85) 1.05 (0.67-1.64) High 83,640 36 43.0 (31.0-59.7) 1.81 (1.31-2.51)* 1.59 (1.15-2.21)* Continuous 1.11 (1.04-1.18)* 1.08 (1.01-1.15)* Cumulative dose Low 79,230 30 37.9 (26.5-54.2) 2.18 (1.52-3.12)* 1.95 (1.36-2.79)* Medium 80,356 18 22.4 (14.1-35.6) 1.10 (0.69-1.75) 0.98 (0.62-1.56) High 82,824 32 38.6 (27.3-54.6) 1.58 (1.12-2.24)* 1.39 (0.98-1.98) Continuous 1.12 (1.04-1.20)* 1.09 (1.01-1.17)* 2.1. DPP-4 inhibitors Never 51,896,422 7,126 13.7 (13.4-14.1) 1.00 1.00 Ever use 192,222 68 27.8 (20.1-38.6) 1.24 (0.89-1.72) 1.10 (0.80-1.53) Cumulative duration Low 63,002 23 36.5 (24.3-54.9) 1.74 (1.15-2.61)* 1.56 (1.03-2.34)* Medium 63,244 17 26.9 (16.7-43.2) 1.26 (0.78-2.02) 1.11 (0.69-1.79) High 65,976 28 42.4 (29.3-61.5) 1.68 (1.16-2.43)* 1.48 (1.02-2.14)* Continuous 1.12 (1.04-1.20)* 1.09 (1.01-1.17)* Cumulative dose Low 64,188 23 35.8 (23.8-53.9) 1.69 (1.13-2.55)* 1.52 (1.01-2.29)* Medium 61,937 15 24.2 (14.6-40.2) 1.13 (0.68-1.87) 1.00 (0.60-1.66) High 66,097 30 45.4 (31.7-64.9) 1.80 (1.26-2.58)* 1.59 (1.11-2.27)* Continuous 1.12 (1.04-1.20)* 1.09 (1.01-1.17)* 2.1.2. Sitagliptin Never 51,955,454 7,148 13.8 (13.4-14.1) 1.00 1.00 Ever use 133,190 46 24.4 (14.9-39.8) 1.24 (0.76-2.02) 1.11 (0.68-1.81) Cumulative duration Low 42,249 14 33.1 (19.6-56.0) 1.57 (0.93-2.66) 1.42 (0.84-2.39) Medium 47,499 10 21.1 (11.3-39.1) 1.01 (0.54-1.88) 0.90 (0.48-1.67) High 43,442 22 50.6 (33.3-76.9) 2.11 (1.39-3.21)* 1.85 (1.22-2.82)* Continuous 1.16 (1.06-1.26)* 1.12 (1.03-1.22)* Cumulative dose Low 43,259 14 32.4 (19.2-54.6) 1.53 (0.90-2.58) 1.38 (0.81-2.33) Medium 45,625 Suppressed 19.7 (10.3-37.9) 0.95 (0.49-1.82) 0.84 (0.44-1.62) High 44,306 23 51.9 (34.5-78.1) 2.19 (1.46-3.30)* 1.92 (1.27-2.89)* Continuous 1.16 (1.06-1.26)* 1.13 (1.03-1.23)* 5. Insulin secretagogues Never 51,176,005 6,832 13.4 (13.0-13.7) 1.00 1.00 Ever use 912,639 362 36.4 (31.8-41.7) 1.49 (1.30-1.71)* 1.42 (1.23-1.63)* Cumulative duration Low 360,923 111 30.8 (25.5-37.0) 1.36 (1.13-1.64)* 1.32 (1.09-1.59)* Medium 315,845 132 41.8 (35.2-49.6) 1.72 (1.45-2.04)* 1.62 (1.37-1.93)* High 235,871 119 50.5 (42.2-60.4) 1.62 (1.36-1.95)* 1.50 (1.25-1.80)* Continuous 1.06 (1.05-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 372,575 121 32.5 (27.2-38.8) 1.36 (1.13-1.62)* 1.32 (1.10-1.58)* 164 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 314,231 121 38.5 (32.2-46.0) 1.53 (1.28-1.83)* 1.44 (1.21-1.73)* High 225,833 120 53.1 (44.4-63.5) 1.89 (1.58-2.27)* 1.73 (1.45-2.08)* Continuous 1.03 (1.02-1.03)* 1.02 (1.02-1.03)* 5.2. Sulfonylureas Never 51,188,413 6,836 13.4 (13.0-13.7) 1.00 1.00 Ever use 900,231 358 36.4 (31.7-41.7) 1.49 (1.29-1.71)* 1.41 (1.23-1.62)* Cumulative duration Low 359,009 114 31.8 (26.4-38.2) 1.40 (1.16-1.68)* 1.36 (1.13-1.63)* Medium 309,407 125 40.4 (33.9-48.1) 1.66 (1.39-1.98)* 1.57 (1.31-1.87)* High 231,815 119 51.3 (42.9-61.4) 1.65 (1.38-1.98)* 1.53 (1.28-1.83)* Continuous 1.06 (1.04-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 367,838 122 33.2 (27.8-39.6) 1.38 (1.16-1.65)* 1.34 (1.12-1.61)* Medium 309,412 118 38.1 (31.8-45.7) 1.51 (1.26-1.82)* 1.43 (1.19-1.71)* High 222,981 118 52.9 (44.2-63.4) 1.88 (1.57-2.26)* 1.73 (1.44-2.07)* Continuous 1.03 (1.02-1.03)* 1.02 (1.01-1.03)* 5.2.1. Gliclazide Never 51,695,028 7,025 13.6 (13.3-13.9) 1.00 1.00 Ever use 393,616 169 37.7 (30.9-46.0) 1.47 (1.21-1.80)* 1.36 (1.11-1.66)* Cumulative duration Low 126,908 55 43.3 (33.3-56.4) 1.85 (1.42-2.41)* 1.73 (1.32-2.25)* Medium 136,638 51 37.3 (28.4-49.1) 1.51 (1.15-1.99)* 1.39 (1.05-1.83)* High 130,070 63 48.4 (37.8-62.0) 1.64 (1.28-2.10)* 1.49 (1.16-1.91)* Continuous 1.07 (1.03-1.10)* 1.05 (1.02-1.09)* Cumulative dose Low 133,699 53 39.6 (30.3-51.9) 1.64 (1.25-2.14)* 1.53 (1.17-2.00)* Medium 136,394 57 41.8 (32.2-54.2) 1.64 (1.26-2.12)* 1.50 (1.16-1.95)* High 123,523 59 47.8 (37.0-61.6) 1.70 (1.31-2.19)* 1.54 (1.19-1.99)* Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 5.2.2. Glyburide Never 51,418,210 6,916 13.5 (13.1-13.8) 1.00 1.00 Ever use 670,434 278 36.0 (29.9-43.3) 1.51 (1.25-1.82)* 1.48 (1.23-1.79)* Cumulative duration Low 283,215 85 30.0 (24.3-37.1) 1.25 (1.01-1.55)* 1.22 (0.98-1.51) Medium 224,722 108 48.1 (39.8-58.0) 1.95 (1.61-2.36)* 1.87 (1.55-2.26)* High 162,497 85 52.3 (42.3-64.7) 1.67 (1.35-2.07)* 1.57 (1.26-1.94)* Continuous 1.07 (1.05-1.09)* 1.06 (1.04-1.09)* Cumulative dose Low 296,014 95 32.1 (26.2-39.2) 1.28 (1.05-1.57)* 1.25 (1.02-1.53)* Medium 230,574 102 44.2 (36.4-53.7) 1.72 (1.41-2.09)* 1.65 (1.35-2.00)* High 143,846 81 56.3 (45.3-70.0) 2.00 (1.61-2.49)* 1.86 (1.49-2.32)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.05)* 6. Thiazolidinediones Never 51,871,508 7,105 13.7 (13.4-14.0) 1.00 1.00 Ever use 217,136 89 16.6 (9.4-29.3) 0.92 (0.52-1.61) 0.90 (0.51-1.59) Cumulative duration Low 76,357 25 32.7 (22.1-48.5) 1.52 (1.03-2.25)* 1.44 (0.97-2.13) Medium 72,351 28 38.7 (26.7-56.1) 1.79 (1.24-2.60)* 1.69 (1.17-2.45)* High 68,428 36 52.6 (37.9-72.9) 2.12 (1.53-2.94)* 1.94 (1.40-2.70)* Continuous 1.12 (1.07-1.17)* 1.11 (1.05-1.16)* Cumulative dose Low 75,982 24 31.6 (21.2-47.1) 1.44 (0.97-2.15) 1.37 (0.92-2.04) Medium 74,257 35 47.1 (33.8-65.6) 2.16 (1.55-3.01)* 2.04 (1.46-2.84)* High 66,897 30 44.8 (31.4-64.1) 1.85 (1.29-2.65)* 1.69 (1.18-2.42)* Continuous 1.11 (1.06-1.16)* 1.10 (1.05-1.15)* 6.2. Rosiglitazone Never 51,946,176 7,135 13.7 (13.4-14.1) 1.00 1.00 Ever use 142,468 59 15.9 (7.1-35.4) 0.95 (0.43-2.12) 0.97 (0.43-2.15) Cumulative duration Low 49,170 16 32.5 (19.9-53.1) 1.49 (0.91-2.43) 1.41 (0.86-2.30) Medium 48,028 20 41.6 (26.9-64.5) 1.92 (1.24-2.97)* 1.81 (1.17-2.80)* High 45,270 23 50.8 (33.8-76.5) 2.14 (1.42-3.22)* 1.97 (1.31-2.96)* Continuous 1.15 (1.08-1.24)* 1.14 (1.06-1.22)* Cumulative dose Low 49,567 16 32.3 (19.8-52.7) 1.47 (0.90-2.40) 1.39 (0.85-2.27) 165 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 49,349 22 44.6 (29.4-67.7) 2.03 (1.34-3.08)* 1.92 (1.26-2.91)* High 43,552 21 48.2 (31.4-74.0) 2.05 (1.34-3.15)* 1.88 (1.23-2.89)* Continuous 1.15 (1.08-1.22)* 1.13 (1.06-1.20)* 7. Insulins and analogues Never 51,772,245 7,008 13.5 (13.2-13.9) 1.00 1.00 Ever use 316,399 186 66.3 (56.6-77.6) 3.12 (2.66-3.66)* 2.82 (2.40-3.31)* Cumulative duration Low 143,015 63 44.1 (34.4-56.4) 2.66 (2.08-3.41)* 2.48 (1.94-3.18)* Medium 113,499 86 75.8 (61.3-93.6) 3.44 (2.78-4.25)* 3.11 (2.51-3.85)* High 59,885 37 61.8 (44.8-85.3) 2.55 (1.84-3.52)* 2.24 (1.62-3.10)* Continuous 1.16 (1.13-1.20)* 1.14 (1.11-1.18)* Cumulative dose Low 146,186 67 45.8 (36.1-58.2) 2.68 (2.10-3.40)* 2.49 (1.96-3.17)* Medium 108,141 86 79.5 (64.4-98.2) 3.60 (2.91-4.46)* 3.26 (2.64-4.04)* High 62,072 33 53.2 (37.8-74.8) 2.32 (1.64-3.26)* 2.03 (1.44-2.86)* Continuous 1.05 (1.04-1.06)* 1.04 (1.03-1.06)* 7.1. Basal insulins Never 51,784,863 7,015 13.5 (13.2-13.9) 1.00 1.00 Ever use 303,781 179 67.8 (57.6-79.6) 3.21 (2.73-3.78)* 2.90 (2.46-3.42)* Cumulative duration Low 135,289 59 43.6 (33.8-56.3) 2.65 (2.05-3.42)* 2.46 (1.91-3.18)* Medium 109,417 81 74.0 (59.5-92.0) 3.39 (2.72-4.22)* 3.06 (2.46-3.82)* High 59,075 39 66.0 (48.2-90.4) 2.70 (1.97-3.70)* 2.38 (1.73-3.26)* Continuous 1.19 (1.14-1.23)* 1.16 (1.12-1.21)* Cumulative dose Low 136,909 63 46.0 (35.9-58.9) 2.71 (2.11-3.47)* 2.51 (1.96-3.22)* Medium 106,571 82 76.9 (62.0-95.5) 3.50 (2.82-4.35)* 3.17 (2.55-3.94)* High 60,301 34 56.4 (40.3-78.9) 2.44 (1.74-3.42)* 2.14 (1.53-3.01)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* 7.2. Bolus insulins Never 51,947,122 7,092 13.7 (13.3-14.0) 1.00 1.00 Ever use 141,522 102 83.0 (65.7-105.0) 4.49 (3.55-5.68)* 4.03 (3.18-5.10)* Cumulative duration Low 68,567 51 74.4 (56.5-97.9) 4.86 (3.69-6.39)* 4.50 (3.42-5.93)* Medium 48,161 31 64.4 (45.3-91.5) 3.41 (2.40-4.85)* 3.05 (2.14-4.34)* High 24,794 20 80.7 (52.0-125.0) 3.90 (2.52-6.06)* 3.41 (2.20-5.29)* Continuous 1.27 (1.20-1.35)* 1.24 (1.17-1.32)* Cumulative dose Low 71,251 51 71.6 (54.4-94.2) 4.55 (3.46-5.99)* 4.21 (3.20-5.55)* Medium 44,054 29 65.8 (45.7-94.7) 3.47 (2.41-4.99)* 3.11 (2.16-4.48)* High 26,217 22 83.9 (55.3-127.4) 4.26 (2.81-6.48)* 3.71 (2.44-5.63)* Continuous 1.07 (1.04-1.09)* 1.06 (1.04-1.09)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table summarized the associations between select diabetes medications and pancreatic adenocarcinoma. Risk estimates are shown only for associations that were statistically significant in the primary analysis. The full results for all diabetes medications assessed can be found in Supplementary Table D-5. * denotes p<0.05. 7.5 Discussion 7.5.1 Key findings Insulin secretagogues, sulfonylurea, glyburide, and basal and bolus insulins, were associated with higher pancreatic cancer risks, even after adjusting for other diabetes medications and sociodemographic and lifestyle factors. Diabetes might confound the positive relationships 166 between metformin, glyburide, and pancreatic cancer risk based on the active comparator analysis results. The association with basal insulins remained in the active comparator analysis, suggesting it was not confounded by diabetes; however, the assessment for bolus was unattainable due to insufficient cases. 7.5.2 Comparison with other studies Our study found a link between insulins and increased pancreatic cancer risk. Both basal and bolus insulins were significantly associated with this risk, with the basal insulins demonstrating a consistent positive relationship in the active comparator analysis. Although not significant, a similar positive association was reported by Gu et al. in a Chinese study 248. A cohort study pooled data from Belgium and Italy observed a significantly higher risk for insulin use 249, suggesting a consistent positive association between insulin and pancreatic cancer risk across diverse demographics. Our findings of higher pancreatic cancer risk with shorter cumulative durations and lower cumulative doses of bolus insulin use were also consistent with Bodmer et al. 246. The variation in risk trends seen in Bosetti et al.’s pooled analysis, where pancreatic cancer risk reduced to null as duration increased, may arise from different study populations and methodological approaches, indicating the need for further research 250. 7.5.3 Strengths and limitations The research has several key strengths. The large population-based cohort was observed for up to 24 years, allowing for a detailed study of diabetes medications and pancreatic cancer links. Use of administrative health data ensured accurate and reliable data, minimizing recall and 167 misclassification biases. Exposures were constructed as time-varying variables to reduce the immortal time bias 237. Incorporation of a lag period was used to alleviate protopathic 213 and detection biases 236. The introduction of a washout period effectively mitigates biases associated with prevalent users 221. Finally, the application of diverse exposure definitions enhanced the validity of the study’s findings on the associations between diabetes medications and pancreatic cancer risk. We acknowledge there are several limitations. PharmaNet’s inability to capture medication adherence potentially led to misclassification in exposure 238. However, the misclassification was likely to be non-differential, which attenuated rather than biased the effect estimates. The cohort demographics may limit the generalizability of the findings due to our exclusion criteria. The exclusion of prevalent users of diabetes medications in particular reduced the sample size. The sample size of pancreatic cancers was also limiting in some instances, particularly with respect to sensitivity analyses and active comparator analyses. 7.6 Conclusion This study evaluated the relationships between multiple diabetes medications, ranging from common to uncommon medications, and pancreatic cancer risk. Most diabetes medications indicated null associations. The exception was insulins, especially the basal insulin subclass which were associated with increased pancreatic cancer risk. These risk associations may contribute to identifying pancreatic cancer prevention strategies, possibly influencing prescribing practices in populations at high risk of pancreatic cancer. However, verification of these results 168 in larger-scale studies in diverse demographic settings is vital. Moreover, the study evaluated various associations individually at the class, subclass, and individual levels, stressing the importance of in-depth examination in future research. 169 Chapter 8: Discussion and Conclusions 8.1 Key findings 8.1.1 Breast cancer The analysis showed that the SGLT-2 inhibitor class was significantly associated with a reduced risk of overall breast cancer, especially for low and medium cumulative duration and dose categories. The inverse relationship was also observed after adjusting for the use of other diabetes medications. The direction of the risk estimate between SGLT-2 inhibitor and breast cancer risk was consistent in the BCGP analysis after adjusting for additional sociodemographic and lifestyle-related factors. Moreover, a significant inverse association was found between SGLT-2 inhibitors and the risk of ductal breast cancer. Metformin, the class of insulins and bolus insulin subclass were all associated with increased risks of breast cancer. The protective effect on breast cancer risk in the low duration or dose category requires additional research. It may be associated with healthier lifestyles among low-dose users instead of the exposure itself, resulting in a lower risk of breast cancer. All associations remained with further adjustment for the use of other diabetes medications. In the BCGP analysis, Model 1 accounted for age, birth cohort, health authority, and neighbourhood income quintile in PopData; and Model 2 applied the identical adjustment to the BCGP subset. Model 3 further adjusted sociodemographic and lifestyle variables in the BCGP subset. The association direction with breast cancer for metformin in Models 2 and 3 of BCGP analysis was inconclusive across ever/never use, continuous cumulative duration and continuous cumulative dose definitions; thus, the impact of additional sociodemographic and lifestyle factors on the 170 association from the primary analysis (Model 1) has yet to be determined. In BCGP analysis, the association direction with breast cancer for insulins and analogues appeared to be positive, suggesting the primary analysis findings were less susceptible to confounding introduced by unmeasured sociodemographic and lifestyle factors. Although the association direction for bolus insulins varied between Models 3 and 1 from the BCGP analysis, it remains uncertain whether the results from the primary analysis were affected by confounding factors, such as sociodemographic and lifestyle factors. The differing risk estimate directions in Model 2 and Model 1 might indicate the variation in sample demographics (i.e., age, birth cohort, health authority, and neighbourhood income quintile) could also be attributable to the differences. In addition, the smaller sample size in the BCGP analysis may have resulted in diminished statistical power, hence reducing the capacity to detect significant relationships. Positive associations were detected between these medications and the risk of ductal breast cancer. Insulin secretagogues including the subclass sulfonylureas, and the individual medications gliclazide, and basal insulin subclass exhibited positive relationships with breast cancer risk in the primary analyses. However, after further adjusting for other diabetes medications, associations either changed direction or were attenuated, indicating the positive associations from the primary analyses were likely introduced by bias related to multiple diabetes medications. In the BCGP analyses, insulin secretagogue class, sulfonylureas and gliclazide, and basal insulins remained positively associated with the risk of breast cancer, suggesting the associations found in the primary analyses were less susceptible to confounding from 171 unmeasured sociodemographic and lifestyle factors. Positive associations were also observed in the ductal breast cancer subtype for these medications. Although not significant, the active comparator analyses suggest that the positive associations observed between metformin, gliclazide, basal insulins and breast cancer risk from the primary analysis were susceptible to confounding by diabetes. Conversely, the inverse association between SGLT2 inhibitors and breast cancer risk observed in the primary analysis was consistent with the active comparator analysis. 8.1.2 Colorectal cancer The use of metformin, insulin secretagogues class, and individual medications gliclazide and glyburide in the sulfonylurea subclass, were significantly associated with higher risks of colorectal cancer, although a protective effect was observed in the low duration or dose category. This may be attributable to healthier lifestyles among low-dose users as opposed to low-dose exposure, contributing to the lower risk of colorectal cancer. The positive relationships with colorectal cancer risk were observed when the use of other diabetes medications was additionally adjusted, indicating the results from the primary analysis were not likely affected by the confounding effect of multiple diabetes medication use. The direction of associations between metformin, insulin secretagogues, and colorectal cancer risk were consistently observed in the BCGP analysis, while the directions of the associations with glyburide and bolus insulins were different from findings in the primary analyses (see Models 1 and 3 in Table 6-5). The inconsistency in findings for glyburide and bolus insulins might suggest that other factors (e.g., 172 sample demographics) could be confounding the association with colorectal cancer risk in the primary analyses. Except for the null association between bolus insulins and rectal cancer risk, positive associations were consistently observed in all of these medications with all anatomic location subtypes: proximal and distal colon cancer and rectal cancer. Positive associations with colorectal cancer risk were found for thiazolidinediones, rosiglitazone, and insulins (both basal and bolus insulin subclasses) in the primary analysis. All associations were attenuated to null in the sensitivity analysis adjusting for other diabetes medications, suggesting results from primary analyses were susceptible to bias related to multiple diabetes medications. In the BCGP analysis, the direction of associations was consistent for thiazolidinediones, but there were too few events that occurred to evaluate associations with rosiglitazone. The direction of risk estimates for insulin class and basal insulin subclass in the BCGP differed from those in the primary analysis, suggesting that confounding factors may have influenced risk estimates in the primary analyses. Positive associations were consistently found across colorectal cancer subtypes, except for null associations between thiazolidinediones and distal colon cancer risk and between bolus insulins and the risk of rectal cancer. Although not statistically significant, the positive directions observed in the active comparator analysis for metformin, gliclazide, and glyburide indicated that the findings from the primary analysis were likely not confounded by diabetes. 173 8.1.3 Pancreatic cancer The class of insulin secretagogues, glyburide in the sulfonylurea subclass, class of insulins, basal and bolus insulin subclasses were positively associated with the risk of pancreatic cancer. Associations remained consistent after adjusting for other diabetes medications. After adjusting for additional sociodemographic and lifestyle-related factors in the BCGP analysis, consistent positive associations with pancreatic cancer risk were detected in the insulin secretagogue class and the sulfonylurea subclass. Associations with pancreatic cancer risk for insulin class, basal insulins, and bolus insulins in the BCGP subset appeared to be consistent with those from the primary analyses; however, the findings in BCGP should be interpreted with caution due to the small number of cases. Positive associations with pancreatic adenocarcinoma were found in insulin secretagogues, sulfonylurea, glyburide, insulins, basal and bolus insulin. Given that adenocarcinoma represents the vast majority of pancreatic cancers, this may be an important driver in the consistency of the results. In the primary analysis, the use of metformin, incretin-based medicines, sitagliptin in the DPP-4 inhibitor subclass, gliclazide, thiazolidinediones and rosiglitazone were associated with higher risks of pancreatic cancer. After adjusting for the use of other diabetes medications, associations with pancreatic cancer risk were all attenuated to null, indicating results from primary analyses were likely affected by bias related to multiple diabetes medications. It is conceivable that various diabetes medications were acting in combination or had synergistic or antagonistic effects. Thus, adjusting for use in Model 2 helped to isolate the contributions of each medication of interest. In the BCGP analysis, after controlling for additional sociodemographic and lifestyle- 174 related characteristics, positive relationships with pancreatic cancer risk were observed in metformin, incretin-based medicines (and sitagliptin in the DPP-4 inhibitor subclass), gliclazide, and thiazolidinediones. However, as noted above, the findings from the BCGP analyses should be interpreted with caution due to the low number of events. These medications showed positive associations with pancreatic adenocarcinoma as well. Based on results from the active comparator analysis, the positive associations observed between metformin, gliclazide, glyburide, and pancreatic cancer risk from the primary analysis may be confounded by diabetes. The positive association between basal insulins and pancreatic cancer risk however, remained consistent in the active comparator analysis, suggesting it was not confounded by diabetes. 8.2 Comparison with other studies 8.2.1 Breast cancer 8.2.1.1 The class of SGLT-2 inhibitors The current study found an inverse relationship between the use of SGLT-2 inhibitors and the risk of breast cancer and ductal breast cancer, even after adjusting for the use of other diabetes medications. More importantly, low and medium cumulative duration and dose categories of the SGLT-2 inhibitors showed a protective effect against breast cancer but not high cumulative duration or dose. Further research is needed to better understand if these findings are an intrinsic association characteristic or are affected by confounding. The observed inverse link contradicts existing literature. However, most previous studies have predominantly focused on clinical trials 175 data, rather than observational studies. Several studies have found predominately null results 230 or suggested a higher breast cancer risk with SGLT-2 inhibitor use 231. A meta-analysis of randomized controlled trials (RCTs) reported a non-significant higher cancer risk for SGLT-2 inhibitors in comparison to placebo or other diabetes medications 231. Another systematic review aimed to examine the relationships with cardiovascular disease, mortality and safety outcomes of RCTs and related reports from 2015 to mid-2017 230. The results indicated no links between the use of SGLT-2 inhibitors and total or site-specific cancer, including breast, bladder, or kidney 230. The systematic review and meta-analysis in Chapter 3 focused on observational studies and RCTs published between 2011 and 2021 and found no eligible studies for SGLT-2 inhibitors. It is possible the inconsistency between findings from the current study and those from RCTs and previous studies reflect the limitations of clinical trials. Factors such as stringent inclusion criteria and brief follow-up periods frequently limit the applicability of RCTs to broader populations 230,231. Consequently, these limitations may affect not only the generalizability of the findings, but also the observed direction of associations, as the trial population may have responded differently than a more diverse, real-world population. In addition, different SGLT-2 inhibitor medications were included in the current study versus RCTs. In the administrative health data from PharmaNet, only canagliflozin, dapagliflozin, and empagliflozin were prescribed, but Rådholm et al.’s meta-analysis included other novel SGLT-2 inhibitors, such as ipragliflozin, luseogliflozin, and tofogliflozin which may have different effects on biological 176 pathways 230. The limited number of large-scale, observational studies examining the effects of SGLT-2 inhibitors on breast cancer risk reflects that this class of medications is relatively new. The first SGLT-2 inhibitor, canagliflozin, was approved for the treatment of diabetes in Canada in 2014 87. There is thus a pressing need for additional research both observational, and RCTs with a longer follow-up time, to better understand the potential association between these medications and the risk of breast cancer. SGLT-2 inhibitors impede glucose reabsorption in the renal proximal tubules, resulting in increased glucose excretion via urine, a process known as glycosuria 232. The postulated biological basis for this connection is based on the interplay of SGLT-2 inhibitors and insulin signalling. SGLT-2 inhibitors reduce blood glucose levels via increasing glycosuria, lowering the need for insulin production by pancreatic β cells 232. Certain characteristics of SGLT-2 inhibitors may contribute to their unique protective effect against breast cancer. The influence of SGLT-2 inhibitors on the energy metabolism of cancer cells is one potential mechanism. In contrast to most normal cells, cancer cells frequently rely on glycolysis, even under aerobic conditions, a phenomenon known as the Warburg effect 233. By targeting the AMPK/mTOR pathway, SGLT-2 inhibitors, such as dapagliflozin and canagliflozin, have shown anti-proliferative effects on breast cancer cells 234. The SGLT-2 inhibitor ipragliflozin inhibits the proliferation of breast cancer cells via increased membrane hyperpolarization and mitochondrial membrane destabilization 235. 177 8.2.1.2 The class of biguanides (i.e., metformin) Our study observed a positive association between metformin use and breast cancer risk, as well as the ductal subtype, even after controlling for other diabetes medications. This finding contrast with the conclusions drawn by the systematic review, which indicated no significant association between metformin and breast cancer risk. A study by Soffer et al. 215 risk that followed women aged 18 years and older from 1998 to 2009 (with a median follow-up of 6 years), focusing exclusively on those newly diagnosed with diabetes 215. Relative to metformin monotherapy, the use of diabetes medications other than metformin either alone or in combination with metformin was associated with a non-significant lower breast cancer risk after adjusting for race/ethnicity, estrogen status, statin use, Charlson comorbidity index, and outpatient utilization 215. Calip et al. conducted a study of women with diabetes aged 40 and older (mean: 61.6, SD: 12.3) followed from 1996 to 2011, with a median follow-up of 6.7 years 251. They similarly found non-significant associations of invasive breast cancer among metformin ever-users compared to never-users with adjustment for other diabetes medications, smoking, menopausal status, Charlson comorbidity index, statin use, and menopausal hormone therapy. When exposure was categorized into four categories (under 1, 1 to 2.9, and 3 or more years verse never use 251, use of metformin for 3 or more years was associated with a higher risk of invasive breast cancer, although findings did not reach statistical significance. 178 The discrepancies between our finding and these studies may arise from differences in methodology. In our study, the cohort included women with and without diabetes, but Soffer et al.’s study 215 and Calip et al.’s research 251 focused exclusively on women with diabetes. Different lengths of follow-up may have also contributed to the incongruent findings: the median follow-up in people diagnosed with breast cancer is 13 years in the current study, which is substantially longer than those in the Soffer et al.’s 215 and Calip et al.’s 251 studies. The potentially greater risk of breast cancer associated with prolonged use of metformin (3 or more years) may imply that the absence of a relationship between metformin use and breast cancer in previous studies might be partially ascribed to relatively short follow-up. Additionally, different adjustment for potential confounders might have contributed to the differences in risk estimates between our current findings and existing literature. More importantly, previous studies were susceptible to time-related biases cautioned by Suissa and Azoulay 252,253. These biases can result in an overestimation of the anti-tumor effects of metformin. We mitigated immortal time bias by constructing distinct exposure variables for each medication and employing the time-dependent Cox regression method. Moreover, by incorporating washout and latency periods, we were able to alleviate biases associated with prevalent diabetes medication users and reverse causality. Our research contributes to this body of evidence by providing a new perspective on the association between metformin use and cancer risk. 179 8.2.1.3 The class of insulins and analogues, and bolus insulin subclass Our study revealed a significant positive relationship between insulin use and breast cancer risk, although the positive association between basal insulin and breast cancer risk was attenuated when models were adjusted for use of other diabetes medication indicating potential risk differences between subclasses. Notably, effect estimates for the bolus insulin subclass seemed to show stronger associations with breast cancer risk than the basal insulin subclass. The findings of our study align with previous studies. For example, Tseng 254 followed women with diabetes from 2004 to 2009. Age, diabetes duration, major comorbidities, diabetes-related complications, other cancer prior to baseline, other diabetes medications, commonly used medications, non-steroidal anti-inflammatory drugs (NSAID), and estrogen were adjusted as covariates 254. Ever use of insulin was associated with a non-significant higher risk of breast cancer compared to never use 254. The highest tertile of cumulative dose or cumulative duration of insulin use had significantly higher risk of breast cancer in comparison to never use 254. To our knowledge, there are no studies that have compared breast cancer risk among insulins as a class, basal insulin subclass, and bolus insulin subclass relative to never-users. Previous studies have compared breast cancer incidence across different types of insulins in people with diabetes: such as insulin glargine (long-acting insulin) vs. intermediate/long-acting human insulin 255, insulin glargine vs Neutral Protamine Hagedorn (NPH) insulin (intermediate-acting insulin) 256, or insulin glargine vs other insulin treatment (including human long-acting insulins, human biphasic insulins, short-acting analogue, and animal insulins) 257. This makes it difficult to situate 180 our findings in the context of the evidence base, and additional studies are required to clarify the findings of our study. 8.2.2 Colorectal cancer 8.2.2.1 The class of biguanides (i.e., metformin) Our study found a positive relationship between metformin use and colorectal cancer risk. The increased risk of colorectal cancer observed in our study was consistent across all subtypes and persisted after adjustment for use of other diabetes medications. These findings are inconsistent with the systematic review, which reported an overall significant association between metformin use and a lower risk of colorectal cancer (Chapter 3). For instance, one of the individual studies in the systematic review, Bradley et al. 239, was a cohort study that followed people in the Kaiser Permanente Northern California (KPNC) Diabetes Registry who were aged 40 or older between 1995 to 2012 (mean 9.0 years, SD 5.3 years). Among the study sample, 48.7% of metformin ever-users and 69.0% of never-users were greater than 60 years old 239. They observed long-term use (5 or more years) of metformin was related to a lower risk of colorectal cancer in men with diabetes with adjustment for race/ethnicity, diabetes duration, BMI, alcohol use, smoking, Charlson comorbidity index, education, income, creatinine, HbA1c, history of lower endoscopy, and use of other types of diabetes medications 239. 181 However, some previous studies do align with our findings. A nested case-control study by Bodmer et al. (2012) used data from the United Kingdom-based General Practice Research Database (GPRD) 241. They classified metformin use in people with diabetes into five levels based on the number of prescriptions (≥50, 30 to 49, 10 to 29, 1 to 9 vs never use) 241. The use of ≥50 prescriptions of metformin was related to a significant increase in the risk of colorectal cancer relative to never use in people with diabetes 241. Models were adjusted for use of sulfonylureas and insulin, BMI, smoking, diabetes duration, prior use of aspirin, NSAID, and statins 241. The discrepancies between our findings and those of the previous research could be ascribed to differences in study design, methodology, demographics, and potential confounding. Factors such as including prevalent metformin use and missing data in covariates in the study by Bradley et al. 239 could contribute to these discrepancies, although the study by Bodmer et al. (2012) 241 faces similar limitations. Our study’s positive association between metformin use and colorectal cancer risk warrants further research to clarify potential risk relationships and possible underlying mechanisms. 8.2.2.2 The class of insulin secretagogues, sulfonylureas subclass, gliclazide and glyburide individual medications In the current study, the use of insulin secretagogues was found to be significantly associated with an increased risk of colorectal cancer across all anatomic site subgroups and after adjusting 182 for the use of other diabetes medications. This is inconsistent with the systematic review which found a non-significant association (Chapter 3). The above described case-control study by Bodmer et al. (2012) 241 found that use of sulfonylureas were not associated with risk of colorectal cancer in comparison to never use after adjustment for the use of metformin or insulin, BMI, smoking, diabetes duration, prior use of aspirin, NSAID, and statins. This inconsistency in results from the current and Bodmer et al. study may be due to differences in study designs, demographics and the possibility of residual confounding in the current study. Our results are consistent with those reported by Lee et al. 242 who followed people aged 20 or older with diabetes from 2009 to 2015 (median: 5.4 years). In this cohort, 45.5% of those without colorectal cancer and 68.7% of those diagnosed with colorectal cancer were greater than 60 years old. They found use of sulfonylureas was significantly associated with a higher risk of colorectal cancer in models adjusted for smoking, alcohol consumption, regular exercise, income, BMI, waist circumference, hypertension, dyslipidemia, complications of diabetes, use of other diabetes medications, and duration of diabetes. However, Lee et al. did not examine associations of sulfonylureas with colorectal cancer, which limits comparison with our findings. In addition, the relationship observed in the present study echoes the results of a nested case-control study by Shin et al. 243, in which an increased risk of colorectal cancer was associated with the longest duration of sulfonylurea use (more than 730 days) after adjusting for smoking, 183 drinking, waist circumference, exercise, and insulin use, and diabetes duration. Regarding individual medications within the sulfonylurea subclass, Shin et al. found that ever use of gliclazide was associated with a possible lower but non-significant risk of colorectal cancer 243, which may be due to the limited sample size. There were few studies examining the effect of glyburide on colorectal cancer risk. Tuccori et al. focused on people with newly diagnosed diabetes using the U.K. Clinical Practice Research Datalink (CPRD) 244. They compared the use of glyburide with other second-generation sulfonylureas 244, which differs from our approach and makes comparisons difficult. The lack of comparable studies was a reoccurring challenge across most of the analyses in this thesis, reflecting heterogeneity in the characterization of medication use, comparator group, and other broad methodological differences. 8.2.3 Pancreatic cancer 8.2.3.1 The class of insulin secretagogues, sulfonylureas subclass, and glyburide individual medication In the present study, we detected a significant increase in the risk of pancreatic cancer with ever use of insulin secretagogues, which is consistent with our prior systematic review reporting a greater risk of pancreatic cancer associated with insulin secretagogue use (Chapter 3). Our findings are in agreement with a study by Lee et al., that followed a cohort of people aged 30 and older with diabetes 258 from 2009 to 2015 (median: 4.9 years, IQR: 3.9 to 6.0 years). Findings demonstrated an increased risk of pancreatic cancer associated with sulfonylurea use in models 184 adjusted for chronic pancreatitis, acute pancreatitis, hepatitis B, hepatitis C, biliary disease, alcoholism, non-alcoholic fatty liver disease, income, place of residence, and the use of other diabetes medications. The findings are also consistent with a case-control study on pancreatic cancer 246 which found a significant positive association between sulfonylureas and pancreatic cancer risk and a significant relationship among people with diabetes, especially women. Sulfonylureas use in the highest cumulative duration category (30 or more prescriptions) was significantly associated with a higher risk of pancreatic cancer 246. While several studies such as those summarized above, have examined the effect of the insulin secretagogue class or sulfonylureas subclass on the risk of pancreatic cancer, research on the individual medication glyburide is scarce. Thus, our study stands out as one of the few population-based studies to evaluate the association between glyburide use and pancreatic cancer risk. In contrast to the overall positive associations observed for the insulin secretagogue class and the sulfonylurea subclass, our study found no significant association between gliclazide use and pancreatic cancer risk. This discrepancy may be attributable to differences in the pharmacokinetics or pharmacodynamics of gliclazide compared to other sulfonylureas 259 or limited sample size, necessitating further research to clarify risk associations. 185 8.2.3.2 The class of insulins and analogues, and basal and bolus insulin subclasses Our study found a positive relationship between the use of insulins and analogues and the risk of pancreatic cancer, similar to the findings from the systematic review that reported an elevated risk of pancreatic cancers with insulin use (Chapter 3). Both basal and bolus insulin subclasses exhibited significant associations with pancreatic cancer risk, with bolus insulins seemingly showing a more pronounced relationship. The positive association with insulins and analogues may be robust across diverse demographics. Gu et al. conducted a cohort study in Shanghai among people with diabetes, reporting an increased, although not significant, risk of pancreatic cancer in insulin users relative to nonusers after adjusting for smoking status, diabetes duration, macrovascular complications, HbA1c and the use of other diabetes medications 248. A cohort study pooling data from Belgium and Italy also concluded that the use of insulin was associated with a higher risk of pancreatic cancer in people with diabetes 249. Furthermore, our results revealed significant relationships for insulins and analogues, basal insulins, and bolus insulins, indicating a higher risk of pancreatic cancer with longer cumulative durations and higher doses. These findings are consistent with those reported by Bosetti et al. They compiled 15 case-control studies from the Pancreatic Cancer Case-Control Consortium 250. Duration of insulin use was categorized into five groups: ≥15 years, 10 to 14 years, 5 to 9 years, 1 to 5 years, and no use. In comparison with no use, the risk of pancreatic cancer was most prominent in short insulin use (1 to 5 years) 250. The risk declined with increasing duration of 186 use, although the trend was non-significant 250. Relationship with pancreatic cancer risk was also explored in Bodmer et al. 246. Use of insulin was grouped into four levels: 1 to 14, 15 to 39, and 40 or more prescriptions in comparison with never use 246. In comparison to never use, people who received 40 or more insulin prescriptions had higher odds of being diagnosed with pancreatic cancer 246. The pattern regarding diminishing risk with increasing duration or dose of insulin use found in Bosetti et al. was not observed in the current study; these inconsistencies may stem from differences in study populations and methodologies such as the definitions of dose and case control versus cohort design. 8.3 Strengths The study’s use of administrative health data to gather precise exposure and outcome data is one of its main advantages. The study minimizes the possibility of recall and misclassification bias which is common in self-reported medication data and self-reported cancer diagnoses by using objective data from MSP records, PharmaNet prescriptions and cancers ascertained in the cancer registry. Integrating these databases enables a thorough analysis of medication prescription patterns, and cancer diagnoses. As a result, the study’s internal validity is improved, risk estimates are more reliable, and risk estimates are less likely to be affected by biases that may otherwise lead to misguided conclusions. The large population-based cohort of individuals aged 35 years or older who had been followed for at least five and up to 24 years resulted in identification of a large number of individuals with incident breast, colorectal, or pancreatic cancer as well as a large number of individuals who 187 were prescribed a given diabetes medication (even for less commonly prescribed medications like acarbose). A more thorough understanding of diabetes medications-cancer links is made possible by the large sample size, providing the opportunity to explore multiple secondary analyses such as adjustment for using other diabetes medications and exploration of cancer subtypes. As a result of the large sample size, and detailed medication data, diabetes-cancer links were evaluated by class, subclass and individual medication. This yielded a more nuanced understanding of the potential relationships between various diabetes medications and study cancer risk, than prior studies have been able to achieve. Indeed, the findings suggest a need to study granular information on diabetes medications, as there appears to be at least some specific effects of diabetes medications at the subclasses and individual medication level that may not be detected using broader classes or mixing classes (i.e., any diabetes medication use). In addition, the study was able to adjust for potential confounding effects from other diabetes medications, which enhances the validity of the findings. Crucially, this level of specificity provides more relevant information that may be useful to guide clinical practice and decision-making. The use of administrative health data and a population-based design reduces selection bias that is common in volunteer-based cohort studies 260. Conversely, as individuals do not ‘opt-in’ to administrative data collection, the cohort in this thesis is likely to be a more representative sample that mirrors exposure and outcomes in BC. Also, the prolonged follow-up time enables 188 the evaluation of long-term impacts of diabetes medication use which is ideal for studying cancer links, given the long latency period of breast, colorectal and pancreatic cancer development 261. Individuals who had used any diabetes medication during their first eligible year of follow-up were excluded to minimize biases of including prevalent users who had been taking diabetes medications for some time before study entry. Implementing a washout period permits us to control potential variations in baseline characteristics or outcomes of interest associated with the duration of medication use and mitigates selection biases 221 introduced by different characteristics between prevalent and new users of study medications. Thus, this method assists in isolating the actual effects of the study medications in new users. In addition, the chosen length of the washout period was likely sufficient to reduce potential biases, as seen by Table 5-6’s results that were comparable between analyses employing a 1-year (Model 1) and 2-year (Model 5) washout period. Another strength is the incorporation of a lag period – a minimum delay between use of any specified diabetes medication and the development of the outcome – to reduce protopathic 213 and detection biases 236. A 1-year lag period was used based on best practices 207 for pharmacoepidemiologic studies evaluating medications with cancer risk. A lag period reduces the likelihood of reverse causality, making it less likely that the incidence of cancer leads to diagnosis of diabetes and use of diabetes medication (i.e., reverse causality). A lag period also minimizes the likelihood of finding spurious associations. The consistent risk estimates from 189 studies using a 1-year (Model 1) and 2-year (Model 3) lag period in Table 5-6 suggest that the length of the lag period chosen was appropriate. Exposure to each diabetes medication was evaluated in a time-dependent manner. A time-varying exposure updates the exposure status throughout the follow-up period, enabling a more detailed evaluation of the association between diabetes medication use and cancer risk. In addition, the immortal time bias has been reduced by considering individuals at risk for study cancer only after they have been exposed to a diabetes medication of interest 237. Immortal time bias happens when a part of the follow-up time is incorrectly classified as unexposed or when the exposure status is misclassified 237. This results in biased estimates and challenges to find out how exposure and outcome are associated. By structuring exposure in a time-dependent fashion and considering the timing of medication use, the risk of such bias has been minimized, and the study is more likely to yield valid and reliable results. Lastly, utilizing binary, continuous (cumulative duration and dose), and categorized (none, low, medium, or high duration or dose) exposure definitions is a notable strength of this study. Using different exposure definitions, the study obtains a more comprehensive view of the associations between diabetes medications and cancer risk, strengthening the validity and generalizability of the findings. 190 8.4 Limitations PharmaNet, which provides information on prescription medications in BC, has limitations that should be acknowledged 262. Medication adherence is not possibly to directly measure. It is possible that medication use from prescription databases do not reflect adherence. For instance, the prevalence of medication nonadherence ranged from 5.1% to 10.2% in Canada 238 may have introduced a misclassification bias which could affect risk estimates. Supplementing the information obtained from PharmaNet with data from other sources, for example, patient-reported data could be advantageous although not feasible in a cohort of this size. Possible misclassification due to disconnect between use and adherence also was presumably non-differential between cases and non-cases, which would attenuate, not bias the effect estimates. Due to the limitations of administrative data, it was not possible to determine whether a participant had extended medical insurance that may provide funds to cover out of pocket expenses for some medications. The lack of insurance coverage information is a significant limitation considering it affects medication accessibility and, consequently, health outcomes. Until recently, SGLT-2 inhibitors were not covered under the MSP. For example, PharmaCare did not list empagliflozin as a limited coverage benefit until May 2019 263. However, canagliflozin and dapagliflozin are still not covered by the public drug plan. Therefore, people taking these medications likely paid out of pocket or had extended medical insurance which may make them inherently different than those who were not able to access medications not covered by MSP. Higher SES is associated with higher healthcare accessibility, as are risk factors for breast cancer; such as delayed childbirth and fewer births 129.These variables may function as 191 potential confounding variables in the association between SGLT-2 inhibitors and breast cancer risk. In addition, because of the restricted coverage of SGLT-2 inhibitors, the number of individuals exposed in our study was also limited. The lack of exposure may have limited the statistical power and could partially explain the absence of duration- and dose-response effects on breast cancer risk. As outlined above, the substantive cohort and use of administrative health data likely resulted in a population that is more similar to the population in BC than other cohort studies. However, it is also important to acknowledge that not all individuals living in BC have an MSP number (e.g., recent residents in the province and people who were not eligible for MSP). The application of exclusion criteria: individuals who passed away prior to reaching the age of 35 (or those who had not yet attained the age of 35 as of December 31, 2019); previous or prevalent cancer (other than non-melanoma skin cancer) from 1985 to the study baseline; <5 consecutive years of MSP data; people who were no longer registered in the MSP since January 1, 1996; follow-up for fewer than 5 years; use of diabetes medication in the first year of follow-up, and initiation of diabetes medications less than 1 year before the endpoint, may have resulted in a population that differed from those in the wider population. Collectively, this might limit the generalizability of the findings to the wider population in BC. For pancreatic cancer, there is the possibility of undiagnosed cases. Unlike breast and colorectal cancers, there is no population-based screening program for pancreatic cancer in BC. Although this study design included a 1-year lag period to minimize the occurrence of reverse causality 192 where the incidence of cancer might lead to the diagnosis of diabetes and subsequent use of diabetes medication, it may not be sufficient for pancreatic cancer, which is often diagnosed at a late stage. This study observed several positive relationships between diabetes medications and pancreatic cancer risk that could be influenced by differential detection. Individuals treated for diabetes typically have frequent medical consultations, potentially leading to earlier detection of pancreatic cancer compared to unexposed individuals. This differential detection could contribute to an overestimation of the observed associations. Changes in screening, diagnostic, and treatment practices for diabetes may increase people’s exposure to diabetes medication. For example, the recommended age for regular diabetes screening, which should occur at least every three years, was lowered from 45 13 to 40 years old 63 in 2003 264. Changes in the availability of cancer screening over the course of the study period may have influenced the detection and incidence of cancer. In BC, publicly-funded, population-based breast cancer screening (mammogram) was initiated in the 1980s before the study baseline, while the colon screening program (particularly fecal immunochemical test) was not available until 2013 265. The presence of missing data, particularly for demographic covariates such as health authority and neighbourhood income quintile at baseline, is a study limitation. Single imputation 212 was employed to impute missing data in baseline health authority and neighbourhood income quintile, but the accuracy of the imputed values is contingent on the validity of the underlying assumptions. Assumptions, such as the missing-at-random assumption and the relationships 193 among the variables used for imputation 266, could not be confirmed with certainty. If these assumptions are false, the imputation process might impose unnecessary bias or distort the relationship among variables. There is also potential for unmeasured or residual confounding, as administrative health data does not capture factors that may influence the association between diabetes medications and the risk of study cancers such as a family history of cancer, genetic predispositions, and lifestyle factors (smoking, alcohol consumption, diet, weight and physical exercise). The sensitivity analysis in the BCGP subset provided insight into the potential influence of residual confounding on effect estimates. Yet, lifestyle variables in the BCGP were self-reported, which is prone to bias and misreporting. Besides, small sample sizes limited detailed examination of individual diabetes medications and pancreatic cancer. Though the BCGP sensitivity analysis provided important insights into the role of additional lifestyle factors, it was limited by its small sample size and a demographic distribution that differed from the primary analysis. Thus, its findings should be regarded as supplementary. Our study lacked information on weight changes over time. Medications like glyburide 267 are often accompanied by weight gain which may increase cancer risk. However, change in weight is likely a mediator in the relationship between diabetes medications and cancer, and thus including it in models could obscure the total effect of diabetes medications on cancer risk 268. This study examined numerous relationships between 20 diabetes medications and three cancer outcomes but did not apply a conservative multiple testing correction as Bonferroni correction 194 269. The associations with breast cancer for SGLT2 inhibitors, insulin secretagogues (and gliclazide in the sulfonylurea subclass) and insulins and analogues (and basal and bolus insulin subclasses) and the association with pancreatic cancer for DPP-4 inhibitors were susceptible to false discoveries using the False Discovery Rate 270. P value cut-off of 0.05 was used to promote consistency among scientific studies and facilitate the determination of statistical significance. 8.5 Public health implications This study focuses on the complex relationships between numerous diabetes medications and the risk of breast, colorectal, and pancreatic cancer. These results highlight the need for a more contextualized understanding of diabetes medications and their potential long-term health risks. The majority of classes, subclasses and individual medications had null associations, suggesting possible safety with respect to breast, colorectal and pancreatic cancer risk. The significant risk relationships observed for SGLT-2 inhibitors, insulin secretagogues, and insulins and analogues provide a foundational step towards developing an evidence base that may help to identify approaches to reduce the risk of cancer (i.e., through preferential or avoidance of prescription of a given medication). Identifying novel strategies to reduce the risk of breast, colorectal and pancreatic cancers is critical to improving public health since cancer prevention strategies such as lifestyle interventions have generally achieved incremental impact on the burden of cancer. To substantiate our findings and assure their wide applicability, further large-scale observational studies are crucial. While incorporating lifestyle factors, these studies should also extend to 195 diverse populations across various Canadian provinces or international jurisdictions with comparable administrative health data. Given the potential variations in healthcare practices, diabetes medication prescription patterns, and demographic distributions, it is paramount to account for these influences. By replicating this study in different settings, the reliability and generalizability of the findings can be determined, thereby fostering a deeper understanding of the risk associations. Since some SGLT-2 inhibitors have recently gained approval under public health insurance in BC, Canada 263; future studies will be better positioned to evaluate relationships with SGLT-2 inhibitors with enhanced statistical power. In addition, in the future, RCTs may help to verify the findings and understand cause-effect relationships. Collectively, this evidence may ultimately improve public health and individual care of the substantive number of Canadians, and adults worldwide, living with diabetes. 8.6 Future Research Given the scarcity of cancer outcomes particularly pancreatic cancer, future research would benefit greatly from a nested case-control study within a larger cohort 271. This study design is effective for determining the temporal relationship between exposure to diabetes medications and cancer incidence. In addition, relationships with two or more medications can be explored using an active comparator analysis. This strategy can effectively mitigate confounding by indication. This nuanced approach takes into consideration the potential long-term effects of medication exposure, given the extended latency period associated with the development of cancer. 196 Along with the aforementioned modifications to the study design, the issue of potential biases – the healthy user bias and disease severity confounding – must be addressed directly in future research. Advanced statistical techniques, such as propensity score matching 272, can be applied appropriately to alleviate these biases, resulting in more reliable findings. Future research should consider employing restricted cubic spline models to investigate the associations between the cumulative duration and dose of diabetes medications and the risk of cancer. This method allows for the flexible modelling of potential nonlinearities in exposure-response relationships over time and the adjustment of time-dependent confounders 273. Meanwhile, incorporating information on medication adherence patterns into the research design will improve exposure classification accuracy. Such adherence data, which could be collected from patient surveys, may provide invaluable insight into the intricate relationship between medication use and cancer risk. The potential overlap between polycystic ovary syndrome (PCOS) and type 2 diabetes might affect our study and must be considered. Indeed, the prevalence of PCOS in women of reproductive age is 4 to 20% 274, and women with PCOS were at a higher risk of developing diabetes before age 40 275. The co-occurrence of these conditions might occur due to shared major risk factors, such as being overweight, family history, and insulin resistance 276. Therefore, the use of metformin in our cohort might be associated not only with diabetes but also with a concurrent diagnosis of PCOS. In order to disentangle the effects of metformin for the treatment of diabetes from its effects for PCOS, future research should consider adjusting other medical conditions such as PCOS. This will enable a more accurate assessment of the association between metformin and cancer risk. 197 To strengthen the external validity of the findings, future research ought to reach beyond the initial study population and settings. Consideration of diverse populations and healthcare systems in future research is essential for examining potential variations in healthcare practices, prescription patterns, and the demographic makeup of populations served. Replication in diverse settings can significantly improve the robustness and generalizability of the findings, thereby enhancing the comprehension of the potential influence of these factors on the observed associations. Additionally, it is critical to obtain additional data on lifestyle variables and other cancer and diabetes risk factors. This method can help control residual confounding and provide a fuller understanding of the complex relationship between these variables, diabetes medications, and cancer risk. 8.7 Conclusions Leveraging data held at Population Data BC and methodological advancements, this cohort study elucidated the associations between diabetes medications and the risk of breast, colorectal, and pancreatic cancers, considering duration- and dose-response relationships, latency, and key confounding variables. The findings highlighted a complex mixture of associations that often differed within a class or subclass of medications, and were specific to a cancer type. Hence, it is important to conclude highly granular levels of diabetes medications and cancer in future studies. The findings suggest that many diabetes medications carry no or lower risk, while some increase cancer risk. 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Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18, 774–800 (1997). 220 Appendices Appendix A Supplementary tables for Chapter 3 Supplementary Table A-1. MEDLINE (Ovid) search strategy # Query 1 exp Hypoglycemic Agents/ 2 exp Diabetes Mellitus, Type 2/dt [drug therapy] 3 exp Diabetes Mellitus/dt [drug therapy] 4 exp Hyperglycemia/dt [drug therapy] 5 or/1-4 6 ((diabet* or antidiabet* or anti-diabet* or hypoglycemic or antihyperglycem* or anti-hyperglycem*) adj5 (drug* or medication* or medicine* or treatment* or intervention* or therap* or medicament* or pharmaceut* or regimen)).mp. 7 ((insulin resistan* or pre-diabet* or prediabet* or pre diabet*) adj5 (drug* or medication* or medicine* or treatment* or intervention* or therap* or medicament* or pharmaceut* or regimen)).mp. 8 (metformin or biguanide or AGI or AGIs or Alpha-glucosidase inhibitor* or dipeptidyl-peptidase 4 inhibitor* or DPP 4 inhibitor* or Dipeptidyl peptidase-4 inhibitor* or glucagon-like peptide-1 or incretin* or Sitagliptin or glucagon-like peptide-1 or chemoprevention or alpha-glucosidase inhibitor or Gastric inhibitory polypeptide* or gastric inhibitory peptide*or glucose-dependent insulinotropic polypeptide* or sodium-glucose cotransporter 2 inhibitor* or SGLT-2 inhibitor* or Canagliflozin or Acarbose or Miglitol or Voglibose or Exenatide or Liraglutide or Glipizide or Glybenclamide or Glibenclamide or Pioglitazone or Glitazones or Insulin glargine or insulin or Alogliptin or Linagliptin or Saxagliptin or Sitagliptin or Albiglutide or Dulaglutide or Exenatide or Liraglutide or Lixisenatide or Semaglutide or Gliptin* or Sodium Glucose Transporter 2 Inhibitor* or Sodium-Glucose Transporter 2 Inhibitor* or SGLT-2 Inhibitor* or SGLT 2 Inhibitor* or Gliflozin* or DPP-4 Inhibitor* or DPP 4 Inhibitor* or DPP-IV Inhibitor* or DPP IV Inhibitor* or Dipeptidyl Peptidase 4 Inhibitor* or Dipeptidyl-Peptidase IV Inhibitor* or Dipeptidyl Peptidase IV Inhibitor* or thiazolidinedione*).mp. 9 or/6-8 10 5 or 9 11 exp Neoplasms/ 12 exp Carcinoma/ 13 exp Carcinoma, Hepatocellular/ 14 exp Liver Neoplasms/ 15 exp Pancreatic Neoplasms/ 16 exp Colorectal Neoplasms/ 17 exp Breast Neoplasms/ 18 exp Prostatic Neoplasms/ 19 exp lung neoplasms/ 20 or/12-19 21 morbidity/ or incidence/ or mortality/ or "cause of death"/ or fatal outcome/ or mortality, premature/ or survival rate/ 22 20 and 21 23 ((neoplasm* or carcinogen* or cancer* or tumor or tumour or carcinoma or tumorigen*) adj5 (inciden* or diagnos* or occurrence or risk or mortality or death* or fatal*)).mp. 24 ((Breast or lung or prostate or colorectal or colon or rectal or rectum or liver or hepatic or hepato* or pancrea*) adj5 (cancer* or tumor* or tumour* or carcinoma or neoplasm*)).mp. 25 (inciden* or diagnos* or occurrence or risk or mortality or death* or fatal*).mp. 26 24 and 25 27 22 or 23 or 26 28 10 and 27 29 limit 28 to "humans only (removes records about animals)" 30 limit 29 to children 31 29 not 30 32 limit 31 to yr="2011 -Current" 33 (randomi?ed controlled trial or controlled clinical trial).pt. 34 (Randomi?ed or randomly or trial or groups).ab. 35 drug therapy.fs. 36 33 or 34 or 35 221 37 Epidemiologic studies/ 38 exp case control studies/ 39 exp cohort studies/ 40 Case control.tw. 41 (cohort adj (study or studies)).tw. 42 Cohort analy$.tw. 43 (Follow up adj (study or studies)).tw. 44 (observational adj (study or studies)).tw. 45 Longitudinal.tw. 46 Retrospective.tw. 47 or/37-46 48 36 or 47 49 32 and 48 222 Supplementary Table A-2. Characteristics of included studies assessing cancer risk with diabetes medications Study Location or setting Time period; mean/median follow-up (years) Age range, mean/median and standard deviation/IQR (years) Percent male (%) Exposure or treatment categories Outcome Matched, adjusted, or randomized factors Risk of bias NOS score 3 Randomized controlled trials (RCTs) Hernandez 2018 28 countries; hospital-based 2015 to 2018; median 1.6 40+; 64.1 (8.7) in albiglutide group; 64.2 (8.7) in placebo group 69.4 Class 2, albiglutide vs no use of albiglutide Pancreatic cancer Randomized by age, sex, race/ethnicity, geographic region, current smoking, medical history, body mass index, glycated haemoglobin, estimated glomerular filtration rate (EGFR), duration of diabetes, history of microvascular disease, cardiovascular medications, and glucose-lowering medications High NA Jones 2015 364 centers in 25 countries in Europe and Australasia; hospital-based 2008 to 2012; NA 40 to 75; 58.4 (8.3) in rosiglitazone group; 58.5 (8.3) in metformin/sulfonylurea group 51.4 in rosiglitazone group; 51.7 in metformin/sulfonylurea group Class 5, rosiglitazone combined with sulfonylurea or metformin vs metformin and sulfonylurea Breast, colorectal, and pancreatic cancers Randomized by age, gender, ethnicity, body weight, body mass index, menopause status, duration of diabetes, HbA1c High NA Bethel 2017 38 countries; hospital-based NA; median 2.9 50+; 82% were <75 71.1 Class 2, sitagliptin vs no use of sitagliptin Pancreatic cancer NA High NA 42 Cohort studies Soffer 2015 United States; population-based 1998 to 2009; median 6 18+; 55.5 (16.1) NA Class 1, metformin vs no use of metformin Breast cancer Adjusted for age of index diabetes diagnosis, race/ethnicity, ERT status, statin use, Charlson comorbidity index, and outpatient utilization Low 9 223 Habel 2013 United States; population-based 2001 to 2009; median 3.3 ~60% were >50 53.1 in glargine users; 49.7 in neutral protamine hagedorn (NPH) insulin users Class 6, glargine vs NPH insulin use only Breast, colorectal, and cancers Adjusted for Kaiser Permanente region, calendar year, age, metformin use, and use of short-acting insulin Moderate 6 Knapen 2016 United Kingdom; population-based 2007 to 2012; mean 4.1 18+; 58.1 (11.8) in incretins exposed group; 62.4 (14.9) in the exposed group of other noninsulin antidiabetic medications 56.3 Class 2, incretins vs use of other noninsulin antidiabetic medications Pancreatic cancer Matched on sex, year of birth (within 5 years) and practice; Adjusted for alcoholism, alcohol use, body mass index, smoking, neuropathy, and retinopathy Low 8 Funch 2018 United States; population-based 2010 to 2014; NA 18+; median 52.0 (IQR: 44.0, 58.0) in liraglutide exposed group; 51.0 (IQR: 39, 59) in liraglutide unexposed group NA Class 2, liraglutide vs all comparator drugs except exenatide (to remove any GLP-1 RA effect) Breast cancer Propensity score matched on demography, smoking, alcohol, comorbidity, concomitant medications, and intensity of health care utilization Moderate 6 Chang 2011 Taiwan; population-based 2004 to 2007; mean 2.0 18+; 60.7 (12.8) in insulin glargine users; 62.1 (13.4) in intermediate/long-acting human insulin (HI) users 49.5 in insulin glargine initiators; 47.7 in intermediate/long-acting HI users Class 6, insulin glargine vs intermediate/long-acting HI Breast, colorectal, and pancreatic cancers Propensity score adjusted for age category, sex (if shared sites), initiation year, diabetes-related late complications, major comorbidities, Charlson Index (not include diabetes), other diabetes medications, statins, aspirin, resource utilization, and physician characteristics, time-varying medication use, and dosage of studied insulin Low 7 Suissa 2011 United Kingdom; population-based 2002 to 2009; NA 40+; 60.9 (13.1) in glargine group; 61.2 (12.2) in other insulin group NA Class 6, insulin glargine vs other insulin treatment (including human long-acting Breast cancer Adjusted for age categories, age, excessive alcohol use, smoking status, obesity (body mass Low 8 224 insulins, human biphasic insulins, short-acting analogue, and animal insulins) index>30 kg/m2), HbA1c, diabetes duration, duration of insulin use, oophorectomy, history of cancer, use of hormone replacement therapy, sulfonylureas, thiazolidinediones, metformin and statins Funch 2014 United States; population-based 2010 to 2012; NA 18+; median 53.0 45.8 in liraglutide users; 50.5 in other users Class 2, liraglutide vs pooled comparator drugs (excluding exenatide and DPP-4 inhibitors) Pancreatic cancer Adjusted for age, gender, healthcare utilization, and Diabetes Complications and Severity Index Low 7 Vallarino 2013 United States; population-based 2000 to 2010; mean 2.2 for pioglitazone and 1.9 for insulin patients 45+; 58.1 (8.7) in pioglitazone cohort and 59.7 (10.3) in insulin cohort 59.6 in pioglitazone cohort; 53.0 in insulin cohort Class 5, pioglitazone vs insulin Breast, colorectal, and pancreatic cancers Adjusted for demographics (age, tobacco use), use of medications (other antidiabetic drugs, commonly used cardiovascular medications, aspirins, NSAIDs, anticoagulants, antiplatelets, etc.) and medical history (obesity, hyperlipidemia, myocardial infarction, coronary heart disease, coronary revascularization stroke, congestive heart failure, hypertension, arrhythmias, cancer, bone fracture, renal impairment, gout) Low 7 Gu 2013 Shanghai, China; population-based 2002 to 2010; NA 30+; 62.2 (18.0) in insulin users; 61.0 (17.0) in non-insulin users 51.5 in insulin users; 54.4 in non-insulin users Class 6, insulin vs not use of insulin Breast, colorectal, and pancreatic cancers Adjusted for age, smoking status, diabetes duration, macrovascular, HbA1c and Low 7 225 concomitant oral glucose-lowering agents (including metformin, sulfonylureas, and acarbose) Kao 2013 Taiwan; population-based 2001 to 2009; NA 20+; 56.5 (13.2) 55.1 Class 5, thiazolidinediones vs no use of thiazolidinediones Breast, colorectal, and pancreatic cancers Matched on birth year, sex, and calendar year of diabetes diagnosis Low 7 Fagot 2013 France; population-based 2007 to 2009; median 2.67, 2.75, and 2.83 in patients exposed to insulin glargine, insulin detemir, and BHI, respectively. 40+; overall population (both men and women) 63.2; 10.10 NA Class 6, insulin glargine or insulin detemir or basal human insulin (BHI) vs no use of Insulin glargine, insulin detemir BHI Breast cancer Adjusted for use of other hypoglycemic agents and duration of diabetes Moderate 6 Redaniel 2012 United Kingdom; population-based 1987 to 2007; NA 35+; ~51.5% were >60 NA Class 4, sulfonylurea vs no use of sulfonylurea; Class 6, insulin vs no use of insulin Breast cancer Adjusted for age, period, region, body mass index, year of diagnosis, and weighted HbA1c Low 9 Calip 2016 United States; population-based 1996 to 2011; median 6.7 40+; 61.6 (12.3) NA Class 1, metformin vs no use of metformin; Class 4, sulfonylureas vs no use of sulfonylureas; Class 6, all insulins vs no use of insulin Breast cancer Adjusted for other diabetes medications, age at cohort entry, study entry year, smoking status, menopausal status, Charlson score, statin use, and menopausal hormone therapy Low 8 Erdmann 2016 19 European countries; population-based 10 years; mean 7.8 35 to 75; 61.8 (7.7) 66.1 Class 5, pioglitazone vs no use of any diabetes medications Breast, colorectal, and pancreatic cancers NA Low 7 Tseng 2016 Taiwan; population-based 1999 to 2010; NA 25+; 52.6 (11.5) in ever-users of sitagliptin; 56.4 (13.8) in never users 53.8 in ever-users of sitagliptin; 52.9 in never-users of sitagliptin Class 2, sitagliptin vs no use of sitagliptin Pancreatic cancer Propensity score adjusted for age, sex, major comorbidities, diabetes-related complications, acute Low 8 226 pancreatitis, gallstone, commonly used medications, other diabetes medications, aspirin, and anticoagulants Tseng 2015 Taiwan; population-based 1996 to 2009; NA NA; 63.7 (12.7) in ever-users of human insulin; 62.5 (12.2) in never-users of human insulin NA Class 6, human insulin vs no use of human insulin Breast cancer Adjusted for age, diabetes duration, major comorbidities, diabetes-related complications, other cancer prior to baseline, other diabetes medications, commonly used medications, non-steroidal anti-inflammatory drugs, and estrogen Low 8 Tuccori 2015 United Kingdom; population-based 1988 to 2013; mean 5.3 40+; 64.0 (11.9) in users of glyburide; 64.0 (12.5) in users of other second-generation sulfonylureas 66.4 in users of glyburide; 73.3 in users of other second-generation sulfonylureas Class 4, glyburide vs use of other second-generation sulfonylureas Breast and colorectal cancers Adjusted for age, body mass index, smoking status, excessive alcohol use, HbA1c, duration of treated diabetes, comedications, use of other antidiabetic medications, ever use of oral contraceptives, hormone replacement therapy, and previous mammography screening Low 8 Gokhale 2014 United States; population-based 2007 to 2011; median 10 months (IQR: 5, 18 months) 65+; mean 75.0 35.0 Class 2, dipeptidyl peptidase-4 inhibitors vs sulfonylureas or thiazolidinediones Pancreatic cancer Propensity score weighted for comorbidities and health care utilization Low 7 Tsilidis 2014 United Kingdom; population-based 1987 to 2010; median 5.1 35 to 90; 61.1 in users of metformin monotherapy; 65.3 in users of sulfonylurea monotherapy 56.1 in users of metformin monotherapy; 57.9 in users of sulfonylurea monotherapy Class 1, metformin monotherapy vs sulfonylurea monotherapy Breast (postmenopausal breast cancer), colorectal, and pancreatic cancers Adjusted for smoking status, body mass index, alcohol consumption, use of aspirin or NSAIDs, statins, diabetes duration, and year of Low 8 227 first anti-diabetes prescription Tseng 2014c Taiwan; population-based 1998 to 2009; NA NA; 56.5 (12.3) in ever-users of metformin; 54.9 (16.7) in never-users of metformin NA Class 1, metformin vs no use of metformin Breast cancer Adjusted for age, major comorbidities, diabetes-related complications, other cancer, commonly used medications, other antidiabetic medications, aspirin, nonsteroidal anti-inflammatory drugs, and anticoagulants Low 7 Vicentini 2018 Italy; population-based 2009 to 2014; NA 20 to 84; 66.1 (11.1) 55.6 Class 1, metformin vs untreated diabetes (diet only) Breast, colorectal, and pancreatic cancers Adjusted for age, citizenship, and time since diagnosis of diabetes Moderate 6 Bradley 2018 United States; population-based 1995 to 2012; mean 9.0 40+; 48.7% of ever users and 69.0% never users of metformin were >60, respectively 53.95; 52.3 in ever users; 55.3 in never users Class 1, metformin vs never use of metformin Colorectal cancer Adjusted for gender, race/ethnicity, birth year, diabetes duration, body mass index, alcohol use, smoking status, Charlson comorbidity index, education, income level, creatinine, HbA1c, history of lower endoscopy; first lower endoscopy after baseline (time-varying) and use of other types of diabetes medications (time-varying) Low 8 Tseng 2017b Taiwan; population-based 1995 to 2005; median 5.5 25 to 75; 62.0 (10.1) 54.2 Class 1, metformin vs no use of metformin Colorectal cancer Inverse probability of treatment weighting using propensity score adjusted for age, gender, occupation, region of residence, major comorbidities, diabetes-related complications, antidiabetic drugs, diagnosis possibly Low 9 228 associated with cancer risk, medications commonly used for diabetes that may affect cancer risk, and entry date Abrahami 2018 United Kingdom; population-based Up to 9.5 years; NA NA; 64.0 (12.0) 58.2 Class 2, GLP-1 analogues or DPP-4 inhibitors vs use of other diabetes medication(s) Colorectal cancer Adjusted for age, sex, year of cohort entry, body mass index, smoking, alcohol-related disorders (including, e.g., alcoholism, alcoholic cirrhosis of the liver, alcoholic hepatitis, and hepatic failure), hemoglobin A1c, duration of treated diabetes, previous cancer, presence of inflammatory bowel disease, Charlson comorbidity score, neuropathy, renal disease, retinopathy, peripheral arteriopathy, aspirin, statins, the number of unique antidiabetic drugs, and the total number of unique nondiabetic drugs in the year before cohort entry Low 9 Boniol 2018 Belgium and Italy; population-based NA; Belgium exposed mean 1.81; Belgium unexposed mean 2.83; Italy exposed mean 1.25; Italy unexposed mean 2.55 18+; >70% are 50+ 49.5 Class 2, GLP-1 RA (sexenatide and liraglutide) and the DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin) vs noninsulin antidiabetic drug; Pancreatic cancer Stratified by age and sex and adjusted for use of insulin Moderate 6 229 Class 6, insulin vs no prescription of insulin You 2020 South Korea; population-based 2005 to 2014; NA NA; 60.7 (15.4) in users of metformin; 60.9 (13.9) in non-users of metformin 49.9 in users of metformin; 50.9 in non-users of metformin Class 1, metformin vs no use of metformin Colon, and pancreatic cancers Adjusted for age, sex, economic status, region of residency, and antidiabetic medications (sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, alpha-glucosidase inhibitors, and meglitinide) Low 8 Tseng 2017c Taiwan; population-based 1999 to 2010; NA 25+; 53.6 (11.3) in ever users of sitagliptin; 55.9 (13.3) in never users of sitagliptin NA Class 2, sitagliptin vs no use of sitagliptin Breast cancer Inverse probability of treatment weighting using propensity score adjusted for age, diabetes-related comorbidities, acute pancreatitis, commonly used medications, other diabetes medications, aspirin, anticoagulant medications, estrogen, and potential detection examinations Low 8 Tseng 2017d Taiwan; population-based 1996 to 2009; NA Over 85% were aged >50 NA Class 5, rosiglitazone vs no use of rosiglitazone Breast cancer Adjusted for age, diabetes duration, hypertension, COPD, cerebrovascular disease, nephropathy, ischemic heart disease, peripheral arterial disease, eye disease, obesity, dyslipidemia, benign breast conditions, other cancer prior to baseline, sulfonylurea, metformin, acarbose, insulin, estrogen, potential detection examinations Low 8 230 Bowker 2017 United States; population-based 6 years; NA 30+; 53.0 (9.2) NA Class 1, metformin vs no use of metformin; Class 4, sulfonylurea vs use of other diabetes medication(s); Class 5, thiazolidinedione vs no use of thiazolidinedione; Class 6, insulin vs no use of insulin Breast cancer Adjusted for age at drug index Moderate 6 Tseng 2017e Taiwan; population-based 1997 to 2012; NA 18+; 64.1 (12.2) in incretin cohort; 63.6 (12.2) in non-incretin cohort 50.5 Class 2, incretin-based medicines (including saxagliptin, vildagliptin, sitagliptin, exenatide, and linagliptin) vs no use of incretin-based medicines Pancreatic cancer Matched on age (±1 year), gender, Diabetes Complication Severity Index; Adjusted for gallstone disease, alcohol-related disease, hypertriglyceridemia, pancreatic disease, obesity, and tobacco use Low 7 Erkinantti 2020 Finland; population-based 1996 to 2011; NA 40+; over 50% were >70 52.3 Class 1, metformin vs no use of metformin; Class 6, insulin vs no use of insulin Colon cancer Adjusted for age, sex, and the duration of diabetes Low 7 Lee 2019a South Korea; population-based 2007 to 2013; mean 3.6 in DPP-4i users; 3.4 in nonusers 40 to 79; 62.1; 9.2 57.8 Class 2, dipeptidyl peptidase 4 inhibitors (including sitagliptin, vildagliptin, linagliptin, saxagliptin, and gemigliptin) vs no use of dipeptidyl peptidase 4 inhibitors Pancreatic cancer Adjusted for age, sex, body mass index, smoking status, alcohol intake, Charlson comorbidity index, residential region, use of antidiabetic drug (biguanides, sulfonylureas, TZDs, and insulin), histories of cholecystectomy, and gastrectomy Low 8 231 Liang 2019 United States; population-based 2005 to 2015; median 0.9 in exposed group; median 1.3 in unexposed group NA; more than 60% were aged >50 50.0 Class 2, exenatide vs no use of exenatide Pancreatic cancer Adjusted for unbalanced propensity score model variables that were identified from a separate database, including number of antidiabetic drugs, metformin, pharmacy cost, and number of unique drugs dispensed at baseline Low 7 Chang 2018 Taiwan; population-based 1996 to 2008; mean 7.2 15+; 54.4 (14.2) 53.1 Class 1, metformin vs no use of metformin Colorectal cancer Adjusted for age, gender, modified Charlson comorbidity index score (subtracting two diabetic conditions from the original Charlson Comorbidity Index score) Low 7 Albai 2020 Romania; hospital-based 2015 to 2018; NA 41 to 88; 66.3 (10.0) 43.4 Class 1, metformin vs no use of metformin; Class 2, incretins vs no incretins; Class 4, sulfonylureas vs no sulfonylureas; Class 6, insulin vs no insulin Colorectal cancer Adjusted for age, gender, body mass index, abdominal circumference, smoking, alcohol, diabetes mellitus duration, HbA1, triglycerides, total cholesterol, HDLc, LDLc, hypertension Moderate 5 Bradley 2020 United States; population-based 2006 to 2017; median 2.9 in glargine users, median 2.5 in detemir users, and 2.3 in NPH users 65+; ~50% were aged between 65 and 74 NA Class 6, glargine vs neutral protamine hagedorn insulin or detemir insulin Breast cancer Inverse probability of treatment weighting using propensity score adjusted for age, race, low-income status, zip code-level income, metropolitan statistical area, medication use, medical conditions, alcohol abuse, smoking, and health care utilization Low 7 232 Chen 2020 Taiwan; population-based 1998 to 2010; mean 6.8 20+; 57.6 (13.2) 53.5 Class 6, insulin vs no use of insulin Colorectal cancer Adjusted for age, sex, urbanization level, comorbidities, insulin usage and examinations Low 7 Lee 2018 South Korea; population-based 2009 to 2015; median 4.9 30+; 57.2 (12.5) 55.6 Class 1, metformin vs no use of metformin; Class 2, dipeptidyl peptidase-4 inhibitor vs no use of dipeptidyl peptidase-4 inhibitor; Class 3, alpha-glucosidase inhibitor vs no use of alpha-glucosidase inhibitor; Class 4, sulfonylurea or meglitinide vs no sulfonylurea and no meglitinide; Class 5, thiazolidinedione vs no use of thiazolidinedione; Class 6, insulin vs no use of insulin Pancreatic cancer Adjusted for age, sex, chronic pancreatitis, acute pancreatitis, hepatitis B, hepatitis C, biliary disease, alcoholism, non-alcoholic fatty liver disease, income of lowest quartile, place of residence, and the number of different exposed anti-diabetic medications Low 8 Lee 2019c South Korea; population-based 2009 to 2015; median 5.4 20+; 68.7% of colorectal cancer cases and 45.5% of controls were >60 66.7 in colorectal cancer cases; 59.9 in controls Class 1, metformin vs no use of metformin; Class 2, dipeptidyl peptidase-4 inhibitor vs no use of dipeptidyl peptidase-4 inhibitor; Class 3, acarbose vs no use of acarbose; Class 4, sulfonylurea or meglitinide vs no use of sulfonylurea and meglitinide; Class 5, Colorectal cancer Adjusted for age, sex, smoking, alcohol consumption, regular exercise, yearly income, residency, body mass index, waist circumference, hypertension, dyslipidemia, complications of diabetes, antidiabetic medications, and duration of diabetes Low 8 233 thiazolidinedione vs no use of thiazolidinedione; Class 6 insulin vs use of insulin Lee 2011 Taiwan; population-based 2000 to 2007; mean 3.9 in metformin users 20+; 41.9% of metformin user and 48.6% non-users were >60 54.9 in metformin users; 54.6 in metformin non-users Class 1, metformin vs no use of metformin Colorectal and pancreatic cancers Adjusted for age group, gender, other oral anti-hyperglycemic medication, Charlson comorbidity index score, and duration of metformin exposure which was treated as a time dependent variable Moderate 6 Carstensen 2012 Denmark; population-based 1995 to 2009; NA NA NA Class 6, insulin vs no use of insulin Breast, colorectal, and pancreatic cancers Adjusted for age, calendar time, and date of birth Low 7 Tseng 2012 Taiwan; population-based 2003 to 2005; NA NA; 77.9% were >40 45.3 Class 1, metformin vs no use of metformin Colon cancer Adjusted for age, sex, region of residence, occupation, major comorbidities, diabetes-related complications, other cancer before baseline, commonly used medications, aspirin, nonsteroidal anti-inflammatory drug, anticoagulants, other diabetes medications, and potential colon cancer detection examinations Low 7 16 Case-control studies Bodmer 2012a United Kingdom; population-based 1995 to 2009; NA <90; 69.5 (11.0) 46.2 Class 1, metformin vs no prior use of metformin; Class 4, sulfonylureas vs no prior use of sulfonylureas; Pancreatic cancer Matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD before the index date; Adjusted for Low 8 234 Class 6, insulin vs no prior use of insulin sulfonylureas, insulin, body mass index, smoking, alcohol consumption, and diabetes duration Bodmer 2011 United Kingdom; population-based 1995 to 2009; NA NA; 70.2 (8.6) 63.3 Class 1, metformin vs no prior use of metformin; Class 4, sulfonylureas vs no prior use of sulfonylureas; Class 6, insulin vs no prior use of insulin Colorectal cancer Matched on calendar time (same index date), age (same year of birth), sex, general practice, and number of years of active history in the General Practice Research Database (GPRD) prior to the index date; Adjusted for each other, body mass index, smoking, diabetes duration, prior use of aspirin, NSAIDs, and statins. Low 7 Chang 2012 Taiwan; population-based 2000 to 2007; median 7.9 30 to 100; 67.0 (10.0) 64.0 Class 5, pioglitazone and rosiglitazone vs no use of thiazolidinediones Colorectal cancer Matched on age (within 5 years), sex, and the number of days of follow-up; Adjusted for pioglitazone, rosiglitazone, short-acting human insulin, metformin (mean daily dosage in quartiles), sulfonylurea (mean daily dosage in quartiles), number of oral anti-diabetic agents, glinides, retinopathy, calcium channel blockers, chronic kidney disease, statins, angiotensin receptor blockers, chronic liver disease, alpha-glucosidase inhibitors Low 7 235 Bosco 2011 Denmark; population-based 1989 to 2008; NA 50+; 58% of breast cancer cases and 52% of controls were >70 NA Class 1, metformin vs no use of metformin Breast cancer Conditional logistic regression used to adjust for confounding and selection bias introduced by matching on county and adjusting for complications due to diabetes, clinical obesity, age at index date, postmenopausal hormone use, and multiple imputations to impute missing parity Moderate 6 Smiechowski 2013a United Kingdom; population-based 1998 to 2009; mean 4.5 40+; 72.8 (8.7) in colorectal cancer cases and 72.5 (8.5) in controls 63.3 in colorectal cancer cases; 63.6 in controls Class 1, metformin vs no use of metformin Colorectal cancer Matched on age (year of birth), sex, calendar year of cohort entry, and duration of follow-up; Adjusted for obesity, smoking, statins, nonsteroidal anti-inflammatory drugs, aspirin, excessive alcohol use, HbA1c, diabetes duration, cholecystectomy, inflammatory bowel diseases, referrals to colonoscopy, referrals to sigmoidoscopy, history of polyps, previous cancer (other than nonmelanoma skin cancer), and use of sulfonylureas, thiazolidinediones, insulins, and other antidiabetic agents Low 7 Chen 2013 Taiwan; population-based 1997 to 2008; NA NA; median 71.2 54.6 Class 5, rosiglitazone and pioglitazone vs no use of thiazolidinediones Colorectal cancer Matched on sex, age (i.e., with the same birth calendar year), and the age at the time of diabetes diagnosis Low 8 236 (the same calendar year of the initial diabetes diagnosis date); Adjusted for urbanization, income, colorectal polyp disorder, inflammatory bowel disease, hypertension, hyperlipidemia, biliary stone disease, alcohol-related disease, chronic kidney disease, diabetes-related complications, ischemic heart disease, cerebrovascular disease, heart failure, chronic obstructive pulmonary disease, and hormone therapy Rosato 2016 Italy and Spain; hospital-based and population-based, respectively 2007 to 2013; NA Study in Italy: range 35 to 80, median 67.0 in colorectal cancer cases; range 31 to 80, median 66.0 in controls. Study in Spain: range 22 to 85, median 68.0 in colorectal cancer cases; range 28 to 85; median 66.0 in controls. 65.4 in colorectal cancer cases; 62.6 in controls Class 1, metformin vs no use of metformin; Class 4, sulfonylurea derivatives vs no use of sulfonylurea derivatives; Class 6, insulin vs no use of insulin Colorectal cancer Adjusted for study center, sex, age, education, tobacco smoking, alcohol drinking, body mass index, physical activity, statin use, and aspirin use Moderate 5 Sehdev 2015 United States; hospital-based 2005 to 2010; NA Range 26 to 64; mean 57.4 (5.5) in colorectal cancer cases; range 23 to 64; mean 55.23 (5.69) in controls 59.8 Class 1, metformin vs no use of metformin; Class 4, sulfonylurea vs no use of sulfonylurea; Class 5, thiazolidinediones cs no use of thiazolidinediones; Colorectal cancer Matched on age, sex, and geographical region; Adjusted for obesity, polycystic ovary disease, inflammatory bowel disease, sulfonylurea use, coronary artery disease, prescribed nonsteroidal antiinflammatory drugs (NSAIDs), Moderate 6 237 Class 6, insulin vs no use of insulin insulin use, thiazolidinedione use, Charlson comorbidity index, number of hospital admissions, and number of outpatient visits Walker 2015 United States; hospital-based 2006 to 2011; NA 21 to 85; 63.0 in pancreatic cancer cases and 60.0 in controls 53.0 in pancreatic cancer cases; 48.30 in controls Class 1, metformin to no use of metformin; Class 4, insulin secretagogues vs no use of insulin secretagogues; Class 5, thiazolidinediones cs no use of thiazolidinediones; Class 6, insulin vs no use of insulin Pancreatic cancer Adjusted for age, sex and other classes of diabetes drugs (insulin secretagogues, thiazolidinediones, and insulin) Moderate 4 Azoulay 2016 Canada, United States, United Kingdom; population-based 2007 to 2013; NA 19+; 68.20 in pancreatic cancer cases and 68.10 in controls 50.9 Class 2, dipeptidyl peptidase-4 inhibitors (linagliptin, sitagliptin, vildagliptin, saxagliptin) or glucagon-like peptide-1 receptor agonists (exenatide, liraglutide) vs use of other diabetes medication(s) Pancreatic cancer Matched on age (365 days either way), sex, date of entry to the study cohort (180 days either way), duration of treated diabetes before entry to the study cohort (defined as time between entry to the base cohort and entry to the study cohort; 90 days either way), and duration of follow-up; Adjusted for alcohol related disorders, history of acute or chronic pancreatitis, microvascular complications of diabetes (neuropathy, renal disease, retinopathy, and peripheral arteriopathy), number of hospital Low 7 238 admissions, number of unique non-diabetic drugs in previous year, number of antidiabetic drugs received before entry to study cohort, ever use of statins. In the clinical practice research datalink, models were further adjusted for body mass index, smoking status, and glycated hemoglobin a1c level (<7. 0 % (53 mmol/mol), 7.1-8.0% (54-64 mmol/mol), >8.0% (64 mmol/mol)) Lu 2015 United Kingdom; population-based 1996 to 2010; NA 20 to 79; ~75% were > 65 58.0 in pancreatic cancer cases; 57.1 in controls Class 1, metformin vs no use of metformin; Class 4, sulfonylureas vs no use of sulfonylureas; Class 5, glitazones vs no use of glitazones; Class 6, insulin vs no use of insulin Pancreatic cancer Adjusted for age, sex, body mass index, smoking, alcohol drinking, Townsend deprivation index, calendar year, GP visit 1 year before index date, and diabetes Low 8 Cardel 2014 Denmark; population-based 2000 to 2004 and 2005 to 2009; NA NA; median 73.0 (IQR: 66.0, 80.0) in colorectal cancer cases and 69.0 (IQR: 61.0, 77.0) in controls 55.0 Class 1, metformin vs no use of metformin Colorectal cancer Adjusted for age, gender, calendar year, tobacco, obesity, alcohol use, aspirin, NSAIDs, statins, glibenclamide, and gliclazide Low 7 Liao 2019 Taiwan; population-based 2000 to 2011; NA 20 to 84; 68.2 (9.7) in colorectal cancer cases and 68.1 (9.6) in controls 56.0 in colorectal cancer cases; 55.2 in controls Class 5, thiazolidinediones (pioglitazone and rosiglitazone) vs no use of thiazolidinediones Colorectal cancer Adjusted for other anti-diabetic drugs and alcohol-related disease Moderate 6 239 Shin 2020 South Korea; population-based 2007 to 2014; NA 30+; 61.3 (9.5) in colorectal cancer cases and 61.4 (9.1) in controls 65.3 in colorectal cancer cases; 23.5 in controls Class 1, metformin vs no use of metformin; Class 2, dipeptidyl peptidase-4 inhibitor vs no use of dipeptidyl peptidase-4 inhibitor; Class 3, alpha-glucosidase inhibitor vs no use of alpha-glucosidase inhibitor; Class 4, sulfonylurea or meglitinide vs no use of sulfonylurea or meglitinide; Class 5, thiazolidinedione vs no use of thiazolidinedione; Class 6, insulin vs no use of insulin Colorectal cancer Matched on age, sex, and the year of diagnosis of type 2 diabetes; Adjusted for smoking, drinking, waist circumference, exercise, insulin use, and the time from diabetes mellitus diagnosis to index date Low 7 Demb 2019 United States; US Veterans NA; NA NA; median 69.0 (IQR: 62.0, 76.0) in colorectal cancer cases and 63.0 (IQR: 58.0, 70.0) in controls; 99 in colorectal cancer cases; 97 in controls Class 1, metformin vs no use of metformin Colorectal cancer Adjusted for Age, sex, race/ethnicity, body mass index, smoking status, and aspirin exposure Moderate 6 Hosio 2019 Finland; population-based 1996 to 2011; mean 5.4 40+; ~50% aged > 70 NA Class 1, metformin vs no use of metformin; Class 6, insulin vs no use of insulin Breast cancer Matched on age and duration of diabetes Moderate 6 240 Appendix B Supplementary tables for Chapter 5 Supplementary Table B-1. Associations between all diabetes medications and the risk of breast cancer Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 25,974,019 50,695 195.2 (193.5-196.9) 1.00 1.00 Ever use 942,941 2,889 310.6 (297.6-324.2) 1.14 (1.09-1.19)* 1.09 (1.04-1.14)* Cumulative duration Low 363,231 876 241.2 (225.7-257.7) 0.97 (0.91-1.04) 0.93 (0.87-0.99)* Medium 323,170 1,090 337.3 (317.8-357.9) 1.24 (1.17-1.32)* 1.19 (1.12-1.26)* High 256,540 923 359.8 (337.3-383.8) 1.22 (1.14-1.30)* 1.14 (1.07-1.21)* Continuous 1.02 (1.02-1.03)* 1.02 (1.01-1.02)* Cumulative dose Low 383,543 947 246.9 (231.7-263.1) 0.98 (0.92-1.04) 0.94 (0.88-1.00)* Medium 327,502 1,146 349.9 (330.2-370.8) 1.28 (1.21-1.36)* 1.22 (1.15-1.30)* High 231,896 796 343.3 (320.2-368.0) 1.18 (1.10-1.27)* 1.10 (1.02-1.18)* Continuous 1.03 (1.02-1.03)* 1.02 (1.01-1.02)* 2. Incretin-based medicines Never 26,807,130 53,289 198.8 (197.1-200.5) 1.00 1.00 Ever use 109,830 295 255.7 (222.1-294.3) 0.96 (0.83-1.10) 0.86 (0.75-1.00)* Cumulative duration Low 37,699 86 228.1 (184.7-281.8) 0.91 (0.74-1.13) 0.82 (0.66-1.01) Medium 36,916 103 279.0 (230.0-338.5) 1.06 (0.87-1.29) 0.96 (0.79-1.16) High 35,215 106 301.0 (248.8-364.1) 1.05 (0.87-1.27) 0.94 (0.78-1.14) Continuous 1.01 (0.97-1.05) 0.98 (0.95-1.02) Cumulative dose Low 41,738 101 242.0 (199.1-294.1) 0.98 (0.81-1.19) 0.88 (0.72-1.07) Medium 34,741 97 279.2 (228.8-340.7) 1.03 (0.85-1.26) 0.93 (0.77-1.14) High 33,351 97 290.8 (238.4-354.9) 1.01 (0.83-1.23) 0.91 (0.74-1.11) Continuous 1.00 (0.96-1.05) 0.97 (0.93-1.02) 2.1. DPP-4 inhibitors Never 26,838,141 53,352 198.8 (197.1-200.5) 1.00 1.00 Ever use 78,819 232 283.5 (241.5-332.9) 1.01 (0.86-1.19) 0.92 (0.78-1.08) Cumulative duration Low 26,904 81 301.1 (242.2-374.3) 1.12 (0.90-1.39) 1.01 (0.81-1.26) Medium 25,479 74 290.4 (231.3-364.8) 1.05 (0.84-1.32) 0.96 (0.76-1.20) High 26,436 77 291.3 (233.0-364.2) 1.00 (0.80-1.25) 0.90 (0.72-1.12) Continuous 1.00 (0.95-1.04) 0.97 (0.93-1.02) Cumulative dose Low 27,412 84 306.4 (247.4-379.5) 1.14 (0.92-1.41) 1.03 (0.83-1.27) Medium 24,971 73 292.3 (232.4-367.7) 1.06 (0.84-1.33) 0.96 (0.76-1.21) High 26,436 75 283.7 (226.2-355.8) 0.97 (0.78-1.22) 0.88 (0.70-1.10) Continuous 1.00 (0.95-1.04) 0.97 (0.93-1.02) 2.1.1. Linagliptin Never 26,888,522 53,506 199.0 (197.3-200.7) 1.00 1.00 Ever use 28,438 78 301.8 (237.1-384.2) 1.04 (0.82-1.33) 0.94 (0.74-1.20) Cumulative duration Low 8,744 20 228.7 (147.6-354.5) 0.82 (0.53-1.26) 0.74 (0.48-1.14) Medium 9,355 21 224.5 (146.4-344.3) 0.79 (0.51-1.21) 0.72 (0.47-1.10) High 10,339 37 357.9 (259.3-493.9) 1.20 (0.87-1.66) 1.09 (0.79-1.50) Continuous 1.03 (0.94-1.13) 0.99 (0.90-1.09) Cumulative dose Low 8,785 20 227.7 (146.9-352.9) 0.81 (0.52-1.26) 0.73 (0.47-1.14) Medium 9,402 21 223.4 (145.6-342.6) 0.78 (0.51-1.20) 0.71 (0.46-1.09) High 10,251 37 360.9 (261.5-498.2) 1.21 (0.88-1.68) 1.10 (0.79-1.51) Continuous 1.03 (0.94-1.13) 0.99 (0.91-1.09) 2.1.2. Sitagliptin Never 26,862,992 53,416 198.8 (197.2-200.5) 1.00 1.00 Ever use 53,968 168 306.8 (245.4-383.6) 1.14 (0.91-1.43) 1.03 (0.83-1.29) Cumulative duration Low 18,434 56 303.8 (233.8-394.7) 1.12 (0.86-1.45) 1.02 (0.78-1.32) Medium 18,909 65 343.8 (269.6-438.4) 1.25 (0.98-1.59) 1.13 (0.89-1.44) High 16,625 47 282.7 (212.4-376.3) 0.98 (0.74-1.30) 0.88 (0.66-1.18) Continuous 1.01 (0.95-1.07) 0.98 (0.92-1.04) 241 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 18,897 57 301.6 (232.7-391.0) 1.11 (0.86-1.44) 1.01 (0.78-1.31) Medium 18,211 64 351.4 (275.1-449.0) 1.27 (1.00-1.63) 1.16 (0.91-1.48) High 16,860 47 278.8 (209.4-371.0) 0.97 (0.73-1.29) 0.87 (0.66-1.16) Continuous 1.01 (0.95-1.07) 0.98 (0.92-1.04) 2.2. GLP-1 receptor agonists Never 26,874,721 53,484 199.0 (197.3-200.7) 1.00 1.00 Ever use 42,239 100 198.1 (150.5-260.6) 0.83 (0.63-1.09) 0.74 (0.56-0.97)* Cumulative duration Low 13,930 29 208.2 (144.7-299.6) 0.91 (0.63-1.30) 0.80 (0.56-1.16) Medium 14,541 28 192.6 (133.0-278.9) 0.83 (0.57-1.20) 0.73 (0.51-1.06) High 13,768 43 312.3 (231.6-421.1) 1.19 (0.88-1.61) 1.06 (0.78-1.42) Continuous 1.06 (0.97-1.15) 1.02 (0.94-1.11) Cumulative dose Low 13,597 30 220.6 (154.3-315.6) 0.94 (0.66-1.34) 0.84 (0.59-1.20) Medium 14,567 34 233.4 (166.8-326.7) 0.99 (0.71-1.38) 0.88 (0.63-1.23) High 14,075 36 255.8 (184.5-354.6) 1.01 (0.73-1.40) 0.89 (0.64-1.23) Continuous 1.11 (0.81-1.52) 1.00 (0.72-1.39) 3. SGLT-2 inhibitors Never 26,879,533 53,509 199.1 (197.4-200.8) 1.00 1.00 Ever use 37,427 75 189.0 (142.4-250.8) 0.72 (0.54-0.95)* 0.64 (0.48-0.85)* Cumulative duration Low 12,099 15 124.0 (74.7-205.6) 0.47 (0.28-0.78)* 0.42 (0.25-0.70)* Medium 12,583 21 166.9 (108.8-256.0) 0.63 (0.41-0.97)* 0.57 (0.37-0.87)* High 12,745 39 306.0 (223.6-418.8) 1.12 (0.82-1.53) 1.00 (0.73-1.37) Continuous 1.01 (0.91-1.13) 0.97 (0.86-1.08) Cumulative dose Low 12,132 16 131.9 (80.8-215.3) 0.50 (0.31-0.82)* 0.44 (0.27-0.72)* Medium 12,532 20 159.6 (103.0-247.4) 0.61 (0.39-0.94)* 0.54 (0.35-0.84)* High 12,763 39 305.6 (223.3-418.2) 1.13 (0.83-1.55) 1.01 (0.74-1.38) Continuous 1.03 (0.94-1.12) 0.99 (0.91-1.08) 4. AGIs (i.e., acarbose) Never 26,894,718 53,529 199.0 (197.4-200.7) 1.00 1.00 Ever use 22,242 55 246.1 (148.4-408.3) 0.91 (0.55-1.51) 0.90 (0.54-1.49) Cumulative duration Low 9,033 23 254.6 (169.2-383.2) 0.93 (0.62-1.40) 0.90 (0.60-1.35) Medium 7,396 19 256.9 (163.9-402.8) 0.93 (0.59-1.46) 0.89 (0.57-1.40) High 5,813 13 223.6 (129.9-385.1) 0.77 (0.45-1.33) 0.74 (0.43-1.27) Continuous 0.95 (0.85-1.06) 0.94 (0.84-1.05) Cumulative dose Low 8,762 24 273.9 (183.6-408.7) 1.00 (0.67-1.49) 0.97 (0.65-1.44) Medium 7,780 18 231.4 (145.8-367.2) 0.83 (0.52-1.32) 0.80 (0.50-1.27) High 5,700 13 228.1 (132.4-392.8) 0.79 (0.46-1.37) 0.76 (0.44-1.30) Continuous 0.90 (0.74-1.10) 0.89 (0.73-1.08) 5. Insulin secretagogues Never 26,526,445 52,414 197.6 (195.9-199.3) 1.00 1.00 Ever use 390,515 1,170 308.1 (286.6-331.3) 1.11 (1.03-1.19)* 1.08 (1.00-1.16) Cumulative duration Low 157,864 389 246.4 (223.1-272.2) 0.92 (0.83-1.02) 0.90 (0.82-1.00)* Medium 132,423 427 322.5 (293.3-354.5) 1.16 (1.05-1.27)* 1.11 (1.01-1.22)* High 100,228 354 353.2 (318.3-392.0) 1.18 (1.07-1.31)* 1.12 (1.01-1.24)* Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.02)* Cumulative dose Low 164,182 404 246.1 (223.2-271.3) 0.91 (0.82-1.00)* 0.89 (0.81-0.98)* Medium 131,919 458 347.2 (316.8-380.5) 1.24 (1.13-1.36)* 1.19 (1.09-1.31)* High 94,414 308 326.2 (291.8-364.8) 1.11 (1.00-1.25) 1.04 (0.93-1.16) Continuous 1.01 (1.00-1.01) 1.00 (1.00-1.01) 5.1. Meglitinides Never 26,898,154 53,518 199.0 (197.3-200.7) 1.00 1.00 Ever use 18,806 66 495.4 (346.4-708.5) 1.83 (1.28-2.62)* 1.79 (1.25-2.57)* Cumulative duration Low 6,377 15 235.2 (141.8-390.2) 0.85 (0.51-1.42) 0.81 (0.49-1.35) Medium 6,194 30 484.3 (338.6-692.7) 1.79 (1.25-2.56)* 1.74 (1.22-2.48)* High 6,235 21 336.8 (219.6-516.6) 1.17 (0.76-1.80) 1.10 (0.72-1.69) Continuous 1.04 (0.97-1.12) 1.03 (0.96-1.11) 242 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 6,983 22 315.1 (207.4-478.5) 1.13 (0.75-1.72) 1.08 (0.71-1.64) Medium 6,354 27 424.9 (291.4-619.6) 1.56 (1.07-2.28)* 1.50 (1.03-2.19)* High 5,469 17 310.8 (193.2-500.0) 1.10 (0.68-1.76) 1.03 (0.64-1.65) Continuous 1.01 (0.95-1.08) 1.00 (0.94-1.07) 5.1.1. Repaglinide Never 26,898,506 53,518 199.0 (197.3-200.7) 1.00 1.00 Ever use 18,454 66 501.3 (350.5-716.9) 1.85 (1.30-2.65)* 1.81 (1.27-2.60)* Cumulative duration Low 6,246 15 240.2 (144.8-398.4) 0.87 (0.52-1.44) 0.83 (0.50-1.38) Medium 6,097 30 492.0 (344.0-703.7) 1.81 (1.27-2.59)* 1.74 (1.22-2.49)* High 6,111 21 343.6 (224.1-527.1) 1.20 (0.78-1.84) 1.13 (0.74-1.73) Continuous 1.05 (0.98-1.12) 1.03 (0.97-1.11) Cumulative dose Low 6,907 22 318.5 (209.7-483.7) 1.14 (0.75-1.74) 1.09 (0.72-1.66) Medium 6,162 27 438.2 (300.5-638.9) 1.61 (1.11-2.35)* 1.55 (1.07-2.26)* High 5,385 17 315.7 (196.3-507.8) 1.12 (0.69-1.80) 1.04 (0.65-1.68) Continuous 1.01 (0.95-1.08) 1.00 (0.94-1.07) 5.2. Sulfonylureas Never 26,532,030 52,431 197.6 (195.9-199.3) 1.00 1.00 Ever use 384,930 1,153 303.9 (282.3-327.2) 1.09 (1.01-1.18)* 1.06 (0.98-1.14) Cumulative duration Low 157,130 386 245.7 (222.3-271.4) 0.92 (0.83-1.01) 0.90 (0.81-0.99)* Medium 129,438 421 325.3 (295.6-357.9) 1.17 (1.06-1.28)* 1.12 (1.02-1.23)* High 98,362 346 351.8 (316.6-390.9) 1.18 (1.06-1.31)* 1.11 (1.00-1.24) Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.02)* Cumulative dose Low 161,924 393 242.7 (219.9-267.9) 0.89 (0.81-0.99)* 0.88 (0.80-0.97)* Medium 129,793 457 352.1 (321.3-385.9) 1.26 (1.15-1.38)* 1.21 (1.10-1.33)* High 93,213 303 325.1 (290.4-363.8) 1.11 (0.99-1.24) 1.04 (0.93-1.16) Continuous 1.01 (1.00-1.01) 1.00 (1.00-1.01) 5.2.1. Gliclazide Never 26,747,400 53,057 198.4 (196.7-200.1) 1.00 1.00 Ever use 169,560 527 307.7 (276.3-342.6) 1.10 (0.98-1.22) 1.02 (0.92-1.14) Cumulative duration Low 56,423 154 272.9 (233.1-319.6) 1.00 (0.86-1.17) 0.94 (0.81-1.11) Medium 57,402 157 273.5 (233.9-319.8) 0.98 (0.84-1.15) 0.92 (0.79-1.07) High 55,735 216 387.5 (339.2-442.8) 1.32 (1.15-1.50)* 1.22 (1.06-1.39)* Continuous 1.03 (1.01-1.05)* 1.02 (1.00-1.04)* Cumulative dose Low 59,361 146 246.0 (209.1-289.3) 0.90 (0.76-1.06) 0.85 (0.72-1.00)* Medium 57,663 201 348.6 (303.6-400.3) 1.24 (1.08-1.43)* 1.16 (1.01-1.33)* High 52,536 180 342.6 (296.1-396.5) 1.17 (1.01-1.36)* 1.08 (0.94-1.26) Continuous 1.01 (1.00-1.01) 1.00 (1.00-1.01) 5.2.2. Glyburide Never 26,626,770 52,734 198.0 (196.4-199.7) 1.00 1.00 Ever use 290,190 850 298.5 (270.0-330.0) 1.09 (0.98-1.20) 1.08 (0.98-1.20) Cumulative duration Low 127,512 327 256.4 (230.1-285.8) 0.94 (0.84-1.05) 0.92 (0.83-1.03) Medium 94,753 293 309.2 (275.8-346.7) 1.11 (0.99-1.24) 1.08 (0.96-1.21) High 67,925 230 338.6 (297.6-385.3) 1.14 (1.00-1.29) 1.09 (0.95-1.24) Continuous 1.01 (1.00-1.03) 1.01 (0.99-1.02) Cumulative dose Low 134,397 355 264.1 (238.0-293.1) 0.96 (0.86-1.06) 0.94 (0.85-1.05) Medium 96,766 305 315.2 (281.7-352.6) 1.12 (1.00-1.26)* 1.10 (0.98-1.23) High 59,027 190 321.9 (279.2-371.1) 1.10 (0.95-1.27) 1.04 (0.91-1.21) Continuous 1.00 (0.99-1.01) 1.00 (0.99-1.01) 6. Thiazolidinediones Never 26,823,978 53,289 198.7 (197.0-200.4) 1.00 1.00 Ever use 92,982 295 265.8 (212.9-331.8) 1.03 (0.82-1.28) 1.00 (0.80-1.25) Cumulative duration Low 34,084 95 278.7 (228.0-340.8) 1.04 (0.85-1.27) 0.98 (0.80-1.20) Medium 31,481 102 324.0 (266.9-393.4) 1.19 (0.98-1.44) 1.12 (0.92-1.36) High 27,417 98 357.4 (293.2-435.7) 1.24 (1.02-1.51)* 1.15 (0.94-1.40) Continuous 1.03 (0.99-1.06) 1.01 (0.98-1.04) 243 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 34,463 98 284.4 (233.3-346.6) 1.05 (0.86-1.28) 1.00 (0.82-1.22) Medium 32,401 106 327.2 (270.4-395.8) 1.20 (0.99-1.45) 1.13 (0.93-1.36) High 26,118 91 348.4 (283.7-427.9) 1.22 (0.99-1.49) 1.13 (0.92-1.38) Continuous 1.02 (0.99-1.05) 1.01 (0.97-1.04) 6.1. Pioglitazone Never 26,873,788 53,445 198.9 (197.2-200.6) 1.00 1.00 Ever use 43,172 139 234.4 (167.5-328.0) 0.89 (0.63-1.24) 0.85 (0.60-1.18) Cumulative duration Low 15,538 47 302.5 (227.3-402.6) 1.11 (0.84-1.48) 1.04 (0.78-1.39) Medium 14,666 41 279.6 (205.8-379.7) 1.02 (0.75-1.38) 0.95 (0.70-1.29) High 12,968 51 393.3 (298.9-517.5) 1.35 (1.03-1.78)* 1.25 (0.95-1.65) Continuous 1.02 (0.97-1.07) 1.00 (0.95-1.05) Cumulative dose Low 15,616 47 301.0 (226.1-400.6) 1.11 (0.83-1.47) 1.04 (0.78-1.38) Medium 15,085 46 304.9 (228.4-407.1) 1.10 (0.83-1.47) 1.03 (0.77-1.38) High 12,471 46 368.9 (276.3-492.4) 1.27 (0.95-1.70) 1.18 (0.88-1.57) Continuous 1.01 (0.96-1.06) 1.00 (0.95-1.05) 6.2. Rosiglitazone Never 26,855,904 53,391 198.8 (197.1-200.5) 1.00 1.00 Ever use 61,056 193 297.4 (222.8-397.1) 1.18 (0.89-1.58) 1.18 (0.88-1.57) Cumulative duration Low 21,872 64 292.6 (229.0-373.8) 1.08 (0.84-1.38) 1.02 (0.80-1.31) Medium 21,102 58 274.9 (212.5-355.5) 1.01 (0.78-1.31) 0.96 (0.74-1.24) High 18,082 71 392.7 (311.2-495.5) 1.38 (1.09-1.74)* 1.28 (1.02-1.62)* Continuous 1.04 (0.99-1.09) 1.02 (0.98-1.07) Cumulative dose Low 22,279 66 296.2 (232.7-377.1) 1.09 (0.86-1.39) 1.04 (0.81-1.32) Medium 21,514 67 311.4 (245.1-395.7) 1.14 (0.90-1.45) 1.07 (0.84-1.36) High 17,263 60 347.6 (269.9-447.6) 1.22 (0.95-1.58) 1.14 (0.89-1.47) Continuous 1.03 (0.98-1.08) 1.01 (0.97-1.07) 7. Insulins and analogues Never 26,763,779 53,186 198.7 (197.0-200.4) 1.00 1.00 Ever use 153,181 398 279.2 (248.3-313.9) 1.07 (0.95-1.20) 0.99 (0.88-1.12) Cumulative duration Low 79,227 160 202.0 (173.0-235.8) 0.97 (0.83-1.14) 0.90 (0.77-1.06) Medium 48,672 138 283.5 (240.0-335.0) 1.05 (0.89-1.24) 0.98 (0.83-1.15) High 25,282 100 395.5 (325.1-481.2) 1.38 (1.13-1.67)* 1.25 (1.03-1.53)* Continuous 1.04 (1.02-1.07)* 1.03 (1.01-1.05)* Cumulative dose Low 80,901 163 201.5 (172.8-234.9) 0.96 (0.82-1.12) 0.89 (0.76-1.04) Medium 46,657 133 285.1 (240.5-337.9) 1.06 (0.89-1.25) 0.98 (0.83-1.16) High 25,623 102 398.1 (327.9-483.3) 1.40 (1.16-1.70)* 1.28 (1.06-1.56)* Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 7.1. Basal insulins Never 26,770,645 53,201 198.7 (197.0-200.4) 1.00 1.00 Ever use 146,315 383 280.8 (248.8-316.9) 1.08 (0.96-1.22) 1.00 (0.89-1.13) Cumulative duration Low 74,490 152 204.1 (174.1-239.2) 0.98 (0.83-1.15) 0.91 (0.77-1.06) Medium 47,092 133 282.4 (238.3-334.7) 1.05 (0.88-1.24) 0.97 (0.82-1.15) High 24,733 98 396.2 (325.1-483.0) 1.37 (1.13-1.68)* 1.26 (1.03-1.53)* Continuous 1.05 (1.02-1.08)* 1.03 (1.01-1.06)* Cumulative dose Low 75,643 151 199.6 (170.2-234.1) 0.95 (0.81-1.11) 0.88 (0.75-1.03) Medium 45,900 132 287.6 (242.5-341.1) 1.07 (0.90-1.26) 0.99 (0.83-1.17) High 24,772 100 403.7 (331.8-491.1) 1.42 (1.17-1.73)* 1.30 (1.07-1.58)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.04)* 7.2. Bolus insulins Never 26,844,167 53,388 198.9 (197.2-200.6) 1.00 1.00 Ever use 72,793 196 343.4 (288.4-408.9) 1.41 (1.18-1.68)* 1.30 (1.10-1.55)* Cumulative duration Low 41,607 80 192.3 (154.4-239.4) 1.02 (0.82-1.26) 0.93 (0.75-1.16) Medium 21,239 79 372.0 (298.3-463.7) 1.48 (1.19-1.84)* 1.36 (1.09-1.70)* High 9,947 37 372.0 (269.5-513.4) 1.34 (0.97-1.85) 1.22 (0.88-1.68) Continuous 1.09 (1.04-1.15)* 1.07 (1.02-1.13)* 244 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 43,110 86 199.5 (161.5-246.4) 1.04 (0.84-1.29) 0.96 (0.78-1.18) Medium 19,439 64 329.2 (257.7-420.6) 1.30 (1.01-1.66)* 1.20 (0.94-1.53) High 10,244 46 449.0 (336.3-599.5) 1.66 (1.24-2.21)* 1.50 (1.12-2.00)* Continuous 1.03 (1.01-1.06)* 1.03 (1.01-1.05)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income quintile. This table displays associations between all diabetes medications and breast cancer. For a summary of selected medications with significant associations, please refer to Table 5-2. * denotes p<0.05. 245 Supplementary Table B-2. Associations between all diabetes medications and the risk of breast cancer with adjustment for other diabetes medications Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 25,974,019 50,695 195.2 (193.5-196.9) 1.00 1.00 Ever use 942,941 2,889 310.6 (297.6-324.2) 1.09 (1.04-1.14)* 1.11 (1.05-1.16)* Cumulative duration Low 363,231 876 241.2 (225.7-257.7) 0.93 (0.87-0.99)* 0.96 (0.90-1.03) Medium 323,170 1,090 337.3 (317.8-357.9) 1.19 (1.12-1.26)* 1.24 (1.16-1.33)* High 256,540 923 359.8 (337.3-383.8) 1.14 (1.07-1.21)* 1.21 (1.12-1.31)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.03)* Cumulative dose Low 383,543 947 246.9 (231.7-263.1) 0.94 (0.88-1.00)* 0.97 (0.90-1.03) Medium 327,502 1,146 349.9 (330.2-370.8) 1.22 (1.15-1.30)* 1.28 (1.20-1.36)* High 231,896 796 343.3 (320.2-368.0) 1.10 (1.02-1.18)* 1.19 (1.08-1.30)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.03)* 2. Incretin-based medicines Never 26,807,130 53,289 198.8 (197.1-200.5) 1.00 1.00 Ever use 109,830 295 255.7 (222.1-294.3) 0.86 (0.75-1.00)* 0.84 (0.72-0.98)* Cumulative duration Low 37,699 86 228.1 (184.7-281.8) 0.82 (0.66-1.01) 0.79 (0.64-0.98)* Medium 36,916 103 279.0 (230.0-338.5) 0.96 (0.79-1.16) 0.91 (0.74-1.11) High 35,215 106 301.0 (248.8-364.1) 0.94 (0.78-1.14) 0.89 (0.72-1.09) Continuous 0.98 (0.95-1.02) 0.95 (0.91-0.99)* Cumulative dose Low 41,738 101 242.0 (199.1-294.1) 0.88 (0.72-1.07) 0.84 (0.69-1.03) Medium 34,741 97 279.2 (228.8-340.7) 0.93 (0.77-1.14) 0.89 (0.72-1.09) High 33,351 97 290.8 (238.4-354.9) 0.91 (0.74-1.11) 0.88 (0.71-1.09) Continuous 0.97 (0.93-1.02) 0.95 (0.90-1.00)* 2.1. DPP-4 inhibitors Never 26,838,141 53,352 198.8 (197.1-200.5) 1.00 1.00 Ever use 78,819 232 283.5 (241.5-332.9) 0.92 (0.78-1.08) 0.89 (0.76-1.06) Cumulative duration Low 26,904 81 301.1 (242.2-374.3) 1.01 (0.81-1.26) 0.99 (0.79-1.24) Medium 25,479 74 290.4 (231.3-364.8) 0.96 (0.76-1.20) 0.92 (0.73-1.17) High 26,436 77 291.3 (233.0-364.2) 0.90 (0.72-1.12) 0.86 (0.68-1.09) Continuous 0.97 (0.93-1.02) 0.94 (0.89-0.99)* Cumulative dose Low 27,412 84 306.4 (247.4-379.5) 1.03 (0.83-1.27) 1.00 (0.80-1.25) Medium 24,971 73 292.3 (232.4-367.7) 0.96 (0.76-1.21) 0.93 (0.74-1.19) High 26,436 75 283.7 (226.2-355.8) 0.88 (0.70-1.10) 0.87 (0.68-1.10) Continuous 0.97 (0.93-1.02) 0.95 (0.90-1.00)* 2.1.1. Linagliptin Never 26,888,522 53,506 199.0 (197.3-200.7) 1.00 1.00 Ever use 28,438 78 301.8 (237.1-384.2) 0.94 (0.74-1.20) 0.94 (0.74-1.21) Cumulative duration Low 8,744 20 228.7 (147.6-354.5) 0.74 (0.48-1.14) 0.76 (0.49-1.18) Medium 9,355 21 224.5 (146.4-344.3) 0.72 (0.47-1.10) 0.73 (0.47-1.13) High 10,339 37 357.9 (259.3-493.9) 1.09 (0.79-1.50) 1.06 (0.76-1.48) Continuous 0.99 (0.90-1.09) 0.97 (0.88-1.07) Cumulative dose Low 8,785 20 227.7 (146.9-352.9) 0.73 (0.47-1.14) 0.75 (0.48-1.18) Medium 9,402 21 223.4 (145.6-342.6) 0.71 (0.46-1.09) 0.73 (0.47-1.12) High 10,251 37 360.9 (261.5-498.2) 1.10 (0.79-1.51) 1.10 (0.78-1.53) Continuous 0.99 (0.91-1.09) 0.98 (0.89-1.08) 2.1.2. Sitagliptin Never 26,862,992 53,416 198.8 (197.2-200.5) 1.00 1.00 Ever use 53,968 168 306.8 (245.4-383.6) 1.03 (0.83-1.29) 0.99 (0.79-1.25) Cumulative duration Low 18,434 56 303.8 (233.8-394.7) 1.02 (0.78-1.32) 1.02 (0.78-1.34) Medium 18,909 65 343.8 (269.6-438.4) 1.13 (0.89-1.44) 1.11 (0.86-1.43) High 16,625 47 282.7 (212.4-376.3) 0.88 (0.66-1.18) 0.87 (0.65-1.18) Continuous 0.98 (0.92-1.04) 0.95 (0.89-1.01) Cumulative dose Low 18,897 57 301.6 (232.7-391.0) 1.01 (0.78-1.31) 1.01 (0.78-1.32) 246 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 18,211 64 351.4 (275.1-449.0) 1.16 (0.91-1.48) 1.15 (0.89-1.48) High 16,860 47 278.8 (209.4-371.0) 0.87 (0.66-1.16) 0.89 (0.66-1.20) Continuous 0.98 (0.92-1.04) 0.96 (0.89-1.02) 2.2. GLP-1 receptor agonists Never 26,874,721 53,484 199.0 (197.3-200.7) 1.00 1.00 Ever use 42,239 100 198.1 (150.5-260.6) 0.74 (0.56-0.97)* 0.75 (0.57-0.99)* Cumulative duration Low 13,930 29 208.2 (144.7-299.6) 0.80 (0.56-1.16) 0.82 (0.57-1.18) Medium 14,541 28 192.6 (133.0-278.9) 0.73 (0.51-1.06) 0.74 (0.51-1.07) High 13,768 43 312.3 (231.6-421.1) 1.06 (0.78-1.42) 1.04 (0.76-1.42) Continuous 1.02 (0.94-1.11) 0.99 (0.91-1.09) Cumulative dose Low 13,597 30 220.6 (154.3-315.6) 0.84 (0.59-1.20) 0.83 (0.58-1.19) Medium 14,567 34 233.4 (166.8-326.7) 0.88 (0.63-1.23) 0.86 (0.61-1.21) High 14,075 36 255.8 (184.5-354.6) 0.89 (0.64-1.23) 0.88 (0.63-1.24) Continuous 1.00 (0.72-1.39) 0.94 (0.66-1.33) 3. SGLT-2 inhibitors Never 26,879,533 53,509 199.1 (197.4-200.8) 1.00 1.00 Ever use 37,427 75 189.0 (142.4-250.8) 0.64 (0.48-0.85)* 0.63 (0.47-0.85)* Cumulative duration Low 12,099 15 124.0 (74.7-205.6) 0.42 (0.25-0.70)* 0.40 (0.24-0.67)* Medium 12,583 21 166.9 (108.8-256.0) 0.57 (0.37-0.87)* 0.53 (0.34-0.82)* High 12,745 39 306.0 (223.6-418.8) 1.00 (0.73-1.37) 0.91 (0.65-1.26) Continuous 0.97 (0.86-1.08) 0.94 (0.84-1.06) Cumulative dose Low 12,132 16 131.9 (80.8-215.3) 0.44 (0.27-0.72)* 0.42 (0.26-0.70)* Medium 12,532 20 159.6 (103.0-247.4) 0.54 (0.35-0.84)* 0.51 (0.33-0.79)* High 12,763 39 305.6 (223.3-418.2) 1.01 (0.74-1.38) 0.94 (0.68-1.31) Continuous 0.99 (0.91-1.08) 0.98 (0.89-1.07) 4. AGIs (i.e., acarbose) Never 26,894,718 53,529 199.0 (197.4-200.7) 1.00 1.00 Ever use 22,242 55 246.1 (148.4-408.3) 0.90 (0.54-1.49) 0.86 (0.52-1.44) Cumulative duration Low 9,033 23 254.6 (169.2-383.2) 0.90 (0.60-1.35) 0.86 (0.57-1.30) Medium 7,396 19 256.9 (163.9-402.8) 0.89 (0.57-1.40) 0.84 (0.53-1.32) High 5,813 13 223.6 (129.9-385.1) 0.74 (0.43-1.27) 0.67 (0.39-1.17) Continuous 0.94 (0.84-1.05) 0.92 (0.82-1.03) Cumulative dose Low 8,762 24 273.9 (183.6-408.7) 0.97 (0.65-1.44) 0.92 (0.62-1.38) Medium 7,780 18 231.4 (145.8-367.2) 0.80 (0.50-1.27) 0.75 (0.47-1.20) High 5,700 13 228.1 (132.4-392.8) 0.76 (0.44-1.30) 0.71 (0.41-1.23) Continuous 0.89 (0.73-1.08) 0.87 (0.71-1.07) 5. Insulin secretagogues Never 26,526,445 52,414 197.6 (195.9-199.3) 1.00 1.00 Ever use 390,515 1,170 308.1 (286.6-331.3) 1.08 (1.00-1.16) 1.05 (0.97-1.14) Cumulative duration Low 157,864 389 246.4 (223.1-272.2) 0.90 (0.82-1.00)* 0.85 (0.76-0.94)* Medium 132,423 427 322.5 (293.3-354.5) 1.11 (1.01-1.22)* 1.02 (0.91-1.13) High 100,228 354 353.2 (318.3-392.0) 1.12 (1.01-1.24)* 1.03 (0.91-1.18) Continuous 1.01 (1.00-1.02)* 1.00 (0.98-1.01) Cumulative dose Low 164,182 404 246.1 (223.2-271.3) 0.89 (0.81-0.98)* 0.82 (0.74-0.92)* Medium 131,919 458 347.2 (316.8-380.5) 1.19 (1.09-1.31)* 1.08 (0.97-1.21) High 94,414 308 326.2 (291.8-364.8) 1.04 (0.93-1.16) 0.98 (0.85-1.13) Continuous 1.00 (1.00-1.01) 1.00 (0.99-1.00) 5.1. Meglitinides Never 26,898,154 53,518 199.0 (197.3-200.7) 1.00 1.00 Ever use 18,806 66 495.4 (346.4-708.5) 1.79 (1.25-2.57)* 1.75 (1.22-2.50)* Cumulative duration Low 6,377 15 235.2 (141.8-390.2) 0.81 (0.49-1.35) 0.80 (0.48-1.32) Medium 6,194 30 484.3 (338.6-692.7) 1.74 (1.22-2.48)* 1.66 (1.15-2.39)* High 6,235 21 336.8 (219.6-516.6) 1.10 (0.72-1.69) 1.05 (0.68-1.62) Continuous 1.03 (0.96-1.11) 1.02 (0.95-1.09) Cumulative dose Low 6,983 22 315.1 (207.4-478.5) 1.08 (0.71-1.64) 1.05 (0.69-1.60) 247 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 6,354 27 424.9 (291.4-619.6) 1.50 (1.03-2.19)* 1.43 (0.97-2.09) High 5,469 17 310.8 (193.2-500.0) 1.03 (0.64-1.65) 0.98 (0.61-1.58) Continuous 1.00 (0.94-1.07) 0.99 (0.92-1.06) 5.1.1. Repaglinide Never 26,898,506 53,518 199.0 (197.3-200.7) 1.00 1.00 Ever use 18,454 66 501.3 (350.5-716.9) 1.81 (1.27-2.60)* 1.77 (1.23-2.53)* Cumulative duration Low 6,246 15 240.2 (144.8-398.4) 0.83 (0.50-1.38) 0.81 (0.49-1.35) Medium 6,097 30 492.0 (344.0-703.7) 1.74 (1.22-2.49)* 1.69 (1.17-2.42)* High 6,111 21 343.6 (224.1-527.1) 1.13 (0.74-1.73) 1.08 (0.70-1.66) Continuous 1.03 (0.97-1.11) 1.02 (0.95-1.09) Cumulative dose Low 6,907 22 318.5 (209.7-483.7) 1.09 (0.72-1.66) 1.06 (0.70-1.62) Medium 6,162 27 438.2 (300.5-638.9) 1.55 (1.07-2.26)* 1.47 (1.01-2.16)* High 5,385 17 315.7 (196.3-507.8) 1.04 (0.65-1.68) 1.00 (0.62-1.62) Continuous 1.00 (0.94-1.07) 0.99 (0.93-1.06) 5.2. Sulfonylureas Never 26,532,030 52,431 197.6 (195.9-199.3) 1.00 1.00 Ever use 384,930 1,153 303.9 (282.3-327.2) 1.06 (0.98-1.14) 1.03 (0.95-1.12) Cumulative duration Low 157,130 386 245.7 (222.3-271.4) 0.90 (0.81-0.99)* 0.84 (0.75-0.94)* Medium 129,438 421 325.3 (295.6-357.9) 1.12 (1.02-1.23)* 1.02 (0.92-1.14) High 98,362 346 351.8 (316.6-390.9) 1.11 (1.00-1.24) 1.03 (0.91-1.17) Continuous 1.01 (1.00-1.02)* 1.00 (0.98-1.01) Cumulative dose Low 161,924 393 242.7 (219.9-267.9) 0.88 (0.80-0.97)* 0.81 (0.73-0.90)* Medium 129,793 457 352.1 (321.3-385.9) 1.21 (1.10-1.33)* 1.10 (0.98-1.22) High 93,213 303 325.1 (290.4-363.8) 1.04 (0.93-1.16) 0.98 (0.85-1.12) Continuous 1.00 (1.00-1.01) 1.00 (0.99-1.00) 5.2.1. Gliclazide Never 26,747,400 53,057 198.4 (196.7-200.1) 1.00 1.00 Ever use 169,560 527 307.7 (276.3-342.6) 1.02 (0.92-1.14) 1.01 (0.90-1.14) Cumulative duration Low 56,423 154 272.9 (233.1-319.6) 0.94 (0.81-1.11) 0.92 (0.78-1.09) Medium 57,402 157 273.5 (233.9-319.8) 0.92 (0.79-1.07) 0.88 (0.75-1.04) High 55,735 216 387.5 (339.2-442.8) 1.22 (1.06-1.39)* 1.20 (1.03-1.39)* Continuous 1.02 (1.00-1.04)* 1.01 (0.99-1.03) Cumulative dose Low 59,361 146 246.0 (209.1-289.3) 0.85 (0.72-1.00)* 0.82 (0.69-0.97)* Medium 57,663 201 348.6 (303.6-400.3) 1.16 (1.01-1.33)* 1.11 (0.96-1.29) High 52,536 180 342.6 (296.1-396.5) 1.08 (0.94-1.26) 1.08 (0.92-1.27) Continuous 1.00 (1.00-1.01) 1.00 (0.99-1.01) 5.2.2. Glyburide Never 26,626,770 52,734 198.0 (196.4-199.7) 1.00 1.00 Ever use 290,190 850 298.5 (270.0-330.0) 1.08 (0.98-1.20) 1.03 (0.93-1.15) Cumulative duration Low 127,512 327 256.4 (230.1-285.8) 0.92 (0.83-1.03) 0.86 (0.76-0.96)* Medium 94,753 293 309.2 (275.8-346.7) 1.08 (0.96-1.21) 0.98 (0.86-1.11) High 67,925 230 338.6 (297.6-385.3) 1.09 (0.95-1.24) 0.98 (0.85-1.14) Continuous 1.01 (0.99-1.02) 0.99 (0.97-1.01) Cumulative dose Low 134,397 355 264.1 (238.0-293.1) 0.94 (0.85-1.05) 0.87 (0.77-0.97)* Medium 96,766 305 315.2 (281.7-352.6) 1.10 (0.98-1.23) 0.98 (0.87-1.11) High 59,027 190 321.9 (279.2-371.1) 1.04 (0.91-1.21) 0.95 (0.81-1.11) Continuous 1.00 (0.99-1.01) 0.99 (0.98-1.00)* 6. Thiazolidinediones Never 26,823,978 53,289 198.7 (197.0-200.4) 1.00 1.00 Ever use 92,982 295 265.8 (212.9-331.8) 1.00 (0.80-1.25) 0.93 (0.75-1.17) Cumulative duration Low 34,084 95 278.7 (228.0-340.8) 0.98 (0.80-1.20) 0.93 (0.76-1.15) Medium 31,481 102 324.0 (266.9-393.4) 1.12 (0.92-1.36) 1.04 (0.85-1.28) High 27,417 98 357.4 (293.2-435.7) 1.15 (0.94-1.40) 1.09 (0.88-1.34) Continuous 1.01 (0.98-1.04) 0.99 (0.96-1.03) Cumulative dose Low 34,463 98 284.4 (233.3-346.6) 1.00 (0.82-1.22) 0.94 (0.77-1.16) 248 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 32,401 106 327.2 (270.4-395.8) 1.13 (0.93-1.36) 1.05 (0.86-1.28) High 26,118 91 348.4 (283.7-427.9) 1.13 (0.92-1.38) 1.09 (0.88-1.35) Continuous 1.01 (0.97-1.04) 0.99 (0.96-1.03) 6.1. Pioglitazone Never 26,873,788 53,445 198.9 (197.2-200.6) 1.00 1.00 Ever use 43,172 139 234.4 (167.5-328.0) 0.85 (0.60-1.18) 0.79 (0.57-1.11) Cumulative duration Low 15,538 47 302.5 (227.3-402.6) 1.04 (0.78-1.39) 1.00 (0.74-1.33) Medium 14,666 41 279.6 (205.8-379.7) 0.95 (0.70-1.29) 0.89 (0.65-1.22) High 12,968 51 393.3 (298.9-517.5) 1.25 (0.95-1.65) 1.19 (0.90-1.58) Continuous 1.00 (0.95-1.05) 0.99 (0.93-1.04) Cumulative dose Low 15,616 47 301.0 (226.1-400.6) 1.04 (0.78-1.38) 0.99 (0.74-1.32) Medium 15,085 46 304.9 (228.4-407.1) 1.03 (0.77-1.38) 0.99 (0.73-1.32) High 12,471 46 368.9 (276.3-492.4) 1.18 (0.88-1.57) 1.15 (0.85-1.55) Continuous 1.00 (0.95-1.05) 0.99 (0.94-1.04) 6.2. Rosiglitazone Never 26,855,904 53,391 198.8 (197.1-200.5) 1.00 1.00 Ever use 61,056 193 297.4 (222.8-397.1) 1.18 (0.88-1.57) 1.09 (0.81-1.46) Cumulative duration Low 21,872 64 292.6 (229.0-373.8) 1.02 (0.80-1.31) 0.97 (0.75-1.24) Medium 21,102 58 274.9 (212.5-355.5) 0.96 (0.74-1.24) 0.88 (0.68-1.15) High 18,082 71 392.7 (311.2-495.5) 1.28 (1.02-1.62)* 1.20 (0.94-1.52) Continuous 1.02 (0.98-1.07) 1.00 (0.95-1.05) Cumulative dose Low 22,279 66 296.2 (232.7-377.1) 1.04 (0.81-1.32) 0.98 (0.76-1.25) Medium 21,514 67 311.4 (245.1-395.7) 1.07 (0.84-1.36) 0.98 (0.77-1.26) High 17,263 60 347.6 (269.9-447.6) 1.14 (0.89-1.47) 1.08 (0.83-1.40) Continuous 1.01 (0.97-1.07) 1.00 (0.94-1.05) 7. Insulins and analogues Never 26,763,779 53,186 198.7 (197.0-200.4) 1.00 1.00 Ever use 153,181 398 279.2 (248.3-313.9) 0.99 (0.88-1.12) 0.98 (0.87-1.11) Cumulative duration Low 79,227 160 202.0 (173.0-235.8) 0.90 (0.77-1.06) 0.88 (0.75-1.04) Medium 48,672 138 283.5 (240.0-335.0) 0.98 (0.83-1.15) 0.95 (0.79-1.13) High 25,282 100 395.5 (325.1-481.2) 1.25 (1.03-1.53)* 1.24 (1.01-1.53)* Continuous 1.03 (1.01-1.05)* 1.02 (0.99-1.04) Cumulative dose Low 80,901 163 201.5 (172.8-234.9) 0.89 (0.76-1.04) 0.87 (0.74-1.02) Medium 46,657 133 285.1 (240.5-337.9) 0.98 (0.83-1.16) 0.95 (0.79-1.13) High 25,623 102 398.1 (327.9-483.3) 1.28 (1.06-1.56)* 1.26 (1.02-1.54)* Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.03)* 7.1. Basal insulins Never 26,770,645 53,201 198.7 (197.0-200.4) 1.00 1.00 Ever use 146,315 383 280.8 (248.8-316.9) 1.00 (0.89-1.13) 0.84 (0.71-0.98)* Cumulative duration Low 74,490 152 204.1 (174.1-239.2) 0.91 (0.77-1.06) 0.85 (0.71-1.02) Medium 47,092 133 282.4 (238.3-334.7) 0.97 (0.82-1.15) 0.83 (0.68-1.02) High 24,733 98 396.2 (325.1-483.0) 1.26 (1.03-1.53)* 1.05 (0.81-1.37) Continuous 1.03 (1.01-1.06)* 1.00 (0.97-1.04) Cumulative dose Low 75,643 151 199.6 (170.2-234.1) 0.88 (0.75-1.03) 0.83 (0.69-0.99)* Medium 45,900 132 287.6 (242.5-341.1) 0.99 (0.83-1.17) 0.87 (0.70-1.07) High 24,772 100 403.7 (331.8-491.1) 1.30 (1.07-1.58)* 1.07 (0.82-1.39) Continuous 1.02 (1.01-1.04)* 1.02 (1.00-1.03) 7.2. Bolus insulins Never 26,844,167 53,388 198.9 (197.2-200.6) 1.00 1.00 Ever use 72,793 196 343.4 (288.4-408.9) 1.30 (1.10-1.55)* 1.52 (1.22-1.91)* Cumulative duration Low 41,607 80 192.3 (154.4-239.4) 0.93 (0.75-1.16) 1.04 (0.81-1.34) Medium 21,239 79 372.0 (298.3-463.7) 1.36 (1.09-1.70)* 1.50 (1.15-1.97)* High 9,947 37 372.0 (269.5-513.4) 1.22 (0.88-1.68) 1.23 (0.84-1.81) Continuous 1.07 (1.02-1.13)* 1.05 (0.98-1.13) Cumulative dose Low 43,110 86 199.5 (161.5-246.4) 0.96 (0.78-1.18) 1.07 (0.84-1.36) 249 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 19,439 64 329.2 (257.7-420.6) 1.20 (0.94-1.53) 1.27 (0.95-1.70) High 10,244 46 449.0 (336.3-599.5) 1.50 (1.12-2.00)* 1.47 (1.03-2.10)* Continuous 1.03 (1.01-1.05)* 1.01 (0.98-1.04) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, birth cohort, health authority, and neighbourhood income quintile. Model 2 further adjusted for other mutually exclusive diabetes medications. This table displays associations between all diabetes medications and breast cancer. For a summary of selected medications with significant associations, please refer to Table 5-3. * denotes p<0.05. 250 Supplementary Table B-3. Associations between all diabetes medications and the risk of breast cancer with variation in washout and lag periods Exposure Model 1 Model 2 Model 3 Model 4 Model 5 1. Biguanides (i.e., metformin) Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.09 (1.04-1.14)* 1.23 (1.18-1.27)* 1.08 (1.03-1.13)* 1.03 (0.99-1.07) 1.09 (1.05-1.15)* Cumulative duration Low 0.93 (0.87-0.99)* 1.28 (1.21-1.35)* 0.91 (0.84-0.97)* 0.85 (0.80-0.90)* 0.94 (0.88-1.01) Medium 1.19 (1.12-1.26)* 1.20 (1.13-1.26)* 1.11 (1.04-1.18)* 1.10 (1.04-1.16)* 1.18 (1.11-1.26)* High 1.14 (1.07-1.21)* 1.11 (1.05-1.18)* 1.16 (1.08-1.24)* 1.10 (1.05-1.16)* 1.15 (1.08-1.24)* Continuous 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 1.02 (1.01-1.02)* Cumulative dose Low 0.94 (0.88-1.00)* 1.27 (1.21-1.34)* 0.88 (0.82-0.94)* 0.86 (0.81-0.92)* 0.95 (0.89-1.01) Medium 1.22 (1.15-1.30)* 1.20 (1.14-1.27)* 1.19 (1.12-1.26)* 1.12 (1.06-1.18)* 1.22 (1.15-1.30)* High 1.10 (1.02-1.18)* 1.10 (1.03-1.17)* 1.11 (1.03-1.19)* 1.08 (1.02-1.14)* 1.11 (1.04-1.20)* Continuous 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 1.02 (1.01-1.03)* 1.01 (1.00-1.01)* 1.02 (1.01-1.03)* 2. Incretin-based medicines Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.86 (0.75-1.00)* 1.12 (1.01-1.25)* 0.82 (0.70-0.97)* 0.81 (0.72-0.92)* 0.88 (0.76-1.02) Cumulative duration Low 0.82 (0.66-1.01) 1.13 (0.97-1.32) 0.83 (0.65-1.04) 0.76 (0.63-0.92)* 0.84 (0.68-1.05) Medium 0.96 (0.79-1.16) 1.21 (1.04-1.41)* 0.91 (0.73-1.13) 0.86 (0.73-1.03) 0.91 (0.74-1.11) High 0.94 (0.78-1.14) 1.02 (0.87-1.21) 0.83 (0.66-1.03) 0.92 (0.78-1.08) 0.97 (0.80-1.19) Continuous 0.98 (0.95-1.02) 1.01 (0.98-1.04) 0.95 (0.91-1.00)* 0.97 (0.94-1.00) 0.99 (0.95-1.03) Cumulative dose Low 0.88 (0.72-1.07) 1.14 (0.99-1.33) 0.88 (0.71-1.09) 0.83 (0.69-0.98)* 0.86 (0.71-1.06) Medium 0.93 (0.77-1.14) 1.20 (1.03-1.40)* 0.88 (0.70-1.10) 0.86 (0.72-1.03) 0.93 (0.76-1.15) High 0.91 (0.74-1.11) 1.02 (0.86-1.21) 0.80 (0.64-1.01) 0.86 (0.73-1.02) 0.94 (0.76-1.15) Continuous 0.97 (0.93-1.02) 1.00 (0.97-1.04) 0.94 (0.89-0.99)* 0.96 (0.92-1.00)* 0.98 (0.93-1.03) 2.1. DPP-4 inhibitors Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.92 (0.78-1.08) 1.16 (1.02-1.31)* 0.88 (0.74-1.06) 0.83 (0.72-0.96)* 0.94 (0.80-1.11) Cumulative duration Low 1.01 (0.81-1.26) 1.26 (1.06-1.48)* 1.04 (0.82-1.32) 0.89 (0.73-1.08) 1.02 (0.81-1.27) Medium 0.96 (0.76-1.20) 1.20 (1.00-1.43)* 0.95 (0.73-1.22) 0.83 (0.68-1.03) 0.96 (0.76-1.22) High 0.90 (0.72-1.12) 0.98 (0.81-1.19) 0.77 (0.59-1.00)* 0.85 (0.71-1.03) 0.93 (0.74-1.17) Continuous 0.97 (0.93-1.02) 1.00 (0.96-1.04) 0.94 (0.89-0.99)* 0.96 (0.92-1.00)* 0.98 (0.93-1.02) Cumulative dose Low 1.03 (0.83-1.27) 1.27 (1.08-1.50)* 1.05 (0.83-1.33) 0.90 (0.74-1.09) 1.02 (0.82-1.28) Medium 0.96 (0.76-1.21) 1.20 (1.00-1.44)* 0.94 (0.73-1.22) 0.84 (0.68-1.04) 0.98 (0.77-1.24) High 0.88 (0.70-1.10) 0.95 (0.78-1.16) 0.76 (0.58-0.98)* 0.84 (0.69-1.02) 0.90 (0.72-1.14) Continuous 0.97 (0.93-1.02) 1.00 (0.96-1.04) 0.94 (0.89-0.99)* 0.96 (0.92-1.00)* 0.98 (0.93-1.03) 2.1.1. Linagliptin Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.94 (0.74-1.20) 1.11 (0.93-1.34) 0.85 (0.64-1.14) 0.82 (0.66-1.01) 1.01 (0.79-1.28) Cumulative duration Low 0.74 (0.48-1.14) 0.95 (0.70-1.30) 0.69 (0.41-1.17) 0.62 (0.42-0.93)* 0.77 (0.49-1.20) Medium 0.72 (0.47-1.10) 1.09 (0.82-1.45) 0.73 (0.45-1.19) 0.67 (0.47-0.97)* 0.77 (0.50-1.19) High 1.09 (0.79-1.50) 1.11 (0.83-1.48) 0.82 (0.54-1.23) 0.93 (0.70-1.24) 1.14 (0.82-1.58) Continuous 0.99 (0.90-1.09) 1.02 (0.94-1.10) 0.92 (0.82-1.04) 0.96 (0.88-1.04) 1.01 (0.92-1.11) Cumulative dose Low 0.73 (0.47-1.14) 0.95 (0.69-1.29) 0.69 (0.41-1.16) 0.62 (0.42-0.92)* 0.76 (0.49-1.20) Medium 0.71 (0.46-1.09) 1.09 (0.82-1.44) 0.73 (0.45-1.18) 0.67 (0.46-0.97)* 0.77 (0.50-1.18) High 1.10 (0.79-1.51) 1.12 (0.84-1.49) 0.82 (0.55-1.24) 0.94 (0.71-1.25) 1.15 (0.83-1.60) Continuous 0.99 (0.91-1.09) 1.02 (0.94-1.10) 0.93 (0.83-1.04) 0.96 (0.88-1.04) 1.01 (0.92-1.11) 2.1.2. Sitagliptin Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.03 (0.83-1.29) 1.24 (1.03-1.48)* 1.04 (0.82-1.32) 0.93 (0.77-1.14) 1.03 (0.82-1.30) Cumulative duration Low 1.02 (0.78-1.32) 1.29 (1.05-1.60)* 0.97 (0.73-1.30) 0.90 (0.71-1.13) 1.01 (0.77-1.33) Medium 1.13 (0.89-1.44) 1.21 (0.98-1.50) 1.04 (0.79-1.36) 0.98 (0.79-1.22) 1.14 (0.88-1.46) High 0.88 (0.66-1.18) 0.97 (0.75-1.24) 0.86 (0.63-1.17) 0.87 (0.68-1.10) 0.91 (0.68-1.22) Continuous 0.98 (0.92-1.04) 1.01 (0.96-1.06) 0.96 (0.90-1.03) 0.96 (0.91-1.02) 0.98 (0.92-1.05) Cumulative dose Low 1.01 (0.78-1.31) 1.28 (1.04-1.58)* 0.97 (0.73-1.29) 0.89 (0.71-1.12) 1.00 (0.76-1.32) 251 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 1.16 (0.91-1.48) 1.21 (0.97-1.50) 1.03 (0.78-1.36) 1.00 (0.80-1.24) 1.16 (0.90-1.50) High 0.87 (0.66-1.16) 0.98 (0.77-1.26) 0.87 (0.64-1.18) 0.87 (0.68-1.10) 0.90 (0.67-1.21) Continuous 0.98 (0.92-1.04) 1.01 (0.96-1.06) 0.97 (0.90-1.03) 0.96 (0.91-1.02) 0.98 (0.92-1.05) 2.2. GLP-1 receptor agonists Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.74 (0.56-0.97)* 1.02 (0.84-1.25) 0.68 (0.49-0.93)* 0.75 (0.59-0.95)* 0.74 (0.56-0.98)* Cumulative duration Low 0.80 (0.56-1.16) 1.10 (0.85-1.44) 0.67 (0.43-1.05) 0.77 (0.55-1.06) 0.76 (0.52-1.11) Medium 0.73 (0.51-1.06) 1.03 (0.78-1.35) 0.74 (0.49-1.12) 0.70 (0.50-0.98)* 0.72 (0.49-1.06) High 1.06 (0.78-1.42) 1.12 (0.86-1.47) 0.86 (0.61-1.22) 1.07 (0.83-1.38) 1.03 (0.75-1.40) Continuous 1.02 (0.94-1.11) 1.04 (0.97-1.12) 0.98 (0.89-1.08) 1.01 (0.94-1.08) 1.02 (0.93-1.11) Cumulative dose Low 0.84 (0.59-1.20) 1.10 (0.84-1.43) 0.73 (0.48-1.11) 0.80 (0.58-1.09) 0.79 (0.54-1.16) Medium 0.88 (0.63-1.23) 1.02 (0.77-1.35) 0.81 (0.55-1.20) 0.84 (0.62-1.14) 0.85 (0.60-1.21) High 0.89 (0.64-1.23) 1.14 (0.87-1.48) 0.74 (0.50-1.10) 0.92 (0.69-1.22) 0.87 (0.62-1.23) Continuous 1.00 (0.72-1.39) 1.17 (0.91-1.50) 0.88 (0.58-1.34) 0.95 (0.70-1.30) 1.02 (0.72-1.43) 3. SGLT-2 inhibitors Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.64 (0.48-0.85)* 1.03 (0.86-1.24) 0.53 (0.37-0.75)* 0.69 (0.55-0.87)* 0.65 (0.48-0.87)* Cumulative duration Low 0.42 (0.25-0.70)* 0.89 (0.67-1.17) 0.37 (0.20-0.69)* 0.47 (0.31-0.71)* 0.42 (0.25-0.71)* Medium 0.57 (0.37-0.87)* 0.96 (0.73-1.26) 0.50 (0.29-0.84)* 0.58 (0.41-0.84)* 0.58 (0.38-0.90)* High 1.00 (0.73-1.37) 1.20 (0.92-1.55) 0.72 (0.48-1.08) 0.96 (0.73-1.26) 0.99 (0.71-1.37) Continuous 0.97 (0.86-1.08) 1.05 (0.96-1.14) 0.87 (0.76-1.00)* 0.95 (0.86-1.04) 0.97 (0.87-1.09) Cumulative dose Low 0.44 (0.27-0.72)* 0.93 (0.71-1.22) 0.41 (0.23-0.74)* 0.55 (0.38-0.80)* 0.45 (0.27-0.74)* Medium 0.54 (0.35-0.84)* 0.91 (0.69-1.21) 0.46 (0.27-0.80)* 0.56 (0.39-0.81)* 0.55 (0.35-0.86)* High 1.01 (0.74-1.38) 1.20 (0.92-1.55) 0.71 (0.47-1.07) 0.92 (0.70-1.22) 1.00 (0.72-1.39) Continuous 0.99 (0.91-1.08) 1.04 (0.97-1.12) 0.91 (0.81-1.02) 0.97 (0.90-1.05) 0.99 (0.91-1.09) 4. AGIs (i.e., acarbose) Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.90 (0.54-1.49) 0.97 (0.63-1.49) 1.01 (0.61-1.68) 0.80 (0.59-1.10) 0.75 (0.41-1.40) Cumulative duration Low 0.90 (0.60-1.35) 0.94 (0.65-1.36) 0.97 (0.64-1.46) 1.08 (0.88-1.34) 0.98 (0.63-1.52) Medium 0.89 (0.57-1.40) 1.09 (0.75-1.60) 0.73 (0.43-1.23) 0.93 (0.73-1.19) 0.89 (0.53-1.47) High 0.74 (0.43-1.27) 0.87 (0.56-1.37) 0.82 (0.47-1.41) 0.88 (0.69-1.14) 0.76 (0.41-1.41) Continuous 0.94 (0.84-1.05) 0.96 (0.88-1.05) 0.95 (0.85-1.06) 0.98 (0.94-1.03) 0.96 (0.85-1.08) Cumulative dose Low 0.97 (0.65-1.44) 1.03 (0.72-1.48) 1.00 (0.66-1.50) 1.07 (0.86-1.33) 0.97 (0.62-1.52) Medium 0.80 (0.50-1.27) 0.88 (0.58-1.32) 0.68 (0.41-1.15) 0.89 (0.70-1.15) 0.88 (0.54-1.43) High 0.76 (0.44-1.30) 0.99 (0.65-1.53) 0.84 (0.49-1.45) 0.95 (0.74-1.21) 0.79 (0.43-1.47) Continuous 0.89 (0.73-1.08) 0.95 (0.81-1.10) 0.91 (0.74-1.10) 0.96 (0.88-1.04) 0.92 (0.74-1.14) 5. Insulin secretagogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.08 (1.00-1.16) 1.16 (1.09-1.24)* 1.09 (1.00-1.17)* 0.92 (0.87-0.98)* 1.09 (1.01-1.18)* Cumulative duration Low 0.90 (0.82-1.00)* 1.11 (1.02-1.20)* 0.90 (0.81-1.00)* 0.81 (0.74-0.88)* 0.88 (0.79-0.98)* Medium 1.11 (1.01-1.22)* 1.14 (1.05-1.24)* 1.06 (0.95-1.17) 0.91 (0.85-0.99)* 1.12 (1.01-1.24)* High 1.12 (1.01-1.24)* 1.10 (1.00-1.22)* 1.11 (0.99-1.24) 1.05 (0.98-1.13) 1.16 (1.04-1.30)* Continuous 1.01 (1.00-1.02)* 1.01 (1.00-1.02)* 1.01 (1.00-1.02) 1.00 (0.99-1.01) 1.02 (1.01-1.03)* Cumulative dose Low 0.89 (0.81-0.98)* 1.09 (1.01-1.18)* 0.88 (0.80-0.98)* 0.82 (0.76-0.90)* 0.87 (0.79-0.97)* Medium 1.19 (1.09-1.31)* 1.19 (1.09-1.30)* 1.17 (1.06-1.29)* 0.98 (0.91-1.05) 1.20 (1.09-1.32)* High 1.04 (0.93-1.16) 1.07 (0.96-1.18) 1.01 (0.89-1.13) 0.98 (0.92-1.06) 1.08 (0.96-1.22) Continuous 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 1.00 (1.00-1.01) 5.1. Meglitinides Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.79 (1.25-2.57)* 1.73 (1.24-2.41)* 1.74 (1.19-2.56)* 1.31 (0.96-1.78) 1.79 (1.22-2.63)* Cumulative duration Low 0.81 (0.49-1.35) 0.95 (0.61-1.47) 0.91 (0.55-1.50) 0.76 (0.53-1.09) 0.96 (0.58-1.59) Medium 1.74 (1.22-2.48)* 1.73 (1.24-2.40)* 1.71 (1.18-2.49)* 1.49 (1.14-1.95)* 1.89 (1.30-2.73)* High 1.10 (0.72-1.69) 1.08 (0.73-1.61) 1.04 (0.66-1.65) 0.96 (0.69-1.34) 1.19 (0.76-1.87) Continuous 1.03 (0.96-1.11) 1.03 (0.96-1.10) 1.03 (0.96-1.11) 1.01 (0.95-1.07) 1.04 (0.97-1.12) Cumulative dose Low 1.08 (0.71-1.64) 1.23 (0.86-1.77) 1.14 (0.74-1.75) 0.82 (0.58-1.16) 1.26 (0.83-1.91) 252 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 1.50 (1.03-2.19)* 1.52 (1.07-2.14)* 1.54 (1.04-2.28)* 1.41 (1.07-1.86)* 1.68 (1.14-2.48)* High 1.03 (0.64-1.65) 0.94 (0.59-1.49) 0.93 (0.55-1.57) 0.98 (0.70-1.37) 1.08 (0.65-1.79) Continuous 1.00 (0.94-1.07) 1.00 (0.93-1.06) 0.98 (0.90-1.07) 0.99 (0.94-1.04) 1.00 (0.92-1.08) 5.1.1. Repaglinide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.81 (1.27-2.60)* 1.75 (1.25-2.43)* 1.76 (1.20-2.59)* 1.32 (0.97-1.80) 1.81 (1.23-2.66)* Cumulative duration Low 0.83 (0.50-1.38) 0.96 (0.62-1.49) 0.92 (0.56-1.53) 0.77 (0.54-1.11) 0.98 (0.59-1.62) Medium 1.74 (1.22-2.49)* 1.73 (1.24-2.41)* 1.74 (1.20-2.53)* 1.51 (1.15-1.97)* 1.93 (1.33-2.80)* High 1.13 (0.74-1.73) 1.10 (0.74-1.65) 1.06 (0.67-1.69) 0.98 (0.70-1.37) 1.21 (0.77-1.90) Continuous 1.03 (0.97-1.11) 1.03 (0.97-1.10) 1.03 (0.96-1.11) 1.01 (0.95-1.07) 1.04 (0.97-1.12) Cumulative dose Low 1.09 (0.72-1.66) 1.25 (0.87-1.79) 1.15 (0.75-1.77) 0.83 (0.58-1.17) 1.27 (0.83-1.92) Medium 1.55 (1.07-2.26)* 1.56 (1.10-2.20)* 1.59 (1.07-2.35)* 1.45 (1.10-1.91)* 1.75 (1.19-2.58)* High 1.04 (0.65-1.68) 0.96 (0.60-1.52) 0.94 (0.56-1.59) 0.99 (0.71-1.39) 1.10 (0.66-1.82) Continuous 1.00 (0.94-1.07) 1.00 (0.93-1.06) 0.98 (0.91-1.07) 0.99 (0.94-1.04) 1.00 (0.93-1.08) 5.2. Sulfonylureas Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.06 (0.98-1.14) 1.15 (1.08-1.23)* 1.07 (0.99-1.16) 0.91 (0.86-0.97)* 1.08 (1.00-1.17) Cumulative duration Low 0.90 (0.81-0.99)* 1.10 (1.01-1.19)* 0.89 (0.80-0.99)* 0.81 (0.74-0.88)* 0.88 (0.79-0.98)* Medium 1.12 (1.02-1.23)* 1.15 (1.06-1.25)* 1.07 (0.97-1.19) 0.92 (0.85-0.99)* 1.13 (1.02-1.25)* High 1.11 (1.00-1.24) 1.10 (1.00-1.21) 1.10 (0.98-1.23) 1.05 (0.98-1.12) 1.15 (1.03-1.29)* Continuous 1.01 (1.00-1.02)* 1.01 (1.00-1.02)* 1.01 (1.00-1.02) 1.00 (0.99-1.01) 1.02 (1.00-1.03)* Cumulative dose Low 0.88 (0.80-0.97)* 1.08 (0.99-1.17) 0.86 (0.78-0.96)* 0.82 (0.75-0.89)* 0.86 (0.77-0.96)* Medium 1.21 (1.10-1.33)* 1.20 (1.11-1.31)* 1.18 (1.07-1.31)* 0.98 (0.91-1.06) 1.22 (1.10-1.34)* High 1.04 (0.93-1.16) 1.07 (0.96-1.18) 1.00 (0.89-1.13) 0.98 (0.91-1.05) 1.08 (0.95-1.22) Continuous 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 1.00 (1.00-1.01) 5.2.1. Gliclazide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.02 (0.92-1.14) 1.12 (1.02-1.22)* 1.04 (0.93-1.17) 0.91 (0.83-1.00)* 1.03 (0.92-1.16) Cumulative duration Low 0.94 (0.81-1.11) 1.11 (0.98-1.27) 0.98 (0.83-1.16) 0.92 (0.81-1.04) 0.96 (0.82-1.13) Medium 0.92 (0.79-1.07) 1.04 (0.91-1.19) 0.84 (0.70-1.00)* 0.86 (0.76-0.98)* 0.93 (0.79-1.09) High 1.22 (1.06-1.39)* 1.19 (1.05-1.35)* 1.19 (1.04-1.38)* 1.03 (0.92-1.15) 1.25 (1.09-1.44)* Continuous 1.02 (1.00-1.04)* 1.02 (1.01-1.04)* 1.01 (0.99-1.04) 1.00 (0.98-1.01) 1.03 (1.01-1.05)* Cumulative dose Low 0.85 (0.72-1.00)* 1.05 (0.92-1.19) 0.87 (0.73-1.04) 0.86 (0.75-0.97)* 0.86 (0.72-1.01) Medium 1.16 (1.01-1.33)* 1.21 (1.07-1.37)* 1.14 (0.98-1.32) 0.99 (0.88-1.11) 1.18 (1.02-1.36)* High 1.08 (0.94-1.26) 1.09 (0.96-1.24) 1.02 (0.87-1.19) 0.96 (0.86-1.08) 1.11 (0.95-1.30) Continuous 1.00 (1.00-1.01) 1.00 (1.00-1.01) 1.00 (0.99-1.01) 1.00 (0.99-1.00) 1.01 (1.00-1.01) 5.2.2. Glyburide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.08 (0.98-1.20) 1.18 (1.08-1.29)* 1.10 (0.99-1.22) 0.92 (0.85-0.99)* 1.12 (1.00-1.25)* Cumulative duration Low 0.92 (0.83-1.03) 1.08 (0.98-1.18) 0.90 (0.80-1.01) 0.83 (0.76-0.91)* 0.91 (0.81-1.03) Medium 1.08 (0.96-1.21) 1.11 (1.00-1.23) 1.02 (0.90-1.15) 0.86 (0.79-0.94)* 1.08 (0.95-1.22) High 1.09 (0.95-1.24) 1.07 (0.95-1.21) 1.12 (0.98-1.28) 1.06 (0.98-1.15) 1.13 (0.98-1.30) Continuous 1.01 (0.99-1.02) 1.01 (1.00-1.02) 1.01 (0.99-1.02) 1.00 (0.99-1.01) 1.01 (1.00-1.03) Cumulative dose Low 0.94 (0.85-1.05) 1.09 (1.00-1.19) 0.91 (0.82-1.02) 0.86 (0.79-0.94)* 0.93 (0.83-1.04) Medium 1.10 (0.98-1.23) 1.10 (0.99-1.22) 1.06 (0.94-1.20) 0.88 (0.81-0.97)* 1.10 (0.98-1.25) High 1.04 (0.91-1.21) 1.05 (0.92-1.19) 1.06 (0.91-1.23) 1.01 (0.93-1.10) 1.07 (0.92-1.26) Continuous 1.00 (0.99-1.01) 1.00 (0.99-1.01) 1.00 (0.99-1.01) 1.00 (0.99-1.00) 1.00 (0.99-1.01) 6. Thiazolidinediones Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.00 (0.80-1.25) 1.04 (0.85-1.27) 1.08 (0.86-1.35) 1.09 (0.94-1.26) 0.95 (0.74-1.22) Cumulative duration Low 0.98 (0.80-1.20) 1.01 (0.84-1.21) 1.01 (0.82-1.24) 0.95 (0.82-1.09) 1.00 (0.81-1.23) Medium 1.12 (0.92-1.36) 1.10 (0.92-1.32) 1.11 (0.90-1.36) 1.05 (0.91-1.22) 1.15 (0.94-1.42) High 1.15 (0.94-1.40) 1.13 (0.94-1.36) 1.17 (0.95-1.44) 1.16 (1.01-1.33)* 1.15 (0.93-1.43) Continuous 1.01 (0.98-1.04) 1.01 (0.98-1.04) 1.02 (0.98-1.05) 1.02 (1.00-1.04) 1.01 (0.98-1.05) Cumulative dose Low 1.00 (0.82-1.22) 1.03 (0.86-1.23) 1.01 (0.82-1.24) 0.96 (0.83-1.11) 1.03 (0.84-1.27) 253 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 1.13 (0.93-1.36) 1.12 (0.93-1.33) 1.10 (0.90-1.35) 1.05 (0.91-1.21) 1.17 (0.96-1.44) High 1.13 (0.92-1.38) 1.10 (0.91-1.33) 1.18 (0.95-1.46) 1.15 (1.00-1.32)* 1.09 (0.86-1.37) Continuous 1.01 (0.97-1.04) 1.00 (0.97-1.03) 1.01 (0.98-1.05) 1.01 (0.99-1.03) 1.00 (0.96-1.04) 6.1. Pioglitazone Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.85 (0.60-1.18) 0.84 (0.62-1.15) 0.93 (0.66-1.30) 1.14 (0.92-1.40) 0.75 (0.51-1.10) Cumulative duration Low 1.04 (0.78-1.39) 1.01 (0.77-1.32) 1.05 (0.78-1.42) 1.02 (0.83-1.26) 1.06 (0.78-1.44) Medium 0.95 (0.70-1.29) 0.99 (0.75-1.30) 0.93 (0.67-1.29) 0.89 (0.71-1.12) 0.96 (0.70-1.34) High 1.25 (0.95-1.65) 1.16 (0.89-1.50) 1.32 (1.00-1.75) 1.30 (1.07-1.57)* 1.23 (0.91-1.66) Continuous 1.00 (0.95-1.05) 0.99 (0.94-1.04) 1.01 (0.96-1.06) 1.03 (1.00-1.06) 1.00 (0.94-1.05) Cumulative dose Low 1.04 (0.78-1.38) 1.02 (0.78-1.33) 1.02 (0.75-1.38) 1.03 (0.84-1.27) 1.04 (0.77-1.42) Medium 1.03 (0.77-1.38) 1.05 (0.81-1.37) 1.04 (0.76-1.41) 0.92 (0.74-1.15) 1.09 (0.81-1.48) High 1.18 (0.88-1.57) 1.08 (0.82-1.43) 1.26 (0.93-1.69) 1.26 (1.03-1.53)* 1.11 (0.80-1.53) Continuous 1.00 (0.95-1.05) 0.98 (0.94-1.03) 1.01 (0.96-1.06) 1.02 (0.99-1.05) 0.99 (0.93-1.05) 6.2. Rosiglitazone Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.18 (0.88-1.57) 1.25 (0.96-1.61) 1.24 (0.92-1.67) 1.03 (0.84-1.27) 1.18 (0.86-1.62) Cumulative duration Low 1.02 (0.80-1.31) 1.06 (0.85-1.32) 1.09 (0.85-1.40) 0.94 (0.78-1.12) 1.00 (0.77-1.31) Medium 0.96 (0.74-1.24) 0.95 (0.75-1.21) 0.96 (0.73-1.25) 0.97 (0.81-1.16) 1.00 (0.76-1.32) High 1.28 (1.02-1.62)* 1.29 (1.05-1.60)* 1.23 (0.96-1.58) 1.16 (0.99-1.37) 1.32 (1.02-1.70)* Continuous 1.02 (0.98-1.07) 1.03 (0.98-1.07) 1.02 (0.97-1.07) 1.01 (0.98-1.05) 1.03 (0.98-1.08) Cumulative dose Low 1.04 (0.81-1.32) 1.08 (0.87-1.35) 1.09 (0.85-1.39) 0.98 (0.82-1.17) 1.04 (0.80-1.35) Medium 1.07 (0.84-1.36) 1.06 (0.85-1.32) 1.03 (0.80-1.33) 0.99 (0.83-1.18) 1.12 (0.87-1.44) High 1.14 (0.89-1.47) 1.15 (0.91-1.45) 1.15 (0.88-1.50) 1.10 (0.92-1.30) 1.15 (0.87-1.52) Continuous 1.01 (0.97-1.07) 1.02 (0.98-1.07) 1.01 (0.96-1.07) 1.00 (0.97-1.04) 1.02 (0.96-1.07) 7. Insulins and analogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.99 (0.88-1.12) 1.20 (1.09-1.33)* 0.93 (0.82-1.06) 0.98 (0.91-1.05) 1.01 (0.89-1.14) Cumulative duration Low 0.90 (0.77-1.06) 1.20 (1.06-1.35)* 0.89 (0.76-1.05) 0.83 (0.73-0.94)* 0.93 (0.79-1.10) Medium 0.98 (0.83-1.15) 1.09 (0.94-1.27) 0.83 (0.69-1.00) 0.89 (0.80-1.00) 1.01 (0.85-1.21) High 1.25 (1.03-1.53)* 1.21 (1.00-1.46) 1.21 (0.98-1.49) 1.17 (1.07-1.29)* 1.18 (0.95-1.48) Continuous 1.03 (1.01-1.05)* 1.03 (1.01-1.05)* 1.02 (0.99-1.05) 1.01 (1.00-1.02)* 1.03 (1.00-1.06) Cumulative dose Low 0.89 (0.76-1.04) 1.19 (1.05-1.34)* 0.86 (0.73-1.02) 0.84 (0.75-0.95)* 0.91 (0.78-1.07) Medium 0.98 (0.83-1.16) 1.10 (0.95-1.28) 0.84 (0.69-1.02) 0.86 (0.77-0.96)* 1.03 (0.87-1.23) High 1.28 (1.06-1.56)* 1.21 (1.00-1.46) 1.25 (1.02-1.53)* 1.19 (1.09-1.31)* 1.19 (0.96-1.49) Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 1.01 (1.00-1.03)* 1.01 (1.00-1.01)* 1.02 (1.00-1.03)* 7.1. Basal insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.00 (0.89-1.13) 1.21 (1.09-1.34)* 0.94 (0.83-1.08) 0.99 (0.92-1.06) 1.02 (0.89-1.16) Cumulative duration Low 0.91 (0.77-1.06) 1.20 (1.06-1.36)* 0.88 (0.75-1.05) 0.84 (0.74-0.95)* 0.92 (0.78-1.10) Medium 0.97 (0.82-1.15) 1.08 (0.93-1.26) 0.84 (0.70-1.02) 0.86 (0.77-0.97)* 1.01 (0.85-1.21) High 1.26 (1.03-1.53)* 1.20 (0.99-1.45) 1.21 (0.98-1.49) 1.19 (1.09-1.31)* 1.19 (0.95-1.49) Continuous 1.03 (1.01-1.06)* 1.03 (1.01-1.06)* 1.02 (0.99-1.05) 1.02 (1.01-1.03)* 1.03 (1.00-1.06) Cumulative dose Low 0.88 (0.75-1.03) 1.15 (1.01-1.30)* 0.84 (0.71-1.00) 0.83 (0.73-0.94)* 0.90 (0.76-1.06) Medium 0.99 (0.83-1.17) 1.12 (0.96-1.31) 0.86 (0.71-1.04) 0.86 (0.77-0.96)* 1.04 (0.87-1.24) High 1.30 (1.07-1.58)* 1.24 (1.03-1.50)* 1.27 (1.04-1.56)* 1.20 (1.09-1.32)* 1.22 (0.98-1.53) Continuous 1.02 (1.01-1.04)* 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 1.01 (1.01-1.02)* 1.02 (1.01-1.04)* 7.2. Bolus insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.30 (1.10-1.55)* 1.42 (1.22-1.66)* 1.20 (0.99-1.45) 1.14 (1.03-1.25)* 1.31 (1.08-1.58)* Cumulative duration Low 0.93 (0.75-1.16) 1.14 (0.95-1.37) 0.84 (0.66-1.07) 0.97 (0.84-1.13) 0.91 (0.71-1.17) Medium 1.36 (1.09-1.70)* 1.36 (1.10-1.68)* 1.23 (0.97-1.57) 1.07 (0.93-1.23) 1.34 (1.05-1.70)* High 1.22 (0.88-1.68) 1.16 (0.85-1.59) 1.15 (0.82-1.61) 1.18 (1.04-1.35)* 1.13 (0.78-1.63) Continuous 1.07 (1.02-1.13)* 1.07 (1.01-1.12)* 1.05 (0.99-1.11) 1.02 (1.00-1.04)* 1.06 (1.00-1.13)* Cumulative dose Low 0.96 (0.78-1.18) 1.13 (0.95-1.35) 0.85 (0.67-1.08) 0.96 (0.83-1.10) 0.95 (0.75-1.20) 254 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 1.20 (0.94-1.53) 1.24 (0.98-1.56) 1.07 (0.82-1.40) 1.06 (0.92-1.22) 1.17 (0.90-1.53) High 1.50 (1.12-2.00)* 1.44 (1.09-1.90)* 1.44 (1.07-1.95)* 1.22 (1.07-1.39)* 1.39 (1.00-1.94)* Continuous 1.03 (1.01-1.05)* 1.03 (1.01-1.05)* 1.02 (1.00-1.05) 1.01 (1.00-1.02)* 1.03 (1.00-1.06) Model 1 adjusted for age, birth cohort, health authority, and neighbourhood income with 1-year washout and 1-year lag periods in the primary analysis. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income with 1-year washout and 0-year lag periods. Model 3 adjusted for age, birth cohort, health authority, and neighbourhood income with 1-year washout and 2-year lag periods. Model 4 adjusted for age, birth cohort, health authority, and neighbourhood income with 0-year washout and 1-year lag periods. Model 5 adjusted for age, birth cohort, health authority, and neighbourhood income with 2-year washout and 1-year lag periods. This table displays associations between all diabetes medications and breast cancer. For a summary of selected medications with significant associations, please refer to Table 5-4. * denotes p<0.05. 255 Supplementary Table B-4. Associations between all diabetes medications and the risk of breast cancer among people in the BCGP Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 1. Biguanides (i.e., metformin) Never 369,350 1,158 313.5 (296.0-332.1) 1.00 1.00 1.00 Ever use 4,755 16 336.5 (206.1-549.3) 1.09 (1.04-1.14)* 0.82 (0.50-1.35) 0.75 (0.45-1.23) Cumulative duration - continuous 1.02 (1.01-1.02)* 1.01 (0.94-1.07) 1.00 (0.93-1.06) Cumulative dose - continuous 1.02 (1.01-1.02)* 1.01 (0.93-1.09) 0.99 (0.92-1.08) 2. Incretin-based medicines Never 373,258 1,170 313.5 (296.0-331.9) 1.00 1.00 1.00 Ever use 847 Suppressed 472.3 (177.2-1258.3) 0.86 (0.75-1.00)* 1.20 (0.45-3.21) 1.11 (0.41-2.98) Cumulative duration - continuous 0.98 (0.95-1.02) 1.11 (0.88-1.39) 1.09 (0.87-1.38) Cumulative dose - continuous 0.97 (0.93-1.02) 1.19 (0.96-1.49) 1.18 (0.94-1.47) 2.1. DPP-4 inhibitors Never 373,680 1,171 313.4 (295.9-331.8) 1.00 1.00 1.00 Ever use 425 Suppressed 705.9 (227.7-2188.7) 0.92 (0.78-1.08) 1.76 (0.56-5.47) 1.61 (0.52-5.02) Cumulative duration - continuous 0.97 (0.93-1.02) 1.16 (0.91-1.49) 1.15 (0.90-1.47) Cumulative dose - continuous 0.97 (0.93-1.02) 1.16 (0.91-1.49) 1.15 (0.89-1.47) 2.1.1. Linagliptin Never 373,959 1,173 313.7 (296.2-332.1) 1.00 1.00 1.00 Ever use 146 Suppressed 684.9 (96.5-4862.6) 0.94 (0.74-1.20) Not shown Not shown Cumulative duration - continuous 0.99 (0.90-1.09) 1.34 (0.70-2.58) 1.31 (0.68-2.53) Cumulative dose - continuous 0.99 (0.91-1.09) 1.34 (0.70-2.58) 1.31 (0.68-2.53) 2.1.2. Sitagliptin Never 373,875 1,173 313.7 (296.3-332.2) 1.00 1.00 1.00 Ever use 230 Suppressed 434.8 (61.2-3086.7) 1.03 (0.83-1.29) 1.06 (0.15-7.57) 0.97 (0.14-6.88) Cumulative duration - continuous 0.98 (0.92-1.04) 1.20 (0.89-1.63) 1.18 (0.87-1.60) Cumulative dose - continuous 0.98 (0.92-1.04) 1.20 (0.89-1.63) 1.18 (0.87-1.60) 2.2. GLP-1 receptor agonists Never 373,645 1,173 313.9 (296.5-332.4) 1.00 1.00 1.00 Ever use 460 Suppressed 217.4 (30.6-1543.3) 0.74 (0.56-0.97)* 0.57 (0.08-4.01) 0.54 (0.08-3.79) Cumulative duration - continuous 1.02 (0.94-1.11) 0.93 (0.48-1.80) 0.91 (0.46-1.80) Cumulative dose - continuous 1.00 (0.72-1.39) 1.85 (0.95-3.59) 1.82 (0.93-3.56) 3. SGLT-2 inhibitors Never 373,830 1,173 313.8 (296.3-332.3) 1.00 1.00 1.00 Ever use 275 Suppressed 363.6 (51.2-2581.6) 0.64 (0.48-0.85)* 0.94 (0.13-6.70) 0.88 (0.12-6.24) Cumulative duration - continuous 0.97 (0.86-1.08) 0.90 (0.33-2.47) 0.88 (0.32-2.42) Cumulative dose - continuous 0.99 (0.91-1.08) 0.80 (0.28-2.32) 0.78 (0.27-2.30) 5. Insulin secretagogues Never 372,854 1,170 313.8 (296.3-332.3) 1.00 1.00 1.00 Ever use 1,251 Suppressed 319.7 (120.0-851.9) 1.08 (1.00-1.16) 0.78 (0.29-2.07) 0.70 (0.26-1.89) Cumulative duration - continuous 1.01 (1.00-1.02)* 1.07 (0.98-1.16) 1.05 (0.97-1.15) Cumulative dose - continuous 1.00 (1.00-1.01) 1.04 (1.01-1.06)* 1.03 (1.01-1.06)* 5.2. Sulfonylureas Never 372,886 1,170 313.8 (296.3-332.3) 1.00 1.00 1.00 Ever use 1,219 Suppressed 328.1 (123.2-874.3) 1.06 (0.98-1.14) 0.80 (0.30-2.12) 0.72 (0.27-1.93) Cumulative duration - continuous 1.01 (1.00-1.02)* 1.07 (0.98-1.17) 1.06 (0.97-1.16) 256 Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 Cumulative dose - continuous 1.00 (1.00-1.01) 1.04 (1.02-1.06)* 1.04 (1.01-1.06)* 5.2.1. Gliclazide Never 373,384 1,171 313.6 (296.2-332.1) 1.00 1.00 1.00 Ever use 721 Suppressed 416.1 (134.2-1290.1) 1.02 (0.92-1.14) 1.00 (0.32-3.11) 0.90 (0.29-2.80) Cumulative duration - continuous 1.02 (1.00-1.04)* 1.11 (1.01-1.22)* 1.09 (1.00-1.20) Cumulative dose - continuous 1.00 (1.00-1.01) 1.04 (1.02-1.07)* 1.04 (1.01-1.06)* 5.2.2. Glyburide Never 373,578 1,173 314.0 (296.5-332.5) 1.00 1.00 1.00 Ever use 527 Suppressed 189.8 (26.7-1347.1) 1.08 (0.98-1.20) 0.46 (0.07-3.29) 0.42 (0.06-3.01) Cumulative duration - continuous 1.01 (0.99-1.02) 1.00 (0.82-1.21) 0.99 (0.81-1.20) Cumulative dose - continuous 1.00 (0.99-1.01) 1.02 (0.93-1.12) 1.01 (0.92-1.11) 7. Insulins and analogues Never 373,247 1,171 313.7 (296.3-332.2) 1.00 1.00 1.00 Ever use 858 Suppressed 349.7 (112.8-1084.1) 0.99 (0.88-1.12) 0.88 (0.28-2.73) 0.81 (0.26-2.52) Cumulative duration - continuous 1.03 (1.01-1.05)* 1.00 (0.79-1.27) 0.99 (0.77-1.26) Cumulative dose - continuous 1.02 (1.01-1.03)* 1.02 (0.92-1.14) 1.02 (0.91-1.13) 7.1. Basal insulins Never 373,296 1,171 313.7 (296.2-332.2) 1.00 1.00 1.00 Ever use 809 Suppressed 370.8 (119.6-1149.8) 1.00 (0.89-1.13) 0.92 (0.30-2.87) 0.85 (0.27-2.65) Cumulative duration - continuous 1.03 (1.01-1.06)* 1.01 (0.76-1.35) 0.99 (0.74-1.33) Cumulative dose - continuous 1.02 (1.01-1.04)* 1.04 (0.92-1.17) 1.03 (0.91-1.16) 7.2. Bolus insulins Never 373,717 1,171 313.3 (295.9-331.8) 1.00 1.00 1.00 Ever use 388 Suppressed 773.2 (249.4-2397.4) 1.30 (1.10-1.55)* 2.06 (0.66-6.39) 1.90 (0.61-5.91) Cumulative duration - continuous 1.07 (1.02-1.13)* 0.92 (0.48-1.77) 0.90 (0.46-1.76) Cumulative dose - continuous 1.03 (1.01-1.05)* 0.90 (0.55-1.49) 0.89 (0.53-1.49) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, birth cohort, health authority, and neighbourhood income quintile in the primary analysis using Population Data BC. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income quintile in the BCGP subset. Model 3 further adjusted for sociodemographic and lifestyle-related factors: race/ethnicity, marital status, physical activity, education, individual-level income, reproductive history, fruit and vegetable consumption, alcohol consumption, smoking status, waist to hip ratio, and body mass index using the BCGP subset. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. Effect estimates denoted as “Not shown” have been omitted due to low number of events, which may result in unreliable estimates. This table displays associations between all diabetes medications and breast cancer. For a summary of selected medications with significant associations, please refer to Table 5-5. * denotes p<0.05. 257 Supplementary Table B-5. Associations between all diabetes medications and the risk of breast cancer morphological subtype: ductal Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 25,974,019 33,684 129.7 (128.3-131.1) 1.00 1.00 Ever use 942,941 1,965 210.7 (200.0-221.9) 1.17 (1.11-1.24)* 1.11 (1.05-1.17)* Cumulative duration Low 363,231 605 166.6 (153.8-180.4) 1.01 (0.94-1.10) 0.97 (0.89-1.05) Medium 323,170 726 224.6 (208.9-241.6) 1.26 (1.17-1.36)* 1.19 (1.11-1.28)* High 256,540 634 247.1 (228.6-267.1) 1.28 (1.19-1.39)* 1.18 (1.09-1.27)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* Cumulative dose Low 383,543 645 168.2 (155.7-181.7) 1.01 (0.93-1.09) 0.96 (0.89-1.04) Medium 327,502 763 233.0 (217.0-250.1) 1.30 (1.21-1.40)* 1.23 (1.14-1.32)* High 231,896 557 240.2 (221.1-261.0) 1.26 (1.16-1.37)* 1.16 (1.06-1.26)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* 2. Incretin-based medicines Never 26,807,130 35,450 132.2 (130.9-133.6) 1.00 1.00 Ever use 109,830 199 159.5 (133.5-190.6) 0.91 (0.76-1.08) 0.80 (0.67-0.96)* Cumulative duration Low 37,699 64 169.8 (132.9-216.9) 1.02 (0.80-1.30) 0.90 (0.71-1.16) Medium 36,916 64 173.4 (135.7-221.5) 0.99 (0.78-1.27) 0.88 (0.69-1.13) High 35,215 71 201.6 (159.8-254.4) 1.07 (0.85-1.35) 0.94 (0.74-1.18) Continuous 1.01 (0.96-1.06) 0.98 (0.93-1.02) Cumulative dose Low 41,738 74 177.3 (141.2-222.7) 1.08 (0.86-1.36) 0.95 (0.76-1.20) Medium 34,741 62 178.5 (139.1-228.9) 1.00 (0.78-1.28) 0.89 (0.69-1.14) High 33,351 63 188.9 (147.6-241.8) 0.99 (0.78-1.27) 0.88 (0.68-1.12) Continuous 1.00 (0.94-1.05) 0.97 (0.91-1.02) 2.1. DPP-4 inhibitors Never 26,838,141 35,494 132.3 (130.9-133.6) 1.00 1.00 Ever use 78,819 155 175.1 (142.7-214.8) 0.95 (0.77-1.16) 0.85 (0.69-1.04) Cumulative duration Low 26,904 57 211.9 (163.4-274.7) 1.18 (0.91-1.53) 1.06 (0.82-1.37) Medium 25,479 47 184.5 (138.6-245.5) 1.01 (0.76-1.35) 0.90 (0.68-1.20) High 26,436 51 192.9 (146.6-253.8) 1.00 (0.76-1.32) 0.88 (0.67-1.16) Continuous 1.00 (0.94-1.05) 0.97 (0.91-1.02) Cumulative dose Low 27,412 58 211.6 (163.6-273.7) 1.18 (0.91-1.53) 1.06 (0.82-1.37) Medium 24,971 48 192.2 (144.9-255.1) 1.05 (0.79-1.40) 0.94 (0.71-1.25) High 26,436 49 185.4 (140.1-245.2) 0.96 (0.73-1.28) 0.85 (0.64-1.13) Continuous 1.00 (0.94-1.05) 0.97 (0.91-1.02) 2.1.1. Linagliptin Never 26,888,522 35,599 132.4 (131.0-133.8) 1.00 1.00 Ever use 28,438 50 192.1 (141.9-259.9) 1.00 (0.74-1.36) 0.89 (0.66-1.21) Cumulative duration Low 8,744 12 137.2 (77.9-241.7) 0.74 (0.42-1.31) 0.66 (0.38-1.16) Medium 9,355 14 149.7 (88.6-252.7) 0.80 (0.47-1.35) 0.71 (0.42-1.20) High 10,339 24 232.1 (155.6-346.3) 1.19 (0.80-1.77) 1.04 (0.70-1.56) Continuous 1.02 (0.91-1.15) 0.98 (0.87-1.10) Cumulative dose Low 8,785 12 136.6 (77.6-240.5) 0.74 (0.42-1.30) 0.66 (0.37-1.16) Medium 9,402 14 148.9 (88.2-251.4) 0.79 (0.47-1.34) 0.70 (0.42-1.19) High 10,251 24 234.1 (156.9-349.3) 1.20 (0.80-1.79) 1.05 (0.71-1.57) Continuous 1.02 (0.91-1.15) 0.98 (0.87-1.10) 2.1.2. Sitagliptin Never 26,862,992 35,533 132.3 (130.9-133.7) 1.00 1.00 Ever use 53,968 116 187.3 (140.7-249.3) 1.04 (0.78-1.39) 0.94 (0.71-1.26) Cumulative duration Low 18,434 40 217.0 (159.2-295.8) 1.21 (0.89-1.65) 1.09 (0.80-1.48) Medium 18,909 41 216.8 (159.7-294.5) 1.19 (0.87-1.61) 1.07 (0.79-1.45) High 16,625 35 210.5 (151.2-293.2) 1.11 (0.79-1.54) 0.98 (0.70-1.37) Continuous 1.01 (0.94-1.09) 0.98 (0.91-1.06) Cumulative dose Low 18,897 40 211.7 (155.3-288.6) 1.18 (0.86-1.61) 1.06 (0.78-1.44) 258 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 18,211 44 241.6 (179.8-324.7) 1.32 (0.98-1.78) 1.19 (0.88-1.59) High 16,860 32 189.8 (134.2-268.4) 1.00 (0.71-1.41) 0.89 (0.63-1.25) Continuous 1.01 (0.94-1.09) 0.98 (0.91-1.06) 2.2. GLP-1 receptor agonists Never 26,874,721 35,579 132.4 (131.0-133.8) 1.00 1.00 Ever use 42,239 70 124.3 (87.9-175.7) 0.78 (0.55-1.10) 0.68 (0.48-0.96)* Cumulative duration Low 13,930 22 157.9 (104.0-239.9) 1.03 (0.68-1.56) 0.90 (0.59-1.36) Medium 14,541 21 144.4 (94.2-221.5) 0.93 (0.61-1.42) 0.81 (0.53-1.24) High 13,768 27 196.1 (134.5-286.0) 1.13 (0.78-1.65) 0.98 (0.67-1.42) Continuous 1.05 (0.95-1.16) 1.01 (0.91-1.12) Cumulative dose Low 13,597 23 169.2 (112.4-254.6) 1.08 (0.72-1.63) 0.94 (0.63-1.42) Medium 14,567 25 171.6 (116.0-254.0) 1.09 (0.74-1.61) 0.95 (0.64-1.40) High 14,075 22 156.3 (102.9-237.4) 0.93 (0.61-1.41) 0.80 (0.53-1.22) Continuous 1.12 (0.77-1.63) 0.97 (0.64-1.47) 3. SGLT-2 inhibitors Never 26,879,533 35,599 132.4 (131.1-133.8) 1.00 1.00 Ever use 37,427 50 126.0 (89.1-178.2) 0.72 (0.51-1.02) 0.63 (0.45-0.89)* Cumulative duration Low 12,099 Suppressed 41.3 (17.2-99.3) 0.24 (0.10-0.57)* 0.21 (0.09-0.50)* Medium 12,583 18 143.1 (90.1-227.1) 0.82 (0.51-1.30) 0.72 (0.45-1.14) High 12,745 27 211.8 (145.3-308.9) 1.17 (0.80-1.70) 1.01 (0.69-1.48) Continuous 1.03 (0.91-1.18) 0.97 (0.85-1.11) Cumulative dose Low 12,132 Suppressed 57.7 (27.5-121.0) 0.33 (0.16-0.69)* 0.29 (0.14-0.60)* Medium 12,532 16 127.7 (78.2-208.4) 0.72 (0.44-1.18) 0.63 (0.39-1.03) High 12,763 27 211.5 (145.1-308.5) 1.18 (0.81-1.72) 1.02 (0.70-1.49) Continuous 1.04 (0.94-1.16) 1.00 (0.89-1.11) 4. AGIs (i.e., acarbose) Never 26,894,718 35,610 132.4 (131.0-133.8) 1.00 1.00 Ever use 22,242 39 180.5 (100.0-325.9) 1.00 (0.55-1.81) 1.00 (0.55-1.81) Cumulative duration Low 9,033 17 188.2 (117.0-302.7) 1.04 (0.65-1.68) 1.00 (0.62-1.60) Medium 7,396 13 175.8 (102.1-302.7) 0.97 (0.56-1.66) 0.93 (0.54-1.60) High 5,813 Suppressed 154.8 (80.6-297.6) 0.83 (0.43-1.58) 0.77 (0.40-1.48) Continuous 0.96 (0.84-1.09) 0.95 (0.83-1.08) Cumulative dose Low 8,762 20 228.3 (147.3-353.8) 1.26 (0.82-1.96) 1.21 (0.78-1.88) Medium 7,780 10 128.5 (69.2-238.9) 0.70 (0.38-1.30) 0.67 (0.36-1.25) High 5,700 Suppressed 157.9 (82.2-303.5) 0.84 (0.43-1.61) 0.79 (0.41-1.52) Continuous 0.96 (0.79-1.18) 0.94 (0.77-1.16) 5. Insulin secretagogues Never 26,526,445 34,818 131.3 (129.9-132.6) 1.00 1.00 Ever use 390,515 831 213.9 (196.0-233.4) 1.17 (1.07-1.27)* 1.13 (1.03-1.23)* Cumulative duration Low 157,864 283 179.3 (159.6-201.4) 1.02 (0.91-1.14) 0.99 (0.88-1.12) Medium 132,423 294 222.0 (198.0-248.9) 1.21 (1.08-1.36)* 1.16 (1.03-1.30)* High 100,228 254 253.4 (224.1-286.6) 1.30 (1.15-1.47)* 1.21 (1.07-1.37)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* Cumulative dose Low 164,182 292 177.9 (158.6-199.5) 1.00 (0.89-1.12) 0.98 (0.87-1.10) Medium 131,919 310 235.0 (210.2-262.7) 1.28 (1.15-1.43)* 1.22 (1.09-1.37)* High 94,414 229 242.5 (213.1-276.1) 1.26 (1.11-1.44)* 1.17 (1.02-1.33)* Continuous 1.01 (1.00-1.02)* 1.01 (1.00-1.01) 5.1. Meglitinides Never 26,898,154 35,604 132.4 (131.0-133.7) 1.00 1.00 Ever use 18,806 45 379.8 (252.4-571.5) 2.13 (1.42-3.21)* 2.09 (1.39-3.15)* Cumulative duration Low 6,377 12 188.2 (106.9-331.4) 1.03 (0.59-1.82) 0.98 (0.56-1.73) Medium 6,194 19 306.7 (195.7-480.9) 1.74 (1.11-2.71)* 1.65 (1.05-2.58)* High 6,235 14 224.5 (133.0-379.1) 1.19 (0.70-2.00) 1.11 (0.66-1.88) Continuous 1.04 (0.95-1.13) 1.03 (0.94-1.12) Cumulative dose Low 6,983 15 214.8 (129.5-356.3) 1.17 (0.71-1.94) 1.12 (0.67-1.85) 259 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 6,354 18 283.3 (178.5-449.6) 1.58 (1.00-2.51) 1.51 (0.95-2.40) High 5,469 12 219.4 (124.6-386.4) 1.18 (0.67-2.07) 1.09 (0.62-1.92) Continuous 1.00 (0.92-1.09) 0.99 (0.91-1.08) 5.1.1. Repaglinide Never 26,898,506 35,604 132.4 (131.0-133.7) 1.00 1.00 Ever use 18,454 45 384.3 (255.4-578.3) 2.16 (1.43-3.25)* 2.11 (1.41-3.18)* Cumulative duration Low 6,246 12 192.1 (109.1-338.3) 1.05 (0.60-1.86) 1.00 (0.57-1.77) Medium 6,097 19 311.6 (198.8-488.6) 1.74 (1.11-2.72)* 1.68 (1.07-2.63)* High 6,111 14 229.1 (135.7-386.8) 1.21 (0.72-2.05) 1.14 (0.67-1.92) Continuous 1.04 (0.96-1.14) 1.03 (0.94-1.12) Cumulative dose Low 6,907 15 217.2 (130.9-360.2) 1.18 (0.71-1.96) 1.13 (0.68-1.87) Medium 6,162 18 292.1 (184.0-463.6) 1.63 (1.03-2.58)* 1.56 (0.99-2.48) High 5,385 12 222.8 (126.6-392.4) 1.20 (0.68-2.11) 1.11 (0.63-1.95) Continuous 1.00 (0.92-1.09) 0.99 (0.91-1.08) 5.2. Sulfonylureas Never 26,532,030 34,831 131.3 (129.9-132.7) 1.00 1.00 Ever use 384,930 818 210.0 (192.1-229.5) 1.15 (1.05-1.25)* 1.11 (1.01-1.21)* Cumulative duration Low 157,130 281 178.8 (159.1-201.0) 1.01 (0.90-1.14) 0.99 (0.88-1.11) Medium 129,438 288 222.5 (198.2-249.7) 1.21 (1.08-1.36)* 1.16 (1.03-1.30)* High 98,362 249 253.1 (223.6-286.6) 1.30 (1.15-1.47)* 1.21 (1.07-1.37)* Continuous 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* Cumulative dose Low 161,924 284 175.4 (156.1-197.0) 0.98 (0.87-1.10) 0.96 (0.86-1.08) Medium 129,793 307 236.5 (211.5-264.5) 1.29 (1.15-1.44)* 1.23 (1.10-1.37)* High 93,213 227 243.5 (213.8-277.4) 1.27 (1.11-1.45)* 1.17 (1.03-1.33)* Continuous 1.01 (1.00-1.02)* 1.01 (1.00-1.01) 5.2.1. Gliclazide Never 26,747,400 35,272 131.9 (130.5-133.3) 1.00 1.00 Ever use 169,560 377 216.8 (190.8-246.5) 1.17 (1.03-1.33)* 1.08 (0.95-1.23) Cumulative duration Low 56,423 108 191.4 (158.5-231.1) 1.07 (0.88-1.29) 0.99 (0.82-1.20) Medium 57,402 113 196.9 (163.7-236.7) 1.07 (0.89-1.29) 0.99 (0.83-1.19) High 55,735 156 279.9 (239.2-327.5) 1.45 (1.24-1.70)* 1.32 (1.13-1.55)* Continuous 1.05 (1.03-1.08)* 1.04 (1.02-1.06)* Cumulative dose Low 59,361 107 180.3 (149.1-217.9) 1.00 (0.83-1.21) 0.93 (0.77-1.13) Medium 57,663 136 235.9 (199.4-279.0) 1.28 (1.08-1.51)* 1.18 (1.00-1.40) High 52,536 134 255.1 (215.3-302.1) 1.33 (1.12-1.58)* 1.21 (1.02-1.44)* Continuous 1.01 (1.01-1.02)* 1.01 (1.00-1.02)* 5.2.2. Glyburide Never 26,626,770 35,050 131.6 (130.3-133.0) 1.00 1.00 Ever use 290,190 599 201.6 (178.4-227.8) 1.11 (0.98-1.25) 1.11 (0.98-1.26) Cumulative duration Low 127,512 239 187.4 (165.1-212.8) 1.05 (0.92-1.19) 1.02 (0.90-1.16) Medium 94,753 197 207.9 (180.8-239.1) 1.13 (0.98-1.30) 1.10 (0.96-1.27) High 67,925 163 240.0 (205.8-279.8) 1.23 (1.06-1.44)* 1.17 (1.00-1.36) Continuous 1.02 (1.00-1.04)* 1.01 (1.00-1.03) Cumulative dose Low 134,397 259 192.7 (170.6-217.7) 1.06 (0.94-1.20) 1.04 (0.92-1.18) Medium 96,766 212 219.1 (191.5-250.7) 1.19 (1.04-1.36)* 1.16 (1.01-1.32)* High 59,027 128 216.8 (182.4-257.9) 1.13 (0.95-1.34) 1.06 (0.89-1.27) Continuous 1.01 (1.00-1.02) 1.00 (0.99-1.01) 6. Thiazolidinediones Never 26,823,978 35,426 132.1 (130.7-133.5) 1.00 1.00 Ever use 92,982 223 197.6 (152.8-255.7) 1.15 (0.89-1.49) 1.13 (0.88-1.47) Cumulative duration Low 34,084 77 225.9 (180.7-282.5) 1.27 (1.02-1.59)* 1.20 (0.96-1.50) Medium 31,481 71 225.5 (178.7-284.6) 1.25 (0.99-1.58) 1.18 (0.93-1.48) High 27,417 75 273.6 (218.1-343.0) 1.45 (1.15-1.81)* 1.33 (1.06-1.66)* Continuous 1.05 (1.02-1.09)* 1.04 (1.00-1.08) Cumulative dose Low 34,463 78 226.3 (181.3-282.6) 1.27 (1.02-1.59)* 1.20 (0.96-1.49) 260 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 32,401 74 228.4 (181.9-286.8) 1.26 (1.01-1.59)* 1.19 (0.94-1.49) High 26,118 71 271.8 (215.4-343.0) 1.44 (1.14-1.82)* 1.32 (1.05-1.67)* Continuous 1.05 (1.01-1.08)* 1.03 (0.99-1.07) 6.1. Pioglitazone Never 26,873,788 35,543 132.3 (130.9-133.6) 1.00 1.00 Ever use 43,172 106 186.1 (127.6-271.4) 1.06 (0.72-1.54) 1.02 (0.70-1.48) Cumulative duration Low 15,538 39 251.0 (183.4-343.5) 1.40 (1.02-1.92)* 1.30 (0.95-1.78) Medium 14,666 30 204.6 (143.0-292.6) 1.12 (0.79-1.61) 1.04 (0.73-1.49) High 12,968 37 285.3 (206.7-393.8) 1.50 (1.08-2.06)* 1.37 (0.99-1.89) Continuous 1.04 (0.98-1.10) 1.02 (0.97-1.08) Cumulative dose Low 15,616 39 249.7 (182.5-341.8) 1.39 (1.02-1.90)* 1.29 (0.95-1.77) Medium 15,085 35 232.0 (166.6-323.2) 1.27 (0.91-1.77) 1.18 (0.85-1.65) High 12,471 32 256.6 (181.5-362.8) 1.35 (0.95-1.90) 1.23 (0.87-1.74) Continuous 1.03 (0.98-1.09) 1.02 (0.96-1.08) 6.2. Rosiglitazone Never 26,855,904 35,502 132.2 (130.8-133.6) 1.00 1.00 Ever use 61,056 147 213.4 (151.7-300.1) 1.28 (0.91-1.80) 1.28 (0.91-1.81) Cumulative duration Low 21,872 47 214.9 (161.5-286.0) 1.20 (0.90-1.60) 1.13 (0.85-1.51) Medium 21,102 44 208.5 (155.2-280.2) 1.16 (0.86-1.56) 1.09 (0.81-1.47) High 18,082 56 309.7 (238.3-402.4) 1.65 (1.27-2.14)* 1.53 (1.18-1.99)* Continuous 1.07 (1.02-1.13)* 1.05 (1.00-1.11)* Cumulative dose Low 22,279 49 219.9 (166.2-291.0) 1.23 (0.93-1.63) 1.16 (0.88-1.54) Medium 21,514 49 227.8 (172.1-301.4) 1.26 (0.95-1.67) 1.18 (0.89-1.56) High 17,263 49 283.8 (214.5-375.6) 1.52 (1.15-2.01)* 1.41 (1.06-1.86)* Continuous 1.07 (1.01-1.13)* 1.05 (1.00-1.11) 7. Insulins and analogues Never 26,763,779 35,356 132.1 (130.7-133.5) 1.00 1.00 Ever use 153,181 293 211.1 (184.5-241.6) 1.22 (1.07-1.40)* 1.12 (0.98-1.28) Cumulative duration Low 79,227 115 145.2 (120.9-174.3) 1.05 (0.88-1.26) 0.96 (0.80-1.16) Medium 48,672 96 197.2 (161.5-240.9) 1.11 (0.91-1.35) 1.01 (0.83-1.24) High 25,282 82 324.3 (261.2-402.7) 1.71 (1.38-2.12)* 1.53 (1.23-1.90)* Continuous 1.07 (1.04-1.10)* 1.05 (1.03-1.08)* Cumulative dose Low 80,901 116 143.4 (119.5-172.0) 1.03 (0.86-1.23) 0.94 (0.78-1.13) Medium 46,657 94 201.5 (164.6-246.6) 1.13 (0.92-1.38) 1.03 (0.85-1.27) High 25,623 83 323.9 (261.2-401.7) 1.73 (1.39-2.14)* 1.56 (1.26-1.93)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 7.1. Basal insulins Never 26,770,645 35,364 132.1 (130.7-133.5) 1.00 1.00 Ever use 146,315 285 213.5 (185.9-245.3) 1.24 (1.08-1.42)* 1.13 (0.99-1.30) Cumulative duration Low 74,490 112 150.4 (124.9-180.9) 1.08 (0.90-1.30) 0.99 (0.82-1.19) Medium 47,092 94 199.6 (163.1-244.3) 1.12 (0.92-1.37) 1.03 (0.84-1.26) High 24,733 79 319.4 (256.2-398.2) 1.68 (1.35-2.09)* 1.51 (1.21-1.88)* Continuous 1.08 (1.05-1.11)* 1.06 (1.03-1.09)* Cumulative dose Low 75,643 111 146.7 (121.8-176.7) 1.04 (0.87-1.26) 0.96 (0.79-1.15) Medium 45,900 91 198.3 (161.4-243.5) 1.11 (0.91-1.37) 1.02 (0.83-1.25) High 24,772 83 335.1 (270.2-415.5) 1.78 (1.44-2.21)* 1.60 (1.29-1.99)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.05)* 7.2. Bolus insulins Never 26,844,167 35,499 132.2 (130.9-133.6) 1.00 1.00 Ever use 72,793 150 272.5 (224.0-331.5) 1.68 (1.38-2.05)* 1.54 (1.27-1.88)* Cumulative duration Low 41,607 57 137.0 (105.7-177.6) 1.08 (0.83-1.40) 0.98 (0.76-1.28) Medium 21,239 61 287.2 (223.5-369.1) 1.72 (1.34-2.21)* 1.57 (1.22-2.01)* High 9,947 32 321.7 (227.5-454.9) 1.75 (1.24-2.47)* 1.57 (1.11-2.22)* Continuous 1.13 (1.07-1.19)* 1.10 (1.04-1.17)* Cumulative dose Low 43,110 63 146.1 (114.2-187.1) 1.14 (0.89-1.46) 1.04 (0.81-1.33) 261 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 19,439 49 252.1 (190.5-333.5) 1.50 (1.13-1.98)* 1.36 (1.03-1.80)* High 10,244 38 370.9 (269.9-509.8) 2.05 (1.49-2.81)* 1.83 (1.33-2.51)* Continuous 1.04 (1.02-1.07)* 1.04 (1.02-1.06)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table displays associations between all diabetes medications and ductal breast cancer. For a summary of selected medications with significant associations, please refer to Table 5-7. * denotes p<0.05. 262 Supplementary Table B-6. Associations between all diabetes medications and the risk of breast cancer morphological subtype: lobular Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 25,974,019 4,035 15.5 (15.1-16.0) 1.00 1.00 Ever use 942,941 218 23.5 (20.1-27.5) 0.98 (0.84-1.15) 0.96 (0.82-1.13) Cumulative duration Low 363,231 60 16.5 (12.8-21.3) 0.78 (0.61-1.01) 0.76 (0.59-0.99)* Medium 323,170 87 26.9 (21.8-33.2) 1.13 (0.91-1.40) 1.10 (0.89-1.37) High 256,540 71 27.7 (21.9-34.9) 1.02 (0.80-1.29) 0.97 (0.76-1.23) Continuous 1.01 (0.99-1.03) 1.00 (0.98-1.02) Cumulative dose Low 383,543 69 18.0 (14.2-22.8) 0.83 (0.65-1.05) 0.81 (0.64-1.03) Medium 327,502 95 29.0 (23.7-35.5) 1.20 (0.98-1.48) 1.17 (0.96-1.44) High 231,896 54 23.3 (17.8-30.4) 0.88 (0.68-1.16) 0.84 (0.64-1.10) Continuous 1.00 (0.97-1.03) 1.00 (0.97-1.03) 2. Incretin-based medicines Never 26,807,130 4,232 15.8 (15.3-16.3) 1.00 1.00 Ever use 109,830 21 19.8 (11.9-32.8) 0.88 (0.53-1.46) 0.81 (0.49-1.35) Cumulative duration Low 37,699 Suppressed 10.6 (4.0-28.3) 0.51 (0.19-1.37) 0.47 (0.18-1.26) Medium 36,916 Suppressed 24.4 (12.7-46.9) 1.11 (0.58-2.13) 1.02 (0.53-1.97) High 35,215 Suppressed 22.7 (11.4-45.4) 0.91 (0.45-1.82) 0.83 (0.41-1.66) Continuous 0.97 (0.85-1.12) 0.95 (0.82-1.10) Cumulative dose Low 41,738 Suppressed 14.4 (6.5-32.0) 0.72 (0.32-1.60) 0.66 (0.29-1.46) Medium 34,741 10 28.8 (15.5-53.5) 1.26 (0.68-2.34) 1.16 (0.62-2.16) High 33,351 Suppressed 15.0 (6.2-36.0) 0.60 (0.25-1.43) 0.54 (0.23-1.31) Continuous 0.96 (0.81-1.13) 0.94 (0.79-1.11) 2.1. DPP-4 inhibitors Never 26,838,141 4,235 15.8 (15.3-16.3) 1.00 1.00 Ever use 78,819 18 20.9 (11.6-37.8) 0.86 (0.48-1.56) 0.81 (0.45-1.46) Cumulative duration Low 26,904 Suppressed 22.3 (10.0-49.6) 0.96 (0.43-2.14) 0.90 (0.40-2.00) Medium 25,479 Suppressed 27.5 (13.1-57.6) 1.16 (0.55-2.44) 1.08 (0.52-2.28) High 26,436 Suppressed 18.9 (7.9-45.4) 0.73 (0.30-1.76) 0.67 (0.28-1.62) Continuous 0.95 (0.80-1.13) 0.93 (0.78-1.11) Cumulative dose Low 27,412 Suppressed 25.5 (12.2-53.6) 1.10 (0.52-2.31) 1.03 (0.49-2.16) Medium 24,971 Suppressed 24.0 (10.8-53.5) 1.01 (0.46-2.26) 0.95 (0.42-2.11) High 26,436 Suppressed 18.9 (7.9-45.4) 0.73 (0.31-1.76) 0.68 (0.28-1.62) Continuous 0.95 (0.80-1.13) 0.93 (0.78-1.11) 2.1.1. Linagliptin Never 26,888,522 4,248 15.8 (15.3-16.3) 1.00 1.00 Ever use 28,438 Suppressed 18.3 (6.9-48.7) 0.71 (0.27-1.90) 0.67 (0.25-1.77) Cumulative duration Low 8,744 - N/A N/A N/A Medium 9,355 Suppressed 21.4 (5.3-85.5) 0.85 (0.21-3.41) 0.80 (0.20-3.19) High 10,339 Suppressed 29.0 (9.4-90.0) 1.08 (0.35-3.33) 0.99 (0.32-3.09) Continuous 1.00 (0.73-1.38) 0.98 (0.71-1.35) Cumulative dose Low 8,785 - N/A N/A N/A Medium 9,402 Suppressed 21.3 (5.3-85.1) 0.85 (0.21-3.39) 0.79 (0.20-3.17) High 10,251 Suppressed 29.3 (9.4-90.7) 1.08 (0.35-3.36) 1.00 (0.32-3.11) Continuous 1.01 (0.74-1.38) 0.99 (0.72-1.35) 2.1.2. Sitagliptin Never 26,862,992 4,241 15.8 (15.3-16.3) 1.00 1.00 Ever use 53,968 12 23.9 (10.7-53.2) 1.04 (0.47-2.33) 0.98 (0.44-2.18) Cumulative duration Low 18,434 Suppressed 21.7 (8.1-57.8) 0.93 (0.35-2.49) 0.87 (0.33-2.33) Medium 18,909 Suppressed 31.7 (14.3-70.6) 1.35 (0.60-3.00) 1.26 (0.57-2.81) High 16,625 Suppressed 12.0 (3.0-48.1) 0.48 (0.12-1.90) 0.44 (0.11-1.75) Continuous 0.92 (0.71-1.18) 0.90 (0.69-1.16) Cumulative dose Low 18,897 Suppressed 21.2 (7.9-56.4) 0.91 (0.34-2.42) 0.85 (0.32-2.26) 263 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 18,211 Suppressed 32.9 (14.8-73.3) 1.40 (0.63-3.11) 1.31 (0.59-2.91) High 16,860 Suppressed 11.9 (3.0-47.4) 0.47 (0.12-1.89) 0.43 (0.11-1.74) Continuous 0.92 (0.71-1.19) 0.90 (0.70-1.17) 2.2. GLP-1 receptor agonists Never 26,874,721 4,249 15.8 (15.3-16.3) 1.00 1.00 Ever use 42,239 Suppressed 15.5 (5.8-41.4) 0.83 (0.31-2.22) 0.74 (0.28-1.98) Cumulative duration Low 13,930 - N/A N/A N/A Medium 14,541 Suppressed 6.9 (1.0-48.8) 0.38 (0.05-2.71) 0.34 (0.05-2.41) High 13,768 Suppressed 21.8 (7.0-67.6) 1.02 (0.33-3.17) 0.90 (0.29-2.81) Continuous 1.05 (0.79-1.40) 1.01 (0.75-1.36) Cumulative dose Low 13,597 - N/A N/A N/A Medium 14,567 Suppressed 6.9 (1.0-48.7) 0.37 (0.05-2.65) 0.33 (0.05-2.35) High 14,075 Suppressed 21.3 (6.9-66.1) 1.05 (0.34-3.24) 0.92 (0.30-2.86) Continuous 1.12 (0.38-3.33) 1.01 (0.31-3.22) 3. SGLT-2 inhibitors Never 26,879,533 4,247 15.8 (15.3-16.3) 1.00 1.00 Ever use 37,427 Suppressed 11.8 (3.8-36.6) 0.55 (0.18-1.71) 0.50 (0.16-1.55) Cumulative duration Low 12,099 Suppressed 24.8 (8.0-76.9) 1.13 (0.37-3.51) 1.03 (0.33-3.20) Medium 12,583 - N/A N/A N/A High 12,745 Suppressed 23.5 (7.6-73.0) 1.04 (0.34-3.22) 0.93 (0.30-2.89) Continuous 0.96 (0.64-1.45) 0.91 (0.60-1.39) Cumulative dose Low 12,132 Suppressed 16.5 (4.1-65.9) 0.75 (0.19-2.98) 0.68 (0.17-2.72) Medium 12,532 Suppressed 8.0 (1.1-56.6) 0.37 (0.05-2.60) 0.34 (0.05-2.37) High 12,763 Suppressed 23.5 (7.6-72.9) 1.06 (0.34-3.28) 0.95 (0.31-2.95) Continuous 1.03 (0.75-1.40) 0.99 (0.72-1.36) 5. Insulin secretagogues Never 26,526,445 4,176 15.7 (15.3-16.2) 1.00 1.00 Ever use 390,515 77 20.7 (15.7-27.4) 0.84 (0.64-1.12) 0.84 (0.63-1.11) Cumulative duration Low 157,864 23 14.6 (9.7-21.9) 0.62 (0.42-0.94)* 0.62 (0.41-0.94)* Medium 132,423 31 23.4 (16.5-33.3) 0.95 (0.67-1.35) 0.93 (0.66-1.33) High 100,228 23 22.9 (15.2-34.5) 0.83 (0.55-1.25) 0.80 (0.53-1.21) Continuous 0.98 (0.94-1.02) 0.98 (0.94-1.02) Cumulative dose Low 164,182 27 16.4 (11.3-24.0) 0.69 (0.47-1.00) 0.69 (0.47-1.01) Medium 131,919 34 25.8 (18.4-36.1) 1.04 (0.74-1.45) 1.02 (0.73-1.43) High 94,414 16 16.9 (10.4-27.7) 0.64 (0.39-1.04) 0.61 (0.37-1.00)* Continuous 0.99 (0.97-1.01) 0.99 (0.97-1.01) 5.2. Sulfonylureas Never 26,532,030 4,176 15.7 (15.3-16.2) 1.00 1.00 Ever use 384,930 77 21.1 (16.0-28.0) 0.86 (0.65-1.14) 0.86 (0.65-1.13) Cumulative duration Low 157,130 24 15.3 (10.2-22.8) 0.65 (0.44-0.97)* 0.65 (0.44-0.98)* Medium 129,438 30 23.2 (16.2-33.1) 0.94 (0.65-1.34) 0.92 (0.64-1.32) High 98,362 23 23.4 (15.5-35.2) 0.84 (0.56-1.27) 0.82 (0.54-1.23) Continuous 0.98 (0.94-1.02) 0.98 (0.94-1.02) Cumulative dose Low 161,924 27 16.7 (11.4-24.3) 0.69 (0.48-1.01) 0.70 (0.48-1.02) Medium 129,793 34 26.2 (18.7-36.7) 1.05 (0.75-1.48) 1.03 (0.74-1.45) High 93,213 16 17.2 (10.5-28.0) 0.65 (0.40-1.05) 0.62 (0.38-1.01) Continuous 0.99 (0.97-1.01) 0.99 (0.97-1.01) 5.2.1. Gliclazide Never 26,747,400 4,221 15.8 (15.3-16.3) 1.00 1.00 Ever use 169,560 32 18.5 (12.0-28.7) 0.74 (0.48-1.15) 0.71 (0.46-1.10) Cumulative duration Low 56,423 10 17.7 (9.5-32.9) 0.74 (0.40-1.38) 0.72 (0.39-1.33) Medium 57,402 10 17.4 (9.4-32.4) 0.71 (0.38-1.32) 0.68 (0.36-1.26) High 55,735 12 21.5 (12.2-37.9) 0.80 (0.45-1.41) 0.75 (0.43-1.33) Continuous 0.94 (0.85-1.03) 0.92 (0.84-1.02) Cumulative dose Low 59,361 Suppressed 11.8 (5.6-24.7) 0.49 (0.23-1.03) 0.47 (0.22-0.99)* 264 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 57,663 13 22.5 (13.1-38.8) 0.90 (0.52-1.56) 0.86 (0.50-1.49) High 52,536 12 22.8 (13.0-40.2) 0.86 (0.49-1.52) 0.81 (0.46-1.43) Continuous 0.98 (0.94-1.01) 0.97 (0.94-1.01) 5.2.2. Glyburide Never 26,626,770 4,192 15.7 (15.3-16.2) 1.00 1.00 Ever use 290,190 61 24.2 (17.0-34.4) 1.00 (0.70-1.42) 1.03 (0.73-1.47) Cumulative duration Low 127,512 18 14.1 (8.9-22.4) 0.59 (0.37-0.93)* 0.59 (0.37-0.94)* Medium 94,753 27 28.5 (19.5-41.6) 1.15 (0.79-1.68) 1.16 (0.79-1.69) High 67,925 16 23.6 (14.4-38.4) 0.86 (0.52-1.40) 0.84 (0.52-1.38) Continuous 0.99 (0.94-1.05) 0.99 (0.94-1.04) Cumulative dose Low 134,397 20 14.9 (9.6-23.1) 0.61 (0.39-0.95)* 0.61 (0.40-0.95)* Medium 96,766 28 28.9 (20.0-41.9) 1.16 (0.80-1.68) 1.16 (0.80-1.69) High 59,027 13 22.0 (12.8-37.9) 0.83 (0.48-1.43) 0.81 (0.47-1.40) Continuous 1.00 (0.96-1.03) 0.99 (0.96-1.03) 6. Thiazolidinediones Never 26,823,978 4,233 15.8 (15.3-16.3) 1.00 1.00 Ever use 92,982 20 17.0 (7.1-40.9) 0.79 (0.33-1.90) 0.78 (0.32-1.88) Cumulative duration Low 34,084 Suppressed 8.8 (2.8-27.3) 0.38 (0.12-1.18) 0.37 (0.12-1.14) Medium 31,481 10 31.8 (17.1-59.0) 1.36 (0.73-2.53) 1.30 (0.70-2.42) High 27,417 Suppressed 25.5 (12.2-53.6) 1.00 (0.48-2.11) 0.94 (0.45-1.96) Continuous 0.97 (0.85-1.11) 0.96 (0.84-1.09) Cumulative dose Low 34,463 Suppressed 8.7 (2.8-27.0) 0.38 (0.12-1.16) 0.36 (0.12-1.12) Medium 32,401 12 37.0 (21.0-65.2) 1.57 (0.89-2.77) 1.50 (0.85-2.65) High 26,118 Suppressed 19.1 (8.0-46.0) 0.76 (0.32-1.83) 0.71 (0.30-1.71) Continuous 0.95 (0.82-1.10) 0.94 (0.81-1.09) 6.1. Pioglitazone Never 26,873,788 4,245 15.8 (15.3-16.3) 1.00 1.00 Ever use 43,172 Suppressed 6.9 (1.0-48.9) 0.31 (0.04-2.17) 0.30 (0.04-2.13) Cumulative duration Low 15,538 Suppressed 6.4 (0.9-45.7) 0.28 (0.04-1.96) 0.27 (0.04-1.87) Medium 14,666 Suppressed 27.3 (10.2-72.7) 1.15 (0.43-3.08) 1.10 (0.41-2.93) High 12,968 Suppressed 23.1 (7.5-71.7) 0.89 (0.29-2.78) 0.84 (0.27-2.59) Continuous 0.99 (0.83-1.19) 0.98 (0.81-1.17) Cumulative dose Low 15,616 Suppressed 6.4 (0.9-45.5) 0.28 (0.04-1.94) 0.26 (0.04-1.85) Medium 15,085 Suppressed 19.9 (6.4-61.7) 0.84 (0.27-2.60) 0.80 (0.26-2.47) High 12,471 Suppressed 32.1 (12.0-85.5) 1.25 (0.47-3.34) 1.17 (0.44-3.11) Continuous 0.99 (0.83-1.19) 0.98 (0.82-1.17) 6.2. Rosiglitazone Never 26,855,904 4,238 15.8 (15.3-16.3) 1.00 1.00 Ever use 61,056 15 25.9 (9.7-68.9) 1.25 (0.47-3.34) 1.25 (0.47-3.32) Cumulative duration Low 21,872 Suppressed 22.9 (9.5-54.9) 0.98 (0.41-2.35) 0.94 (0.39-2.26) Medium 21,102 Suppressed 23.7 (9.9-56.9) 1.02 (0.42-2.44) 0.97 (0.40-2.33) High 18,082 Suppressed 27.7 (11.5-66.4) 1.11 (0.46-2.67) 1.03 (0.43-2.48) Continuous 0.94 (0.76-1.16) 0.93 (0.75-1.14) Cumulative dose Low 22,279 Suppressed 22.4 (9.3-53.9) 0.96 (0.40-2.31) 0.92 (0.38-2.22) Medium 21,514 Suppressed 32.5 (15.5-68.3) 1.38 (0.66-2.90) 1.31 (0.63-2.75) High 17,263 Suppressed 17.4 (5.6-53.9) 0.70 (0.23-2.18) 0.66 (0.21-2.04) Continuous 0.89 (0.68-1.15) 0.87 (0.67-1.14) 7. Insulins and analogues Never 26,763,779 4,233 15.8 (15.3-16.3) 1.00 1.00 Ever use 153,181 20 13.0 (7.6-22.4) 0.58 (0.34-1.00) 0.55 (0.32-0.95)* Cumulative duration Low 79,227 10 12.6 (6.8-23.5) 0.78 (0.42-1.44) 0.74 (0.40-1.37) Medium 48,672 Suppressed 14.4 (6.9-30.2) 0.62 (0.30-1.30) 0.58 (0.28-1.23) High 25,282 Suppressed 11.9 (3.8-36.8) 0.47 (0.15-1.45) 0.43 (0.14-1.34) Continuous 0.93 (0.82-1.05) 0.91 (0.81-1.04) Cumulative dose Low 80,901 Suppressed 9.9 (4.9-19.8) 0.60 (0.30-1.19) 0.56 (0.28-1.13) 265 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 46,657 Suppressed 19.3 (10.0-37.1) 0.83 (0.43-1.60) 0.78 (0.41-1.50) High 25,623 Suppressed 11.7 (3.8-36.3) 0.47 (0.15-1.47) 0.44 (0.14-1.36) Continuous 0.98 (0.93-1.04) 0.98 (0.92-1.04) 7.1. Basal insulins Never 26,770,645 4,236 15.8 (15.4-16.3) 1.00 1.00 Ever use 146,315 17 11.7 (6.5-21.2) 0.53 (0.29-0.95)* 0.50 (0.27-0.90)* Cumulative duration Low 74,490 Suppressed 8.1 (3.6-17.9) 0.49 (0.22-1.09) 0.46 (0.21-1.03) Medium 47,092 Suppressed 17.0 (8.5-34.0) 0.74 (0.37-1.47) 0.69 (0.35-1.38) High 24,733 Suppressed 12.1 (3.9-37.6) 0.48 (0.15-1.48) 0.44 (0.14-1.37) Continuous 0.93 (0.81-1.07) 0.92 (0.80-1.06) Cumulative dose Low 75,643 Suppressed 7.9 (3.6-17.7) 0.48 (0.21-1.06) 0.45 (0.20-1.00)* Medium 45,900 Suppressed 17.4 (8.7-34.9) 0.75 (0.38-1.50) 0.71 (0.35-1.41) High 24,772 Suppressed 12.1 (3.9-37.6) 0.49 (0.16-1.52) 0.45 (0.15-1.41) Continuous 0.99 (0.93-1.05) 0.98 (0.92-1.05) 7.2. Bolus insulins Never 26,844,167 4,246 15.8 (15.3-16.3) 1.00 1.00 Ever use 72,793 Suppressed 13.6 (5.7-32.7) 0.67 (0.28-1.62) 0.63 (0.26-1.51) Cumulative duration Low 41,607 Suppressed 4.8 (1.2-19.2) 0.34 (0.08-1.34) 0.32 (0.08-1.27) Medium 21,239 Suppressed 18.8 (7.1-50.2) 0.90 (0.34-2.41) 0.84 (0.32-2.25) High 9,947 Suppressed 10.1 (1.4-71.4) 0.43 (0.06-3.01) 0.39 (0.06-2.75) Continuous 0.89 (0.64-1.24) 0.86 (0.61-1.21) Cumulative dose Low 43,110 Suppressed 4.6 (1.2-18.6) 0.32 (0.08-1.27) 0.30 (0.08-1.21) Medium 19,439 Suppressed 20.6 (7.7-54.8) 0.98 (0.37-2.60) 0.91 (0.34-2.43) High 10,244 Suppressed 9.8 (1.4-69.3) 0.42 (0.06-3.00) 0.39 (0.06-2.75) Continuous 0.93 (0.76-1.14) 0.92 (0.74-1.13) Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. * denotes p<0.05. 266 Appendix C Supplementary tables for Chapter 6 Supplementary Table C-1. Associations between all diabetes medications and the risk of colorectal cancer Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 39,259 78.4 (77.6-79.2) 1.00 1.00 Ever use 2,021,426 3,550 176.4 (169.8-183.2) 1.29 (1.24-1.34)* 1.21 (1.17-1.26)* Cumulative duration Low 736,609 807 109.6 (102.3-117.4) 0.93 (0.87-1.00)* 0.89 (0.83-0.95)* Medium 720,912 1,321 183.2 (173.6-193.4) 1.36 (1.29-1.43)* 1.28 (1.21-1.35)* High 563,905 1,422 252.2 (239.4-265.6) 1.49 (1.41-1.57)* 1.41 (1.33-1.48)* Continuous 1.04 (1.04-1.05)* 1.04 (1.03-1.04)* Cumulative dose Low 761,186 897 117.8 (110.4-125.8) 0.95 (0.89-1.02) 0.91 (0.86-0.98)* Medium 720,432 1,307 181.4 (171.8-191.5) 1.31 (1.24-1.38)* 1.24 (1.17-1.31)* High 539,808 1,346 249.3 (236.4-263.0) 1.58 (1.50-1.67)* 1.47 (1.39-1.56)* Continuous 1.05 (1.05-1.06)* 1.04 (1.04-1.05)* 2. Incretin-based medicines Never 51,846,234 42,469 81.9 (81.1-82.7) 1.00 1.00 Ever use 242,410 340 127.3 (111.5-145.4) 1.04 (0.91-1.19) 0.96 (0.84-1.10) Cumulative duration Low 76,647 99 129.2 (106.1-157.3) 1.14 (0.94-1.39) 1.06 (0.87-1.29) Medium 82,123 92 112.0 (91.3-137.4) 0.94 (0.77-1.16) 0.87 (0.71-1.06) High 83,640 149 178.1 (151.7-209.2) 1.27 (1.08-1.49)* 1.19 (1.01-1.39)* Continuous 1.03 (1.00-1.07) 1.02 (0.98-1.05) Cumulative dose Low 79,230 97 122.4 (100.3-149.4) 1.15 (0.94-1.40) 1.06 (0.87-1.30) Medium 80,356 100 124.4 (102.3-151.4) 1.02 (0.84-1.24) 0.94 (0.77-1.14) High 82,824 143 172.7 (146.6-203.4) 1.21 (1.03-1.43)* 1.12 (0.95-1.33) Continuous 1.04 (1.00-1.08)* 1.02 (0.98-1.06) 2.1. DPP-4 inhibitors Never 51,896,422 42,517 81.9 (81.2-82.7) 1.00 1.00 Ever use 192,222 292 136.0 (117.3-157.6) 1.03 (0.89-1.19) 0.95 (0.82-1.10) Cumulative duration Low 63,002 87 138.1 (111.9-170.4) 1.10 (0.90-1.36) 1.02 (0.82-1.26) Medium 63,244 78 123.3 (98.8-154.0) 0.97 (0.77-1.21) 0.88 (0.71-1.10) High 65,976 127 192.5 (161.8-229.1) 1.31 (1.10-1.56)* 1.22 (1.03-1.45)* Continuous 1.04 (1.00-1.07) 1.02 (0.98-1.06) Cumulative dose Low 64,188 89 138.7 (112.6-170.7) 1.10 (0.90-1.36) 1.02 (0.83-1.25) Medium 61,937 75 121.1 (96.6-151.8) 0.95 (0.76-1.19) 0.87 (0.69-1.09) High 66,097 128 193.7 (162.9-230.3) 1.32 (1.11-1.57)* 1.23 (1.04-1.47)* Continuous 1.04 (1.00-1.08)* 1.02 (0.99-1.06) 2.1.1. Linagliptin Never 52,023,970 42,713 82.1 (81.3-82.9) 1.00 1.00 Ever use 64,674 96 144.6 (114.8-182.2) 0.96 (0.76-1.21) 0.91 (0.72-1.15) Cumulative duration Low 19,887 31 155.9 (109.6-221.7) 1.11 (0.78-1.58) 1.04 (0.73-1.48) Medium 21,325 22 103.2 (67.9-156.7) 0.71 (0.47-1.08) 0.67 (0.44-1.01) High 23,462 43 183.3 (135.9-247.1) 1.13 (0.84-1.52) 1.08 (0.80-1.46) Continuous 1.00 (0.92-1.09) 0.99 (0.90-1.08) Cumulative dose Low 19,952 31 155.4 (109.3-220.9) 1.11 (0.78-1.57) 1.04 (0.73-1.47) Medium 21,425 23 107.4 (71.3-161.5) 0.74 (0.49-1.11) 0.69 (0.46-1.05) High 23,297 42 180.3 (133.2-243.9) 1.11 (0.82-1.50) 1.07 (0.79-1.44) Continuous 1.00 (0.92-1.09) 0.99 (0.90-1.08) 2.1.2. Sitagliptin Never 51,955,454 42,603 82.0 (81.2-82.8) 1.00 1.00 Ever use 133,190 206 123.3 (99.2-153.3) 1.03 (0.83-1.28) 0.93 (0.75-1.16) Cumulative duration Low 42,249 63 149.1 (116.5-190.9) 1.19 (0.93-1.52) 1.10 (0.86-1.41) Medium 47,499 63 132.6 (103.6-169.8) 1.06 (0.83-1.36) 0.97 (0.76-1.24) High 43,442 80 184.2 (147.9-229.3) 1.31 (1.05-1.63)* 1.20 (0.96-1.49) Continuous 1.04 (0.99-1.09) 1.02 (0.97-1.07) 267 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 43,259 65 150.3 (117.8-191.6) 1.19 (0.94-1.52) 1.11 (0.87-1.41) Medium 45,625 60 131.5 (102.1-169.4) 1.05 (0.82-1.35) 0.96 (0.74-1.23) High 44,306 81 182.8 (147.0-227.3) 1.31 (1.05-1.63)* 1.20 (0.96-1.49) Continuous 1.04 (0.99-1.09) 1.02 (0.97-1.07) 2.2. GLP-1 receptor agonists Never 52,013,587 42,726 82.1 (81.4-82.9) 1.00 1.00 Ever use 75,057 83 101.1 (75.9-134.5) 1.10 (0.83-1.46) 1.02 (0.76-1.35) Cumulative duration Low 23,429 19 81.1 (51.7-127.1) 0.92 (0.59-1.44) 0.86 (0.55-1.35) Medium 25,502 31 121.6 (85.5-172.9) 1.37 (0.97-1.95) 1.27 (0.89-1.80) High 26,126 33 126.3 (89.8-177.7) 1.17 (0.83-1.64) 1.09 (0.78-1.54) Continuous 1.04 (0.94-1.14) 1.01 (0.92-1.11) Cumulative dose Low 23,693 20 84.4 (54.5-130.8) 0.93 (0.60-1.44) 0.87 (0.56-1.34) Medium 25,629 31 121.0 (85.1-172.0) 1.32 (0.93-1.88) 1.22 (0.86-1.74) High 25,735 32 124.3 (87.9-175.8) 1.20 (0.85-1.70) 1.13 (0.80-1.60) Continuous 1.08 (0.74-1.57) 1.02 (0.69-1.51) 3. SGLT-2 inhibitors Never 51,997,074 42,717 82.2 (81.4-82.9) 1.00 1.00 Ever use 91,570 92 73.5 (55.6-97.3) 0.68 (0.51-0.90)* 0.61 (0.46-0.81)* Cumulative duration Low 26,625 18 67.6 (42.6-107.3) 0.60 (0.38-0.95)* 0.56 (0.35-0.88)* Medium 30,375 41 135.0 (99.4-183.3) 1.21 (0.89-1.64) 1.10 (0.81-1.50) High 34,570 33 95.5 (67.9-134.3) 0.83 (0.59-1.17) 0.76 (0.54-1.07) Continuous 0.99 (0.89-1.10) 0.95 (0.86-1.06) Cumulative dose Low 26,825 19 70.8 (45.2-111.0) 0.62 (0.39-0.96)* 0.57 (0.36-0.89)* Medium 30,296 32 105.6 (74.7-149.4) 0.94 (0.67-1.33) 0.86 (0.61-1.21) High 34,449 41 119.0 (87.6-161.6) 1.06 (0.78-1.44) 0.96 (0.71-1.31) Continuous 0.99 (0.90-1.08) 0.96 (0.87-1.05) 4. AGIs (i.e., acarbose) Never 52,043,873 42,742 82.1 (81.4-82.9) 1.00 1.00 Ever use 44,771 67 107.2 (63.5-181.0) 0.77 (0.46-1.30) 0.76 (0.45-1.28) Cumulative duration Low 16,863 26 154.2 (105.0-226.5) 1.16 (0.79-1.70) 1.14 (0.77-1.67) Medium 15,151 23 151.8 (100.9-228.4) 1.06 (0.70-1.59) 1.03 (0.69-1.55) High 12,757 18 141.1 (88.9-224.0) 0.87 (0.55-1.38) 0.83 (0.52-1.32) Continuous 0.98 (0.90-1.07) 0.98 (0.90-1.06) Cumulative dose Low 15,946 26 163.1 (111.0-239.5) 1.19 (0.81-1.75) 1.19 (0.81-1.75) Medium 16,084 21 130.6 (85.1-200.3) 0.91 (0.59-1.40) 0.89 (0.58-1.36) High 12,741 20 157.0 (101.3-243.3) 0.98 (0.63-1.51) 0.94 (0.61-1.46) Continuous 0.97 (0.84-1.11) 0.95 (0.83-1.10) 5. Insulin secretagogues Never 51,176,005 41,019 80.2 (79.4-80.9) 1.00 1.00 Ever use 912,639 1,790 197.8 (186.6-209.7) 1.41 (1.33-1.50)* 1.33 (1.25-1.41)* Cumulative duration Low 360,923 506 140.2 (128.5-153.0) 1.07 (0.98-1.17) 1.03 (0.94-1.12) Medium 315,845 638 202.0 (186.9-218.3) 1.44 (1.33-1.56)* 1.35 (1.25-1.46)* High 235,871 646 273.9 (253.6-295.8) 1.59 (1.47-1.71)* 1.49 (1.38-1.61)* Continuous 1.05 (1.04-1.06)* 1.05 (1.04-1.05)* Cumulative dose Low 372,575 572 153.5 (141.4-166.6) 1.12 (1.03-1.22)* 1.08 (0.99-1.17) Medium 314,231 655 208.4 (193.1-225.0) 1.45 (1.34-1.56)* 1.36 (1.26-1.47)* High 225,833 563 249.3 (229.5-270.8) 1.57 (1.44-1.70)* 1.46 (1.34-1.59)* Continuous 1.02 (1.02-1.02)* 1.02 (1.01-1.02)* 5.1. Meglitinides Never 52,048,818 42,732 82.1 (81.3-82.9) 1.00 1.00 Ever use 39,826 77 168.9 (112.3-254.2) 1.27 (0.84-1.91) 1.21 (0.80-1.82) Cumulative duration Low 12,831 28 218.2 (150.7-316.1) 1.58 (1.10-2.29)* 1.53 (1.05-2.21)* Medium 13,013 20 153.7 (99.2-238.2) 1.15 (0.74-1.78) 1.10 (0.71-1.70) High 13,982 29 207.4 (144.1-298.5) 1.35 (0.94-1.94) 1.26 (0.88-1.81) Continuous 1.06 (1.00-1.12)* 1.05 (0.99-1.11) 268 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 13,858 30 216.5 (151.4-309.6) 1.52 (1.06-2.17)* 1.47 (1.03-2.10)* Medium 13,470 22 163.3 (107.5-248.0) 1.19 (0.79-1.81) 1.14 (0.75-1.73) High 12,498 25 200.0 (135.2-296.0) 1.36 (0.92-2.01) 1.26 (0.85-1.86) Continuous 1.03 (0.99-1.08) 1.03 (0.98-1.07) 5.1.1. Repaglinide Never 52,049,428 42,734 82.1 (81.3-82.9) 1.00 1.00 Ever use 39,216 75 170.6 (113.4-256.8) 1.28 (0.85-1.92) 1.22 (0.81-1.84) Cumulative duration Low 12,566 27 214.9 (147.3-313.3) 1.56 (1.07-2.27)* 1.50 (1.03-2.19)* Medium 12,873 19 147.6 (94.1-231.4) 1.10 (0.70-1.73) 1.05 (0.67-1.65) High 13,777 29 210.5 (146.3-302.9) 1.37 (0.95-1.97) 1.28 (0.89-1.84) Continuous 1.06 (1.00-1.12)* 1.05 (0.99-1.11) Cumulative dose Low 13,676 29 212.1 (147.4-305.1) 1.49 (1.03-2.14)* 1.44 (1.00-2.07)* Medium 13,159 21 159.6 (104.1-244.8) 1.16 (0.76-1.78) 1.11 (0.72-1.70) High 12,381 25 201.9 (136.4-298.8) 1.37 (0.93-2.03) 1.27 (0.86-1.88) Continuous 1.03 (0.99-1.08) 1.03 (0.98-1.07) 5.2. Sulfonylureas Never 51,188,413 41,033 80.2 (79.4-80.9) 1.00 1.00 Ever use 900,231 1,776 198.5 (187.2-210.5) 1.41 (1.33-1.50)* 1.33 (1.26-1.41)* Cumulative duration Low 359,009 517 144.0 (132.1-157.0) 1.10 (1.01-1.20)* 1.05 (0.97-1.15) Medium 309,407 624 201.7 (186.5-218.1) 1.44 (1.33-1.55)* 1.35 (1.24-1.46)* High 231,815 635 273.9 (253.4-296.1) 1.58 (1.47-1.71)* 1.49 (1.38-1.61)* Continuous 1.05 (1.04-1.06)* 1.05 (1.04-1.05)* Cumulative dose Low 367,838 575 156.3 (144.0-169.6) 1.14 (1.05-1.24)* 1.09 (1.01-1.19)* Medium 309,412 644 208.1 (192.7-224.8) 1.45 (1.34-1.56)* 1.36 (1.25-1.46)* High 222,981 557 249.8 (229.9-271.4) 1.57 (1.44-1.70)* 1.46 (1.35-1.59)* Continuous 1.02 (1.02-1.02)* 1.02 (1.01-1.02)* 5.2.1. Gliclazide Never 51,695,028 42,011 81.3 (80.5-82.0) 1.00 1.00 Ever use 393,616 798 207.0 (190.2-225.4) 1.43 (1.31-1.55)* 1.32 (1.22-1.44)* Cumulative duration Low 126,908 224 176.5 (154.8-201.2) 1.31 (1.15-1.49)* 1.23 (1.08-1.40)* Medium 136,638 250 183.0 (161.6-207.1) 1.29 (1.14-1.46)* 1.20 (1.06-1.35)* High 130,070 324 249.1 (223.4-277.8) 1.51 (1.35-1.68)* 1.42 (1.27-1.58)* Continuous 1.06 (1.05-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 133,699 232 173.5 (152.6-197.4) 1.25 (1.10-1.42)* 1.18 (1.04-1.34)* Medium 136,394 267 195.8 (173.6-220.7) 1.34 (1.19-1.52)* 1.25 (1.11-1.41)* High 123,523 299 242.1 (216.1-271.1) 1.52 (1.36-1.71)* 1.43 (1.28-1.60)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 5.2.2. Glyburide Never 51,418,210 41,454 80.6 (79.8-81.4) 1.00 1.00 Ever use 670,434 1,355 192.7 (177.9-208.7) 1.40 (1.29-1.52)* 1.34 (1.24-1.45)* Cumulative duration Low 283,215 462 163.1 (148.9-178.7) 1.19 (1.09-1.31)* 1.15 (1.05-1.26)* Medium 224,722 438 194.9 (177.5-214.0) 1.37 (1.25-1.51)* 1.30 (1.18-1.43)* High 162,497 455 280.0 (255.4-307.0) 1.61 (1.47-1.77)* 1.51 (1.38-1.66)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* Cumulative dose Low 296,014 499 168.6 (154.4-184.0) 1.18 (1.08-1.29)* 1.14 (1.05-1.25)* Medium 230,574 499 216.4 (198.2-236.3) 1.48 (1.35-1.61)* 1.40 (1.28-1.53)* High 143,846 357 248.2 (223.7-275.3) 1.55 (1.40-1.72)* 1.45 (1.31-1.61)* Continuous 1.03 (1.02-1.03)* 1.02 (1.02-1.03)* 6. Thiazolidinediones Never 51,871,508 42,418 81.8 (81.0-82.6) 1.00 1.00 Ever use 217,136 391 141.3 (116.4-171.5) 1.27 (1.05-1.55)* 1.21 (0.99-1.46) Cumulative duration Low 76,357 113 148.0 (123.1-178.0) 1.17 (0.97-1.40) 1.10 (0.92-1.33) Medium 72,351 125 172.8 (145.0-205.9) 1.35 (1.13-1.61)* 1.27 (1.06-1.51)* High 68,428 153 223.6 (190.8-262.0) 1.55 (1.33-1.82)* 1.42 (1.22-1.67)* Continuous 1.07 (1.05-1.10)* 1.06 (1.03-1.08)* 269 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 75,982 112 147.4 (122.5-177.4) 1.15 (0.95-1.38) 1.09 (0.90-1.31) Medium 74,257 134 180.5 (152.3-213.7) 1.40 (1.18-1.66)* 1.31 (1.11-1.56)* High 66,897 145 216.8 (184.2-255.1) 1.53 (1.30-1.80)* 1.40 (1.19-1.65)* Continuous 1.07 (1.04-1.09)* 1.05 (1.03-1.08)* 6.1. Pioglitazone Never 51,987,564 42,639 82.0 (81.2-82.8) 1.00 1.00 Ever use 101,080 170 161.7 (125.0-209.1) 1.36 (1.05-1.76)* 1.27 (0.98-1.64) Cumulative duration Low 33,963 47 138.4 (104.0-184.2) 1.07 (0.80-1.42) 1.01 (0.76-1.34) Medium 34,409 57 165.7 (127.8-214.8) 1.28 (0.99-1.66) 1.19 (0.92-1.54) High 32,708 66 201.8 (158.5-256.8) 1.35 (1.06-1.72)* 1.24 (0.97-1.58) Continuous 1.05 (1.02-1.09)* 1.04 (1.00-1.08)* Cumulative dose Low 33,724 45 133.4 (99.6-178.7) 1.02 (0.76-1.37) 0.97 (0.72-1.29) Medium 34,952 60 171.7 (133.3-221.1) 1.30 (1.01-1.68)* 1.22 (0.94-1.57) High 32,404 65 200.6 (157.3-255.8) 1.37 (1.07-1.75)* 1.25 (0.98-1.60) Continuous 1.05 (1.01-1.09)* 1.03 (1.00-1.07) 6.2. Rosiglitazone Never 51,946,176 42,536 81.9 (81.1-82.7) 1.00 1.00 Ever use 142,468 273 121.8 (91.2-162.6) 1.18 (0.89-1.58) 1.14 (0.85-1.52) Cumulative duration Low 49,170 80 162.7 (130.7-202.6) 1.26 (1.01-1.57)* 1.20 (0.96-1.49) Medium 48,028 87 181.1 (146.8-223.5) 1.41 (1.14-1.74)* 1.33 (1.08-1.64)* High 45,270 106 234.2 (193.6-283.3) 1.68 (1.39-2.03)* 1.54 (1.28-1.87)* Continuous 1.10 (1.07-1.14)* 1.09 (1.05-1.12)* Cumulative dose Low 49,567 82 165.4 (133.2-205.4) 1.28 (1.03-1.59)* 1.21 (0.98-1.51) Medium 49,349 90 182.4 (148.3-224.2) 1.41 (1.14-1.73)* 1.32 (1.08-1.63)* High 43,552 101 231.9 (190.8-281.8) 1.68 (1.38-2.04)* 1.54 (1.27-1.87)* Continuous 1.10 (1.07-1.14)* 1.08 (1.05-1.12)* 7. Insulins and analogues Never 51,772,245 42,325 81.8 (81.0-82.5) 1.00 1.00 Ever use 316,399 484 168.0 (152.1-185.6) 1.33 (1.20-1.47)* 1.21 (1.10-1.34)* Cumulative duration Low 143,015 129 90.2 (75.9-107.2) 0.90 (0.76-1.07) 0.84 (0.70-1.00)* Medium 113,499 216 190.3 (166.5-217.5) 1.45 (1.27-1.66)* 1.33 (1.16-1.52)* High 59,885 139 232.1 (196.6-274.1) 1.61 (1.37-1.91)* 1.50 (1.27-1.77)* Continuous 1.07 (1.05-1.09)* 1.05 (1.03-1.08)* Cumulative dose Low 146,186 137 93.7 (79.3-110.8) 0.91 (0.77-1.08) 0.85 (0.72-1.00) Medium 108,141 202 186.8 (162.7-214.4) 1.42 (1.24-1.64)* 1.30 (1.14-1.50)* High 62,072 145 233.6 (198.5-274.9) 1.70 (1.44-2.00)* 1.54 (1.31-1.82)* Continuous 1.03 (1.02-1.04)* 1.02 (1.02-1.03)* 7.1. Basal insulins Never 51,784,863 42,336 81.8 (81.0-82.5) 1.00 1.00 Ever use 303,781 473 169.2 (152.7-187.4) 1.34 (1.21-1.49)* 1.23 (1.11-1.36)* Cumulative duration Low 135,289 135 99.8 (84.3-118.1) 1.00 (0.84-1.18) 0.93 (0.78-1.10) Medium 109,417 205 187.4 (163.4-214.8) 1.44 (1.26-1.65)* 1.32 (1.15-1.51)* High 59,075 133 225.1 (189.9-266.8) 1.56 (1.31-1.85)* 1.44 (1.21-1.71)* Continuous 1.08 (1.05-1.10)* 1.06 (1.04-1.09)* Cumulative dose Low 136,909 135 98.6 (83.3-116.7) 0.96 (0.81-1.14) 0.90 (0.76-1.06) Medium 106,571 195 183.0 (159.0-210.5) 1.40 (1.22-1.61)* 1.28 (1.12-1.48)* High 60,301 143 237.1 (201.3-279.4) 1.71 (1.45-2.02)* 1.56 (1.32-1.84)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 7.2. Bolus insulins Never 51,947,122 42,600 82.0 (81.2-82.8) 1.00 1.00 Ever use 141,522 209 169.7 (144.0-199.9) 1.52 (1.29-1.79)* 1.38 (1.17-1.62)* Cumulative duration Low 68,567 73 106.5 (84.6-133.9) 1.16 (0.92-1.46) 1.08 (0.86-1.36) Medium 48,161 76 157.8 (126.0-197.6) 1.38 (1.10-1.73)* 1.25 (1.00-1.57) High 24,794 60 242.0 (187.9-311.7) 1.93 (1.50-2.48)* 1.75 (1.36-2.25)* Continuous 1.10 (1.05-1.15)* 1.08 (1.03-1.13)* 270 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 71,251 78 109.5 (87.7-136.7) 1.17 (0.94-1.46) 1.09 (0.87-1.36) Medium 44,054 71 161.2 (127.7-203.4) 1.40 (1.11-1.77)* 1.27 (1.01-1.61)* High 26,217 60 228.9 (177.7-294.8) 1.89 (1.47-2.44)* 1.70 (1.32-2.19)* Continuous 1.04 (1.03-1.06)* 1.04 (1.02-1.06)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. This table displays associations between all diabetes medications and colorectal cancer. For a summary of selected medications with significant associations, please refer to Table 6-2. * denotes p<0.05. 271 Supplementary Table C-2. Associations between all diabetes medications and the risk of colorectal cancer with adjustment for other diabetes medications Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 39,259 78.4 (77.6-79.2) 1.00 1.00 Ever use 2,021,426 3,550 176.4 (169.8-183.2) 1.21 (1.17-1.26)* 1.17 (1.11-1.22)* Cumulative duration Low 736,609 807 109.6 (102.3-117.4) 0.89 (0.83-0.95)* 0.89 (0.83-0.96)* Medium 720,912 1,321 183.2 (173.6-193.4) 1.28 (1.21-1.35)* 1.26 (1.19-1.34)* High 563,905 1,422 252.2 (239.4-265.6) 1.41 (1.33-1.48)* 1.35 (1.26-1.45)* Continuous 1.04 (1.03-1.04)* 1.03 (1.03-1.04)* Cumulative dose Low 761,186 897 117.8 (110.4-125.8) 0.91 (0.86-0.98)* 0.92 (0.86-0.98)* Medium 720,432 1,307 181.4 (171.8-191.5) 1.24 (1.17-1.31)* 1.24 (1.17-1.32)* High 539,808 1,346 249.3 (236.4-263.0) 1.47 (1.39-1.56)* 1.47 (1.36-1.58)* Continuous 1.04 (1.04-1.05)* 1.04 (1.04-1.05)* 2. Incretin-based medicines Never 51,846,234 42,469 81.9 (81.1-82.7) 1.00 1.00 Ever use 242,410 340 127.3 (111.5-145.4) 0.96 (0.84-1.10) 0.82 (0.71-0.94)* Cumulative duration Low 76,647 99 129.2 (106.1-157.3) 1.06 (0.87-1.29) 0.85 (0.69-1.04) Medium 82,123 92 112.0 (91.3-137.4) 0.87 (0.71-1.06) 0.66 (0.54-0.82)* High 83,640 149 178.1 (151.7-209.2) 1.19 (1.01-1.39)* 0.90 (0.75-1.07) Continuous 1.02 (0.98-1.05) 0.94 (0.90-0.98)* Cumulative dose Low 79,230 97 122.4 (100.3-149.4) 1.06 (0.87-1.30) 0.84 (0.68-1.03) Medium 80,356 100 124.4 (102.3-151.4) 0.94 (0.77-1.14) 0.70 (0.57-0.86)* High 82,824 143 172.7 (146.6-203.4) 1.12 (0.95-1.33) 0.82 (0.69-0.98)* Continuous 1.02 (0.98-1.06) 0.94 (0.90-0.98)* 2.1. DPP-4 inhibitors Never 51,896,422 42,517 81.9 (81.2-82.7) 1.00 1.00 Ever use 192,222 292 136.0 (117.3-157.6) 0.95 (0.82-1.10) 0.79 (0.68-0.93)* Cumulative duration Low 63,002 87 138.1 (111.9-170.4) 1.02 (0.82-1.26) 0.80 (0.65-0.99)* Medium 63,244 78 123.3 (98.8-154.0) 0.88 (0.71-1.10) 0.67 (0.54-0.85)* High 65,976 127 192.5 (161.8-229.1) 1.22 (1.03-1.45)* 0.92 (0.76-1.11) Continuous 1.02 (0.98-1.06) 0.94 (0.90-0.98)* Cumulative dose Low 64,188 89 138.7 (112.6-170.7) 1.02 (0.83-1.25) 0.79 (0.64-0.98)* Medium 61,937 75 121.1 (96.6-151.8) 0.87 (0.69-1.09) 0.65 (0.52-0.82)* High 66,097 128 193.7 (162.9-230.3) 1.23 (1.04-1.47)* 0.91 (0.76-1.10) Continuous 1.02 (0.99-1.06) 0.94 (0.90-0.98)* 2.1.1. Linagliptin Never 52,023,970 42,713 82.1 (81.3-82.9) 1.00 1.00 Ever use 64,674 96 144.6 (114.8-182.2) 0.91 (0.72-1.15) 0.78 (0.62-0.99)* Cumulative duration Low 19,887 31 155.9 (109.6-221.7) 1.04 (0.73-1.48) 0.87 (0.61-1.25) Medium 21,325 22 103.2 (67.9-156.7) 0.67 (0.44-1.01) 0.54 (0.36-0.83)* High 23,462 43 183.3 (135.9-247.1) 1.08 (0.80-1.46) 0.86 (0.63-1.17) Continuous 0.99 (0.90-1.08) 0.89 (0.81-0.97)* Cumulative dose Low 19,952 31 155.4 (109.3-220.9) 1.04 (0.73-1.47) 0.87 (0.61-1.24) Medium 21,425 23 107.4 (71.3-161.5) 0.69 (0.46-1.05) 0.57 (0.38-0.86)* High 23,297 42 180.3 (133.2-243.9) 1.07 (0.79-1.44) 0.84 (0.62-1.15) Continuous 0.99 (0.90-1.08) 0.89 (0.81-0.98)* 2.1.2. Sitagliptin Never 51,955,454 42,603 82.0 (81.2-82.8) 1.00 1.00 Ever use 133,190 206 123.3 (99.2-153.3) 0.93 (0.75-1.16) 0.77 (0.62-0.96)* Cumulative duration Low 42,249 63 149.1 (116.5-190.9) 1.10 (0.86-1.41) 0.90 (0.70-1.15) Medium 47,499 63 132.6 (103.6-169.8) 0.97 (0.76-1.24) 0.76 (0.59-0.98)* High 43,442 80 184.2 (147.9-229.3) 1.20 (0.96-1.49) 0.96 (0.76-1.21) Continuous 1.02 (0.97-1.07) 0.94 (0.89-0.99)* Cumulative dose Low 43,259 65 150.3 (117.8-191.6) 1.11 (0.87-1.41) 0.89 (0.69-1.14) 272 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 45,625 60 131.5 (102.1-169.4) 0.96 (0.74-1.23) 0.74 (0.57-0.96)* High 44,306 81 182.8 (147.0-227.3) 1.20 (0.96-1.49) 0.94 (0.75-1.18) Continuous 1.02 (0.97-1.07) 0.94 (0.89-0.99)* 2.2. GLP-1 receptor agonists Never 52,013,587 42,726 82.1 (81.4-82.9) 1.00 1.00 Ever use 75,057 83 101.1 (75.9-134.5) 1.02 (0.76-1.35) 0.96 (0.72-1.29) Cumulative duration Low 23,429 19 81.1 (51.7-127.1) 0.86 (0.55-1.35) 0.79 (0.50-1.24) Medium 25,502 31 121.6 (85.5-172.9) 1.27 (0.89-1.80) 1.14 (0.80-1.63) High 26,126 33 126.3 (89.8-177.7) 1.09 (0.78-1.54) 0.96 (0.68-1.37) Continuous 1.01 (0.92-1.11) 0.95 (0.86-1.05) Cumulative dose Low 23,693 20 84.4 (54.5-130.8) 0.87 (0.56-1.34) 0.77 (0.49-1.19) Medium 25,629 31 121.0 (85.1-172.0) 1.22 (0.86-1.74) 1.05 (0.74-1.51) High 25,735 32 124.3 (87.9-175.8) 1.13 (0.80-1.60) 0.98 (0.69-1.40) Continuous 1.02 (0.69-1.51) 0.83 (0.52-1.31) 3. SGLT-2 inhibitors Never 51,997,074 42,717 82.2 (81.4-82.9) 1.00 1.00 Ever use 91,570 92 73.5 (55.6-97.3) 0.61 (0.46-0.81)* 0.52 (0.39-0.69)* Cumulative duration Low 26,625 18 67.6 (42.6-107.3) 0.56 (0.35-0.88)* 0.45 (0.28-0.71)* Medium 30,375 41 135.0 (99.4-183.3) 1.10 (0.81-1.50) 0.87 (0.63-1.18) High 34,570 33 95.5 (67.9-134.3) 0.76 (0.54-1.07) 0.56 (0.39-0.80)* Continuous 0.95 (0.86-1.06) 0.85 (0.76-0.96)* Cumulative dose Low 26,825 19 70.8 (45.2-111.0) 0.57 (0.36-0.89)* 0.45 (0.29-0.71)* Medium 30,296 32 105.6 (74.7-149.4) 0.86 (0.61-1.21) 0.67 (0.47-0.95)* High 34,449 41 119.0 (87.6-161.6) 0.96 (0.71-1.31) 0.73 (0.53-1.00)* Continuous 0.96 (0.87-1.05) 0.86 (0.78-0.95)* 4. AGIs (i.e., acarbose) Never 52,043,873 42,742 82.1 (81.4-82.9) 1.00 1.00 Ever use 44,771 67 107.2 (63.5-181.0) 0.76 (0.45-1.28) 0.63 (0.37-1.07) Cumulative duration Low 16,863 26 154.2 (105.0-226.5) 1.14 (0.77-1.67) 0.94 (0.64-1.38) Medium 15,151 23 151.8 (100.9-228.4) 1.03 (0.69-1.55) 0.83 (0.55-1.25) High 12,757 18 141.1 (88.9-224.0) 0.83 (0.52-1.32) 0.63 (0.40-1.01) Continuous 0.98 (0.90-1.06) 0.92 (0.84-1.01) Cumulative dose Low 15,946 26 163.1 (111.0-239.5) 1.19 (0.81-1.75) 0.97 (0.66-1.43) Medium 16,084 21 130.6 (85.1-200.3) 0.89 (0.58-1.36) 0.71 (0.46-1.10) High 12,741 20 157.0 (101.3-243.3) 0.94 (0.61-1.46) 0.71 (0.46-1.11) Continuous 0.95 (0.83-1.10) 0.87 (0.74-1.01) 5. Insulin secretagogues Never 51,176,005 41,019 80.2 (79.4-80.9) 1.00 1.00 Ever use 912,639 1,790 197.8 (186.6-209.7) 1.33 (1.25-1.41)* 1.24 (1.15-1.33)* Cumulative duration Low 360,923 506 140.2 (128.5-153.0) 1.03 (0.94-1.12) 0.96 (0.87-1.05) Medium 315,845 638 202.0 (186.9-218.3) 1.35 (1.25-1.46)* 1.20 (1.10-1.31)* High 235,871 646 273.9 (253.6-295.8) 1.49 (1.38-1.61)* 1.31 (1.19-1.45)* Continuous 1.05 (1.04-1.05)* 1.02 (1.01-1.03)* Cumulative dose Low 372,575 572 153.5 (141.4-166.6) 1.08 (0.99-1.17) 0.97 (0.89-1.06) Medium 314,231 655 208.4 (193.1-225.0) 1.36 (1.26-1.47)* 1.16 (1.06-1.27)* High 225,833 563 249.3 (229.5-270.8) 1.46 (1.34-1.59)* 1.25 (1.12-1.40)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.01)* 5.1. Meglitinides Never 52,048,818 42,732 82.1 (81.3-82.9) 1.00 1.00 Ever use 39,826 77 168.9 (112.3-254.2) 1.21 (0.80-1.82) 1.07 (0.71-1.61) Cumulative duration Low 12,831 28 218.2 (150.7-316.1) 1.53 (1.05-2.21)* 1.25 (0.86-1.82) Medium 13,013 20 153.7 (99.2-238.2) 1.10 (0.71-1.70) 0.91 (0.58-1.41) High 13,982 29 207.4 (144.1-298.5) 1.26 (0.88-1.81) 1.03 (0.72-1.49) Continuous 1.05 (0.99-1.11) 1.01 (0.95-1.07) Cumulative dose Low 13,858 30 216.5 (151.4-309.6) 1.47 (1.03-2.10)* 1.21 (0.84-1.74) 273 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 13,470 22 163.3 (107.5-248.0) 1.14 (0.75-1.73) 0.94 (0.61-1.43) High 12,498 25 200.0 (135.2-296.0) 1.26 (0.85-1.86) 1.00 (0.67-1.48) Continuous 1.03 (0.98-1.07) 0.99 (0.95-1.04) 5.1.1. Repaglinide Never 52,049,428 42,734 82.1 (81.3-82.9) 1.00 1.00 Ever use 39,216 75 170.6 (113.4-256.8) 1.22 (0.81-1.84) 1.08 (0.72-1.62) Cumulative duration Low 12,566 27 214.9 (147.3-313.3) 1.50 (1.03-2.19)* 1.23 (0.84-1.80) Medium 12,873 19 147.6 (94.1-231.4) 1.05 (0.67-1.65) 0.87 (0.55-1.37) High 13,777 29 210.5 (146.3-302.9) 1.28 (0.89-1.84) 1.05 (0.73-1.51) Continuous 1.05 (0.99-1.11) 1.01 (0.95-1.07) Cumulative dose Low 13,676 29 212.1 (147.4-305.1) 1.44 (1.00-2.07)* 1.19 (0.82-1.72) Medium 13,159 21 159.6 (104.1-244.8) 1.11 (0.72-1.70) 0.91 (0.59-1.40) High 12,381 25 201.9 (136.4-298.8) 1.27 (0.86-1.88) 1.01 (0.68-1.50) Continuous 1.03 (0.98-1.07) 0.99 (0.95-1.05) 5.2. Sulfonylureas Never 51,188,413 41,033 80.2 (79.4-80.9) 1.00 1.00 Ever use 900,231 1,776 198.5 (187.2-210.5) 1.33 (1.26-1.41)* 1.24 (1.16-1.33)* Cumulative duration Low 359,009 517 144.0 (132.1-157.0) 1.05 (0.97-1.15) 0.98 (0.89-1.08) Medium 309,407 624 201.7 (186.5-218.1) 1.35 (1.24-1.46)* 1.20 (1.09-1.31)* High 231,815 635 273.9 (253.4-296.1) 1.49 (1.38-1.61)* 1.31 (1.19-1.45)* Continuous 1.05 (1.04-1.05)* 1.02 (1.01-1.03)* Cumulative dose Low 367,838 575 156.3 (144.0-169.6) 1.09 (1.01-1.19)* 0.99 (0.90-1.08) Medium 309,412 644 208.1 (192.7-224.8) 1.36 (1.25-1.46)* 1.16 (1.06-1.27)* High 222,981 557 249.8 (229.9-271.4) 1.46 (1.35-1.59)* 1.26 (1.13-1.40)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.01)* 5.2.1. Gliclazide Never 51,695,028 42,011 81.3 (80.5-82.0) 1.00 1.00 Ever use 393,616 798 207.0 (190.2-225.4) 1.32 (1.22-1.44)* 1.24 (1.13-1.36)* Cumulative duration Low 126,908 224 176.5 (154.8-201.2) 1.23 (1.08-1.40)* 1.07 (0.93-1.23) Medium 136,638 250 183.0 (161.6-207.1) 1.20 (1.06-1.35)* 1.02 (0.90-1.17) High 130,070 324 249.1 (223.4-277.8) 1.42 (1.27-1.58)* 1.22 (1.08-1.38)* Continuous 1.05 (1.04-1.07)* 1.02 (1.01-1.04)* Cumulative dose Low 133,699 232 173.5 (152.6-197.4) 1.18 (1.04-1.34)* 1.01 (0.88-1.16) Medium 136,394 267 195.8 (173.6-220.7) 1.25 (1.11-1.41)* 1.05 (0.92-1.19) High 123,523 299 242.1 (216.1-271.1) 1.43 (1.28-1.60)* 1.20 (1.06-1.37)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.01) 5.2.2. Glyburide Never 51,418,210 41,454 80.6 (79.8-81.4) 1.00 1.00 Ever use 670,434 1,355 192.7 (177.9-208.7) 1.34 (1.24-1.45)* 1.21 (1.11-1.32)* Cumulative duration Low 283,215 462 163.1 (148.9-178.7) 1.15 (1.05-1.26)* 1.02 (0.93-1.13) Medium 224,722 438 194.9 (177.5-214.0) 1.30 (1.18-1.43)* 1.12 (1.01-1.24)* High 162,497 455 280.0 (255.4-307.0) 1.51 (1.38-1.66)* 1.27 (1.14-1.42)* Continuous 1.05 (1.04-1.06)* 1.02 (1.01-1.03)* Cumulative dose Low 296,014 499 168.6 (154.4-184.0) 1.14 (1.05-1.25)* 0.99 (0.90-1.09) Medium 230,574 499 216.4 (198.2-236.3) 1.40 (1.28-1.53)* 1.17 (1.06-1.29)* High 143,846 357 248.2 (223.7-275.3) 1.45 (1.31-1.61)* 1.18 (1.04-1.33)* Continuous 1.02 (1.02-1.03)* 1.01 (1.00-1.01) 6. Thiazolidinediones Never 51,871,508 42,418 81.8 (81.0-82.6) 1.00 1.00 Ever use 217,136 391 141.3 (116.4-171.5) 1.21 (0.99-1.46) 0.99 (0.81-1.21) Cumulative duration Low 76,357 113 148.0 (123.1-178.0) 1.10 (0.92-1.33) 0.88 (0.73-1.06) Medium 72,351 125 172.8 (145.0-205.9) 1.27 (1.06-1.51)* 0.97 (0.81-1.17) High 68,428 153 223.6 (190.8-262.0) 1.42 (1.22-1.67)* 1.10 (0.93-1.30) Continuous 1.06 (1.03-1.08)* 1.01 (0.98-1.03) Cumulative dose Low 75,982 112 147.4 (122.5-177.4) 1.09 (0.90-1.31) 0.85 (0.71-1.03) 274 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 74,257 134 180.5 (152.3-213.7) 1.31 (1.11-1.56)* 0.99 (0.83-1.19) High 66,897 145 216.8 (184.2-255.1) 1.40 (1.19-1.65)* 1.06 (0.89-1.26) Continuous 1.05 (1.03-1.08)* 1.00 (0.98-1.03) 6.1. Pioglitazone Never 51,987,564 42,639 82.0 (81.2-82.8) 1.00 1.00 Ever use 101,080 170 161.7 (125.0-209.1) 1.27 (0.98-1.64) 1.06 (0.81-1.37) Cumulative duration Low 33,963 47 138.4 (104.0-184.2) 1.01 (0.76-1.34) 0.78 (0.59-1.05) Medium 34,409 57 165.7 (127.8-214.8) 1.19 (0.92-1.54) 0.91 (0.69-1.18) High 32,708 66 201.8 (158.5-256.8) 1.24 (0.97-1.58) 0.96 (0.75-1.22) Continuous 1.04 (1.00-1.08)* 0.99 (0.95-1.03) Cumulative dose Low 33,724 45 133.4 (99.6-178.7) 0.97 (0.72-1.29) 0.75 (0.56-1.01) Medium 34,952 60 171.7 (133.3-221.1) 1.22 (0.94-1.57) 0.92 (0.71-1.19) High 32,404 65 200.6 (157.3-255.8) 1.25 (0.98-1.60) 0.96 (0.74-1.23) Continuous 1.03 (1.00-1.07) 0.98 (0.95-1.02) 6.2. Rosiglitazone Never 51,946,176 42,536 81.9 (81.1-82.7) 1.00 1.00 Ever use 142,468 273 121.8 (91.2-162.6) 1.14 (0.85-1.52) 0.92 (0.69-1.23) Cumulative duration Low 49,170 80 162.7 (130.7-202.6) 1.20 (0.96-1.49) 0.97 (0.77-1.21) Medium 48,028 87 181.1 (146.8-223.5) 1.33 (1.08-1.64)* 1.05 (0.84-1.30) High 45,270 106 234.2 (193.6-283.3) 1.54 (1.28-1.87)* 1.22 (1.00-1.48) Continuous 1.09 (1.05-1.12)* 1.03 (0.99-1.07) Cumulative dose Low 49,567 82 165.4 (133.2-205.4) 1.21 (0.98-1.51) 0.97 (0.78-1.22) Medium 49,349 90 182.4 (148.3-224.2) 1.32 (1.08-1.63)* 1.03 (0.83-1.27) High 43,552 101 231.9 (190.8-281.8) 1.54 (1.27-1.87)* 1.19 (0.97-1.46) Continuous 1.08 (1.05-1.12)* 1.03 (0.99-1.06) 7. Insulins and analogues Never 51,772,245 42,325 81.8 (81.0-82.5) 1.00 1.00 Ever use 316,399 484 168.0 (152.1-185.6) 1.21 (1.10-1.34)* 1.11 (1.00-1.23) Cumulative duration Low 143,015 129 90.2 (75.9-107.2) 0.84 (0.70-1.00)* 0.70 (0.59-0.84)* Medium 113,499 216 190.3 (166.5-217.5) 1.33 (1.16-1.52)* 1.04 (0.90-1.20) High 59,885 139 232.1 (196.6-274.1) 1.50 (1.27-1.77)* 1.19 (0.99-1.41) Continuous 1.05 (1.03-1.08)* 1.01 (0.99-1.03) Cumulative dose Low 146,186 137 93.7 (79.3-110.8) 0.85 (0.72-1.00) 0.70 (0.59-0.83)* Medium 108,141 202 186.8 (162.7-214.4) 1.30 (1.14-1.50)* 0.99 (0.86-1.15) High 62,072 145 233.6 (198.5-274.9) 1.54 (1.31-1.82)* 1.18 (0.99-1.41) Continuous 1.02 (1.02-1.03)* 1.01 (1.00-1.02) 7.1. Basal insulins Never 51,784,863 42,336 81.8 (81.0-82.5) 1.00 1.00 Ever use 303,781 473 169.2 (152.7-187.4) 1.23 (1.11-1.36)* 1.03 (0.91-1.18) Cumulative duration Low 135,289 135 99.8 (84.3-118.1) 0.93 (0.78-1.10) 0.77 (0.64-0.93)* Medium 109,417 205 187.4 (163.4-214.8) 1.32 (1.15-1.51)* 1.00 (0.85-1.18) High 59,075 133 225.1 (189.9-266.8) 1.44 (1.21-1.71)* 1.01 (0.81-1.26) Continuous 1.06 (1.04-1.09)* 1.00 (0.97-1.04) Cumulative dose Low 136,909 135 98.6 (83.3-116.7) 0.90 (0.76-1.06) 0.74 (0.61-0.88)* Medium 106,571 195 183.0 (159.0-210.5) 1.28 (1.12-1.48)* 0.96 (0.81-1.14) High 60,301 143 237.1 (201.3-279.4) 1.56 (1.32-1.84)* 1.11 (0.89-1.37) Continuous 1.03 (1.02-1.04)* 1.00 (0.99-1.02) 7.2. Bolus insulins Never 51,947,122 42,600 82.0 (81.2-82.8) 1.00 1.00 Ever use 141,522 209 169.7 (144.0-199.9) 1.38 (1.17-1.62)* 1.26 (1.03-1.55)* Cumulative duration Low 68,567 73 106.5 (84.6-133.9) 1.08 (0.86-1.36) 0.99 (0.77-1.28) Medium 48,161 76 157.8 (126.0-197.6) 1.25 (1.00-1.57) 1.04 (0.80-1.34) High 24,794 60 242.0 (187.9-311.7) 1.75 (1.36-2.25)* 1.45 (1.07-1.97)* Continuous 1.08 (1.03-1.13)* 1.02 (0.96-1.09) Cumulative dose Low 71,251 78 109.5 (87.7-136.7) 1.09 (0.87-1.36) 1.00 (0.78-1.27) 275 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 44,054 71 161.2 (127.7-203.4) 1.27 (1.01-1.61)* 1.03 (0.79-1.34) High 26,217 60 228.9 (177.7-294.8) 1.70 (1.32-2.19)* 1.27 (0.94-1.72) Continuous 1.04 (1.02-1.06)* 1.02 (1.00-1.05) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Model 2 further adjusted for other mutually exclusive diabetes medications. This table displays associations between all diabetes medications and colorectal cancer. For a summary of selected medications with significant associations, please refer to Table 6-3. * denotes p<0.05. 276 Supplementary Table C-3. Associations between all diabetes medications and the risk of colorectal cancer with variation in washout and lag periods Exposure Model 1 Model 2 Model 3 Model 4 Model 5 1. Biguanides (i.e., metformin) Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.21 (1.17-1.26)* 1.36 (1.31-1.41)* 1.20 (1.15-1.25)* 1.20 (1.16-1.24)* 1.21 (1.16-1.26)* Cumulative duration Low 0.89 (0.83-0.95)* 1.36 (1.29-1.43)* 0.86 (0.80-0.93)* 0.85 (0.79-0.90)* 0.89 (0.83-0.96)* Medium 1.28 (1.21-1.35)* 1.30 (1.24-1.37)* 1.20 (1.13-1.27)* 1.23 (1.17-1.28)* 1.28 (1.21-1.36)* High 1.41 (1.33-1.48)* 1.37 (1.31-1.44)* 1.41 (1.33-1.49)* 1.40 (1.34-1.46)* 1.40 (1.32-1.48)* Continuous 1.04 (1.03-1.04)* 1.03 (1.03-1.04)* 1.04 (1.03-1.04)* 1.03 (1.03-1.03)* 1.04 (1.03-1.04)* Cumulative dose Low 0.91 (0.86-0.98)* 1.36 (1.30-1.43)* 0.85 (0.79-0.91)* 0.88 (0.83-0.93)* 0.91 (0.85-0.98)* Medium 1.24 (1.17-1.31)* 1.25 (1.19-1.31)* 1.20 (1.13-1.27)* 1.19 (1.13-1.24)* 1.24 (1.17-1.31)* High 1.47 (1.39-1.56)* 1.43 (1.36-1.50)* 1.48 (1.40-1.57)* 1.43 (1.37-1.49)* 1.47 (1.39-1.56)* Continuous 1.04 (1.04-1.05)* 1.04 (1.03-1.05)* 1.04 (1.04-1.05)* 1.03 (1.03-1.04)* 1.04 (1.04-1.05)* 2. Incretin-based medicines Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.96 (0.84-1.10) 1.18 (1.07-1.31)* 0.96 (0.83-1.12) 0.87 (0.78-0.98)* 0.96 (0.84-1.11) Cumulative duration Low 1.06 (0.87-1.29) 1.37 (1.18-1.58)* 1.01 (0.81-1.26) 1.00 (0.84-1.18) 1.04 (0.85-1.28) Medium 0.87 (0.71-1.06) 1.07 (0.91-1.26) 0.81 (0.64-1.02) 0.93 (0.79-1.10) 0.85 (0.68-1.05) High 1.19 (1.01-1.39)* 1.22 (1.06-1.41)* 1.11 (0.93-1.33) 1.06 (0.92-1.22) 1.21 (1.03-1.43)* Continuous 1.02 (0.98-1.05) 1.03 (1.00-1.06)* 1.01 (0.97-1.05) 1.00 (0.97-1.03) 1.02 (0.99-1.06) Cumulative dose Low 1.06 (0.87-1.30) 1.35 (1.16-1.57)* 0.94 (0.75-1.19) 1.03 (0.87-1.22) 1.05 (0.85-1.30) Medium 0.94 (0.77-1.14) 1.16 (1.00-1.36)* 0.96 (0.77-1.19) 0.95 (0.81-1.12) 0.91 (0.74-1.12) High 1.12 (0.95-1.33) 1.16 (1.00-1.34)* 1.04 (0.86-1.25) 1.01 (0.88-1.17) 1.15 (0.97-1.36) Continuous 1.02 (0.98-1.06) 1.03 (1.00-1.07)* 1.01 (0.97-1.05) 1.00 (0.96-1.03) 1.03 (0.99-1.07) 2.1. DPP-4 inhibitors Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.95 (0.82-1.10) 1.19 (1.06-1.33)* 0.95 (0.81-1.12) 0.85 (0.75-0.97)* 0.96 (0.82-1.12) Cumulative duration Low 1.02 (0.82-1.26) 1.38 (1.18-1.61)* 1.01 (0.80-1.27) 0.94 (0.79-1.13) 0.99 (0.79-1.24) Medium 0.88 (0.71-1.10) 1.08 (0.91-1.28) 0.83 (0.65-1.07) 0.94 (0.78-1.12) 0.88 (0.69-1.11) High 1.22 (1.03-1.45)* 1.26 (1.08-1.47)* 1.16 (0.95-1.40) 1.06 (0.91-1.24) 1.26 (1.05-1.50)* Continuous 1.02 (0.98-1.06) 1.03 (1.00-1.07)* 1.01 (0.97-1.05) 0.99 (0.96-1.03) 1.03 (0.99-1.06) Cumulative dose Low 1.02 (0.83-1.25) 1.40 (1.20-1.62)* 1.01 (0.81-1.28) 0.95 (0.79-1.13) 0.99 (0.80-1.24) Medium 0.87 (0.69-1.09) 1.06 (0.89-1.27) 0.83 (0.64-1.08) 0.92 (0.77-1.11) 0.87 (0.69-1.10) High 1.23 (1.04-1.47)* 1.26 (1.08-1.47)* 1.15 (0.95-1.39) 1.07 (0.92-1.25) 1.26 (1.05-1.51)* Continuous 1.02 (0.99-1.06) 1.04 (1.00-1.07)* 1.01 (0.97-1.05) 1.00 (0.97-1.03) 1.03 (0.99-1.07) 2.1.1. Linagliptin Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.91 (0.72-1.15) 1.25 (1.07-1.48)* 0.84 (0.64-1.11) 0.87 (0.72-1.06) 0.90 (0.70-1.14) Cumulative duration Low 1.04 (0.73-1.48) 1.46 (1.15-1.86)* 1.27 (0.88-1.84) 0.90 (0.66-1.23) 0.95 (0.65-1.39) Medium 0.67 (0.44-1.01) 1.03 (0.78-1.36) 0.66 (0.40-1.07) 0.81 (0.59-1.11) 0.69 (0.45-1.06) High 1.08 (0.80-1.46) 1.24 (0.97-1.59) 0.86 (0.59-1.24) 1.00 (0.77-1.28) 1.08 (0.79-1.48) Continuous 0.99 (0.90-1.08) 1.05 (0.98-1.13) 0.94 (0.85-1.04) 0.97 (0.90-1.04) 0.98 (0.89-1.07) Cumulative dose Low 1.04 (0.73-1.47) 1.46 (1.15-1.85)* 1.26 (0.87-1.83) 0.90 (0.66-1.23) 0.95 (0.64-1.39) Medium 0.69 (0.46-1.05) 1.05 (0.80-1.38) 0.70 (0.43-1.12) 0.82 (0.60-1.12) 0.72 (0.47-1.09) High 1.07 (0.79-1.44) 1.23 (0.96-1.58) 0.83 (0.57-1.21) 0.99 (0.76-1.27) 1.06 (0.77-1.46) Continuous 0.99 (0.90-1.08) 1.05 (0.98-1.13) 0.94 (0.85-1.04) 0.97 (0.90-1.04) 0.98 (0.89-1.07) 2.1.2. Sitagliptin Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.93 (0.75-1.16) 1.14 (0.96-1.35) 0.99 (0.78-1.24) 0.82 (0.68-1.00)* 0.92 (0.74-1.16) Cumulative duration Low 1.10 (0.86-1.41) 1.38 (1.13-1.68)* 1.03 (0.78-1.35) 0.98 (0.79-1.21) 1.15 (0.89-1.48) Medium 0.97 (0.76-1.24) 1.08 (0.87-1.33) 0.88 (0.67-1.16) 1.02 (0.84-1.25) 0.99 (0.77-1.28) High 1.20 (0.96-1.49) 1.22 (1.00-1.48)* 1.20 (0.95-1.52) 1.08 (0.90-1.31) 1.23 (0.98-1.54) Continuous 1.02 (0.97-1.07) 1.03 (0.98-1.07) 1.01 (0.96-1.07) 1.00 (0.95-1.04) 1.02 (0.97-1.08) Cumulative dose Low 1.11 (0.87-1.41) 1.40 (1.15-1.69)* 1.06 (0.81-1.38) 0.98 (0.80-1.22) 1.15 (0.90-1.48) 277 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 0.96 (0.74-1.23) 1.07 (0.87-1.33) 0.82 (0.62-1.10) 1.01 (0.83-1.24) 0.98 (0.76-1.28) High 1.20 (0.96-1.49) 1.19 (0.98-1.45) 1.22 (0.97-1.54) 1.09 (0.90-1.31) 1.23 (0.98-1.54) Continuous 1.02 (0.97-1.07) 1.03 (0.98-1.07) 1.02 (0.97-1.07) 1.00 (0.96-1.04) 1.03 (0.97-1.08) 2.2. GLP-1 receptor agonists Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.02 (0.76-1.35) 1.16 (0.92-1.46) 1.00 (0.73-1.38) 1.00 (0.78-1.28) 1.00 (0.74-1.35) Cumulative duration Low 0.86 (0.55-1.35) 0.96 (0.67-1.38) 0.67 (0.38-1.18) 1.00 (0.70-1.42) 0.87 (0.55-1.39) Medium 1.27 (0.89-1.80) 1.31 (0.97-1.78) 1.09 (0.72-1.66) 1.21 (0.89-1.65) 1.28 (0.89-1.84) High 1.09 (0.78-1.54) 1.18 (0.87-1.60) 1.06 (0.73-1.53) 1.08 (0.81-1.45) 1.08 (0.75-1.54) Continuous 1.01 (0.92-1.11) 1.04 (0.96-1.13) 1.01 (0.91-1.11) 1.03 (0.95-1.11) 1.01 (0.91-1.11) Cumulative dose Low 0.87 (0.56-1.34) 1.03 (0.73-1.45) 0.57 (0.32-1.02) 1.00 (0.71-1.41) 0.88 (0.56-1.39) Medium 1.22 (0.86-1.74) 1.28 (0.94-1.74) 1.19 (0.81-1.77) 1.13 (0.82-1.54) 1.23 (0.86-1.77) High 1.13 (0.80-1.60) 1.16 (0.85-1.58) 1.08 (0.74-1.59) 1.16 (0.86-1.55) 1.11 (0.77-1.60) Continuous 1.02 (0.69-1.51) 1.05 (0.75-1.49) 1.04 (0.69-1.58) 1.01 (0.71-1.41) 0.97 (0.63-1.49) 3. SGLT-2 inhibitors Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.61 (0.46-0.81)* 1.05 (0.88-1.25) 0.52 (0.37-0.74)* 0.58 (0.45-0.75)* 0.61 (0.45-0.81)* Cumulative duration Low 0.56 (0.35-0.88)* 1.12 (0.87-1.44) 0.37 (0.19-0.72)* 0.58 (0.40-0.86)* 0.59 (0.37-0.94)* Medium 1.10 (0.81-1.50) 1.42 (1.14-1.77)* 0.90 (0.61-1.34) 0.87 (0.64-1.16) 1.16 (0.85-1.58) High 0.76 (0.54-1.07) 0.94 (0.71-1.23) 0.51 (0.32-0.82)* 0.78 (0.58-1.04) 0.72 (0.50-1.03) Continuous 0.95 (0.86-1.06) 1.04 (0.95-1.13) 0.85 (0.74-0.98)* 0.92 (0.84-1.02) 0.94 (0.84-1.06) Cumulative dose Low 0.57 (0.36-0.89)* 1.09 (0.85-1.40) 0.45 (0.25-0.81)* 0.59 (0.40-0.85)* 0.61 (0.39-0.95)* Medium 0.86 (0.61-1.21) 1.18 (0.93-1.50) 0.58 (0.36-0.95)* 0.70 (0.50-0.97)* 0.90 (0.63-1.27) High 0.96 (0.71-1.31) 1.22 (0.96-1.56) 0.72 (0.49-1.06) 0.93 (0.71-1.22) 0.94 (0.68-1.30) Continuous 0.96 (0.87-1.05) 1.03 (0.96-1.11) 0.88 (0.78-0.99)* 0.92 (0.85-1.01) 0.95 (0.86-1.05) 4. AGIs (i.e., acarbose) Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.76 (0.45-1.28) 0.99 (0.66-1.48) 0.86 (0.51-1.45) 0.93 (0.72-1.21) 0.77 (0.42-1.38) Cumulative duration Low 1.14 (0.77-1.67) 1.05 (0.73-1.53) 1.06 (0.70-1.61) 1.20 (0.98-1.47) 1.10 (0.71-1.70) Medium 1.03 (0.69-1.55) 1.10 (0.76-1.58) 0.89 (0.56-1.42) 1.03 (0.83-1.27) 1.04 (0.66-1.66) High 0.83 (0.52-1.32) 1.01 (0.69-1.47) 0.82 (0.50-1.33) 1.08 (0.89-1.31) 0.69 (0.38-1.24) Continuous 0.98 (0.90-1.06) 1.00 (0.93-1.07) 0.98 (0.90-1.07) 1.01 (0.97-1.04) 0.99 (0.90-1.09) Cumulative dose Low 1.19 (0.81-1.75) 1.10 (0.76-1.59) 1.06 (0.69-1.62) 1.20 (0.98-1.47) 1.16 (0.75-1.80) Medium 0.89 (0.58-1.36) 1.00 (0.69-1.45) 0.79 (0.49-1.28) 1.05 (0.85-1.30) 0.91 (0.57-1.47) High 0.94 (0.61-1.46) 1.06 (0.73-1.54) 0.93 (0.59-1.48) 1.06 (0.87-1.29) 0.77 (0.44-1.35) Continuous 0.95 (0.83-1.10) 0.99 (0.89-1.11) 0.96 (0.82-1.11) 1.00 (0.95-1.05) 0.97 (0.83-1.14) 5. Insulin secretagogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.33 (1.25-1.41)* 1.45 (1.38-1.53)* 1.35 (1.27-1.44)* 1.19 (1.14-1.25)* 1.33 (1.25-1.42)* Cumulative duration Low 1.03 (0.94-1.12) 1.38 (1.29-1.48)* 1.04 (0.95-1.14) 0.91 (0.84-0.98)* 1.02 (0.93-1.12) Medium 1.35 (1.25-1.46)* 1.38 (1.28-1.48)* 1.29 (1.18-1.40)* 1.20 (1.13-1.28)* 1.34 (1.23-1.45)* High 1.49 (1.38-1.61)* 1.45 (1.35-1.56)* 1.46 (1.35-1.59)* 1.39 (1.32-1.46)* 1.50 (1.38-1.64)* Continuous 1.05 (1.04-1.05)* 1.04 (1.04-1.05)* 1.04 (1.03-1.05)* 1.03 (1.02-1.03)* 1.05 (1.04-1.06)* Cumulative dose Low 1.08 (0.99-1.17) 1.40 (1.31-1.49)* 1.06 (0.98-1.16) 0.96 (0.90-1.04) 1.06 (0.97-1.16) Medium 1.36 (1.26-1.47)* 1.38 (1.29-1.48)* 1.33 (1.22-1.44)* 1.23 (1.16-1.30)* 1.35 (1.24-1.46)* High 1.46 (1.34-1.59)* 1.42 (1.32-1.54)* 1.43 (1.31-1.57)* 1.35 (1.28-1.42)* 1.47 (1.34-1.61)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 1.01 (1.01-1.01)* 1.02 (1.01-1.02)* 5.1. Meglitinides Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.21 (0.80-1.82) 1.43 (1.02-2.01)* 1.16 (0.75-1.79) 1.33 (1.00-1.76)* 1.27 (0.83-1.95) Cumulative duration Low 1.53 (1.05-2.21)* 1.71 (1.24-2.36)* 1.36 (0.90-2.05) 1.32 (1.01-1.72)* 1.28 (0.82-1.98) Medium 1.10 (0.71-1.70) 1.21 (0.82-1.77) 0.97 (0.59-1.58) 0.94 (0.69-1.30) 0.83 (0.48-1.44) High 1.26 (0.88-1.81) 1.33 (0.96-1.84) 1.22 (0.83-1.80) 1.35 (1.05-1.73)* 1.44 (1.00-2.08) Continuous 1.05 (0.99-1.11) 1.05 (1.00-1.10) 1.04 (0.98-1.10) 1.04 (1.00-1.09) 1.06 (1.00-1.12)* Cumulative dose Low 1.47 (1.03-2.10)* 1.64 (1.20-2.24)* 1.39 (0.94-2.04) 1.32 (1.02-1.72)* 1.14 (0.74-1.77) 278 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 1.14 (0.75-1.73) 1.27 (0.88-1.83) 0.96 (0.60-1.55) 0.94 (0.69-1.29) 1.09 (0.69-1.73) High 1.26 (0.85-1.86) 1.32 (0.93-1.88) 1.20 (0.79-1.83) 1.36 (1.06-1.75)* 1.38 (0.92-2.08) Continuous 1.03 (0.98-1.07) 1.03 (0.99-1.07) 1.02 (0.97-1.07) 1.02 (0.98-1.05) 1.04 (1.00-1.08) 5.1.1. Repaglinide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.22 (0.81-1.84) 1.44 (1.03-2.03)* 1.17 (0.75-1.81) 1.34 (1.01-1.77)* 1.28 (0.83-1.96) Cumulative duration Low 1.50 (1.03-2.19)* 1.70 (1.22-2.35)* 1.33 (0.88-2.02) 1.32 (1.01-1.72)* 1.24 (0.79-1.94) Medium 1.05 (0.67-1.65) 1.17 (0.79-1.73) 0.92 (0.55-1.52) 0.95 (0.69-1.31) 0.78 (0.44-1.37) High 1.28 (0.89-1.84) 1.35 (0.97-1.87) 1.24 (0.84-1.82) 1.34 (1.05-1.73)* 1.46 (1.01-2.11)* Continuous 1.05 (0.99-1.11) 1.05 (1.00-1.10) 1.04 (0.98-1.10) 1.04 (1.00-1.09) 1.06 (1.00-1.12)* Cumulative dose Low 1.44 (1.00-2.07)* 1.62 (1.18-2.23)* 1.36 (0.92-2.01) 1.31 (1.01-1.71)* 1.10 (0.70-1.72) Medium 1.11 (0.72-1.70) 1.25 (0.86-1.81) 0.92 (0.57-1.51) 0.93 (0.68-1.28) 1.04 (0.65-1.68) High 1.27 (0.86-1.88) 1.34 (0.94-1.90) 1.22 (0.80-1.85) 1.37 (1.07-1.77)* 1.40 (0.93-2.10) Continuous 1.03 (0.98-1.07) 1.03 (0.99-1.07) 1.02 (0.97-1.07) 1.02 (0.98-1.05) 1.04 (1.00-1.08) 5.2. Sulfonylureas Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.33 (1.26-1.41)* 1.45 (1.38-1.53)* 1.36 (1.28-1.45)* 1.19 (1.14-1.25)* 1.33 (1.25-1.42)* Cumulative duration Low 1.05 (0.97-1.15) 1.40 (1.31-1.50)* 1.07 (0.97-1.17) 0.93 (0.86-1.00)* 1.04 (0.95-1.15) Medium 1.35 (1.24-1.46)* 1.37 (1.27-1.47)* 1.28 (1.18-1.40)* 1.20 (1.13-1.27)* 1.33 (1.22-1.45)* High 1.49 (1.38-1.61)* 1.45 (1.34-1.56)* 1.47 (1.35-1.59)* 1.39 (1.32-1.46)* 1.50 (1.38-1.64)* Continuous 1.05 (1.04-1.05)* 1.04 (1.04-1.05)* 1.04 (1.04-1.05)* 1.03 (1.02-1.03)* 1.05 (1.04-1.06)* Cumulative dose Low 1.09 (1.01-1.19)* 1.41 (1.32-1.51)* 1.08 (0.99-1.18) 0.97 (0.90-1.04) 1.08 (0.99-1.18) Medium 1.36 (1.25-1.46)* 1.37 (1.28-1.48)* 1.32 (1.22-1.44)* 1.23 (1.16-1.30)* 1.34 (1.24-1.46)* High 1.46 (1.35-1.59)* 1.43 (1.32-1.54)* 1.44 (1.32-1.57)* 1.35 (1.28-1.42)* 1.47 (1.34-1.61)* Continuous 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 1.02 (1.01-1.02)* 1.01 (1.01-1.01)* 1.02 (1.01-1.02)* 5.2.1. Gliclazide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.32 (1.22-1.44)* 1.46 (1.36-1.56)* 1.35 (1.23-1.48)* 1.22 (1.14-1.31)* 1.34 (1.22-1.46)* Cumulative duration Low 1.23 (1.08-1.40)* 1.58 (1.42-1.75)* 1.25 (1.09-1.44)* 1.21 (1.10-1.34)* 1.26 (1.10-1.44)* Medium 1.20 (1.06-1.35)* 1.33 (1.19-1.48)* 1.12 (0.97-1.28) 1.12 (1.02-1.24)* 1.21 (1.06-1.38)* High 1.42 (1.27-1.58)* 1.34 (1.21-1.48)* 1.41 (1.26-1.58)* 1.28 (1.17-1.39)* 1.42 (1.26-1.59)* Continuous 1.05 (1.04-1.07)* 1.05 (1.04-1.07)* 1.05 (1.03-1.07)* 1.03 (1.02-1.04)* 1.05 (1.04-1.07)* Cumulative dose Low 1.18 (1.04-1.34)* 1.55 (1.41-1.72)* 1.19 (1.04-1.37)* 1.19 (1.07-1.31)* 1.21 (1.06-1.38)* Medium 1.25 (1.11-1.41)* 1.31 (1.17-1.45)* 1.19 (1.05-1.36)* 1.18 (1.08-1.30)* 1.25 (1.10-1.42)* High 1.43 (1.28-1.60)* 1.37 (1.23-1.52)* 1.40 (1.24-1.59)* 1.24 (1.14-1.36)* 1.44 (1.27-1.62)* Continuous 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 1.02 (1.01-1.02)* 1.01 (1.01-1.01)* 1.01 (1.01-1.02)* 5.2.2. Glyburide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.34 (1.24-1.45)* 1.44 (1.34-1.55)* 1.37 (1.26-1.49)* 1.19 (1.12-1.26)* 1.33 (1.22-1.45)* Cumulative duration Low 1.15 (1.05-1.26)* 1.37 (1.27-1.48)* 1.14 (1.03-1.25)* 1.00 (0.92-1.08) 1.13 (1.02-1.24)* Medium 1.30 (1.18-1.43)* 1.34 (1.23-1.46)* 1.23 (1.11-1.36)* 1.16 (1.08-1.24)* 1.30 (1.17-1.44)* High 1.51 (1.38-1.66)* 1.48 (1.36-1.61)* 1.49 (1.35-1.64)* 1.39 (1.32-1.47)* 1.53 (1.38-1.70)* Continuous 1.05 (1.04-1.06)* 1.05 (1.04-1.06)* 1.05 (1.04-1.06)* 1.03 (1.03-1.04)* 1.05 (1.04-1.06)* Cumulative dose Low 1.14 (1.05-1.25)* 1.35 (1.26-1.46)* 1.11 (1.01-1.22)* 1.03 (0.96-1.11) 1.12 (1.02-1.23)* Medium 1.40 (1.28-1.53)* 1.41 (1.30-1.53)* 1.36 (1.24-1.49)* 1.23 (1.15-1.31)* 1.39 (1.27-1.53)* High 1.45 (1.31-1.61)* 1.42 (1.29-1.57)* 1.43 (1.28-1.60)* 1.33 (1.25-1.41)* 1.47 (1.31-1.65)* Continuous 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 1.01 (1.01-1.02)* 1.03 (1.02-1.03)* 6. Thiazolidinediones Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.21 (0.99-1.46) 1.36 (1.15-1.60)* 1.27 (1.04-1.55)* 1.26 (1.11-1.44)* 1.24 (1.01-1.53)* Cumulative duration Low 1.10 (0.92-1.33) 1.29 (1.10-1.51)* 1.09 (0.89-1.32) 1.14 (1.01-1.30)* 1.13 (0.93-1.38) Medium 1.27 (1.06-1.51)* 1.31 (1.12-1.54)* 1.20 (0.99-1.45) 1.30 (1.16-1.47)* 1.27 (1.05-1.53)* High 1.42 (1.22-1.67)* 1.33 (1.14-1.54)* 1.45 (1.23-1.71)* 1.40 (1.26-1.56)* 1.45 (1.22-1.72)* Continuous 1.06 (1.03-1.08)* 1.05 (1.03-1.07)* 1.06 (1.03-1.09)* 1.05 (1.04-1.07)* 1.06 (1.03-1.09)* Cumulative dose Low 1.09 (0.90-1.31) 1.26 (1.08-1.48)* 1.08 (0.89-1.31) 1.16 (1.02-1.32)* 1.10 (0.90-1.34) 279 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 1.31 (1.11-1.56)* 1.36 (1.17-1.59)* 1.23 (1.02-1.48)* 1.29 (1.14-1.45)* 1.37 (1.14-1.64)* High 1.40 (1.19-1.65)* 1.31 (1.12-1.52)* 1.44 (1.21-1.70)* 1.40 (1.26-1.56)* 1.39 (1.16-1.66)* Continuous 1.05 (1.03-1.08)* 1.05 (1.02-1.07)* 1.05 (1.03-1.08)* 1.05 (1.03-1.06)* 1.05 (1.03-1.08)* 6.1. Pioglitazone Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.27 (0.98-1.64) 1.36 (1.09-1.70)* 1.35 (1.04-1.76)* 1.37 (1.15-1.62)* 1.27 (0.96-1.68) Cumulative duration Low 1.01 (0.76-1.34) 1.10 (0.85-1.41) 0.95 (0.70-1.29) 1.15 (0.95-1.38) 1.05 (0.77-1.42) Medium 1.19 (0.92-1.54) 1.30 (1.04-1.64)* 1.18 (0.90-1.55) 1.22 (1.02-1.45)* 1.24 (0.94-1.64) High 1.24 (0.97-1.58) 1.21 (0.97-1.51) 1.30 (1.01-1.66)* 1.33 (1.13-1.56)* 1.18 (0.90-1.55) Continuous 1.04 (1.00-1.08)* 1.04 (1.00-1.07)* 1.04 (1.00-1.09)* 1.04 (1.01-1.07)* 1.04 (0.99-1.08) Cumulative dose Low 0.97 (0.72-1.29) 1.08 (0.84-1.39) 0.92 (0.67-1.26) 1.14 (0.95-1.38) 1.00 (0.73-1.36) Medium 1.22 (0.94-1.57) 1.33 (1.07-1.66)* 1.22 (0.93-1.59) 1.26 (1.06-1.50)* 1.25 (0.95-1.64) High 1.25 (0.98-1.60) 1.19 (0.95-1.50) 1.29 (1.00-1.66) 1.29 (1.09-1.52)* 1.22 (0.93-1.60) Continuous 1.03 (1.00-1.07) 1.03 (1.00-1.07)* 1.04 (1.00-1.08) 1.03 (1.01-1.06)* 1.03 (0.99-1.07) 6.2. Rosiglitazone Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.14 (0.85-1.52) 1.34 (1.05-1.70)* 1.18 (0.87-1.59) 1.13 (0.94-1.37) 1.19 (0.87-1.62) Cumulative duration Low 1.20 (0.96-1.49) 1.43 (1.19-1.73)* 1.23 (0.98-1.54) 1.25 (1.08-1.45)* 1.22 (0.97-1.55) Medium 1.33 (1.08-1.64)* 1.30 (1.07-1.58)* 1.26 (1.00-1.58)* 1.21 (1.04-1.40)* 1.34 (1.06-1.68)* High 1.54 (1.28-1.87)* 1.40 (1.17-1.68)* 1.52 (1.25-1.86)* 1.47 (1.29-1.67)* 1.59 (1.29-1.95)* Continuous 1.09 (1.05-1.12)* 1.07 (1.04-1.11)* 1.08 (1.05-1.12)* 1.07 (1.05-1.10)* 1.09 (1.05-1.13)* Cumulative dose Low 1.21 (0.98-1.51) 1.44 (1.19-1.73)* 1.23 (0.99-1.55) 1.24 (1.07-1.44)* 1.23 (0.98-1.55) Medium 1.32 (1.08-1.63)* 1.33 (1.10-1.60)* 1.23 (0.98-1.54) 1.20 (1.03-1.39)* 1.36 (1.09-1.69)* High 1.54 (1.27-1.87)* 1.38 (1.14-1.67)* 1.55 (1.26-1.90)* 1.49 (1.31-1.69)* 1.57 (1.27-1.95)* Continuous 1.08 (1.05-1.12)* 1.07 (1.04-1.10)* 1.08 (1.05-1.12)* 1.07 (1.04-1.09)* 1.09 (1.05-1.13)* 7. Insulins and analogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.21 (1.10-1.34)* 1.64 (1.51-1.77)* 1.14 (1.02-1.27)* 1.18 (1.12-1.26)* 1.18 (1.06-1.32)* Cumulative duration Low 0.84 (0.70-1.00)* 1.79 (1.61-1.99)* 0.78 (0.64-0.95)* 0.65 (0.57-0.75)* 0.79 (0.66-0.96)* Medium 1.33 (1.16-1.52)* 1.35 (1.19-1.53)* 1.19 (1.03-1.38)* 1.16 (1.06-1.27)* 1.29 (1.11-1.49)* High 1.50 (1.27-1.77)* 1.45 (1.23-1.70)* 1.43 (1.20-1.70)* 1.43 (1.32-1.54)* 1.55 (1.29-1.85)* Continuous 1.05 (1.03-1.08)* 1.06 (1.04-1.07)* 1.04 (1.02-1.07)* 1.03 (1.02-1.04)* 1.06 (1.04-1.08)* Cumulative dose Low 0.85 (0.72-1.00) 1.72 (1.54-1.91)* 0.79 (0.66-0.95)* 0.68 (0.59-0.78)* 0.81 (0.67-0.97)* Medium 1.30 (1.14-1.50)* 1.38 (1.21-1.56)* 1.13 (0.97-1.32) 1.16 (1.05-1.27)* 1.26 (1.08-1.46)* High 1.54 (1.31-1.82)* 1.50 (1.28-1.76)* 1.53 (1.29-1.81)* 1.42 (1.31-1.53)* 1.61 (1.35-1.92)* Continuous 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 1.02 (1.01-1.03)* 1.01 (1.01-1.01)* 1.03 (1.02-1.04)* 7.1. Basal insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.23 (1.11-1.36)* 1.63 (1.50-1.77)* 1.16 (1.04-1.30)* 1.19 (1.12-1.26)* 1.19 (1.07-1.33)* Cumulative duration Low 0.93 (0.78-1.10) 1.82 (1.63-2.03)* 0.81 (0.67-0.98)* 0.73 (0.63-0.83)* 0.87 (0.72-1.05) Medium 1.32 (1.15-1.51)* 1.35 (1.19-1.54)* 1.21 (1.04-1.41)* 1.14 (1.04-1.25)* 1.29 (1.11-1.49)* High 1.44 (1.21-1.71)* 1.38 (1.17-1.63)* 1.39 (1.16-1.66)* 1.42 (1.31-1.53)* 1.47 (1.22-1.77)* Continuous 1.06 (1.04-1.09)* 1.06 (1.04-1.09)* 1.05 (1.03-1.08)* 1.04 (1.03-1.05)* 1.07 (1.04-1.10)* Cumulative dose Low 0.90 (0.76-1.06) 1.74 (1.56-1.94)* 0.81 (0.67-0.98)* 0.74 (0.64-0.85)* 0.84 (0.70-1.01) Medium 1.28 (1.12-1.48)* 1.34 (1.18-1.53)* 1.14 (0.98-1.34) 1.11 (1.01-1.22)* 1.25 (1.07-1.46)* High 1.56 (1.32-1.84)* 1.51 (1.29-1.77)* 1.52 (1.28-1.80)* 1.44 (1.33-1.55)* 1.61 (1.34-1.92)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 1.02 (1.02-1.02)* 1.03 (1.02-1.04)* 7.2. Bolus insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.38 (1.17-1.62)* 1.72 (1.50-1.97)* 1.27 (1.07-1.52)* 1.26 (1.16-1.38)* 1.30 (1.08-1.56)* Cumulative duration Low 1.08 (0.86-1.36) 1.68 (1.42-1.99)* 1.00 (0.78-1.29) 1.12 (0.97-1.30) 1.01 (0.78-1.30) Medium 1.25 (1.00-1.57) 1.36 (1.11-1.66)* 1.12 (0.87-1.43) 1.23 (1.08-1.40)* 1.21 (0.95-1.55) High 1.75 (1.36-2.25)* 1.63 (1.28-2.09)* 1.65 (1.27-2.16)* 1.32 (1.17-1.48)* 1.80 (1.36-2.37)* Continuous 1.08 (1.03-1.13)* 1.08 (1.03-1.13)* 1.07 (1.02-1.12)* 1.04 (1.02-1.05)* 1.08 (1.02-1.14)* Cumulative dose Low 1.09 (0.87-1.36) 1.66 (1.41-1.96)* 1.00 (0.78-1.27) 1.15 (1.00-1.32) 1.04 (0.82-1.33) 280 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 1.27 (1.01-1.61)* 1.38 (1.12-1.71)* 1.09 (0.84-1.42) 1.17 (1.03-1.34)* 1.24 (0.96-1.60) High 1.70 (1.32-2.19)* 1.59 (1.24-2.03)* 1.69 (1.30-2.19)* 1.36 (1.21-1.53)* 1.67 (1.26-2.22)* Continuous 1.04 (1.02-1.06)* 1.04 (1.02-1.05)* 1.04 (1.02-1.06)* 1.02 (1.01-1.03)* 1.04 (1.02-1.06)* Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 1-year lag periods in the primary analysis. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 0-year lag periods. Model 3 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 2-year lag periods. Model 4 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 0-year washout and 1-year lag periods. Model 5 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 2-year washout and 1-year lag periods. This table displays associations between all diabetes medications and colorectal cancer. For a summary of selected medications with significant associations, please refer to Table 6-4. * denotes p<0.05. 281 Supplementary Table C-4. Associations between all diabetes medications and the risk of colorectal cancer among people in the BCGP Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 1. Biguanides (i.e., metformin) Never 537,721 364 67.7 (61.1-75.0) 1.00 1.00 1.00 Ever use 8,443 13 154.0 (89.4-265.2) 1.21 (1.17-1.26)* 1.31 (0.75-2.29) 1.20 (0.68-2.12) Cumulative duration - trend 1.04 (1.03-1.04)* 1.04 (0.97-1.11) 1.03 (0.96-1.11) Cumulative dose - trend 1.04 (1.04-1.05)* 1.02 (0.94-1.12) 1.01 (0.92-1.11) 2. Incretin-based medicines Never 544,775 374 68.7 (62.0-76.0) 1.00 1.00 1.00 Ever use 1,389 Suppressed 216.0 (69.7-669.7) 0.96 (0.84-1.10) 1.95 (0.62-6.09) 1.86 (0.59-5.86) Cumulative duration - trend 1.02 (0.98-1.05) 1.07 (0.75-1.52) 1.06 (0.74-1.52) Cumulative dose - trend 1.02 (0.98-1.06) 1.09 (0.73-1.62) 1.08 (0.72-1.63) 2.1. DPP-4 inhibitors Never 545,345 375 68.8 (62.1-76.1) 1.00 1.00 1.00 Ever use 819 Suppressed 244.2 (61.1-976.4) 0.95 (0.82-1.10) 2.04 (0.51-8.21) 1.93 (0.48-7.82) Cumulative duration - trend 1.02 (0.98-1.06) 1.09 (0.73-1.63) 1.08 (0.72-1.63) Cumulative dose - trend 1.02 (0.99-1.06) 1.09 (0.73-1.63) 1.09 (0.72-1.64) 2.1.2. Sitagliptin Never 545,712 375 68.7 (62.1-76.0) 1.00 1.00 1.00 Ever use 452 Suppressed 442.5 (110.7-1769.3) 0.93 (0.75-1.16) Not shown Not shown Cumulative duration - trend 1.02 (0.97-1.07) 1.18 (0.78-1.76) 1.18 (0.78-1.78) Cumulative dose - trend 1.02 (0.97-1.07) 1.18 (0.79-1.77) 1.18 (0.78-1.79) 2.2. GLP-1 receptor agonists Never 545,531 376 68.9 (62.3-76.3) 1.00 1.00 1.00 Ever use 633 Suppressed 158.0 (22.3-1121.5) 1.02 (0.76-1.35) Not shown Not shown Cumulative duration - trend 1.01 (0.92-1.11) 0.99 (0.40-2.44) 0.98 (0.40-2.43) Cumulative dose - trend 1.02 (0.69-1.51) 0.67 (0.01-73.59) 0.64 (0.01-81.45) 3. SGLT-2 inhibitors Never 545,638 376 68.9 (62.3-76.2) 1.00 1.00 1.00 Ever use 526 Suppressed 190.1 (26.8-1349.7) 0.61 (0.46-0.81)* Not shown Not shown Cumulative duration - trend 0.95 (0.86-1.06) 1.54 (0.86-2.75) 1.53 (0.85-2.74) Cumulative dose - trend 0.96 (0.87-1.05) 1.44 (0.98-2.11) 1.44 (0.97-2.12) 5. Insulin secretagogues Never 543,809 372 68.4 (61.8-75.7) 1.00 1.00 1.00 Ever use 2,355 Suppressed 212.3 (88.4-510.1) 1.33 (1.25-1.41)* 1.73 (0.71-4.18) 1.63 (0.67-3.97) Cumulative duration - trend 1.05 (1.04-1.05)* 1.07 (0.95-1.20) 1.06 (0.94-1.19) Cumulative dose - trend 1.02 (1.01-1.02)* 1.00 (0.94-1.07) 1.00 (0.93-1.07) 5.1. Meglitinides Never 546,082 376 68.9 (62.2-76.2) 1.00 1.00 1.00 Ever use 82 Suppressed 1219.5 (171.8-8657.7) 1.21 (0.80-1.82) Not shown Not shown Cumulative duration - trend 1.05 (0.99-1.11) 1.53 (1.24-1.90)* 1.55 (1.25-1.92)* Cumulative dose - trend 1.03 (0.98-1.07) 1.11 (0.93-1.33) 1.12 (0.94-1.34) 5.1.1. Repaglinide Never 546,083 376 68.9 (62.2-76.2) 1.00 1.00 1.00 Ever use 81 Suppressed 1234.6 (173.9-8764.6) 1.22 (0.81-1.84) Not shown Not shown Cumulative duration - trend 1.05 (0.99-1.11) 1.53 (1.24-1.90)* 1.55 (1.25-1.92)* 282 Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 Cumulative dose - trend 1.03 (0.98-1.07) 1.11 (0.93-1.33) 1.12 (0.94-1.34) 5.2. Sulfonylureas Never 543,866 373 68.6 (62.0-75.9) 1.00 1.00 1.00 Ever use 2,298 Suppressed 174.1 (65.3-463.8) 1.33 (1.26-1.41)* 1.41 (0.52-3.78) 1.32 (0.49-3.57) Cumulative duration - trend 1.05 (1.04-1.05)* 1.02 (0.87-1.19) 1.01 (0.86-1.18) Cumulative dose - trend 1.02 (1.01-1.02)* 1.00 (0.93-1.08) 0.99 (0.92-1.07) 5.2.1. Gliclazide Never 544,845 374 68.6 (62.0-76.0) 1.00 1.00 1.00 Ever use 1,319 Suppressed 227.4 (73.4-705.2) 1.32 (1.22-1.44)* 1.80 (0.58-5.61) 1.67 (0.53-5.25) Cumulative duration - trend 1.05 (1.04-1.07)* 1.05 (0.85-1.30) 1.04 (0.84-1.29) Cumulative dose - trend 1.02 (1.01-1.02)* 1.00 (0.91-1.10) 0.99 (0.90-1.09) 5.2.2. Glyburide Never 545,144 376 69.0 (62.3-76.3) 1.00 1.00 1.00 Ever use 1,020 Suppressed 98.0 (13.8-696.0) 1.34 (1.24-1.45)* 0.81 (0.11-5.75) 0.76 (0.11-5.45) Cumulative duration - trend 1.05 (1.04-1.06)* 0.99 (0.77-1.28) 0.98 (0.76-1.26) Cumulative dose - trend 1.02 (1.02-1.03)* 1.00 (0.87-1.15) 0.99 (0.87-1.14) 6. Thiazolidinediones Never 545,633 375 68.7 (62.1-76.0) 1.00 1.00 1.00 Ever use 531 Suppressed 376.6 (94.2-1506.0) 1.21 (0.99-1.46) Not shown Not shown Cumulative duration - trend 1.06 (1.03-1.08)* 1.10 (0.88-1.37) 1.09 (0.87-1.36) Cumulative dose - trend 1.05 (1.03-1.08)* 1.07 (0.86-1.33) 1.06 (0.86-1.31) 6.1. Pioglitazone Never 545,943 375 68.7 (62.1-76.0) 1.00 1.00 1.00 Ever use 221 Suppressed 905.0 (226.3-3618.6) 1.27 (0.98-1.64) Not shown Not shown Cumulative duration - trend 1.04 (1.00-1.08)* 1.22 (0.99-1.50) 1.20 (0.98-1.47) Cumulative dose - trend 1.03 (1.00-1.07) 1.14 (0.95-1.37) 1.12 (0.94-1.35) 7. Insulins and analogues Never 544,673 376 69.0 (62.4-76.4) 1.00 1.00 1.00 Ever use 1,491 Suppressed 67.1 (9.4-476.1) 1.21 (1.10-1.34)* 0.55 (0.08-3.91) 0.50 (0.07-3.60) Cumulative duration - trend 1.05 (1.03-1.08)* 0.97 (0.66-1.41) 0.95 (0.65-1.39) Cumulative dose - trend 1.02 (1.02-1.03)* 0.97 (0.77-1.22) 0.96 (0.76-1.21) 7.1. Basal insulins Never 544,761 376 69.0 (62.4-76.4) 1.00 1.00 1.00 Ever use 1,403 Suppressed 71.3 (10.0-506.0) 1.23 (1.11-1.36)* 0.58 (0.08-4.11) 0.53 (0.07-3.78) Cumulative duration - trend 1.06 (1.04-1.09)* 0.99 (0.65-1.50) 0.97 (0.63-1.47) Cumulative dose - trend 1.03 (1.02-1.04)* 0.98 (0.77-1.25) 0.97 (0.75-1.24) 7.2. Bolus insulins Never 545,495 376 68.9 (62.3-76.3) 1.00 1.00 1.00 Ever use 669 Suppressed 149.5 (21.1-1061.2) 1.38 (1.17-1.62)* 1.32 (0.19-9.40) 1.23 (0.17-8.79) Cumulative duration - trend 1.08 (1.03-1.13)* 0.87 (0.31-2.45) 0.85 (0.30-2.44) Cumulative dose - trend 1.04 (1.02-1.06)* 0.91 (0.48-1.71) 0.90 (0.47-1.71) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile in the primary analysis using Population Data BC. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile in the BCGP subset. 283 Model 3 further adjusted for sociodemographic and lifestyle-related factors: race/ethnicity, marital status, physical activity, education, individual-level income, fruit and vegetable consumption, alcohol consumption, smoking status, waist to hip ratio, and body mass index using the BCGP subset. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. Effect estimates denoted as “Not shown” have been omitted due to low number of events, which may result in unreliable estimates. This table displays associations between all diabetes medications and colorectal cancer. For a summary of selected medications with significant associations, please refer to Table 6-5. * denotes p<0.05. 284 Supplementary Table C-5. Associations between all diabetes medications and the risk of colorectal cancer location subtype: colon Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 24,715 49.4 (48.8-50.0) 1.00 1.00 Ever use 2,021,426 2,367 116.9 (111.6-122.4) 1.33 (1.27-1.39)* 1.27 (1.21-1.33)* Cumulative duration Low 736,609 531 72.1 (66.2-78.5) 0.96 (0.88-1.04) 0.92 (0.85-1.01) Medium 720,912 877 121.7 (113.9-130.0) 1.40 (1.31-1.50)* 1.33 (1.25-1.43)* High 563,905 959 170.1 (159.6-181.2) 1.52 (1.43-1.63)* 1.45 (1.36-1.55)* Continuous 1.05 (1.04-1.05)* 1.04 (1.03-1.05)* Cumulative dose Low 761,186 595 78.2 (72.1-84.7) 0.98 (0.90-1.06) 0.95 (0.88-1.03) Medium 720,432 875 121.5 (113.7-129.8) 1.35 (1.26-1.44)* 1.29 (1.21-1.38)* High 539,808 897 166.2 (155.6-177.4) 1.61 (1.51-1.73)* 1.52 (1.43-1.63)* Continuous 1.06 (1.05-1.06)* 1.05 (1.04-1.06)* 2. Incretin-based medicines Never 51,846,234 26,845 51.8 (51.2-52.4) 1.00 1.00 Ever use 242,410 237 88.6 (75.5-103.9) 1.15 (0.98-1.35) 1.08 (0.92-1.26) Cumulative duration Low 76,647 63 82.2 (64.2-105.2) 1.16 (0.91-1.49) 1.09 (0.85-1.39) Medium 82,123 63 76.7 (59.9-98.2) 1.03 (0.81-1.32) 0.96 (0.75-1.23) High 83,640 111 132.7 (110.2-159.8) 1.49 (1.24-1.80)* 1.41 (1.17-1.70)* Continuous 1.07 (1.03-1.11)* 1.05 (1.01-1.09)* Cumulative dose Low 79,230 61 77.0 (59.9-99.0) 1.16 (0.90-1.50) 1.09 (0.84-1.40) Medium 80,356 68 84.6 (66.7-107.3) 1.10 (0.87-1.40) 1.03 (0.81-1.30) High 82,824 108 130.4 (108.0-157.5) 1.43 (1.19-1.73)* 1.35 (1.12-1.63)* Continuous 1.07 (1.03-1.12)* 1.06 (1.02-1.10)* 2.1. DPP-4 inhibitors Never 51,896,422 26,879 51.8 (51.2-52.4) 1.00 1.00 Ever use 192,222 203 95.8 (80.3-114.2) 1.14 (0.96-1.36) 1.07 (0.89-1.27) Cumulative duration Low 63,002 54 85.7 (65.6-111.9) 1.08 (0.83-1.42) 1.01 (0.78-1.32) Medium 63,244 55 87.0 (66.8-113.3) 1.08 (0.83-1.41) 1.00 (0.77-1.31) High 65,976 94 142.5 (116.4-174.4) 1.51 (1.24-1.85)* 1.43 (1.17-1.75)* Continuous 1.07 (1.03-1.11)* 1.06 (1.01-1.10)* Cumulative dose Low 64,188 56 87.2 (67.1-113.4) 1.10 (0.84-1.43) 1.03 (0.79-1.33) Medium 61,937 51 82.3 (62.6-108.3) 1.02 (0.77-1.34) 0.95 (0.72-1.25) High 66,097 96 145.2 (118.9-177.4) 1.55 (1.27-1.90)* 1.46 (1.20-1.79)* Continuous 1.07 (1.03-1.12)* 1.06 (1.02-1.10)* 2.1.1. Linagliptin Never 52,023,970 27,013 51.9 (51.3-52.5) 1.00 1.00 Ever use 64,674 69 102.5 (77.9-134.8) 1.05 (0.80-1.39) 1.01 (0.76-1.32) Cumulative duration Low 19,887 21 105.6 (68.8-162.0) 1.17 (0.76-1.80) 1.11 (0.72-1.70) Medium 21,325 16 75.0 (46.0-122.5) 0.80 (0.49-1.31) 0.76 (0.47-1.24) High 23,462 32 136.4 (96.5-192.9) 1.28 (0.91-1.81) 1.24 (0.88-1.76) Continuous 1.03 (0.93-1.14) 1.02 (0.92-1.13) Cumulative dose Low 19,952 21 105.3 (68.6-161.4) 1.17 (0.76-1.79) 1.11 (0.72-1.70) Medium 21,425 17 79.3 (49.3-127.6) 0.85 (0.53-1.36) 0.80 (0.50-1.29) High 23,297 31 133.1 (93.6-189.2) 1.25 (0.88-1.78) 1.21 (0.85-1.72) Continuous 1.03 (0.93-1.14) 1.02 (0.92-1.13) 2.1.2. Sitagliptin Never 51,955,454 26,940 51.9 (51.2-52.5) 1.00 1.00 Ever use 133,190 142 83.7 (64.3-109.0) 1.13 (0.87-1.47) 1.03 (0.79-1.34) Cumulative duration Low 42,249 39 92.3 (67.4-126.3) 1.17 (0.85-1.60) 1.09 (0.80-1.50) Medium 47,499 45 94.7 (70.7-126.9) 1.21 (0.90-1.62) 1.12 (0.83-1.50) High 43,442 58 133.5 (103.2-172.7) 1.49 (1.15-1.93)* 1.39 (1.07-1.80)* Continuous 1.07 (1.01-1.13)* 1.05 (0.99-1.11) Cumulative dose Low 43,259 41 94.8 (69.8-128.7) 1.19 (0.88-1.62) 1.12 (0.82-1.52) 285 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 45,625 41 89.9 (66.2-122.0) 1.14 (0.84-1.55) 1.06 (0.78-1.44) High 44,306 60 135.4 (105.1-174.4) 1.53 (1.19-1.97)* 1.42 (1.11-1.83)* Continuous 1.07 (1.02-1.14)* 1.06 (1.00-1.12) 2.2. GLP-1 receptor agonists Never 52,013,587 27,025 52.0 (51.3-52.6) 1.00 1.00 Ever use 75,057 57 64.5 (45.1-92.3) 1.17 (0.82-1.68) 1.09 (0.76-1.56) Cumulative duration Low 23,429 15 64.0 (38.6-106.2) 1.21 (0.73-2.01) 1.13 (0.68-1.88) Medium 25,502 21 82.3 (53.7-126.3) 1.57 (1.03-2.41)* 1.45 (0.95-2.22) High 26,126 21 80.4 (52.4-123.3) 1.23 (0.80-1.88) 1.15 (0.75-1.76) Continuous 1.06 (0.95-1.19) 1.05 (0.94-1.17) Cumulative dose Low 23,693 15 63.3 (38.2-105.0) 1.16 (0.70-1.92) 1.08 (0.65-1.80) Medium 25,629 21 81.9 (53.4-125.7) 1.51 (0.98-2.31) 1.39 (0.91-2.13) High 25,735 21 81.6 (53.2-125.2) 1.31 (0.85-2.01) 1.23 (0.80-1.88) Continuous 1.12 (0.71-1.78) 1.05 (0.65-1.71) 3. SGLT-2 inhibitors Never 51,997,074 27,025 52.0 (51.4-52.6) 1.00 1.00 Ever use 91,570 57 45.0 (31.5-64.4) 0.68 (0.48-0.98)* 0.63 (0.44-0.90)* Cumulative duration Low 26,625 12 45.1 (25.6-79.4) 0.65 (0.37-1.14) 0.60 (0.34-1.06) Medium 30,375 26 85.6 (58.3-125.7) 1.25 (0.85-1.84) 1.16 (0.79-1.70) High 34,570 19 55.0 (35.1-86.2) 0.78 (0.50-1.23) 0.72 (0.46-1.13) Continuous 0.98 (0.85-1.12) 0.95 (0.82-1.09) Cumulative dose Low 26,825 11 41.0 (22.7-74.0) 0.58 (0.32-1.04) 0.54 (0.30-0.97)* Medium 30,296 21 69.3 (45.2-106.3) 1.01 (0.66-1.54) 0.93 (0.61-1.43) High 34,449 25 72.6 (49.0-107.4) 1.06 (0.72-1.57) 0.98 (0.66-1.45) Continuous 1.00 (0.89-1.11) 0.97 (0.86-1.09) 4. AGIs (i.e., acarbose) Never 52,043,873 27,037 52.0 (51.3-52.6) 1.00 1.00 Ever use 44,771 45 68.9 (35.9-132.5) 0.76 (0.40-1.47) 0.76 (0.40-1.47) Cumulative duration Low 16,863 20 118.6 (76.5-183.8) 1.38 (0.89-2.13) 1.37 (0.88-2.12) Medium 15,151 15 99.0 (59.7-164.2) 1.06 (0.64-1.75) 1.05 (0.63-1.74) High 12,757 10 78.4 (42.2-145.7) 0.72 (0.39-1.34) 0.71 (0.38-1.32) Continuous 0.99 (0.90-1.09) 0.99 (0.90-1.09) Cumulative dose Low 15,946 18 112.9 (71.1-179.2) 1.28 (0.81-2.03) 1.28 (0.81-2.03) Medium 16,084 15 93.3 (56.2-154.7) 1.00 (0.60-1.66) 0.99 (0.60-1.64) High 12,741 12 94.2 (53.5-165.8) 0.89 (0.50-1.56) 0.87 (0.49-1.53) Continuous 0.96 (0.80-1.14) 0.95 (0.80-1.14) 5. Insulin secretagogues Never 51,176,005 25,895 50.6 (50.0-51.2) 1.00 1.00 Ever use 912,639 1,187 131.8 (122.7-141.6) 1.45 (1.35-1.56)* 1.39 (1.29-1.50)* Cumulative duration Low 360,923 325 90.0 (80.8-100.4) 1.07 (0.96-1.19) 1.03 (0.93-1.15) Medium 315,845 414 131.1 (119.0-144.3) 1.44 (1.31-1.59)* 1.38 (1.25-1.52)* High 235,871 448 189.9 (173.1-208.4) 1.66 (1.51-1.82)* 1.58 (1.44-1.74)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* Cumulative dose Low 372,575 376 100.9 (91.2-111.7) 1.13 (1.02-1.25)* 1.10 (1.00-1.22) Medium 314,231 424 134.9 (122.7-148.4) 1.44 (1.31-1.59)* 1.37 (1.25-1.51)* High 225,833 387 171.4 (155.1-189.3) 1.64 (1.49-1.82)* 1.56 (1.41-1.72)* Continuous 1.02 (1.02-1.03)* 1.02 (1.01-1.02)* 5.1. Meglitinides Never 52,048,818 27,026 51.9 (51.3-52.5) 1.00 1.00 Ever use 39,826 56 124.9 (77.6-200.9) 1.46 (0.91-2.35) 1.41 (0.88-2.27) Cumulative duration Low 12,831 23 179.3 (119.1-269.7) 2.00 (1.33-3.01)* 1.94 (1.29-2.92)* Medium 13,013 11 84.5 (46.8-152.6) 0.99 (0.55-1.78) 0.95 (0.53-1.72) High 13,982 22 157.3 (103.6-239.0) 1.56 (1.03-2.38)* 1.48 (0.98-2.25) Continuous 1.07 (1.01-1.14)* 1.06 (1.00-1.13) Cumulative dose Low 13,858 23 166.0 (110.3-249.8) 1.79 (1.19-2.69)* 1.74 (1.16-2.62)* 286 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 13,470 13 96.5 (56.0-166.2) 1.09 (0.64-1.88) 1.05 (0.61-1.82) High 12,498 20 160.0 (103.2-248.0) 1.67 (1.08-2.60)* 1.58 (1.02-2.44)* Continuous 1.05 (1.01-1.10)* 1.05 (1.00-1.09)* 5.1.1. Repaglinide Never 52,049,428 27,027 51.9 (51.3-52.5) 1.00 1.00 Ever use 39,216 55 126.1 (78.4-202.9) 1.47 (0.92-2.36) 1.42 (0.88-2.28) Cumulative duration Low 12,566 23 183.0 (121.6-275.4) 2.04 (1.36-3.07)* 1.99 (1.32-2.99)* Medium 12,873 10 77.7 (41.8-144.4) 0.90 (0.49-1.68) 0.87 (0.47-1.62) High 13,777 22 159.7 (105.1-242.5) 1.59 (1.04-2.41)* 1.51 (0.99-2.29) Continuous 1.07 (1.01-1.14)* 1.06 (1.00-1.13) Cumulative dose Low 13,676 23 168.2 (111.8-253.1) 1.81 (1.20-2.73)* 1.77 (1.18-2.66)* Medium 13,159 12 91.2 (51.8-160.6) 1.03 (0.58-1.81) 0.99 (0.56-1.74) High 12,381 20 161.5 (104.2-250.4) 1.69 (1.09-2.62)* 1.59 (1.03-2.47)* Continuous 1.05 (1.01-1.10)* 1.05 (1.00-1.09)* 5.2. Sulfonylureas Never 51,188,413 25,904 50.6 (50.0-51.2) 1.00 1.00 Ever use 900,231 1,178 132.2 (123.0-142.0) 1.45 (1.35-1.56)* 1.39 (1.29-1.50)* Cumulative duration Low 359,009 334 93.0 (83.6-103.6) 1.10 (0.99-1.22) 1.06 (0.96-1.19) Medium 309,407 405 130.9 (118.7-144.3) 1.44 (1.31-1.59)* 1.37 (1.24-1.51)* High 231,815 439 189.4 (172.5-207.9) 1.65 (1.50-1.82)* 1.58 (1.43-1.73)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* Cumulative dose Low 367,838 381 103.6 (93.7-114.5) 1.16 (1.05-1.28)* 1.13 (1.02-1.25)* Medium 309,412 416 134.4 (122.1-148.0) 1.44 (1.30-1.58)* 1.37 (1.24-1.51)* High 222,981 381 170.9 (154.5-188.9) 1.64 (1.48-1.81)* 1.55 (1.40-1.72)* Continuous 1.02 (1.02-1.03)* 1.02 (1.01-1.02)* 5.2.1. Gliclazide Never 51,695,028 26,546 51.4 (50.7-52.0) 1.00 1.00 Ever use 393,616 536 136.7 (123.2-151.8) 1.45 (1.30-1.61)* 1.36 (1.23-1.51)* Cumulative duration Low 126,908 154 121.3 (103.6-142.1) 1.39 (1.19-1.63)* 1.32 (1.13-1.55)* Medium 136,638 163 119.3 (102.3-139.1) 1.30 (1.11-1.51)* 1.22 (1.05-1.42)* High 130,070 219 168.4 (147.5-192.2) 1.55 (1.35-1.77)* 1.47 (1.29-1.68)* Continuous 1.07 (1.05-1.09)* 1.06 (1.04-1.08)* Cumulative dose Low 133,699 156 116.7 (99.7-136.5) 1.30 (1.11-1.52)* 1.23 (1.05-1.44)* Medium 136,394 177 129.8 (112.0-150.4) 1.37 (1.18-1.59)* 1.29 (1.11-1.49)* High 123,523 203 164.3 (143.2-188.6) 1.58 (1.38-1.81)* 1.49 (1.30-1.71)* Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.02)* 5.2.2. Glyburide Never 51,418,210 26,180 50.9 (50.3-51.5) 1.00 1.00 Ever use 670,434 902 129.7 (117.7-143.0) 1.47 (1.33-1.62)* 1.42 (1.29-1.57)* Cumulative duration Low 283,215 302 106.6 (95.3-119.4) 1.20 (1.07-1.34)* 1.17 (1.04-1.31)* Medium 224,722 289 128.6 (114.6-144.3) 1.40 (1.25-1.57)* 1.35 (1.20-1.51)* High 162,497 311 191.4 (171.3-213.9) 1.66 (1.49-1.86)* 1.58 (1.42-1.77)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.07)* Cumulative dose Low 296,014 327 110.5 (99.1-123.1) 1.19 (1.07-1.32)* 1.16 (1.04-1.29)* Medium 230,574 331 143.6 (128.9-159.9) 1.50 (1.35-1.68)* 1.44 (1.30-1.61)* High 143,846 244 169.6 (149.6-192.3) 1.62 (1.43-1.84)* 1.54 (1.36-1.75)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.03)* 6. Thiazolidinediones Never 51,871,508 26,830 51.7 (51.1-52.3) 1.00 1.00 Ever use 217,136 252 80.3 (62.1-103.9) 1.16 (0.90-1.51) 1.11 (0.86-1.44) Cumulative duration Low 76,357 87 113.9 (92.3-140.6) 1.41 (1.14-1.74)* 1.35 (1.09-1.66)* Medium 72,351 77 106.4 (85.1-133.1) 1.31 (1.05-1.64)* 1.24 (0.99-1.55) High 68,428 88 128.6 (104.4-158.5) 1.39 (1.13-1.71)* 1.29 (1.05-1.59)* Continuous 1.06 (1.02-1.09)* 1.04 (1.01-1.08)* Cumulative dose Low 75,982 86 113.2 (91.6-139.8) 1.38 (1.12-1.71)* 1.32 (1.07-1.63)* 287 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 74,257 86 115.8 (93.8-143.1) 1.41 (1.14-1.75)* 1.34 (1.08-1.66)* High 66,897 80 119.6 (96.1-148.9) 1.32 (1.06-1.64)* 1.22 (0.98-1.52) Continuous 1.06 (1.02-1.09)* 1.04 (1.01-1.08)* 6.1. Pioglitazone Never 51,987,564 26,980 51.9 (51.3-52.5) 1.00 1.00 Ever use 101,080 102 83.6 (58.5-119.6) 1.13 (0.79-1.61) 1.06 (0.74-1.51) Cumulative duration Low 33,963 33 97.2 (69.1-136.7) 1.17 (0.84-1.65) 1.12 (0.80-1.58) Medium 34,409 34 98.8 (70.6-138.3) 1.20 (0.86-1.68) 1.13 (0.81-1.58) High 32,708 35 107.0 (76.8-149.0) 1.11 (0.80-1.54) 1.03 (0.74-1.44) Continuous 1.02 (0.97-1.08) 1.01 (0.96-1.06) Cumulative dose Low 33,724 31 91.9 (64.6-130.7) 1.10 (0.77-1.56) 1.05 (0.74-1.49) Medium 34,952 42 120.2 (88.8-162.6) 1.44 (1.06-1.95)* 1.35 (1.00-1.83)* High 32,404 29 89.5 (62.2-128.8) 0.95 (0.66-1.37) 0.88 (0.61-1.27) Continuous 1.02 (0.97-1.07) 1.01 (0.96-1.06) 6.2. Rosiglitazone Never 51,946,176 26,903 51.8 (51.2-52.4) 1.00 1.00 Ever use 142,468 179 76.8 (53.4-110.5) 1.21 (0.84-1.74) 1.17 (0.82-1.69) Cumulative duration Low 49,170 55 111.9 (85.9-145.7) 1.36 (1.05-1.77)* 1.30 (1.00-1.70) Medium 48,028 62 129.1 (100.6-165.6) 1.58 (1.23-2.03)* 1.51 (1.18-1.94)* High 45,270 62 137.0 (106.8-175.7) 1.54 (1.20-1.98)* 1.44 (1.12-1.85)* Continuous 1.10 (1.05-1.15)* 1.08 (1.04-1.13)* Cumulative dose Low 49,567 58 117.0 (90.5-151.4) 1.42 (1.10-1.84)* 1.36 (1.05-1.76)* Medium 49,349 60 121.6 (94.4-156.6) 1.47 (1.14-1.90)* 1.40 (1.09-1.81)* High 43,552 61 140.1 (109.0-180.0) 1.59 (1.24-2.05)* 1.49 (1.16-1.91)* Continuous 1.10 (1.06-1.14)* 1.09 (1.04-1.13)* 7. Insulins and analogues Never 51,772,245 26,771 51.7 (51.1-52.3) 1.00 1.00 Ever use 316,399 311 109.6 (96.9-123.9) 1.36 (1.20-1.54)* 1.26 (1.11-1.43)* Cumulative duration Low 143,015 80 55.9 (44.9-69.6) 0.89 (0.71-1.10) 0.83 (0.67-1.03) Medium 113,499 136 119.8 (101.3-141.8) 1.43 (1.21-1.70)* 1.33 (1.12-1.57)* High 59,885 95 158.6 (129.7-194.0) 1.72 (1.41-2.11)* 1.61 (1.31-1.96)* Continuous 1.08 (1.05-1.10)* 1.07 (1.04-1.09)* Cumulative dose Low 146,186 86 58.8 (47.6-72.7) 0.90 (0.73-1.11) 0.85 (0.68-1.05) Medium 108,141 125 115.6 (97.0-137.7) 1.38 (1.16-1.64)* 1.28 (1.07-1.53)* High 62,072 100 161.1 (132.4-196.0) 1.84 (1.51-2.24)* 1.70 (1.40-2.07)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 7.1. Basal insulins Never 51,784,863 26,778 51.7 (51.1-52.3) 1.00 1.00 Ever use 303,781 304 112.0 (98.8-127.0) 1.40 (1.23-1.59)* 1.30 (1.14-1.47)* Cumulative duration Low 135,289 85 62.8 (50.8-77.7) 1.00 (0.81-1.23) 0.93 (0.75-1.15) Medium 109,417 125 114.2 (95.9-136.1) 1.38 (1.16-1.64)* 1.28 (1.07-1.52)* High 59,075 94 159.1 (130.0-194.8) 1.72 (1.40-2.11)* 1.60 (1.31-1.96)* Continuous 1.09 (1.06-1.12)* 1.08 (1.05-1.11)* Cumulative dose Low 136,909 86 62.8 (50.8-77.6) 0.97 (0.78-1.20) 0.91 (0.74-1.12) Medium 106,571 118 110.7 (92.4-132.6) 1.33 (1.11-1.59)* 1.23 (1.03-1.48)* High 60,301 100 165.8 (136.3-201.7) 1.89 (1.55-2.30)* 1.74 (1.43-2.12)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.05)* 7.2. Bolus insulins Never 51,947,122 26,941 51.9 (51.2-52.5) 1.00 1.00 Ever use 141,522 141 116.3 (95.4-141.7) 1.65 (1.36-2.02)* 1.52 (1.25-1.86)* Cumulative duration Low 68,567 43 62.7 (46.5-84.6) 1.08 (0.80-1.45) 1.01 (0.75-1.36) Medium 48,161 59 122.5 (94.9-158.1) 1.71 (1.32-2.20)* 1.57 (1.21-2.02)* High 24,794 39 157.3 (114.9-215.3) 2.00 (1.46-2.74)* 1.84 (1.34-2.52)* Continuous 1.12 (1.06-1.19)* 1.11 (1.05-1.17)* Cumulative dose Low 71,251 47 66.0 (49.6-87.8) 1.11 (0.83-1.47) 1.04 (0.78-1.38) 288 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 44,054 53 120.3 (91.9-157.5) 1.67 (1.27-2.18)* 1.53 (1.17-2.01)* High 26,217 41 156.4 (115.1-212.4) 2.08 (1.53-2.83)* 1.89 (1.39-2.57)* Continuous 1.05 (1.03-1.07)* 1.05 (1.03-1.07)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. This table displays associations between all diabetes medications and colon cancer. For a summary of selected medications with significant associations, please refer to Table 6-7. * denotes p<0.05. 289 Supplementary Table C-6. Associations between all diabetes medications and the risk of colorectal cancer location subtype: proximal colon Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 13,770 27.5 (27.0-28.0) 1.00 1.00 Ever use 2,021,426 1,368 67.5 (63.5-71.8) 1.35 (1.27-1.44)* 1.31 (1.23-1.40)* Cumulative duration Low 736,609 297 40.3 (36.0-45.2) 0.95 (0.85-1.07) 0.93 (0.83-1.04) Medium 720,912 500 69.4 (63.5-75.7) 1.41 (1.29-1.54)* 1.37 (1.25-1.49)* High 563,905 571 101.3 (93.3-109.9) 1.57 (1.44-1.71)* 1.51 (1.39-1.64)* Continuous 1.05 (1.04-1.06)* 1.04 (1.04-1.05)* Cumulative dose Low 761,186 330 43.4 (38.9-48.3) 0.96 (0.86-1.07) 0.94 (0.84-1.05) Medium 720,432 501 69.5 (63.7-75.9) 1.36 (1.24-1.48)* 1.32 (1.21-1.44)* High 539,808 537 99.5 (91.4-108.3) 1.68 (1.55-1.84)* 1.61 (1.48-1.76)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* 2. Incretin-based medicines Never 51,846,234 14,988 28.9 (28.4-29.4) 1.00 1.00 Ever use 242,410 150 54.0 (44.0-66.2) 1.26 (1.03-1.55)* 1.19 (0.97-1.46) Cumulative duration Low 76,647 36 47.0 (33.9-65.1) 1.20 (0.87-1.66) 1.13 (0.81-1.56) Medium 82,123 41 49.9 (36.8-67.8) 1.22 (0.89-1.65) 1.14 (0.84-1.54) High 83,640 73 87.3 (69.4-109.8) 1.74 (1.39-2.20)* 1.65 (1.31-2.08)* Continuous 1.11 (1.06-1.16)* 1.10 (1.05-1.15)* Cumulative dose Low 79,230 38 48.0 (34.9-65.9) 1.32 (0.96-1.82) 1.23 (0.89-1.69) Medium 80,356 41 51.0 (37.6-69.3) 1.20 (0.88-1.63) 1.12 (0.83-1.53) High 82,824 71 85.7 (67.9-108.2) 1.67 (1.32-2.11)* 1.58 (1.25-2.00)* Continuous 1.11 (1.06-1.16)* 1.10 (1.04-1.15)* 2.1. DPP-4 inhibitors Never 51,896,422 15,015 28.9 (28.5-29.4) 1.00 1.00 Ever use 192,222 123 57.2 (45.5-71.8) 1.21 (0.96-1.52) 1.15 (0.91-1.44) Cumulative duration Low 63,002 28 44.4 (30.7-64.4) 1.01 (0.69-1.46) 0.95 (0.65-1.37) Medium 63,244 35 55.3 (39.7-77.1) 1.23 (0.88-1.72) 1.16 (0.83-1.61) High 65,976 60 90.9 (70.6-117.1) 1.70 (1.32-2.19)* 1.62 (1.25-2.08)* Continuous 1.11 (1.06-1.16)* 1.10 (1.04-1.15)* Cumulative dose Low 64,188 29 45.2 (31.4-65.0) 1.02 (0.71-1.46) 0.96 (0.67-1.38) Medium 61,937 32 51.7 (36.5-73.1) 1.15 (0.81-1.62) 1.08 (0.76-1.53) High 66,097 62 93.8 (73.1-120.3) 1.77 (1.38-2.27)* 1.67 (1.30-2.15)* Continuous 1.11 (1.06-1.17)* 1.10 (1.05-1.15)* 2.1.1. Linagliptin Never 52,023,970 15,094 29.0 (28.6-29.5) 1.00 1.00 Ever use 64,674 44 60.3 (42.1-86.2) 1.09 (0.76-1.56) 1.04 (0.73-1.49) Cumulative duration Low 19,887 13 65.4 (38.0-112.6) 1.28 (0.74-2.21) 1.22 (0.71-2.10) Medium 21,325 Suppressed 42.2 (22.0-81.1) 0.79 (0.41-1.52) 0.76 (0.39-1.45) High 23,462 22 93.8 (61.7-142.4) 1.54 (1.02-2.34)* 1.49 (0.98-2.26) Continuous 1.09 (0.97-1.23) 1.08 (0.95-1.21) Cumulative dose Low 19,952 13 65.2 (37.8-112.2) 1.28 (0.74-2.20) 1.21 (0.70-2.09) Medium 21,425 10 46.7 (25.1-86.7) 0.88 (0.47-1.63) 0.84 (0.45-1.55) High 23,297 21 90.1 (58.8-138.3) 1.48 (0.97-2.27) 1.43 (0.93-2.19) Continuous 1.09 (0.97-1.23) 1.08 (0.95-1.21) 2.1.2. Sitagliptin Never 51,955,454 15,049 29.0 (28.5-29.4) 1.00 1.00 Ever use 133,190 89 48.7 (34.4-68.9) 1.18 (0.84-1.67) 1.10 (0.78-1.56) Cumulative duration Low 42,249 22 52.1 (34.3-79.1) 1.18 (0.78-1.79) 1.11 (0.73-1.69) Medium 47,499 29 61.1 (42.4-87.9) 1.40 (0.97-2.02) 1.32 (0.91-1.89) High 43,442 38 87.5 (63.6-120.2) 1.73 (1.26-2.38)* 1.63 (1.19-2.25)* Continuous 1.11 (1.04-1.19)* 1.09 (1.02-1.17)* Cumulative dose Low 43,259 23 53.2 (35.3-80.0) 1.20 (0.79-1.80) 1.13 (0.75-1.70) 290 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 45,625 25 54.8 (37.0-81.1) 1.26 (0.85-1.86) 1.18 (0.79-1.74) High 44,306 41 92.5 (68.1-125.7) 1.86 (1.37-2.52)* 1.75 (1.29-2.37)* Continuous 1.11 (1.04-1.19)* 1.10 (1.03-1.18)* 2.2. GLP-1 receptor agonists Never 52,013,587 15,096 29.0 (28.6-29.5) 1.00 1.00 Ever use 75,057 42 45.2 (29.4-69.3) 1.56 (1.02-2.39)* 1.41 (0.92-2.17) Cumulative duration Low 23,429 12 51.2 (29.1-90.2) 1.82 (1.03-3.20)* 1.66 (0.94-2.93) Medium 25,502 14 54.9 (32.5-92.7) 1.98 (1.17-3.34)* 1.79 (1.06-3.02)* High 26,126 16 61.2 (37.5-100.0) 1.74 (1.07-2.84)* 1.59 (0.97-2.60) Continuous 1.16 (1.03-1.31)* 1.14 (1.01-1.29)* Cumulative dose Low 23,693 11 46.4 (25.7-83.8) 1.60 (0.88-2.88) 1.46 (0.81-2.64) Medium 25,629 17 66.3 (41.2-106.7) 2.31 (1.44-3.71)* 2.08 (1.30-3.35)* High 25,735 14 54.4 (32.2-91.9) 1.63 (0.96-2.75) 1.49 (0.88-2.52) Continuous 1.30 (0.78-2.18) 1.23 (0.72-2.10) 3. SGLT-2 inhibitors Never 51,997,074 15,101 29.0 (28.6-29.5) 1.00 1.00 Ever use 91,570 37 27.0 (17.0-42.9) 0.76 (0.48-1.21) 0.70 (0.44-1.10) Cumulative duration Low 26,625 Suppressed 30.0 (15.0-60.1) 0.79 (0.39-1.57) 0.73 (0.36-1.46) Medium 30,375 18 59.3 (37.3-94.1) 1.60 (1.01-2.54)* 1.48 (0.93-2.35) High 34,570 11 31.8 (17.6-57.5) 0.84 (0.46-1.51) 0.77 (0.42-1.38) Continuous 1.01 (0.85-1.21) 0.98 (0.82-1.17) Cumulative dose Low 26,825 Suppressed 33.6 (17.5-64.5) 0.85 (0.44-1.64) 0.79 (0.41-1.52) Medium 30,296 14 46.2 (27.4-78.0) 1.23 (0.73-2.08) 1.14 (0.67-1.93) High 34,449 14 40.6 (24.1-68.6) 1.10 (0.65-1.86) 1.01 (0.60-1.70) Continuous 1.02 (0.89-1.18) 1.00 (0.86-1.15) 4. AGIs (i.e., acarbose) Never 52,043,873 15,110 29.0 (28.6-29.5) 1.00 1.00 Ever use 44,771 28 30.6 (11.5-81.6) 0.60 (0.23-1.59) 0.62 (0.23-1.65) Cumulative duration Low 16,863 15 89.0 (53.6-147.6) 1.82 (1.10-3.02)* 1.83 (1.10-3.04)* Medium 15,151 Suppressed 52.8 (26.4-105.6) 0.99 (0.49-1.98) 1.00 (0.50-2.01) High 12,757 Suppressed 39.2 (16.3-94.2) 0.62 (0.26-1.50) 0.64 (0.27-1.53) Continuous 0.99 (0.87-1.12) 0.99 (0.87-1.12) Cumulative dose Low 15,946 13 81.5 (47.3-140.4) 1.64 (0.95-2.82) 1.66 (0.96-2.85) Medium 16,084 Suppressed 49.7 (24.9-99.5) 0.94 (0.47-1.87) 0.95 (0.47-1.90) High 12,741 Suppressed 54.9 (26.2-115.2) 0.90 (0.43-1.88) 0.91 (0.44-1.91) Continuous 0.98 (0.79-1.21) 0.98 (0.79-1.21) 5. Insulin secretagogues Never 51,176,005 14,443 28.2 (27.8-28.7) 1.00 1.00 Ever use 912,639 695 76.9 (70.0-84.4) 1.49 (1.35-1.63)* 1.45 (1.32-1.60)* Cumulative duration Low 360,923 177 49.0 (42.3-56.8) 1.02 (0.88-1.19) 1.01 (0.87-1.17) Medium 315,845 239 75.7 (66.7-85.9) 1.47 (1.29-1.67)* 1.43 (1.25-1.62)* High 235,871 279 118.3 (105.2-133.0) 1.78 (1.58-2.01)* 1.73 (1.54-1.95)* Continuous 1.06 (1.05-1.08)* 1.06 (1.05-1.07)* Cumulative dose Low 372,575 217 58.2 (51.0-66.5) 1.15 (1.00-1.31)* 1.14 (0.99-1.30) Medium 314,231 240 76.4 (67.3-86.7) 1.43 (1.26-1.62)* 1.39 (1.22-1.58)* High 225,833 238 105.4 (92.8-119.7) 1.76 (1.55-2.00)* 1.70 (1.49-1.93)* Continuous 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 5.1. Meglitinides Never 52,048,818 15,102 29.0 (28.6-29.5) 1.00 1.00 Ever use 39,826 36 58.8 (29.4-117.5) 1.21 (0.60-2.41) 1.18 (0.59-2.36) Cumulative duration Low 12,831 18 140.3 (88.4-222.7) 2.76 (1.74-4.38)* 2.69 (1.70-4.27)* Medium 13,013 Suppressed 30.7 (11.5-81.9) 0.63 (0.24-1.69) 0.62 (0.23-1.64) High 13,982 14 100.1 (59.3-169.1) 1.74 (1.03-2.94)* 1.66 (0.98-2.80) Continuous 1.09 (1.01-1.18)* 1.08 (1.00-1.17)* Cumulative dose Low 13,858 17 122.7 (76.3-197.3) 2.32 (1.45-3.73)* 2.28 (1.42-3.66)* 291 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 13,470 Suppressed 52.0 (24.8-109.0) 1.04 (0.49-2.18) 1.01 (0.48-2.11) High 12,498 12 96.0 (54.5-169.1) 1.77 (1.00-3.11)* 1.67 (0.95-2.94) Continuous 1.06 (1.00-1.11)* 1.05 (1.00-1.11) 5.1.1. Repaglinide Never 52,049,428 15,102 29.0 (28.6-29.5) 1.00 1.00 Ever use 39,216 36 59.3 (29.7-118.7) 1.22 (0.61-2.43) 1.19 (0.60-2.38) Cumulative duration Low 12,566 18 143.2 (90.2-227.4) 2.81 (1.77-4.47)* 2.75 (1.73-4.36)* Medium 12,873 Suppressed 31.1 (11.7-82.8) 0.64 (0.24-1.70) 0.62 (0.23-1.65) High 13,777 14 101.6 (60.2-171.6) 1.76 (1.05-2.98)* 1.68 (1.00-2.84) Continuous 1.09 (1.01-1.18)* 1.08 (1.01-1.17)* Cumulative dose Low 13,676 17 124.3 (77.3-200.0) 2.36 (1.47-3.79)* 2.32 (1.44-3.72)* Medium 13,159 Suppressed 53.2 (25.4-111.6) 1.05 (0.50-2.21) 1.03 (0.49-2.15) High 12,381 12 96.9 (55.0-170.7) 1.79 (1.01-3.15)* 1.69 (0.96-2.97) Continuous 1.06 (1.00-1.11)* 1.05 (1.00-1.11) 5.2. Sulfonylureas Never 51,188,413 14,448 28.2 (27.8-28.7) 1.00 1.00 Ever use 900,231 690 77.1 (70.1-84.7) 1.49 (1.35-1.64)* 1.46 (1.32-1.60)* Cumulative duration Low 359,009 183 51.0 (44.1-58.9) 1.06 (0.92-1.23) 1.05 (0.91-1.21) Medium 309,407 233 75.3 (66.2-85.6) 1.46 (1.28-1.66)* 1.42 (1.24-1.61)* High 231,815 274 118.2 (105.0-133.1) 1.78 (1.58-2.01)* 1.73 (1.53-1.95)* Continuous 1.06 (1.05-1.08)* 1.06 (1.05-1.07)* Cumulative dose Low 367,838 221 60.1 (52.7-68.5) 1.18 (1.03-1.35)* 1.17 (1.02-1.34)* Medium 309,412 234 75.6 (66.5-86.0) 1.42 (1.24-1.61)* 1.37 (1.21-1.56)* High 222,981 235 105.4 (92.7-119.8) 1.76 (1.55-2.00)* 1.70 (1.49-1.93)* Continuous 1.02 (1.02-1.03)* 1.02 (1.02-1.03)* 5.2.1. Gliclazide Never 51,695,028 14,823 28.7 (28.2-29.1) 1.00 1.00 Ever use 393,616 315 76.9 (66.9-88.4) 1.43 (1.24-1.64)* 1.36 (1.18-1.57)* Cumulative duration Low 126,908 97 76.4 (62.6-93.3) 1.54 (1.26-1.88)* 1.48 (1.21-1.81)* Medium 136,638 91 66.6 (54.2-81.8) 1.27 (1.04-1.56)* 1.21 (0.99-1.49) High 130,070 127 97.6 (82.1-116.2) 1.56 (1.31-1.85)* 1.49 (1.25-1.78)* Continuous 1.07 (1.05-1.10)* 1.06 (1.04-1.09)* Cumulative dose Low 133,699 99 74.0 (60.8-90.2) 1.44 (1.18-1.76)* 1.39 (1.14-1.70)* Medium 136,394 95 69.7 (57.0-85.2) 1.29 (1.05-1.58)* 1.23 (1.00-1.50)* High 123,523 121 98.0 (82.0-117.1) 1.64 (1.37-1.96)* 1.57 (1.31-1.88)* Continuous 1.02 (1.02-1.03)* 1.02 (1.01-1.03)* 5.2.2. Glyburide Never 51,418,210 14,598 28.4 (27.9-28.9) 1.00 1.00 Ever use 670,434 540 76.7 (67.6-87.1) 1.52 (1.34-1.73)* 1.52 (1.34-1.73)* Cumulative duration Low 283,215 167 59.0 (50.7-68.6) 1.16 (1.00-1.35) 1.16 (0.99-1.35) Medium 224,722 178 79.2 (68.4-91.7) 1.52 (1.31-1.76)* 1.49 (1.29-1.73)* High 162,497 195 120.0 (104.3-138.1) 1.80 (1.56-2.07)* 1.75 (1.52-2.02)* Continuous 1.07 (1.05-1.08)* 1.07 (1.05-1.08)* Cumulative dose Low 296,014 187 63.2 (54.7-72.9) 1.19 (1.03-1.37)* 1.18 (1.02-1.36)* Medium 230,574 204 88.5 (77.1-101.5) 1.62 (1.41-1.86)* 1.59 (1.39-1.83)* High 143,846 149 103.6 (88.2-121.6) 1.73 (1.47-2.03)* 1.68 (1.43-1.97)* Continuous 1.03 (1.02-1.04)* 1.03 (1.02-1.04)* 6. Thiazolidinediones Never 51,871,508 14,982 28.9 (28.4-29.3) 1.00 1.00 Ever use 217,136 156 40.2 (27.9-57.8) 1.06 (0.73-1.52) 1.04 (0.72-1.50) Cumulative duration Low 76,357 54 70.7 (54.2-92.3) 1.56 (1.19-2.04)* 1.52 (1.16-1.98)* Medium 72,351 49 67.7 (51.2-89.6) 1.49 (1.12-1.97)* 1.43 (1.08-1.90)* High 68,428 53 77.5 (59.2-101.4) 1.48 (1.13-1.94)* 1.40 (1.07-1.83)* Continuous 1.08 (1.03-1.12)* 1.06 (1.02-1.11)* Cumulative dose Low 75,982 51 67.1 (51.0-88.3) 1.45 (1.11-1.91)* 1.41 (1.07-1.86)* 292 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 74,257 57 76.8 (59.2-99.5) 1.67 (1.29-2.16)* 1.60 (1.24-2.08)* High 66,897 48 71.8 (54.1-95.2) 1.41 (1.06-1.87)* 1.32 (1.00-1.76) Continuous 1.07 (1.03-1.11)* 1.06 (1.02-1.10)* 6.1. Pioglitazone Never 51,987,564 15,077 29.0 (28.5-29.5) 1.00 1.00 Ever use 101,080 61 36.2 (21.0-62.4) 0.88 (0.51-1.51) 0.85 (0.49-1.46) Cumulative duration Low 33,963 19 55.9 (35.7-87.7) 1.20 (0.77-1.89) 1.16 (0.74-1.82) Medium 34,409 22 63.9 (42.1-97.1) 1.39 (0.92-2.12) 1.33 (0.88-2.02) High 32,708 20 61.1 (39.4-94.8) 1.12 (0.72-1.73) 1.05 (0.68-1.63) Continuous 1.05 (0.99-1.11) 1.04 (0.98-1.10) Cumulative dose Low 33,724 19 56.3 (35.9-88.3) 1.20 (0.76-1.88) 1.16 (0.74-1.81) Medium 34,952 26 74.4 (50.6-109.3) 1.60 (1.09-2.34)* 1.52 (1.04-2.23)* High 32,404 16 49.4 (30.2-80.6) 0.93 (0.57-1.52) 0.87 (0.53-1.43) Continuous 1.04 (0.98-1.10) 1.03 (0.97-1.09) 6.2. Rosiglitazone Never 51,946,176 15,024 28.9 (28.5-29.4) 1.00 1.00 Ever use 142,468 114 42.4 (26.0-69.1) 1.22 (0.75-1.99) 1.22 (0.75-2.00) Cumulative duration Low 49,170 36 73.2 (52.8-101.5) 1.59 (1.14-2.20)* 1.54 (1.11-2.13)* Medium 48,028 39 81.2 (59.3-111.1) 1.78 (1.30-2.43)* 1.71 (1.25-2.34)* High 45,270 39 86.1 (62.9-117.9) 1.73 (1.26-2.36)* 1.63 (1.19-2.23)* Continuous 1.12 (1.06-1.18)* 1.10 (1.05-1.17)* Cumulative dose Low 49,567 39 78.7 (57.5-107.7) 1.70 (1.24-2.33)* 1.65 (1.20-2.25)* Medium 49,349 40 81.1 (59.5-110.5) 1.75 (1.29-2.39)* 1.69 (1.24-2.30)* High 43,552 35 80.4 (57.7-111.9) 1.63 (1.17-2.27)* 1.54 (1.10-2.14)* Continuous 1.11 (1.06-1.17)* 1.10 (1.05-1.16)* 7. Insulins and analogues Never 51,772,245 14,952 28.9 (28.4-29.3) 1.00 1.00 Ever use 316,399 186 67.6 (57.8-79.0) 1.50 (1.28-1.75)* 1.39 (1.19-1.63)* Cumulative duration Low 143,015 48 33.6 (25.3-44.5) 0.95 (0.72-1.26) 0.89 (0.67-1.19) Medium 113,499 82 72.2 (58.2-89.7) 1.54 (1.24-1.91)* 1.43 (1.15-1.78)* High 59,885 56 93.5 (72.0-121.5) 1.81 (1.39-2.35)* 1.67 (1.28-2.17)* Continuous 1.09 (1.06-1.12)* 1.08 (1.04-1.11)* Cumulative dose Low 146,186 51 34.9 (26.5-45.9) 0.95 (0.72-1.25) 0.90 (0.68-1.18) Medium 108,141 77 71.2 (57.0-89.0) 1.51 (1.21-1.89)* 1.40 (1.12-1.76)* High 62,072 58 93.4 (72.2-120.9) 1.91 (1.48-2.47)* 1.75 (1.35-2.27)* Continuous 1.03 (1.02-1.05)* 1.03 (1.02-1.04)* 7.1. Basal insulins Never 51,784,863 14,955 28.9 (28.4-29.3) 1.00 1.00 Ever use 303,781 183 69.1 (58.9-81.1) 1.54 (1.31-1.81)* 1.44 (1.22-1.69)* Cumulative duration Low 135,289 52 38.4 (29.3-50.4) 1.09 (0.83-1.43) 1.03 (0.78-1.35) Medium 109,417 77 70.4 (56.3-88.0) 1.51 (1.21-1.89)* 1.40 (1.12-1.76)* High 59,075 54 91.4 (70.0-119.4) 1.75 (1.34-2.29)* 1.62 (1.24-2.12)* Continuous 1.11 (1.07-1.14)* 1.09 (1.06-1.13)* Cumulative dose Low 136,909 51 37.3 (28.3-49.0) 1.03 (0.78-1.35) 0.97 (0.73-1.27) Medium 106,571 72 67.6 (53.6-85.1) 1.44 (1.14-1.82)* 1.34 (1.06-1.69)* High 60,301 60 99.5 (77.3-128.1) 2.02 (1.57-2.61)* 1.86 (1.44-2.40)* Continuous 1.04 (1.03-1.05)* 1.04 (1.02-1.05)* 7.2. Bolus insulins Never 51,947,122 15,063 29.0 (28.5-29.5) 1.00 1.00 Ever use 141,522 75 58.1 (43.9-76.9) 1.50 (1.13-1.98)* 1.37 (1.04-1.82)* Cumulative duration Low 68,567 21 30.6 (20.0-47.0) 0.94 (0.61-1.44) 0.88 (0.57-1.35) Medium 48,161 31 64.4 (45.3-91.5) 1.61 (1.14-2.30)* 1.48 (1.04-2.11)* High 24,794 23 92.8 (61.6-139.6) 2.13 (1.42-3.21)* 1.94 (1.29-2.92)* Continuous 1.12 (1.04-1.21)* 1.10 (1.02-1.19)* Cumulative dose Low 71,251 25 35.1 (23.7-51.9) 1.05 (0.71-1.55) 0.99 (0.67-1.46) 293 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 44,054 29 65.8 (45.7-94.7) 1.64 (1.14-2.36)* 1.51 (1.05-2.17)* High 26,217 21 80.1 (52.2-122.9) 1.93 (1.26-2.97)* 1.74 (1.14-2.68)* Continuous 1.05 (1.03-1.07)* 1.05 (1.02-1.07)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table displays associations between all diabetes medications and proximal colon cancer. For a summary of selected medications with significant associations, please refer to Table 6-8. * denotes p<0.05. 294 Supplementary Table C-7. Associations between all diabetes medications and the risk of colorectal cancer location subtype: distal colon Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 9,490 19.0 (18.6-19.3) 1.00 1.00 Ever use 2,021,426 881 44.8 (41.6-48.3) 1.36 (1.25-1.47)* 1.26 (1.16-1.36)* Cumulative duration Low 736,609 205 27.8 (24.3-31.9) 0.98 (0.85-1.12) 0.92 (0.80-1.06) Medium 720,912 333 46.2 (41.5-51.4) 1.42 (1.27-1.58)* 1.31 (1.18-1.46)* High 563,905 343 60.8 (54.7-67.6) 1.52 (1.36-1.69)* 1.41 (1.27-1.57)* Continuous 1.05 (1.04-1.06)* 1.04 (1.03-1.05)* Cumulative dose Low 761,186 230 30.2 (26.6-34.4) 1.01 (0.89-1.16) 0.96 (0.84-1.10) Medium 720,432 330 45.8 (41.1-51.0) 1.38 (1.23-1.54)* 1.28 (1.15-1.43)* High 539,808 321 59.5 (53.3-66.3) 1.57 (1.41-1.76)* 1.44 (1.29-1.62)* Continuous 1.05 (1.04-1.07)* 1.04 (1.03-1.06)* 2. Incretin-based medicines Never 51,846,234 10,294 19.9 (19.5-20.2) 1.00 1.00 Ever use 242,410 77 32.9 (25.3-42.7) 1.09 (0.83-1.41) 0.99 (0.76-1.28) Cumulative duration Low 76,647 23 30.0 (19.9-45.2) 1.07 (0.71-1.61) 0.98 (0.65-1.48) Medium 82,123 21 25.6 (16.7-39.2) 0.87 (0.56-1.33) 0.78 (0.51-1.20) High 83,640 33 39.5 (28.0-55.5) 1.14 (0.81-1.61) 1.05 (0.75-1.48) Continuous 0.99 (0.92-1.07) 0.97 (0.90-1.05) Cumulative dose Low 79,230 19 24.0 (15.3-37.6) 0.90 (0.57-1.41) 0.83 (0.53-1.30) Medium 80,356 26 32.4 (22.0-47.5) 1.07 (0.73-1.57) 0.97 (0.66-1.42) High 82,824 32 38.6 (27.3-54.6) 1.10 (0.78-1.56) 1.01 (0.71-1.43) Continuous 1.01 (0.93-1.09) 0.99 (0.91-1.07) 2.1. DPP-4 inhibitors Never 51,896,422 10,300 19.8 (19.5-20.2) 1.00 1.00 Ever use 192,222 71 36.3 (27.3-48.3) 1.11 (0.84-1.48) 1.01 (0.76-1.34) Cumulative duration Low 63,002 23 36.5 (24.3-54.9) 1.18 (0.79-1.78) 1.07 (0.71-1.62) Medium 63,244 19 30.0 (19.2-47.1) 0.95 (0.61-1.49) 0.86 (0.55-1.34) High 65,976 29 44.0 (30.5-63.3) 1.22 (0.85-1.76) 1.12 (0.78-1.62) Continuous 1.01 (0.93-1.09) 0.98 (0.91-1.07) Cumulative dose Low 64,188 24 37.4 (25.1-55.8) 1.21 (0.81-1.80) 1.10 (0.73-1.64) Medium 61,937 18 29.1 (18.3-46.1) 0.92 (0.58-1.46) 0.83 (0.52-1.31) High 66,097 29 43.9 (30.5-63.1) 1.22 (0.85-1.76) 1.12 (0.78-1.62) Continuous 1.01 (0.93-1.09) 0.99 (0.91-1.07) 2.1.1. Linagliptin Never 52,023,970 10,349 19.9 (19.5-20.3) 1.00 1.00 Ever use 64,674 22 40.2 (25.9-62.3) 1.11 (0.72-1.72) 1.03 (0.66-1.60) Cumulative duration Low 19,887 Suppressed 35.2 (16.8-73.8) 1.03 (0.49-2.16) 0.95 (0.45-1.99) Medium 21,325 Suppressed 32.8 (15.6-68.9) 0.93 (0.44-1.95) 0.86 (0.41-1.81) High 23,462 Suppressed 34.1 (17.1-68.2) 0.88 (0.44-1.75) 0.83 (0.42-1.67) Continuous 0.90 (0.73-1.11) 0.88 (0.71-1.10) Cumulative dose Low 19,952 Suppressed 35.1 (16.7-73.6) 1.02 (0.49-2.15) 0.95 (0.45-1.99) Medium 21,425 Suppressed 32.7 (15.6-68.5) 0.93 (0.44-1.94) 0.86 (0.41-1.80) High 23,297 Suppressed 34.3 (17.2-68.7) 0.89 (0.44-1.77) 0.84 (0.42-1.68) Continuous 0.90 (0.73-1.12) 0.88 (0.71-1.10) 2.1.2. Sitagliptin Never 51,955,454 10,326 19.9 (19.5-20.3) 1.00 1.00 Ever use 133,190 45 32.0 (20.8-49.0) 1.08 (0.70-1.65) 0.94 (0.61-1.45) Cumulative duration Low 42,249 14 33.1 (19.6-56.0) 1.07 (0.64-1.81) 0.98 (0.58-1.65) Medium 47,499 14 29.5 (17.5-49.8) 0.95 (0.56-1.61) 0.85 (0.50-1.43) High 43,442 17 39.1 (24.3-62.9) 1.13 (0.71-1.82) 1.02 (0.63-1.63) Continuous 1.00 (0.89-1.11) 0.97 (0.87-1.08) Cumulative dose Low 43,259 15 34.7 (20.9-57.5) 1.12 (0.68-1.86) 1.02 (0.61-1.69) 295 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 45,625 14 30.7 (18.2-51.8) 0.99 (0.58-1.67) 0.88 (0.52-1.49) High 44,306 16 36.1 (22.1-58.9) 1.05 (0.64-1.71) 0.94 (0.58-1.54) Continuous 1.00 (0.90-1.12) 0.98 (0.88-1.09) 2.2. GLP-1 receptor agonists Never 52,013,587 10,357 19.9 (19.5-20.3) 1.00 1.00 Ever use 75,057 14 19.4 (10.1-37.2) 0.82 (0.43-1.57) 0.76 (0.40-1.46) Cumulative duration Low 23,429 Suppressed 8.5 (2.1-34.1) 0.38 (0.10-1.51) 0.36 (0.09-1.43) Medium 25,502 Suppressed 27.4 (13.1-57.6) 1.20 (0.57-2.53) 1.12 (0.53-2.35) High 26,126 Suppressed 19.1 (8.0-46.0) 0.69 (0.29-1.66) 0.65 (0.27-1.56) Continuous 0.89 (0.69-1.15) 0.87 (0.67-1.13) Cumulative dose Low 23,693 Suppressed 12.7 (4.1-39.3) 0.55 (0.18-1.70) 0.52 (0.17-1.60) Medium 25,629 Suppressed 15.6 (5.9-41.6) 0.67 (0.25-1.77) 0.62 (0.23-1.65) High 25,735 Suppressed 27.2 (13.0-57.1) 1.03 (0.49-2.15) 0.97 (0.46-2.04) Continuous 0.90 (0.36-2.23) 0.84 (0.33-2.18) 3. SGLT-2 inhibitors Never 51,997,074 10,352 19.9 (19.5-20.3) 1.00 1.00 Ever use 91,570 19 16.5 (9.1-29.8) 0.60 (0.33-1.09) 0.54 (0.30-0.97)* Cumulative duration Low 26,625 Suppressed 15.0 (5.6-40.0) 0.53 (0.20-1.41) 0.49 (0.19-1.30) Medium 30,375 Suppressed 26.3 (13.2-52.7) 0.93 (0.47-1.87) 0.84 (0.42-1.68) High 34,570 Suppressed 20.2 (9.7-42.5) 0.69 (0.33-1.45) 0.63 (0.30-1.32) Continuous 0.94 (0.76-1.18) 0.91 (0.72-1.14) Cumulative dose Low 26,825 Suppressed 7.5 (1.9-29.8) 0.26 (0.07-1.03) 0.24 (0.06-0.94)* Medium 30,296 Suppressed 19.8 (8.9-44.1) 0.70 (0.31-1.55) 0.63 (0.28-1.41) High 34,449 11 31.9 (17.7-57.7) 1.11 (0.62-2.01) 1.01 (0.56-1.82) Continuous 0.98 (0.82-1.17) 0.95 (0.79-1.14) 4. AGIs (i.e., acarbose) Never 52,043,873 10,356 19.9 (19.5-20.3) 1.00 1.00 Ever use 44,771 15 38.3 (15.9-92.0) 1.15 (0.48-2.75) 1.09 (0.45-2.62) Cumulative duration Low 16,863 Suppressed 29.7 (12.3-71.2) 0.91 (0.38-2.18) 0.88 (0.37-2.12) Medium 15,151 Suppressed 33.0 (13.7-79.3) 0.95 (0.40-2.29) 0.91 (0.38-2.19) High 12,757 Suppressed 39.2 (16.3-94.2) 1.00 (0.42-2.41) 0.95 (0.39-2.27) Continuous 1.02 (0.88-1.18) 1.01 (0.87-1.17) Cumulative dose Low 15,946 Suppressed 31.4 (13.1-75.3) 0.95 (0.39-2.27) 0.93 (0.39-2.24) Medium 16,084 Suppressed 31.1 (12.9-74.7) 0.90 (0.38-2.17) 0.86 (0.36-2.06) High 12,741 Suppressed 39.2 (16.3-94.3) 1.02 (0.43-2.46) 0.95 (0.40-2.29) Continuous 0.96 (0.71-1.29) 0.94 (0.70-1.27) 5. Insulin secretagogues Never 51,176,005 9,951 19.4 (19.1-19.8) 1.00 1.00 Ever use 912,639 420 49.2 (43.8-55.3) 1.45 (1.28-1.63)* 1.34 (1.19-1.51)* Cumulative duration Low 360,923 127 35.2 (29.6-41.9) 1.12 (0.94-1.33) 1.05 (0.88-1.25) Medium 315,845 149 47.2 (40.2-55.4) 1.39 (1.18-1.63)* 1.28 (1.09-1.51)* High 235,871 144 61.1 (51.9-71.9) 1.49 (1.26-1.75)* 1.37 (1.16-1.62)* Continuous 1.04 (1.03-1.06)* 1.04 (1.02-1.05)* Cumulative dose Low 372,575 137 36.8 (31.1-43.5) 1.12 (0.95-1.32) 1.06 (0.89-1.25) Medium 314,231 155 49.3 (42.1-57.7) 1.42 (1.21-1.67)* 1.31 (1.12-1.54)* High 225,833 128 56.7 (47.7-67.4) 1.48 (1.24-1.76)* 1.36 (1.14-1.62)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.02)* 5.1. Meglitinides Never 52,048,818 10,354 19.9 (19.5-20.3) 1.00 1.00 Ever use 39,826 17 51.4 (24.5-107.9) 1.60 (0.77-3.35) 1.52 (0.73-3.18) Cumulative duration Low 12,831 Suppressed 31.2 (11.7-83.1) 0.93 (0.35-2.47) 0.89 (0.33-2.37) Medium 13,013 Suppressed 53.8 (25.6-112.8) 1.67 (0.80-3.50) 1.59 (0.76-3.32) High 13,982 Suppressed 42.9 (19.3-95.5) 1.16 (0.52-2.57) 1.08 (0.49-2.41) Continuous 1.04 (0.92-1.18) 1.03 (0.91-1.16) Cumulative dose Low 13,858 Suppressed 36.1 (15.0-86.7) 1.04 (0.43-2.51) 1.01 (0.42-2.42) 296 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 13,470 Suppressed 37.1 (15.4-89.2) 1.12 (0.47-2.69) 1.06 (0.44-2.56) High 12,498 Suppressed 56.0 (26.7-117.5) 1.58 (0.75-3.30) 1.46 (0.70-3.06) Continuous 1.04 (0.96-1.13) 1.03 (0.95-1.12) 5.1.1. Repaglinide Never 52,049,428 10,355 19.9 (19.5-20.3) 1.00 1.00 Ever use 39,216 16 51.9 (24.8-108.9) 1.62 (0.77-3.38) 1.53 (0.73-3.21) Cumulative duration Low 12,566 Suppressed 31.8 (11.9-84.8) 0.95 (0.36-2.52) 0.91 (0.34-2.42) Medium 12,873 Suppressed 46.6 (20.9-103.7) 1.43 (0.65-3.19) 1.37 (0.61-3.04) High 13,777 Suppressed 43.6 (19.6-96.9) 1.17 (0.53-2.61) 1.10 (0.49-2.44) Continuous 1.04 (0.92-1.18) 1.03 (0.91-1.17) Cumulative dose Low 13,676 Suppressed 36.6 (15.2-87.8) 1.06 (0.44-2.54) 1.02 (0.43-2.45) Medium 13,159 Suppressed 30.4 (11.4-81.0) 0.91 (0.34-2.43) 0.87 (0.33-2.31) High 12,381 Suppressed 56.5 (27.0-118.6) 1.60 (0.76-3.34) 1.48 (0.71-3.09) Continuous 1.04 (0.95-1.13) 1.03 (0.95-1.12) 5.2. Sulfonylureas Never 51,188,413 9,954 19.4 (19.1-19.8) 1.00 1.00 Ever use 900,231 417 49.4 (43.9-55.6) 1.45 (1.29-1.64)* 1.34 (1.19-1.51)* Cumulative duration Low 359,009 130 36.2 (30.5-43.0) 1.15 (0.96-1.36) 1.08 (0.91-1.28) Medium 309,407 146 47.2 (40.1-55.5) 1.39 (1.18-1.63)* 1.28 (1.09-1.51)* High 231,815 141 60.8 (51.6-71.7) 1.48 (1.25-1.75)* 1.37 (1.16-1.61)* Continuous 1.05 (1.03-1.06)* 1.04 (1.02-1.05)* Cumulative dose Low 367,838 138 37.5 (31.8-44.3) 1.14 (0.96-1.35) 1.08 (0.91-1.27) Medium 309,412 153 49.4 (42.2-57.9) 1.43 (1.22-1.67)* 1.31 (1.12-1.54)* High 222,981 126 56.5 (47.5-67.3) 1.47 (1.24-1.76)* 1.35 (1.13-1.61)* Continuous 1.02 (1.01-1.02)* 1.01 (1.00-1.02)* 5.2.1. Gliclazide Never 51,695,028 10,179 19.7 (19.3-20.1) 1.00 1.00 Ever use 393,616 192 54.0 (45.7-63.8) 1.54 (1.30-1.82)* 1.40 (1.19-1.66)* Cumulative duration Low 126,908 54 42.6 (32.6-55.6) 1.30 (1.00-1.70) 1.20 (0.92-1.57) Medium 136,638 59 43.2 (33.5-55.7) 1.26 (0.98-1.63) 1.15 (0.89-1.48) High 130,070 79 60.7 (48.7-75.7) 1.54 (1.24-1.93)* 1.43 (1.14-1.78)* Continuous 1.06 (1.03-1.09)* 1.05 (1.02-1.08)* Cumulative dose Low 133,699 52 38.9 (29.6-51.0) 1.17 (0.89-1.53) 1.08 (0.82-1.42) Medium 136,394 67 49.1 (38.7-62.4) 1.40 (1.10-1.78)* 1.28 (1.01-1.63)* High 123,523 73 59.1 (47.0-74.3) 1.55 (1.23-1.95)* 1.43 (1.13-1.80)* Continuous 1.01 (1.00-1.03)* 1.01 (1.00-1.02) 5.2.2. Glyburide Never 51,418,210 10,065 19.6 (19.2-20.0) 1.00 1.00 Ever use 670,434 306 47.5 (40.5-55.8) 1.42 (1.21-1.67)* 1.33 (1.13-1.57)* Cumulative duration Low 283,215 114 40.3 (33.5-48.4) 1.22 (1.01-1.47)* 1.16 (0.96-1.39) Medium 224,722 93 41.4 (33.8-50.7) 1.20 (0.98-1.48) 1.12 (0.91-1.38) High 162,497 99 60.9 (50.0-74.2) 1.48 (1.21-1.80)* 1.36 (1.12-1.66)* Continuous 1.05 (1.03-1.07)* 1.04 (1.02-1.06)* Cumulative dose Low 296,014 117 39.5 (33.0-47.4) 1.16 (0.96-1.39) 1.10 (0.92-1.32) Medium 230,574 108 46.8 (38.8-56.6) 1.33 (1.10-1.61)* 1.24 (1.02-1.49)* High 143,846 81 56.3 (45.3-70.0) 1.47 (1.18-1.82)* 1.34 (1.08-1.67)* Continuous 1.02 (1.01-1.03)* 1.02 (1.00-1.03)* 6. Thiazolidinediones Never 51,871,508 10,283 19.8 (19.4-20.2) 1.00 1.00 Ever use 217,136 88 38.8 (26.8-56.2) 1.41 (0.97-2.04) 1.30 (0.90-1.88) Cumulative duration Low 76,357 27 35.4 (24.2-51.6) 1.14 (0.78-1.66) 1.06 (0.73-1.55) Medium 72,351 27 37.3 (25.6-54.4) 1.18 (0.81-1.73) 1.09 (0.75-1.59) High 68,428 34 49.7 (35.5-69.5) 1.40 (1.00-1.96)* 1.27 (0.90-1.77) Continuous 1.04 (0.99-1.10) 1.03 (0.97-1.08) Cumulative dose Low 75,982 30 39.5 (27.6-56.5) 1.25 (0.88-1.79) 1.17 (0.82-1.68) 297 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 74,257 28 37.7 (26.0-54.6) 1.19 (0.82-1.72) 1.10 (0.76-1.59) High 66,897 30 44.8 (31.4-64.1) 1.28 (0.90-1.84) 1.15 (0.81-1.65) Continuous 1.05 (0.99-1.10) 1.03 (0.98-1.08) 6.1. Pioglitazone Never 51,987,564 10,334 19.9 (19.5-20.3) 1.00 1.00 Ever use 101,080 37 47.4 (29.5-76.2) 1.61 (1.00-2.59)* 1.47 (0.91-2.36) Cumulative duration Low 33,963 11 32.4 (17.9-58.5) 1.02 (0.56-1.84) 0.95 (0.53-1.71) Medium 34,409 12 34.9 (19.8-61.4) 1.09 (0.62-1.92) 1.00 (0.57-1.76) High 32,708 14 42.8 (25.3-72.3) 1.17 (0.69-1.97) 1.06 (0.63-1.79) Continuous 0.99 (0.90-1.09) 0.97 (0.88-1.07) Cumulative dose Low 33,724 Suppressed 26.7 (13.9-51.3) 0.83 (0.43-1.60) 0.78 (0.41-1.50) Medium 34,952 16 45.8 (28.0-74.7) 1.41 (0.87-2.31) 1.30 (0.79-2.12) High 32,404 12 37.0 (21.0-65.2) 1.03 (0.58-1.81) 0.93 (0.53-1.63) Continuous 0.99 (0.91-1.09) 0.97 (0.89-1.07) 6.2. Rosiglitazone Never 51,946,176 10,310 19.8 (19.5-20.2) 1.00 1.00 Ever use 142,468 61 31.8 (18.0-55.9) 1.23 (0.70-2.17) 1.16 (0.66-2.04) Cumulative duration Low 49,170 17 34.6 (21.5-55.6) 1.09 (0.68-1.76) 1.02 (0.63-1.64) Medium 48,028 21 43.7 (28.5-67.1) 1.39 (0.90-2.12) 1.28 (0.84-1.97) High 45,270 23 50.8 (33.8-76.5) 1.49 (0.99-2.23) 1.34 (0.89-2.02) Continuous 1.10 (1.02-1.17)* 1.08 (1.00-1.15)* Cumulative dose Low 49,567 17 34.3 (21.3-55.2) 1.08 (0.67-1.74) 1.01 (0.63-1.63) Medium 49,349 19 38.5 (24.6-60.4) 1.21 (0.77-1.89) 1.12 (0.71-1.75) High 43,552 25 57.4 (38.8-85.0) 1.69 (1.14-2.50)* 1.52 (1.03-2.25)* Continuous 1.10 (1.03-1.17)* 1.08 (1.01-1.15)* 7. Insulins and analogues Never 51,772,245 10,267 19.8 (19.5-20.2) 1.00 1.00 Ever use 316,399 104 35.9 (29.0-44.6) 1.15 (0.93-1.43) 1.05 (0.85-1.31) Cumulative duration Low 143,015 25 17.5 (11.8-25.9) 0.72 (0.48-1.06) 0.66 (0.45-0.98)* Medium 113,499 46 40.5 (30.4-54.1) 1.27 (0.95-1.69) 1.15 (0.86-1.54) High 59,885 33 55.1 (39.2-77.5) 1.57 (1.12-2.21)* 1.44 (1.03-2.03)* Continuous 1.06 (1.02-1.10)* 1.05 (1.00-1.09)* Cumulative dose Low 146,186 29 19.8 (13.8-28.5) 0.79 (0.55-1.14) 0.73 (0.51-1.06) Medium 108,141 41 37.9 (27.9-51.5) 1.18 (0.87-1.61) 1.08 (0.79-1.46) High 62,072 34 54.8 (39.1-76.7) 1.61 (1.15-2.25)* 1.47 (1.05-2.06)* Continuous 1.03 (1.01-1.04)* 1.02 (1.01-1.04)* 7.1. Basal insulins Never 51,784,863 10,269 19.8 (19.5-20.2) 1.00 1.00 Ever use 303,781 102 36.9 (29.6-45.9) 1.19 (0.95-1.48) 1.08 (0.87-1.35) Cumulative duration Low 135,289 28 20.7 (14.3-30.0) 0.85 (0.58-1.23) 0.78 (0.54-1.13) Medium 109,417 40 36.6 (26.8-49.8) 1.15 (0.84-1.57) 1.04 (0.76-1.42) High 59,075 34 57.6 (41.1-80.5) 1.62 (1.16-2.27)* 1.49 (1.06-2.08)* Continuous 1.07 (1.02-1.12)* 1.05 (1.00-1.10)* Cumulative dose Low 136,909 30 21.9 (15.3-31.3) 0.88 (0.61-1.25) 0.81 (0.57-1.16) Medium 106,571 41 38.5 (28.3-52.2) 1.20 (0.89-1.63) 1.10 (0.81-1.49) High 60,301 31 51.4 (36.2-73.1) 1.51 (1.06-2.14)* 1.37 (0.96-1.94) Continuous 1.03 (1.01-1.05)* 1.03 (1.01-1.05)* 7.2. Bolus insulins Never 51,947,122 10,314 19.9 (19.5-20.2) 1.00 1.00 Ever use 141,522 57 51.0 (37.8-68.8) 1.84 (1.36-2.48)* 1.67 (1.24-2.25)* Cumulative duration Low 68,567 16 23.3 (14.3-38.1) 1.05 (0.64-1.72) 0.98 (0.60-1.60) Medium 48,161 25 51.9 (35.1-76.8) 1.83 (1.24-2.71)* 1.66 (1.12-2.46)* High 24,794 16 64.5 (39.5-105.3) 2.07 (1.27-3.37)* 1.88 (1.15-3.07)* Continuous 1.14 (1.05-1.23)* 1.12 (1.03-1.22)* Cumulative dose Low 71,251 17 23.9 (14.8-38.4) 1.05 (0.66-1.70) 0.98 (0.61-1.58) 298 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 44,054 21 47.7 (31.1-73.1) 1.67 (1.09-2.57)* 1.52 (0.99-2.34) High 26,217 19 72.5 (46.2-113.6) 2.41 (1.54-3.77)* 2.16 (1.38-3.39)* Continuous 1.05 (1.03-1.08)* 1.05 (1.02-1.08)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table displays associations between all diabetes medications and distal colon cancer. For a summary of selected medications with significant associations, please refer to Table 6-9. * denotes p<0.05. 299 Supplementary Table C-8. Associations between all diabetes medications and the risk of colorectal cancer location subtype: rectum Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 13,125 26.2 (25.8-26.7) 1.00 1.00 Ever use 2,021,426 1,101 55.5 (51.9-59.4) 1.25 (1.17-1.34)* 1.15 (1.07-1.23)* Cumulative duration Low 736,609 252 34.2 (30.2-38.7) 0.89 (0.78-1.00) 0.83 (0.74-0.94)* Medium 720,912 416 57.7 (52.4-63.5) 1.32 (1.19-1.45)* 1.21 (1.09-1.33)* High 563,905 433 76.8 (69.9-84.4) 1.46 (1.32-1.60)* 1.35 (1.23-1.49)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.04)* Cumulative dose Low 761,186 273 35.9 (31.9-40.4) 0.89 (0.79-1.01) 0.85 (0.75-0.95)* Medium 720,432 406 56.4 (51.1-62.1) 1.26 (1.14-1.40)* 1.17 (1.06-1.29)* High 539,808 422 78.2 (71.1-86.0) 1.56 (1.41-1.72)* 1.42 (1.29-1.56)* Continuous 1.05 (1.04-1.06)* 1.04 (1.03-1.05)* 2. Incretin-based medicines Never 51,846,234 14,132 27.3 (26.8-27.7) 1.00 1.00 Ever use 242,410 94 35.8 (27.8-46.0) 0.86 (0.67-1.11) 0.79 (0.61-1.02) Cumulative duration Low 76,647 31 40.4 (28.4-57.5) 1.06 (0.74-1.50) 0.97 (0.68-1.38) Medium 82,123 27 32.9 (22.5-47.9) 0.81 (0.56-1.19) 0.74 (0.51-1.08) High 83,640 36 43.0 (31.0-59.7) 0.93 (0.67-1.28) 0.86 (0.62-1.19) Continuous 0.97 (0.90-1.03) 0.95 (0.88-1.02) Cumulative dose Low 79,230 29 36.6 (25.4-52.7) 0.99 (0.69-1.43) 0.92 (0.64-1.33) Medium 80,356 32 39.8 (28.2-56.3) 0.96 (0.68-1.36) 0.87 (0.62-1.24) High 82,824 33 39.8 (28.3-56.0) 0.85 (0.60-1.19) 0.78 (0.55-1.09) Continuous 0.96 (0.89-1.04) 0.94 (0.87-1.02) 2.1. DPP-4 inhibitors Never 51,896,422 14,144 27.3 (26.8-27.7) 1.00 1.00 Ever use 192,222 82 39.4 (29.9-51.8) 0.90 (0.68-1.18) 0.81 (0.61-1.07) Cumulative duration Low 63,002 28 44.4 (30.7-64.4) 1.06 (0.73-1.54) 0.96 (0.66-1.39) Medium 63,244 23 36.4 (24.2-54.7) 0.85 (0.56-1.28) 0.76 (0.51-1.14) High 65,976 31 47.0 (33.0-66.8) 0.98 (0.69-1.39) 0.90 (0.63-1.28) Continuous 0.97 (0.90-1.04) 0.95 (0.88-1.02) Cumulative dose Low 64,188 28 43.6 (30.1-63.2) 1.04 (0.72-1.51) 0.94 (0.65-1.36) Medium 61,937 24 38.7 (26.0-57.8) 0.91 (0.61-1.35) 0.81 (0.54-1.21) High 66,097 30 45.4 (31.7-64.9) 0.95 (0.66-1.35) 0.87 (0.61-1.24) Continuous 0.97 (0.90-1.04) 0.95 (0.88-1.02) 2.1.1. Linagliptin Never 52,023,970 14,201 27.3 (26.9-27.7) 1.00 1.00 Ever use 64,674 25 40.2 (25.9-62.3) 0.83 (0.54-1.29) 0.78 (0.50-1.21) Cumulative duration Low 19,887 Suppressed 45.3 (23.5-87.0) 0.99 (0.51-1.90) 0.91 (0.48-1.75) Medium 21,325 Suppressed 28.1 (12.6-62.6) 0.60 (0.27-1.33) 0.56 (0.25-1.24) High 23,462 10 42.6 (22.9-79.2) 0.83 (0.45-1.54) 0.80 (0.43-1.49) Continuous 0.94 (0.79-1.12) 0.92 (0.78-1.10) Cumulative dose Low 19,952 Suppressed 45.1 (23.5-86.7) 0.98 (0.51-1.89) 0.91 (0.47-1.75) Medium 21,425 Suppressed 28.0 (12.6-62.3) 0.60 (0.27-1.33) 0.56 (0.25-1.23) High 23,297 10 42.9 (23.1-79.8) 0.83 (0.45-1.55) 0.80 (0.43-1.50) Continuous 0.94 (0.79-1.12) 0.93 (0.78-1.10) 2.1.2. Sitagliptin Never 51,955,454 14,167 27.3 (26.8-27.7) 1.00 1.00 Ever use 133,190 59 39.6 (26.9-58.1) 0.97 (0.66-1.43) 0.85 (0.58-1.25) Cumulative duration Low 42,249 20 47.3 (30.5-73.4) 1.14 (0.73-1.76) 1.03 (0.66-1.60) Medium 47,499 18 37.9 (23.9-60.1) 0.90 (0.57-1.43) 0.80 (0.50-1.27) High 43,442 21 48.3 (31.5-74.1) 1.03 (0.67-1.59) 0.93 (0.61-1.43) Continuous 0.98 (0.89-1.08) 0.95 (0.86-1.05) Cumulative dose Low 43,259 20 46.2 (29.8-71.7) 1.10 (0.71-1.71) 1.00 (0.65-1.56) 300 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 45,625 19 41.6 (26.6-65.3) 0.99 (0.63-1.55) 0.88 (0.56-1.38) High 44,306 20 45.1 (29.1-70.0) 0.97 (0.63-1.50) 0.87 (0.56-1.35) Continuous 0.98 (0.89-1.08) 0.95 (0.86-1.05) 2.2. GLP-1 receptor agonists Never 52,013,587 14,204 27.3 (26.9-27.8) 1.00 1.00 Ever use 75,057 22 28.0 (16.2-48.1) 0.84 (0.49-1.44) 0.79 (0.46-1.36) Cumulative duration Low 23,429 Suppressed 17.1 (6.4-45.5) 0.54 (0.21-1.44) 0.53 (0.20-1.39) Medium 25,502 Suppressed 31.4 (15.7-62.7) 0.97 (0.49-1.94) 0.92 (0.46-1.84) High 26,126 10 38.3 (20.6-71.1) 0.99 (0.53-1.84) 0.95 (0.51-1.77) Continuous 0.96 (0.79-1.15) 0.94 (0.78-1.14) Cumulative dose Low 23,693 Suppressed 21.1 (8.8-50.7) 0.65 (0.27-1.55) 0.62 (0.26-1.48) Medium 25,629 Suppressed 31.2 (15.6-62.4) 0.94 (0.47-1.88) 0.89 (0.45-1.78) High 25,735 Suppressed 35.0 (18.2-67.2) 0.94 (0.49-1.81) 0.92 (0.48-1.76) Continuous 0.70 (0.27-1.84) 0.68 (0.26-1.81) 3. SGLT-2 inhibitors Never 51,997,074 14,196 27.3 (26.9-27.8) 1.00 1.00 Ever use 91,570 30 27.0 (17.0-42.9) 0.70 (0.44-1.12) 0.62 (0.39-0.99)* Cumulative duration Low 26,625 Suppressed 11.3 (3.6-34.9) 0.29 (0.09-0.89)* 0.27 (0.09-0.82)* Medium 30,375 14 46.1 (27.3-77.8) 1.18 (0.70-1.99) 1.06 (0.63-1.79) High 34,570 13 37.6 (21.8-64.8) 0.93 (0.54-1.60) 0.85 (0.49-1.46) Continuous 1.00 (0.84-1.19) 0.96 (0.81-1.15) Cumulative dose Low 26,825 Suppressed 18.6 (7.8-44.8) 0.47 (0.19-1.12) 0.43 (0.18-1.03) Medium 30,296 10 33.0 (17.8-61.3) 0.84 (0.45-1.56) 0.76 (0.41-1.41) High 34,449 15 43.5 (26.3-72.2) 1.10 (0.66-1.82) 0.99 (0.60-1.65) Continuous 0.96 (0.82-1.13) 0.93 (0.79-1.09) 4. AGIs (i.e., acarbose) Never 52,043,873 14,207 27.3 (26.9-27.8) 1.00 1.00 Ever use 44,771 19 38.3 (15.9-92.0) 0.87 (0.36-2.07) 0.82 (0.34-1.97) Cumulative duration Low 16,863 Suppressed 29.7 (12.3-71.2) 0.68 (0.28-1.63) 0.67 (0.28-1.61) Medium 15,151 Suppressed 46.2 (22.0-96.9) 1.00 (0.48-2.10) 0.97 (0.46-2.03) High 12,757 Suppressed 54.9 (26.2-115.1) 1.07 (0.51-2.25) 1.01 (0.48-2.12) Continuous 0.96 (0.81-1.13) 0.95 (0.80-1.12) Cumulative dose Low 15,946 Suppressed 43.9 (20.9-92.1) 0.99 (0.47-2.07) 0.99 (0.47-2.08) Medium 16,084 Suppressed 31.1 (12.9-74.7) 0.68 (0.28-1.63) 0.65 (0.27-1.56) High 12,741 Suppressed 54.9 (26.2-115.2) 1.09 (0.52-2.28) 1.02 (0.49-2.14) Continuous 0.97 (0.75-1.24) 0.94 (0.73-1.23) 5. Insulin secretagogues Never 51,176,005 13,661 26.7 (26.3-27.1) 1.00 1.00 Ever use 912,639 565 61.8 (55.7-68.6) 1.36 (1.23-1.52)* 1.25 (1.12-1.38)* Cumulative duration Low 360,923 171 47.4 (40.8-55.0) 1.12 (0.97-1.31) 1.05 (0.90-1.22) Medium 315,845 212 67.1 (58.7-76.8) 1.48 (1.29-1.70)* 1.35 (1.18-1.55)* High 235,871 182 77.2 (66.7-89.2) 1.44 (1.24-1.67)* 1.32 (1.14-1.53)* Continuous 1.05 (1.03-1.06)* 1.04 (1.02-1.05)* Cumulative dose Low 372,575 186 49.9 (43.2-57.6) 1.14 (0.99-1.32) 1.07 (0.92-1.23) Medium 314,231 216 68.7 (60.2-78.5) 1.49 (1.31-1.71)* 1.36 (1.19-1.56)* High 225,833 163 72.2 (61.9-84.2) 1.43 (1.23-1.67)* 1.30 (1.12-1.52)* Continuous 1.02 (1.01-1.02)* 1.01 (1.01-1.02)* 5.1. Meglitinides Never 52,048,818 14,206 27.3 (26.8-27.7) 1.00 1.00 Ever use 39,826 20 44.1 (19.8-98.1) 1.00 (0.45-2.24) 0.94 (0.42-2.09) Cumulative duration Low 12,831 Suppressed 31.2 (11.7-83.1) 0.70 (0.26-1.85) 0.66 (0.25-1.77) Medium 13,013 Suppressed 69.2 (36.0-132.9) 1.60 (0.83-3.06) 1.49 (0.78-2.86) High 13,982 Suppressed 50.1 (23.9-105.0) 1.02 (0.49-2.14) 0.93 (0.44-1.95) Continuous 1.03 (0.92-1.15) 1.02 (0.91-1.14) Cumulative dose Low 13,858 Suppressed 43.3 (19.5-96.4) 0.94 (0.42-2.09) 0.90 (0.41-2.01) 301 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 13,470 Suppressed 66.8 (34.8-128.4) 1.51 (0.79-2.90) 1.41 (0.73-2.71) High 12,498 Suppressed 40.0 (16.7-96.1) 0.84 (0.35-2.02) 0.76 (0.32-1.82) Continuous 0.94 (0.80-1.11) 0.92 (0.77-1.09) 5.1.1. Repaglinide Never 52,049,428 14,206 27.3 (26.8-27.7) 1.00 1.00 Ever use 39,216 20 44.5 (20.0-99.1) 1.03 (0.46-2.29) 0.95 (0.43-2.11) Cumulative duration Low 12,566 Suppressed 31.8 (11.9-84.8) 0.71 (0.27-1.89) 0.68 (0.25-1.80) Medium 12,873 Suppressed 69.9 (36.4-134.4) 1.61 (0.84-3.09) 1.51 (0.79-2.89) High 13,777 Suppressed 50.8 (24.2-106.6) 1.03 (0.49-2.17) 0.94 (0.45-1.97) Continuous 1.03 (0.93-1.15) 1.02 (0.91-1.14) Cumulative dose Low 13,676 Suppressed 43.9 (19.7-97.7) 0.95 (0.43-2.12) 0.92 (0.41-2.04) Medium 13,159 Suppressed 68.4 (35.6-131.4) 1.54 (0.80-2.96) 1.44 (0.75-2.76) High 12,381 Suppressed 40.4 (16.8-97.0) 0.85 (0.35-2.04) 0.76 (0.32-1.84) Continuous 0.94 (0.80-1.11) 0.92 (0.78-1.09) 5.2. Sulfonylureas Never 51,188,413 13,666 26.7 (26.3-27.1) 1.00 1.00 Ever use 900,231 560 62.1 (55.9-68.9) 1.37 (1.23-1.52)* 1.25 (1.12-1.39)* Cumulative duration Low 359,009 173 48.2 (41.5-55.9) 1.14 (0.98-1.33) 1.06 (0.91-1.23) Medium 309,407 207 66.9 (58.4-76.7) 1.48 (1.29-1.69)* 1.34 (1.17-1.54)* High 231,815 180 77.6 (67.1-89.9) 1.45 (1.25-1.68)* 1.33 (1.15-1.54)* Continuous 1.05 (1.03-1.06)* 1.04 (1.02-1.05)* Cumulative dose Low 367,838 184 50.0 (43.3-57.8) 1.14 (0.99-1.32) 1.07 (0.92-1.23) Medium 309,412 213 68.8 (60.2-78.7) 1.50 (1.31-1.71)* 1.36 (1.19-1.56)* High 222,981 163 73.1 (62.7-85.2) 1.45 (1.24-1.69)* 1.32 (1.13-1.54)* Continuous 1.02 (1.01-1.03)* 1.01 (1.01-1.02)* 5.2.1. Gliclazide Never 51,695,028 13,977 27.0 (26.6-27.5) 1.00 1.00 Ever use 393,616 249 66.8 (57.5-77.6) 1.44 (1.24-1.67)* 1.31 (1.12-1.52)* Cumulative duration Low 126,908 67 52.8 (41.6-67.1) 1.21 (0.95-1.54) 1.12 (0.88-1.42) Medium 136,638 79 57.8 (46.4-72.1) 1.27 (1.02-1.58)* 1.15 (0.92-1.43) High 130,070 103 79.2 (65.3-96.1) 1.53 (1.26-1.86)* 1.42 (1.17-1.72)* Continuous 1.07 (1.04-1.09)* 1.05 (1.03-1.08)* Cumulative dose Low 133,699 74 55.3 (44.1-69.5) 1.25 (0.99-1.57) 1.15 (0.91-1.44) Medium 136,394 84 61.6 (49.7-76.3) 1.32 (1.07-1.64)* 1.20 (0.97-1.49) High 123,523 91 73.7 (60.0-90.5) 1.47 (1.20-1.80)* 1.35 (1.10-1.66)* Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.02)* 5.2.2. Glyburide Never 51,418,210 13,806 26.9 (26.4-27.3) 1.00 1.00 Ever use 670,434 420 57.8 (49.9-66.9) 1.29 (1.12-1.50)* 1.19 (1.03-1.38)* Cumulative duration Low 283,215 153 54.0 (46.1-63.3) 1.23 (1.05-1.44)* 1.16 (0.99-1.36) Medium 224,722 136 60.5 (51.2-71.6) 1.33 (1.12-1.57)* 1.21 (1.02-1.44)* High 162,497 131 80.6 (67.9-95.7) 1.50 (1.27-1.79)* 1.36 (1.15-1.62)* Continuous 1.05 (1.03-1.07)* 1.03 (1.02-1.05)* Cumulative dose Low 296,014 163 55.1 (47.2-64.2) 1.22 (1.04-1.42)* 1.15 (0.98-1.34) Medium 230,574 156 67.7 (57.8-79.2) 1.45 (1.24-1.70)* 1.33 (1.13-1.56)* High 143,846 101 70.2 (57.8-85.3) 1.39 (1.14-1.69)* 1.25 (1.03-1.52)* Continuous 1.02 (1.01-1.04)* 1.02 (1.01-1.03)* 6. Thiazolidinediones Never 51,871,508 14,096 27.2 (26.7-27.6) 1.00 1.00 Ever use 217,136 130 54.0 (39.5-73.9) 1.43 (1.04-1.95)* 1.30 (0.95-1.78) Cumulative duration Low 76,357 26 34.1 (23.2-50.0) 0.81 (0.55-1.19) 0.75 (0.51-1.11) Medium 72,351 42 58.1 (42.9-78.6) 1.36 (1.01-1.84)* 1.25 (0.92-1.69) High 68,428 62 90.6 (70.6-116.2) 1.91 (1.49-2.45)* 1.71 (1.33-2.19)* Continuous 1.10 (1.06-1.14)* 1.08 (1.04-1.12)* Cumulative dose Low 75,982 26 34.2 (23.3-50.3) 0.81 (0.55-1.19) 0.75 (0.51-1.11) 302 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 74,257 44 59.3 (44.1-79.6) 1.38 (1.03-1.86)* 1.27 (0.95-1.71) High 66,897 60 89.7 (69.6-115.5) 1.91 (1.48-2.46)* 1.70 (1.32-2.19)* Continuous 1.09 (1.05-1.13)* 1.07 (1.03-1.11)* 6.1. Pioglitazone Never 51,987,564 14,162 27.2 (26.8-27.7) 1.00 1.00 Ever use 101,080 64 75.3 (51.6-109.7) 1.86 (1.28-2.72)* 1.68 (1.15-2.45)* Cumulative duration Low 33,963 14 41.2 (24.4-69.6) 0.96 (0.57-1.62) 0.90 (0.53-1.51) Medium 34,409 20 58.1 (37.5-90.1) 1.35 (0.87-2.09) 1.23 (0.79-1.90) High 32,708 30 91.7 (64.1-131.2) 1.88 (1.31-2.69)* 1.69 (1.18-2.41)* Continuous 1.10 (1.04-1.16)* 1.08 (1.02-1.14)* Cumulative dose Low 33,724 14 41.5 (24.6-70.1) 0.96 (0.57-1.63) 0.90 (0.53-1.52) Medium 34,952 16 45.8 (28.0-74.7) 1.05 (0.64-1.71) 0.96 (0.59-1.56) High 32,404 34 104.9 (75.0-146.8) 2.19 (1.56-3.06)* 1.95 (1.39-2.73)* Continuous 1.09 (1.04-1.15)* 1.07 (1.02-1.13)* 6.2. Rosiglitazone Never 51,946,176 14,138 27.2 (26.8-27.7) 1.00 1.00 Ever use 142,468 88 34.4 (20.0-59.3) 0.97 (0.56-1.66) 0.89 (0.52-1.54) Cumulative duration Low 49,170 25 50.8 (34.4-75.2) 1.19 (0.81-1.77) 1.11 (0.75-1.64) Medium 48,028 23 47.9 (31.8-72.1) 1.12 (0.75-1.69) 1.03 (0.69-1.56) High 45,270 40 88.4 (64.8-120.5) 1.91 (1.40-2.61)* 1.71 (1.26-2.34)* Continuous 1.11 (1.05-1.18)* 1.09 (1.03-1.16)* Cumulative dose Low 49,567 24 48.4 (32.5-72.2) 1.14 (0.76-1.70) 1.06 (0.71-1.58) Medium 49,349 27 54.7 (37.5-79.8) 1.27 (0.87-1.85) 1.17 (0.80-1.71) High 43,552 37 85.0 (61.6-117.3) 1.85 (1.34-2.56)* 1.65 (1.20-2.28)* Continuous 1.10 (1.04-1.16)* 1.08 (1.02-1.14)* 7. Insulins and analogues Never 51,772,245 14,071 27.2 (26.7-27.6) 1.00 1.00 Ever use 316,399 155 53.3 (44.6-63.6) 1.27 (1.06-1.52)* 1.13 (0.95-1.36) Cumulative duration Low 143,015 43 30.1 (22.3-40.5) 0.90 (0.67-1.22) 0.82 (0.61-1.11) Medium 113,499 70 61.7 (48.8-78.0) 1.43 (1.13-1.81)* 1.28 (1.01-1.62)* High 59,885 42 70.1 (51.8-94.9) 1.49 (1.10-2.01)* 1.36 (1.00-1.83)* Continuous 1.05 (1.01-1.09)* 1.03 (1.00-1.07) Cumulative dose Low 146,186 45 30.8 (23.0-41.2) 0.91 (0.68-1.21) 0.83 (0.62-1.11) Medium 108,141 66 61.0 (47.9-77.7) 1.42 (1.11-1.80)* 1.27 (1.00-1.62) High 62,072 44 70.9 (52.8-95.3) 1.55 (1.16-2.09)* 1.39 (1.03-1.87)* Continuous 1.02 (1.01-1.04)* 1.02 (1.00-1.03) 7.1. Basal insulins Never 51,784,863 14,074 27.2 (26.7-27.6) 1.00 1.00 Ever use 303,781 152 53.0 (44.2-63.6) 1.27 (1.05-1.52)* 1.13 (0.94-1.36) Cumulative duration Low 135,289 44 32.5 (24.2-43.7) 0.98 (0.73-1.31) 0.89 (0.66-1.19) Medium 109,417 71 64.9 (51.4-81.9) 1.52 (1.20-1.92)* 1.35 (1.07-1.71)* High 59,075 37 62.6 (45.4-86.4) 1.32 (0.95-1.82) 1.20 (0.87-1.65) Continuous 1.05 (1.01-1.10)* 1.03 (0.99-1.08) Cumulative dose Low 136,909 43 31.4 (23.3-42.3) 0.92 (0.69-1.25) 0.85 (0.63-1.14) Medium 106,571 67 62.9 (49.5-79.9) 1.46 (1.15-1.86)* 1.31 (1.03-1.67)* High 60,301 42 69.7 (51.5-94.2) 1.52 (1.12-2.05)* 1.36 (1.00-1.84)* Continuous 1.02 (1.00-1.04)* 1.02 (0.99-1.04) 7.2. Bolus insulins Never 51,947,122 14,164 27.3 (26.8-27.7) 1.00 1.00 Ever use 141,522 62 49.8 (36.8-67.4) 1.31 (0.97-1.78) 1.17 (0.86-1.58) Cumulative duration Low 68,567 28 40.8 (28.2-59.1) 1.35 (0.93-1.95) 1.24 (0.85-1.79) Medium 48,161 15 31.1 (18.8-51.7) 0.80 (0.49-1.34) 0.72 (0.43-1.19) High 24,794 19 76.6 (48.9-120.1) 1.80 (1.15-2.82)* 1.61 (1.03-2.52)* Continuous 1.06 (0.97-1.16) 1.03 (0.94-1.14) Cumulative dose Low 71,251 29 40.7 (28.3-58.6) 1.32 (0.92-1.90) 1.22 (0.85-1.75) 303 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 44,054 15 34.0 (20.5-56.5) 0.88 (0.53-1.45) 0.78 (0.47-1.30) High 26,217 18 68.7 (43.3-109.0) 1.65 (1.04-2.63)* 1.47 (0.93-2.33) Continuous 1.03 (1.00-1.07) 1.02 (0.98-1.06) Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table displays associations between all diabetes medications and rectal cancer. For a summary of selected medications with significant associations, please refer to Table 6-10. * denotes p<0.05. 304 Appendix D Supplementary tables for Chapter 7 Supplementary Table D-1. Associations between all diabetes medications and the risk of pancreatic cancer Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 6,828 13.6 (13.3-14.0) 1.00 1.00 Ever use 2,021,426 712 33.8 (31.0-36.8) 1.38 (1.26-1.51)* 1.29 (1.18-1.41)* Cumulative duration Low 736,609 188 25.5 (22.1-29.4) 1.22 (1.06-1.41)* 1.17 (1.02-1.36)* Medium 720,912 284 39.4 (35.1-44.3) 1.63 (1.45-1.84)* 1.54 (1.36-1.73)* High 563,905 240 42.6 (37.5-48.3) 1.36 (1.20-1.55)* 1.24 (1.09-1.41)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.04)* Cumulative dose Low 761,186 195 25.6 (22.3-29.5) 1.16 (1.00-1.33)* 1.11 (0.97-1.28) Medium 720,432 268 37.2 (33.0-41.9) 1.48 (1.31-1.68)* 1.40 (1.24-1.58)* High 539,808 249 46.1 (40.7-52.2) 1.61 (1.42-1.82)* 1.45 (1.28-1.65)* Continuous 1.06 (1.04-1.07)* 1.04 (1.03-1.06)* 2. Incretin-based medicines Never 51,846,234 7,452 14.4 (14.1-14.7) 1.00 1.00 Ever use 242,410 88 26.4 (19.7-35.4) 1.24 (0.92-1.66) 1.08 (0.81-1.45) Cumulative duration Low 76,647 30 39.1 (27.4-56.0) 2.00 (1.40-2.86)* 1.77 (1.24-2.54)* Medium 82,123 20 24.4 (15.7-37.7) 1.18 (0.76-1.84) 1.04 (0.67-1.61) High 83,640 38 45.4 (33.1-62.4) 1.83 (1.33-2.52)* 1.58 (1.15-2.18)* Continuous 1.12 (1.05-1.19)* 1.08 (1.02-1.15)* Cumulative dose Low 79,230 34 42.9 (30.7-60.1) 2.36 (1.69-3.30)* 2.07 (1.48-2.90)* Medium 80,356 20 24.9 (16.1-38.6) 1.17 (0.75-1.81) 1.03 (0.66-1.59) High 82,824 34 41.1 (29.3-57.5) 1.62 (1.15-2.26)* 1.40 (1.00-1.96) Continuous 1.13 (1.05-1.20)* 1.09 (1.02-1.17)* 2.1. DPP-4 inhibitors Never 51,896,422 7,467 14.4 (14.1-14.7) 1.00 1.00 Ever use 192,222 73 30.1 (22.0-41.2) 1.29 (0.94-1.76) 1.13 (0.82-1.55) Cumulative duration Low 63,002 25 39.7 (26.8-58.7) 1.80 (1.22-2.67)* 1.60 (1.08-2.37)* Medium 63,244 18 28.5 (17.9-45.2) 1.27 (0.80-2.02) 1.11 (0.70-1.77) High 65,976 30 45.5 (31.8-65.0) 1.73 (1.21-2.47)* 1.50 (1.04-2.14)* Continuous 1.12 (1.05-1.20)* 1.09 (1.02-1.17)* Cumulative dose Low 64,188 25 38.9 (26.3-57.6) 1.76 (1.19-2.61)* 1.56 (1.05-2.31)* Medium 61,937 16 25.8 (15.8-42.2) 1.15 (0.71-1.88) 1.01 (0.62-1.65) High 66,097 32 48.4 (34.2-68.5) 1.85 (1.31-2.62)* 1.60 (1.13-2.27)* Continuous 1.13 (1.05-1.20)* 1.09 (1.02-1.17)* 2.1.1. Linagliptin Never 52,023,970 7,515 14.4 (14.1-14.8) 1.00 1.00 Ever use 64,674 25 34.2 (21.2-54.9) 1.25 (0.78-2.02) 1.10 (0.68-1.77) Cumulative duration Low 19,887 Suppressed 30.2 (13.6-67.2) 1.20 (0.54-2.67) 1.04 (0.47-2.33) Medium 21,325 Suppressed 42.2 (22.0-81.1) 1.63 (0.85-3.12) 1.41 (0.73-2.71) High 23,462 10 42.6 (22.9-79.2) 1.43 (0.77-2.66) 1.25 (0.67-2.32) Continuous 1.11 (0.94-1.31) 1.06 (0.90-1.26) Cumulative dose Low 19,952 Suppressed 35.1 (16.7-73.6) 1.40 (0.67-2.92) 1.21 (0.58-2.55) Medium 21,425 Suppressed 37.3 (18.7-74.7) 1.43 (0.71-2.85) 1.24 (0.62-2.49) High 23,297 10 42.9 (23.1-79.8) 1.44 (0.78-2.68) 1.26 (0.68-2.34) Continuous 1.11 (0.94-1.31) 1.06 (0.90-1.26) 2.1.2. Sitagliptin Never 51,955,454 7,491 14.4 (14.1-14.7) 1.00 1.00 Ever use 133,190 49 25.9 (16.1-41.6) 1.25 (0.78-2.02) 1.11 (0.69-1.78) Cumulative duration Low 42,249 14 33.1 (19.6-56.0) 1.51 (0.89-2.54) 1.34 (0.79-2.26) Medium 47,499 11 23.2 (12.8-41.8) 1.06 (0.59-1.92) 0.93 (0.52-1.69) High 43,442 24 55.2 (37.0-82.4) 2.21 (1.48-3.30)* 1.91 (1.28-2.85)* Continuous 1.17 (1.07-1.26)* 1.13 (1.04-1.23)* 305 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 43,259 14 32.4 (19.2-54.6) 1.46 (0.87-2.47) 1.30 (0.77-2.20) Medium 45,625 10 21.9 (11.8-40.7) 1.00 (0.54-1.87) 0.88 (0.47-1.64) High 44,306 25 56.4 (38.1-83.5) 2.29 (1.55-3.38)* 1.97 (1.33-2.92)* Continuous 1.17 (1.08-1.27)* 1.13 (1.04-1.23)* 2.2. GLP-1 receptor agonists Never 52,013,587 7,522 14.5 (14.1-14.8) 1.00 1.00 Ever use 75,057 18 12.9 (5.8-28.7) 0.86 (0.39-1.91) 0.73 (0.33-1.63) Cumulative duration Low 23,429 Suppressed 21.3 (8.9-51.3) 1.47 (0.61-3.54) 1.28 (0.53-3.07) Medium 25,502 Suppressed 23.5 (10.6-52.4) 1.64 (0.74-3.65) 1.40 (0.63-3.12) High 26,126 Suppressed 26.8 (12.8-56.2) 1.49 (0.71-3.11) 1.25 (0.60-2.63) Continuous 1.09 (0.90-1.33) 1.04 (0.85-1.28) Cumulative dose Low 23,693 Suppressed 21.1 (8.8-50.7) 1.41 (0.59-3.38) 1.22 (0.51-2.94) Medium 25,629 Suppressed 35.1 (18.3-67.5) 2.36 (1.23-4.52)* 2.01 (1.05-3.87)* High 25,735 Suppressed 15.5 (5.8-41.4) 0.90 (0.34-2.41) 0.77 (0.29-2.04) Continuous 1.23 (0.56-2.68) 1.07 (0.46-2.51) 3. SGLT-2 inhibitors Never 51,997,074 7,507 14.4 (14.1-14.8) 1.00 1.00 Ever use 91,570 33 37.5 (25.3-55.5) 2.07 (1.40-3.07)* 1.72 (1.16-2.54)* Cumulative duration Low 26,625 Suppressed 15.0 (5.6-40.0) 0.78 (0.29-2.08) 0.66 (0.25-1.76) Medium 30,375 11 36.2 (20.1-65.4) 1.92 (1.06-3.47)* 1.61 (0.89-2.91) High 34,570 18 52.1 (32.8-82.6) 2.69 (1.69-4.27)* 2.22 (1.40-3.53)* Continuous 1.41 (1.22-1.62)* 1.32 (1.14-1.52)* Cumulative dose Low 26,825 Suppressed 26.1 (12.4-54.7) 1.32 (0.63-2.77) 1.11 (0.53-2.34) Medium 30,296 Suppressed 13.2 (5.0-35.2) 0.70 (0.26-1.86) 0.58 (0.22-1.55) High 34,449 22 63.9 (42.0-97.0) 3.40 (2.24-5.17)* 2.79 (1.84-4.25)* Continuous 1.30 (1.16-1.46)* 1.24 (1.10-1.39)* 4. AGIs (i.e., acarbose) Never 52,043,873 7,519 14.4 (14.1-14.8) 1.00 1.00 Ever use 44,771 21 23.0 (7.4-71.2) 0.91 (0.30-2.82) 0.91 (0.29-2.81) Cumulative duration Low 16,863 Suppressed 29.7 (12.3-71.2) 1.23 (0.51-2.96) 1.19 (0.50-2.86) Medium 15,151 11 72.6 (40.2-131.1) 2.76 (1.53-4.99)* 2.68 (1.48-4.84)* High 12,757 Suppressed 39.2 (16.3-94.2) 1.28 (0.53-3.08) 1.23 (0.51-2.95) Continuous 1.05 (0.91-1.20) 1.04 (0.91-1.20) Cumulative dose Low 15,946 Suppressed 31.4 (13.1-75.3) 1.27 (0.53-3.05) 1.24 (0.52-2.98) Medium 16,084 11 68.4 (37.9-123.5) 2.62 (1.45-4.73)* 2.53 (1.40-4.57)* High 12,741 Suppressed 39.2 (16.3-94.3) 1.32 (0.55-3.16) 1.25 (0.52-3.01) Continuous 1.12 (0.93-1.34) 1.11 (0.92-1.33) 5. Insulin secretagogues Never 51,176,005 7,161 14.0 (13.7-14.3) 1.00 1.00 Ever use 912,639 379 38.3 (33.6-43.8) 1.51 (1.32-1.73)* 1.43 (1.25-1.64)* Cumulative duration Low 360,923 116 32.1 (26.8-38.6) 1.37 (1.14-1.64)* 1.32 (1.10-1.59)* Medium 315,845 139 44.0 (37.3-52.0) 1.74 (1.47-2.06)* 1.64 (1.39-1.94)* High 235,871 124 52.6 (44.1-62.7) 1.64 (1.37-1.96)* 1.51 (1.26-1.80)* Continuous 1.06 (1.05-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 372,575 126 33.8 (28.4-40.3) 1.36 (1.14-1.62)* 1.32 (1.11-1.58)* Medium 314,231 127 40.4 (34.0-48.1) 1.55 (1.30-1.84)* 1.45 (1.22-1.73)* High 225,833 126 55.8 (46.9-66.4) 1.92 (1.61-2.29)* 1.74 (1.46-2.08)* Continuous 1.03 (1.02-1.04)* 1.02 (1.02-1.03)* 5.1. Meglitinides Never 52,048,818 7,518 14.4 (14.1-14.8) 1.00 1.00 Ever use 39,826 22 36.7 (15.3-88.2) 1.54 (0.64-3.69) 1.50 (0.63-3.59) Cumulative duration Low 12,831 10 77.9 (41.9-144.8) 3.11 (1.67-5.78)* 2.97 (1.60-5.52)* Medium 13,013 Suppressed 23.1 (7.4-71.5) 0.96 (0.31-2.98) 0.91 (0.30-2.84) High 13,982 Suppressed 64.4 (33.5-123.7) 2.28 (1.19-4.38)* 2.11 (1.10-4.06)* Continuous 1.11 (1.01-1.23)* 1.10 (1.00-1.21) 306 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 13,858 11 79.4 (44.0-143.3) 3.05 (1.69-5.50)* 2.92 (1.62-5.27)* Medium 13,470 Suppressed 14.8 (3.7-59.4) 0.60 (0.15-2.40) 0.57 (0.14-2.30) High 12,498 Suppressed 72.0 (37.5-138.4) 2.69 (1.40-5.17)* 2.46 (1.28-4.73)* Continuous 1.08 (1.03-1.14)* 1.08 (1.03-1.13)* 5.1.1. Repaglinide Never 52,049,428 7,518 14.4 (14.1-14.8) 1.00 1.00 Ever use 39,216 22 37.1 (15.4-89.1) 1.55 (0.65-3.72) 1.51 (0.63-3.62) Cumulative duration Low 12,566 10 79.6 (42.8-147.9) 3.17 (1.71-5.90)* 3.03 (1.63-5.63)* Medium 12,873 Suppressed 23.3 (7.5-72.3) 0.97 (0.31-3.01) 0.92 (0.30-2.86) High 13,777 Suppressed 65.3 (34.0-125.6) 2.31 (1.20-4.44)* 2.14 (1.11-4.12)* Continuous 1.11 (1.01-1.23)* 1.10 (1.00-1.21) Cumulative dose Low 13,676 11 80.4 (44.5-145.2) 3.09 (1.71-5.59)* 2.96 (1.64-5.35)* Medium 13,159 Suppressed 15.2 (3.8-60.8) 0.61 (0.15-2.45) 0.58 (0.15-2.34) High 12,381 Suppressed 72.7 (37.8-139.7) 2.72 (1.41-5.22)* 2.49 (1.29-4.78)* Continuous 1.09 (1.03-1.14)* 1.08 (1.03-1.13)* 5.2. Sulfonylureas Never 51,188,413 7,165 14.0 (13.7-14.3) 1.00 1.00 Ever use 900,231 375 38.3 (33.5-43.8) 1.51 (1.32-1.73)* 1.43 (1.25-1.64)* Cumulative duration Low 359,009 119 33.1 (27.7-39.7) 1.41 (1.17-1.68)* 1.36 (1.13-1.63)* Medium 309,407 133 43.0 (36.3-50.9) 1.70 (1.43-2.02)* 1.60 (1.35-1.90)* High 231,815 123 53.1 (44.5-63.3) 1.65 (1.38-1.97)* 1.52 (1.27-1.82)* Continuous 1.06 (1.05-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 367,838 127 34.5 (29.0-41.1) 1.39 (1.16-1.65)* 1.35 (1.13-1.61)* Medium 309,412 125 40.4 (33.9-48.1) 1.55 (1.29-1.84)* 1.45 (1.22-1.73)* High 222,981 123 55.2 (46.2-65.8) 1.89 (1.58-2.26)* 1.72 (1.44-2.06)* Continuous 1.03 (1.02-1.03)* 1.02 (1.02-1.03)* 5.2.1. Gliclazide Never 51,695,028 7,365 14.2 (13.9-14.6) 1.00 1.00 Ever use 393,616 175 39.2 (32.3-47.7) 1.48 (1.21-1.80)* 1.35 (1.11-1.64)* Cumulative duration Low 126,908 56 44.1 (34.0-57.3) 1.81 (1.39-2.35)* 1.68 (1.29-2.18)* Medium 136,638 52 38.1 (29.0-49.9) 1.48 (1.13-1.94)* 1.35 (1.03-1.77)* High 130,070 67 51.5 (40.5-65.4) 1.68 (1.32-2.14)* 1.51 (1.19-1.93)* Continuous 1.07 (1.04-1.11)* 1.06 (1.02-1.09)* Cumulative dose Low 133,699 54 40.4 (30.9-52.7) 1.60 (1.23-2.10)* 1.49 (1.14-1.95)* Medium 136,394 58 42.5 (32.9-55.0) 1.60 (1.24-2.07)* 1.46 (1.13-1.89)* High 123,523 63 51.0 (39.8-65.3) 1.75 (1.36-2.24)* 1.57 (1.22-2.01)* Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 5.2.2. Glyburide Never 51,418,210 7,250 14.1 (13.8-14.4) 1.00 1.00 Ever use 670,434 290 37.9 (31.6-45.4) 1.53 (1.28-1.84)* 1.50 (1.25-1.80)* Cumulative duration Low 283,215 91 32.1 (26.2-39.5) 1.29 (1.05-1.59)* 1.25 (1.02-1.54)* Medium 224,722 113 50.3 (41.8-60.5) 1.96 (1.63-2.36)* 1.88 (1.56-2.27)* High 162,497 86 52.9 (42.8-65.4) 1.64 (1.32-2.03)* 1.53 (1.23-1.89)* Continuous 1.07 (1.05-1.09)* 1.06 (1.04-1.08)* Cumulative dose Low 296,014 100 33.8 (27.8-41.1) 1.30 (1.07-1.58)* 1.26 (1.04-1.54)* Medium 230,574 108 46.8 (38.8-56.6) 1.75 (1.45-2.12)* 1.68 (1.39-2.03)* High 143,846 82 57.0 (45.9-70.8) 1.95 (1.57-2.43)* 1.81 (1.45-2.25)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.05)* 6. Thiazolidinediones Never 51,871,508 7,448 14.4 (14.0-14.7) 1.00 1.00 Ever use 217,136 92 18.0 (10.5-31.0) 0.94 (0.55-1.62) 0.94 (0.54-1.62) Cumulative duration Low 76,357 26 34.1 (23.2-50.0) 1.51 (1.03-2.23)* 1.43 (0.97-2.10) Medium 72,351 29 40.1 (27.9-57.7) 1.78 (1.23-2.56)* 1.67 (1.16-2.41)* High 68,428 37 54.1 (39.2-74.6) 2.09 (1.52-2.89)* 1.90 (1.38-2.63)* Continuous 1.12 (1.07-1.17)* 1.10 (1.05-1.15)* 307 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 75,982 25 32.9 (22.2-48.7) 1.44 (0.97-2.13) 1.36 (0.92-2.02) Medium 74,257 36 48.5 (35.0-67.2) 2.13 (1.53-2.95)* 2.00 (1.44-2.78)* High 66,897 31 46.3 (32.6-65.9) 1.83 (1.29-2.61)* 1.66 (1.17-2.37)* Continuous 1.11 (1.06-1.16)* 1.09 (1.04-1.14)* 6.1. Pioglitazone Never 51,987,564 7,503 14.4 (14.1-14.8) 1.00 1.00 Ever use 101,080 37 16.7 (7.5-37.2) 0.81 (0.36-1.80) 0.78 (0.35-1.74) Cumulative duration Low 33,963 Suppressed 23.6 (11.8-47.1) 1.02 (0.51-2.04) 0.96 (0.48-1.91) Medium 34,409 13 37.8 (21.9-65.1) 1.65 (0.96-2.85) 1.54 (0.89-2.65) High 32,708 16 48.9 (30.0-79.8) 1.81 (1.11-2.96)* 1.64 (1.01-2.68)* Continuous 1.10 (1.03-1.19)* 1.09 (1.01-1.17)* Cumulative dose Low 33,724 Suppressed 23.7 (11.9-47.4) 1.02 (0.51-2.03) 0.95 (0.48-1.91) Medium 34,952 17 48.6 (30.2-78.2) 2.09 (1.30-3.36)* 1.95 (1.21-3.13)* High 32,404 12 37.0 (21.0-65.2) 1.41 (0.80-2.49) 1.27 (0.72-2.24) Continuous 1.09 (1.01-1.16)* 1.07 (1.00-1.15) 6.2. Rosiglitazone Never 51,946,176 7,478 14.4 (14.1-14.7) 1.00 1.00 Ever use 142,468 62 18.5 (8.8-38.9) 1.06 (0.50-2.22) 1.08 (0.52-2.27) Cumulative duration Low 49,170 17 34.6 (21.5-55.6) 1.51 (0.94-2.43) 1.43 (0.89-2.30) Medium 48,028 21 43.7 (28.5-67.1) 1.93 (1.26-2.96)* 1.81 (1.18-2.78)* High 45,270 24 53.0 (35.5-79.1) 2.14 (1.44-3.20)* 1.96 (1.31-2.92)* Continuous 1.15 (1.08-1.23)* 1.13 (1.06-1.21)* Cumulative dose Low 49,567 17 34.3 (21.3-55.2) 1.50 (0.93-2.41) 1.41 (0.88-2.27) Medium 49,349 23 46.6 (31.0-70.1) 2.03 (1.35-3.06)* 1.91 (1.27-2.88)* High 43,552 22 50.5 (33.3-76.7) 2.06 (1.36-3.13)* 1.88 (1.24-2.86)* Continuous 1.15 (1.08-1.22)* 1.13 (1.06-1.20)* 7. Insulins and analogues Never 51,772,245 7,342 14.2 (13.9-14.5) 1.00 1.00 Ever use 316,399 198 70.2 (60.1-81.8) 3.17 (2.71-3.70)* 2.84 (2.43-3.32)* Cumulative duration Low 143,015 71 49.6 (39.3-62.6) 2.87 (2.27-3.63)* 2.66 (2.11-3.36)* Medium 113,499 89 78.4 (63.7-96.5) 3.41 (2.77-4.21)* 3.06 (2.48-3.78)* High 59,885 38 63.5 (46.2-87.2) 2.51 (1.83-3.45)* 2.18 (1.58-3.00)* Continuous 1.16 (1.13-1.20)* 1.14 (1.11-1.18)* Cumulative dose Low 146,186 75 51.3 (40.9-64.3) 2.87 (2.28-3.60)* 2.65 (2.11-3.33)* Medium 108,141 88 81.4 (66.0-100.3) 3.53 (2.87-4.36)* 3.18 (2.57-3.92)* High 62,072 35 56.4 (40.5-78.5) 2.35 (1.69-3.28)* 2.04 (1.46-2.85)* Continuous 1.05 (1.04-1.06)* 1.04 (1.03-1.05)* 7.1. Basal insulins Never 51,784,863 7,350 14.2 (13.9-14.5) 1.00 1.00 Ever use 303,781 190 71.4 (61.0-83.6) 3.24 (2.77-3.80)* 2.91 (2.48-3.41)* Cumulative duration Low 135,289 67 49.5 (39.0-62.9) 2.87 (2.26-3.65)* 2.66 (2.09-3.38)* Medium 109,417 83 75.9 (61.2-94.1) 3.33 (2.68-4.13)* 2.98 (2.40-3.71)* High 59,075 40 67.7 (49.7-92.3) 2.66 (1.95-3.63)* 2.31 (1.69-3.16)* Continuous 1.18 (1.14-1.23)* 1.16 (1.12-1.20)* Cumulative dose Low 136,909 71 51.9 (41.1-65.4) 2.92 (2.31-3.69)* 2.69 (2.13-3.40)* Medium 106,571 82 76.9 (62.0-95.5) 3.36 (2.70-4.17)* 3.01 (2.42-3.75)* High 60,301 37 61.4 (44.5-84.7) 2.54 (1.84-3.51)* 2.21 (1.60-3.05)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* 7.2. Bolus insulins Never 51,947,122 7,435 14.3 (14.0-14.6) 1.00 1.00 Ever use 141,522 105 86.6 (68.9-108.9) 4.47 (3.55-5.62)* 3.97 (3.15-5.01)* Cumulative duration Low 68,567 53 77.3 (59.1-101.2) 4.82 (3.68-6.31)* 4.44 (3.39-5.82)* Medium 48,161 31 64.4 (45.3-91.5) 3.25 (2.29-4.63)* 2.89 (2.03-4.11)* High 24,794 21 84.7 (55.2-129.9) 3.91 (2.55-6.00)* 3.37 (2.19-5.17)* Continuous 1.26 (1.19-1.34)* 1.24 (1.17-1.32)* 308 Exposure Person-years Events Incidence rate Model 1 Model 2 Cumulative dose Low 71,251 53 74.4 (56.8-97.4) 4.52 (3.45-5.92)* 4.16 (3.17-5.45)* Medium 44,054 29 65.8 (45.7-94.7) 3.31 (2.30-4.76)* 2.94 (2.04-4.24)* High 26,217 23 87.7 (58.3-132.0) 4.25 (2.82-6.40)* 3.64 (2.42-5.49)* Continuous 1.07 (1.04-1.09)* 1.06 (1.04-1.09)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table displays associations between all diabetes medications and pancreatic cancer. For a summary of selected medications with significant associations, please refer to Table 7-2. * denotes p<0.05. 309 Supplementary Table D-2. Associations between all diabetes medications and the risk of pancreatic cancer with adjustment for other diabetes medications Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 6,828 13.6 (13.3-14.0) 1.00 1.00 Ever use 2,021,426 712 33.8 (31.0-36.8) 1.29 (1.18-1.41)* 1.11 (0.99-1.23) Cumulative duration Low 736,609 188 25.5 (22.1-29.4) 1.17 (1.02-1.36)* 1.05 (0.90-1.22) Medium 720,912 284 39.4 (35.1-44.3) 1.54 (1.36-1.73)* 1.32 (1.15-1.51)* High 563,905 240 42.6 (37.5-48.3) 1.24 (1.09-1.41)* 0.91 (0.77-1.09) Continuous 1.03 (1.02-1.04)* 1.01 (0.99-1.02) Cumulative dose Low 761,186 195 25.6 (22.3-29.5) 1.11 (0.97-1.28) 1.02 (0.88-1.18) Medium 720,432 268 37.2 (33.0-41.9) 1.40 (1.24-1.58)* 1.24 (1.08-1.42)* High 539,808 249 46.1 (40.7-52.2) 1.45 (1.28-1.65)* 1.08 (0.90-1.29) Continuous 1.04 (1.03-1.06)* 1.02 (1.00-1.04) 2. Incretin-based medicines Never 51,846,234 7,452 14.4 (14.1-14.7) 1.00 1.00 Ever use 242,410 88 26.4 (19.7-35.4) 1.08 (0.81-1.45) 0.67 (0.49-0.91)* Cumulative duration Low 76,647 30 39.1 (27.4-56.0) 1.77 (1.24-2.54)* 1.11 (0.77-1.62) Medium 82,123 20 24.4 (15.7-37.7) 1.04 (0.67-1.61) 0.64 (0.40-1.01) High 83,640 38 45.4 (33.1-62.4) 1.58 (1.15-2.18)* 0.97 (0.67-1.39) Continuous 1.08 (1.02-1.15)* 0.97 (0.90-1.04) Cumulative dose Low 79,230 34 42.9 (30.7-60.1) 2.07 (1.48-2.90)* 1.24 (0.87-1.77) Medium 80,356 20 24.9 (16.1-38.6) 1.03 (0.66-1.59) 0.60 (0.38-0.96)* High 82,824 34 41.1 (29.3-57.5) 1.40 (1.00-1.96) 0.81 (0.55-1.18) Continuous 1.09 (1.02-1.17)* 0.98 (0.91-1.07) 2.1. DPP-4 inhibitors Never 51,896,422 7,467 14.4 (14.1-14.7) 1.00 1.00 Ever use 192,222 73 30.1 (22.0-41.2) 1.13 (0.82-1.55) 0.73 (0.52-1.01) Cumulative duration Low 63,002 25 39.7 (26.8-58.7) 1.60 (1.08-2.37)* 0.99 (0.66-1.49) Medium 63,244 18 28.5 (17.9-45.2) 1.11 (0.70-1.77) 0.69 (0.43-1.12) High 65,976 30 45.5 (31.8-65.0) 1.50 (1.04-2.14)* 0.94 (0.64-1.40) Continuous 1.09 (1.02-1.17)* 0.99 (0.91-1.07) Cumulative dose Low 64,188 25 38.9 (26.3-57.6) 1.56 (1.05-2.31)* 0.95 (0.63-1.43) Medium 61,937 16 25.8 (15.8-42.2) 1.01 (0.62-1.65) 0.62 (0.37-1.02) High 66,097 32 48.4 (34.2-68.5) 1.60 (1.13-2.27)* 0.93 (0.64-1.38) Continuous 1.09 (1.02-1.17)* 0.98 (0.91-1.07) 2.1.1. Linagliptin Never 52,023,970 7,515 14.4 (14.1-14.8) 1.00 1.00 Ever use 64,674 25 34.2 (21.2-54.9) 1.10 (0.68-1.77) 0.68 (0.42-1.10) Cumulative duration Low 19,887 Suppressed 30.2 (13.6-67.2) 1.04 (0.47-2.33) 0.68 (0.30-1.52) Medium 21,325 Suppressed 42.2 (22.0-81.1) 1.41 (0.73-2.71) 0.91 (0.46-1.77) High 23,462 10 42.6 (22.9-79.2) 1.25 (0.67-2.32) 0.78 (0.41-1.49) Continuous 1.06 (0.90-1.26) 0.90 (0.75-1.09) Cumulative dose Low 19,952 Suppressed 35.1 (16.7-73.6) 1.21 (0.58-2.55) 0.78 (0.37-1.65) Medium 21,425 Suppressed 37.3 (18.7-74.7) 1.24 (0.62-2.49) 0.78 (0.39-1.59) High 23,297 10 42.9 (23.1-79.8) 1.26 (0.68-2.34) 0.74 (0.39-1.41) Continuous 1.06 (0.90-1.26) 0.91 (0.76-1.09) 2.1.2. Sitagliptin Never 51,955,454 7,491 14.4 (14.1-14.7) 1.00 1.00 Ever use 133,190 49 25.9 (16.1-41.6) 1.11 (0.69-1.78) 0.77 (0.48-1.26) Cumulative duration Low 42,249 14 33.1 (19.6-56.0) 1.34 (0.79-2.26) 0.83 (0.48-1.41) Medium 47,499 11 23.2 (12.8-41.8) 0.93 (0.52-1.69) 0.59 (0.32-1.08) High 43,442 24 55.2 (37.0-82.4) 1.91 (1.28-2.85)* 1.28 (0.83-1.98) Continuous 1.13 (1.04-1.23)* 1.03 (0.94-1.13) Cumulative dose Low 43,259 14 32.4 (19.2-54.6) 1.30 (0.77-2.20) 0.79 (0.46-1.35) 310 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 45,625 10 21.9 (11.8-40.7) 0.88 (0.47-1.64) 0.54 (0.29-1.02) High 44,306 25 56.4 (38.1-83.5) 1.97 (1.33-2.92)* 1.23 (0.81-1.89) Continuous 1.13 (1.04-1.23)* 1.03 (0.93-1.13) 2.2. GLP-1 receptor agonists Never 52,013,587 7,522 14.5 (14.1-14.8) 1.00 1.00 Ever use 75,057 18 12.9 (5.8-28.7) 0.73 (0.33-1.63) 0.41 (0.18-0.92)* Cumulative duration Low 23,429 Suppressed 21.3 (8.9-51.3) 1.28 (0.53-3.07) 0.76 (0.32-1.86) Medium 25,502 Suppressed 23.5 (10.6-52.4) 1.40 (0.63-3.12) 0.79 (0.35-1.80) High 26,126 Suppressed 26.8 (12.8-56.2) 1.25 (0.60-2.63) 0.66 (0.31-1.43) Continuous 1.04 (0.85-1.28) 0.84 (0.67-1.06) Cumulative dose Low 23,693 Suppressed 21.1 (8.8-50.7) 1.22 (0.51-2.94) 0.70 (0.29-1.71) Medium 25,629 Suppressed 35.1 (18.3-67.5) 2.01 (1.05-3.87)* 1.12 (0.57-2.19) High 25,735 Suppressed 15.5 (5.8-41.4) 0.77 (0.29-2.04) 0.39 (0.14-1.06) Continuous 1.07 (0.46-2.51) 0.49 (0.15-1.65) 3. SGLT-2 inhibitors Never 51,997,074 7,507 14.4 (14.1-14.8) 1.00 1.00 Ever use 91,570 33 37.5 (25.3-55.5) 1.72 (1.16-2.54)* 1.21 (0.80-1.83) Cumulative duration Low 26,625 Suppressed 15.0 (5.6-40.0) 0.66 (0.25-1.76) 0.42 (0.16-1.13) Medium 30,375 11 36.2 (20.1-65.4) 1.61 (0.89-2.91) 1.07 (0.58-1.97) High 34,570 18 52.1 (32.8-82.6) 2.22 (1.40-3.53)* 1.51 (0.91-2.49) Continuous 1.32 (1.14-1.52)* 1.14 (0.97-1.35) Cumulative dose Low 26,825 Suppressed 26.1 (12.4-54.7) 1.11 (0.53-2.34) 0.72 (0.34-1.54) Medium 30,296 Suppressed 13.2 (5.0-35.2) 0.58 (0.22-1.55) 0.39 (0.14-1.05) High 34,449 22 63.9 (42.0-97.0) 2.79 (1.84-4.25)* 1.87 (1.19-2.96)* Continuous 1.24 (1.10-1.39)* 1.10 (0.96-1.25) 4. AGIs (i.e., acarbose) Never 52,043,873 7,519 14.4 (14.1-14.8) 1.00 1.00 Ever use 44,771 21 23.0 (7.4-71.2) 0.91 (0.29-2.81) 0.68 (0.22-2.12) Cumulative duration Low 16,863 Suppressed 29.7 (12.3-71.2) 1.19 (0.50-2.86) 0.77 (0.32-1.86) Medium 15,151 11 72.6 (40.2-131.1) 2.68 (1.48-4.84)* 1.67 (0.92-3.04) High 12,757 Suppressed 39.2 (16.3-94.2) 1.23 (0.51-2.95) 0.81 (0.34-1.96) Continuous 1.04 (0.91-1.20) 0.97 (0.83-1.13) Cumulative dose Low 15,946 Suppressed 31.4 (13.1-75.3) 1.24 (0.52-2.98) 0.80 (0.33-1.94) Medium 16,084 11 68.4 (37.9-123.5) 2.53 (1.40-4.57)* 1.57 (0.86-2.87) High 12,741 Suppressed 39.2 (16.3-94.3) 1.25 (0.52-3.01) 0.80 (0.33-1.95) Continuous 1.11 (0.92-1.33) 1.01 (0.82-1.24) 5. Insulin secretagogues Never 51,176,005 7,161 14.0 (13.7-14.3) 1.00 1.00 Ever use 912,639 379 38.3 (33.6-43.8) 1.43 (1.25-1.64)* 1.20 (1.03-1.40)* Cumulative duration Low 360,923 116 32.1 (26.8-38.6) 1.32 (1.10-1.59)* 1.04 (0.85-1.27) Medium 315,845 139 44.0 (37.3-52.0) 1.64 (1.39-1.94)* 1.18 (0.96-1.44) High 235,871 124 52.6 (44.1-62.7) 1.51 (1.26-1.80)* 1.05 (0.83-1.32) Continuous 1.05 (1.04-1.07)* 1.03 (1.01-1.05)* Cumulative dose Low 372,575 126 33.8 (28.4-40.3) 1.32 (1.11-1.58)* 1.06 (0.87-1.29) Medium 314,231 127 40.4 (34.0-48.1) 1.45 (1.22-1.73)* 1.05 (0.85-1.29) High 225,833 126 55.8 (46.9-66.4) 1.74 (1.46-2.08)* 1.09 (0.86-1.39) Continuous 1.02 (1.02-1.03)* 1.01 (1.00-1.02)* 5.1. Meglitinides Never 52,048,818 7,518 14.4 (14.1-14.8) 1.00 1.00 Ever use 39,826 22 36.7 (15.3-88.2) 1.50 (0.63-3.59) 1.12 (0.47-2.71) Cumulative duration Low 12,831 10 77.9 (41.9-144.8) 2.97 (1.60-5.52)* 1.74 (0.93-3.26) Medium 13,013 Suppressed 23.1 (7.4-71.5) 0.91 (0.30-2.84) 0.52 (0.17-1.63) High 13,982 Suppressed 64.4 (33.5-123.7) 2.11 (1.10-4.06)* 1.30 (0.67-2.53) Continuous 1.10 (1.00-1.21) 1.05 (0.94-1.17) Cumulative dose Low 13,858 11 79.4 (44.0-143.3) 2.92 (1.62-5.27)* 1.78 (0.98-3.24) 311 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 13,470 Suppressed 14.8 (3.7-59.4) 0.57 (0.14-2.30) 0.33 (0.08-1.34) High 12,498 Suppressed 72.0 (37.5-138.4) 2.46 (1.28-4.73)* 1.40 (0.72-2.72) Continuous 1.08 (1.03-1.13)* 1.05 (1.00-1.11) 5.1.1. Repaglinide Never 52,049,428 7,518 14.4 (14.1-14.8) 1.00 1.00 Ever use 39,216 22 37.1 (15.4-89.1) 1.51 (0.63-3.62) 1.13 (0.47-2.73) Cumulative duration Low 12,566 10 79.6 (42.8-147.9) 3.03 (1.63-5.63)* 1.77 (0.94-3.32) Medium 12,873 Suppressed 23.3 (7.5-72.3) 0.92 (0.30-2.86) 0.53 (0.17-1.65) High 13,777 Suppressed 65.3 (34.0-125.6) 2.14 (1.11-4.12)* 1.32 (0.68-2.57) Continuous 1.10 (1.00-1.21) 1.05 (0.94-1.17) Cumulative dose Low 13,676 11 80.4 (44.5-145.2) 2.96 (1.64-5.35)* 1.81 (0.99-3.29) Medium 13,159 Suppressed 15.2 (3.8-60.8) 0.58 (0.15-2.34) 0.34 (0.09-1.36) High 12,381 Suppressed 72.7 (37.8-139.7) 2.49 (1.29-4.78)* 1.42 (0.73-2.75) Continuous 1.08 (1.03-1.13)* 1.05 (1.00-1.11) 5.2. Sulfonylureas Never 51,188,413 7,165 14.0 (13.7-14.3) 1.00 1.00 Ever use 900,231 375 38.3 (33.5-43.8) 1.43 (1.25-1.64)* 1.20 (1.02-1.40)* Cumulative duration Low 359,009 119 33.1 (27.7-39.7) 1.36 (1.13-1.63)* 1.06 (0.87-1.30) Medium 309,407 133 43.0 (36.3-50.9) 1.60 (1.35-1.90)* 1.15 (0.93-1.40) High 231,815 123 53.1 (44.5-63.3) 1.52 (1.27-1.82)* 1.06 (0.84-1.34) Continuous 1.05 (1.04-1.07)* 1.03 (1.01-1.05)* Cumulative dose Low 367,838 127 34.5 (29.0-41.1) 1.35 (1.13-1.61)* 1.08 (0.89-1.31) Medium 309,412 125 40.4 (33.9-48.1) 1.45 (1.22-1.73)* 1.05 (0.85-1.29) High 222,981 123 55.2 (46.2-65.8) 1.72 (1.44-2.06)* 1.07 (0.84-1.37) Continuous 1.02 (1.02-1.03)* 1.01 (1.00-1.02)* 5.2.1. Gliclazide Never 51,695,028 7,365 14.2 (13.9-14.6) 1.00 1.00 Ever use 393,616 175 39.2 (32.3-47.7) 1.35 (1.11-1.64)* 1.09 (0.88-1.35) Cumulative duration Low 126,908 56 44.1 (34.0-57.3) 1.68 (1.29-2.18)* 1.14 (0.86-1.51) Medium 136,638 52 38.1 (29.0-49.9) 1.35 (1.03-1.77)* 0.92 (0.69-1.23) High 130,070 67 51.5 (40.5-65.4) 1.51 (1.19-1.93)* 1.05 (0.80-1.38) Continuous 1.06 (1.02-1.09)* 1.02 (0.98-1.06) Cumulative dose Low 133,699 54 40.4 (30.9-52.7) 1.49 (1.14-1.95)* 1.04 (0.78-1.38) Medium 136,394 58 42.5 (32.9-55.0) 1.46 (1.13-1.89)* 1.01 (0.77-1.34) High 123,523 63 51.0 (39.8-65.3) 1.57 (1.22-2.01)* 0.99 (0.75-1.32) Continuous 1.02 (1.01-1.03)* 1.01 (1.00-1.02) 5.2.2. Glyburide Never 51,418,210 7,250 14.1 (13.8-14.4) 1.00 1.00 Ever use 670,434 290 37.9 (31.6-45.4) 1.50 (1.25-1.80)* 1.28 (1.05-1.56)* Cumulative duration Low 283,215 91 32.1 (26.2-39.5) 1.25 (1.02-1.54)* 0.96 (0.77-1.20) Medium 224,722 113 50.3 (41.8-60.5) 1.88 (1.56-2.27)* 1.32 (1.07-1.63)* High 162,497 86 52.9 (42.8-65.4) 1.53 (1.23-1.89)* 1.07 (0.84-1.37) Continuous 1.06 (1.04-1.08)* 1.03 (1.01-1.06)* Cumulative dose Low 296,014 100 33.8 (27.8-41.1) 1.26 (1.04-1.54)* 0.99 (0.79-1.22) Medium 230,574 108 46.8 (38.8-56.6) 1.68 (1.39-2.03)* 1.19 (0.96-1.48) High 143,846 82 57.0 (45.9-70.8) 1.81 (1.45-2.25)* 1.13 (0.87-1.47) Continuous 1.03 (1.02-1.05)* 1.02 (1.00-1.03)* 6. Thiazolidinediones Never 51,871,508 7,448 14.4 (14.0-14.7) 1.00 1.00 Ever use 217,136 92 18.0 (10.5-31.0) 0.94 (0.54-1.62) 0.73 (0.42-1.27) Cumulative duration Low 76,357 26 34.1 (23.2-50.0) 1.43 (0.97-2.10) 0.86 (0.57-1.28) Medium 72,351 29 40.1 (27.9-57.7) 1.67 (1.16-2.41)* 1.01 (0.69-1.48) High 68,428 37 54.1 (39.2-74.6) 1.90 (1.38-2.63)* 1.28 (0.91-1.82) Continuous 1.10 (1.05-1.15)* 1.04 (0.98-1.09) Cumulative dose Low 75,982 25 32.9 (22.2-48.7) 1.36 (0.92-2.02) 0.82 (0.55-1.24) 312 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 74,257 36 48.5 (35.0-67.2) 2.00 (1.44-2.78)* 1.20 (0.85-1.70) High 66,897 31 46.3 (32.6-65.9) 1.66 (1.17-2.37)* 1.04 (0.72-1.52) Continuous 1.09 (1.04-1.14)* 1.03 (0.97-1.08) 6.1. Pioglitazone Never 51,987,564 7,503 14.4 (14.1-14.8) 1.00 1.00 Ever use 101,080 37 16.7 (7.5-37.2) 0.78 (0.35-1.74) 0.62 (0.28-1.39) Cumulative duration Low 33,963 Suppressed 23.6 (11.8-47.1) 0.96 (0.48-1.91) 0.55 (0.27-1.11) Medium 34,409 13 37.8 (21.9-65.1) 1.54 (0.89-2.65) 0.89 (0.51-1.56) High 32,708 16 48.9 (30.0-79.8) 1.64 (1.01-2.68)* 1.09 (0.65-1.80) Continuous 1.09 (1.01-1.17)* 1.02 (0.94-1.11) Cumulative dose Low 33,724 Suppressed 23.7 (11.9-47.4) 0.95 (0.48-1.91) 0.55 (0.27-1.11) Medium 34,952 17 48.6 (30.2-78.2) 1.95 (1.21-3.13)* 1.12 (0.69-1.84) High 32,404 12 37.0 (21.0-65.2) 1.27 (0.72-2.24) 0.79 (0.44-1.41) Continuous 1.07 (1.00-1.15) 1.00 (0.93-1.08) 6.2. Rosiglitazone Never 51,946,176 7,478 14.4 (14.1-14.7) 1.00 1.00 Ever use 142,468 62 18.5 (8.8-38.9) 1.08 (0.52-2.27) 0.85 (0.40-1.80) Cumulative duration Low 49,170 17 34.6 (21.5-55.6) 1.43 (0.89-2.30) 0.87 (0.53-1.42) Medium 48,028 21 43.7 (28.5-67.1) 1.81 (1.18-2.78)* 1.12 (0.72-1.75) High 45,270 24 53.0 (35.5-79.1) 1.96 (1.31-2.92)* 1.31 (0.86-1.99) Continuous 1.13 (1.06-1.21)* 1.05 (0.97-1.14) Cumulative dose Low 49,567 17 34.3 (21.3-55.2) 1.41 (0.88-2.27) 0.86 (0.53-1.41) Medium 49,349 23 46.6 (31.0-70.1) 1.91 (1.27-2.88)* 1.18 (0.77-1.81) High 43,552 22 50.5 (33.3-76.7) 1.88 (1.24-2.86)* 1.17 (0.76-1.81) Continuous 1.13 (1.06-1.20)* 1.05 (0.98-1.13) 7. Insulins and analogues Never 51,772,245 7,342 14.2 (13.9-14.5) 1.00 1.00 Ever use 316,399 198 70.2 (60.1-81.8) 2.84 (2.43-3.32)* 2.67 (2.25-3.16)* Cumulative duration Low 143,015 71 49.6 (39.3-62.6) 2.66 (2.11-3.36)* 2.43 (1.90-3.12)* Medium 113,499 89 78.4 (63.7-96.5) 3.06 (2.48-3.78)* 2.84 (2.24-3.61)* High 59,885 38 63.5 (46.2-87.2) 2.18 (1.58-3.00)* 2.03 (1.44-2.87)* Continuous 1.14 (1.11-1.18)* 1.11 (1.07-1.15)* Cumulative dose Low 146,186 75 51.3 (40.9-64.3) 2.65 (2.11-3.33)* 2.42 (1.90-3.09)* Medium 108,141 88 81.4 (66.0-100.3) 3.18 (2.57-3.92)* 2.83 (2.22-3.61)* High 62,072 35 56.4 (40.5-78.5) 2.04 (1.46-2.85)* 1.78 (1.24-2.55)* Continuous 1.04 (1.03-1.05)* 1.04 (1.02-1.05)* 7.1. Basal insulins Never 51,784,863 7,350 14.2 (13.9-14.5) 1.00 1.00 Ever use 303,781 190 71.4 (61.0-83.6) 2.91 (2.48-3.41)* 2.13 (1.70-2.67)* Cumulative duration Low 135,289 67 49.5 (39.0-62.9) 2.66 (2.09-3.38)* 1.87 (1.40-2.48)* Medium 109,417 83 75.9 (61.2-94.1) 2.98 (2.40-3.71)* 2.08 (1.56-2.78)* High 59,075 40 67.7 (49.7-92.3) 2.31 (1.69-3.16)* 1.44 (0.95-2.19) Continuous 1.16 (1.12-1.20)* 1.09 (1.03-1.15)* Cumulative dose Low 136,909 71 51.9 (41.1-65.4) 2.69 (2.13-3.40)* 1.91 (1.45-2.53)* Medium 106,571 82 76.9 (62.0-95.5) 3.01 (2.42-3.75)* 1.95 (1.45-2.63)* High 60,301 37 61.4 (44.5-84.7) 2.21 (1.60-3.05)* 1.19 (0.77-1.84) Continuous 1.05 (1.04-1.06)* 1.04 (1.02-1.06)* 7.2. Bolus insulins Never 51,947,122 7,435 14.3 (14.0-14.6) 1.00 1.00 Ever use 141,522 105 86.6 (68.9-108.9) 3.97 (3.15-5.01)* 1.86 (1.36-2.53)* Cumulative duration Low 68,567 53 77.3 (59.1-101.2) 4.44 (3.39-5.82)* 2.31 (1.66-3.21)* Medium 48,161 31 64.4 (45.3-91.5) 2.89 (2.03-4.11)* 1.44 (0.95-2.18) High 24,794 21 84.7 (55.2-129.9) 3.37 (2.19-5.17)* 1.94 (1.15-3.28)* Continuous 1.24 (1.17-1.32)* 1.09 (1.00-1.20) Cumulative dose Low 71,251 53 74.4 (56.8-97.4) 4.16 (3.17-5.45)* 2.20 (1.58-3.05)* 313 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 44,054 29 65.8 (45.7-94.7) 2.94 (2.04-4.24)* 1.54 (1.00-2.37) High 26,217 23 87.7 (58.3-132.0) 3.64 (2.42-5.49)* 2.27 (1.36-3.79)* Continuous 1.06 (1.04-1.09)* 1.02 (0.98-1.06) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Model 2 further adjusted for other mutually exclusive diabetes medications. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table displays associations between all diabetes medications and pancreatic cancer. For a summary of selected medications with significant associations, please refer to Table 7-3. * denotes p<0.05. 314 Supplementary Table D-3. Associations between all diabetes medications and the risk of pancreatic cancer with variation in washout and lag periods Exposure Model 1 Model 2 Model 3 Model 4 Model 5 1. Biguanides (i.e., metformin) Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.29 (1.18-1.41)* 3.11 (2.94-3.29)* 1.15 (1.04-1.27)* 1.19 (1.10-1.29)* 1.31 (1.20-1.44)* Cumulative duration Low 1.17 (1.02-1.36)* 5.11 (4.78-5.46)* 1.02 (0.87-1.20) 1.09 (0.96-1.24) 1.20 (1.04-1.39)* Medium 1.54 (1.36-1.73)* 2.34 (2.14-2.56)* 1.25 (1.09-1.43)* 1.43 (1.29-1.58)* 1.55 (1.37-1.75)* High 1.24 (1.09-1.41)* 1.79 (1.62-1.98)* 1.17 (1.02-1.34)* 1.27 (1.15-1.41)* 1.24 (1.08-1.42)* Continuous 1.03 (1.02-1.04)* 1.07 (1.06-1.07)* 1.02 (1.01-1.04)* 1.03 (1.02-1.04)* 1.03 (1.02-1.05)* Cumulative dose Low 1.11 (0.97-1.28) 4.55 (4.25-4.87)* 0.93 (0.79-1.10) 1.04 (0.91-1.19) 1.14 (0.98-1.31) Medium 1.40 (1.24-1.58)* 2.40 (2.20-2.62)* 1.18 (1.03-1.36)* 1.33 (1.19-1.48)* 1.42 (1.25-1.61)* High 1.45 (1.28-1.65)* 2.06 (1.87-2.28)* 1.34 (1.17-1.54)* 1.40 (1.27-1.55)* 1.46 (1.27-1.67)* Continuous 1.04 (1.03-1.06)* 1.08 (1.07-1.09)* 1.03 (1.02-1.05)* 1.04 (1.03-1.05)* 1.05 (1.03-1.06)* 2. Incretin-based medicines Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.08 (0.81-1.45) 2.73 (2.36-3.17)* 1.08 (0.78-1.50) 0.97 (0.75-1.25) 1.10 (0.81-1.49) Cumulative duration Low 1.77 (1.24-2.54)* 4.29 (3.57-5.16)* 1.69 (1.12-2.55)* 1.59 (1.16-2.18)* 1.72 (1.18-2.52)* Medium 1.04 (0.67-1.61) 2.56 (2.04-3.21)* 0.72 (0.40-1.30) 1.04 (0.72-1.50) 1.07 (0.68-1.67) High 1.58 (1.15-2.18)* 2.27 (1.81-2.85)* 1.31 (0.89-1.91) 1.42 (1.08-1.88)* 1.55 (1.11-2.18)* Continuous 1.08 (1.02-1.15)* 1.20 (1.15-1.24)* 1.04 (0.97-1.12) 1.07 (1.01-1.13)* 1.08 (1.02-1.16)* Cumulative dose Low 2.07 (1.48-2.90)* 4.17 (3.44-5.05)* 1.87 (1.26-2.76)* 1.78 (1.31-2.41)* 1.97 (1.38-2.82)* Medium 1.03 (0.66-1.59) 2.62 (2.10-3.27)* 0.83 (0.48-1.44) 1.03 (0.71-1.48) 1.06 (0.67-1.66) High 1.40 (1.00-1.96) 2.40 (1.93-2.99)* 1.12 (0.74-1.69) 1.32 (1.00-1.76) 1.40 (0.98-1.99) Continuous 1.09 (1.02-1.17)* 1.22 (1.17-1.27)* 1.04 (0.96-1.13) 1.08 (1.02-1.14)* 1.09 (1.02-1.17)* 2.1. DPP-4 inhibitors Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.13 (0.82-1.55) 2.99 (2.56-3.49)* 1.13 (0.79-1.60) 1.02 (0.77-1.34) 1.14 (0.82-1.58) Cumulative duration Low 1.60 (1.08-2.37)* 4.23 (3.49-5.12)* 1.50 (0.96-2.36) 1.40 (0.99-1.98) 1.60 (1.06-2.40)* Medium 1.11 (0.70-1.77) 2.69 (2.11-3.42)* 0.71 (0.37-1.36) 1.10 (0.75-1.62) 1.14 (0.71-1.84) High 1.50 (1.04-2.14)* 2.27 (1.77-2.90)* 1.28 (0.84-1.95) 1.43 (1.06-1.93)* 1.48 (1.01-2.16)* Continuous 1.09 (1.02-1.17)* 1.21 (1.17-1.26)* 1.04 (0.96-1.13) 1.08 (1.02-1.14)* 1.09 (1.02-1.17)* Cumulative dose Low 1.56 (1.05-2.31)* 4.16 (3.43-5.03)* 1.47 (0.94-2.30) 1.37 (0.97-1.94) 1.56 (1.04-2.35)* Medium 1.01 (0.62-1.65) 2.63 (2.05-3.37)* 0.72 (0.37-1.38) 1.04 (0.70-1.56) 1.03 (0.62-1.71) High 1.60 (1.13-2.27)* 2.34 (1.84-2.99)* 1.29 (0.85-1.96) 1.50 (1.12-2.02)* 1.59 (1.10-2.29)* Continuous 1.09 (1.02-1.17)* 1.22 (1.17-1.27)* 1.04 (0.96-1.13) 1.08 (1.02-1.14)* 1.09 (1.02-1.17)* 2.1.1. Linagliptin Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.10 (0.68-1.77) 2.98 (2.39-3.73)* 1.20 (0.71-2.02) 0.98 (0.65-1.47) 1.13 (0.69-1.84) Cumulative duration Low 1.04 (0.47-2.33) 4.90 (3.72-6.45)* 1.20 (0.50-2.88) 1.30 (0.72-2.35) 1.14 (0.51-2.53) Medium 1.41 (0.73-2.71) 3.06 (2.18-4.29)* 1.08 (0.45-2.59) 1.16 (0.64-2.09) 1.53 (0.80-2.94) High 1.25 (0.67-2.32) 1.90 (1.25-2.88)* 1.07 (0.51-2.25) 1.21 (0.73-2.02) 1.23 (0.64-2.37) Continuous 1.06 (0.90-1.26) 1.27 (1.15-1.40)* 1.03 (0.85-1.25) 1.05 (0.91-1.20) 1.06 (0.89-1.27) Cumulative dose Low 1.21 (0.58-2.55) 5.05 (3.85-6.62)* 1.43 (0.65-3.19) 1.42 (0.81-2.50) 1.32 (0.63-2.78) Medium 1.24 (0.62-2.49) 2.87 (2.03-4.07)* 0.86 (0.32-2.28) 1.05 (0.56-1.95) 1.34 (0.67-2.69) High 1.26 (0.68-2.34) 1.91 (1.26-2.91)* 1.08 (0.51-2.27) 1.22 (0.74-2.03) 1.24 (0.65-2.39) Continuous 1.06 (0.90-1.26) 1.27 (1.15-1.39)* 1.03 (0.85-1.25) 1.05 (0.91-1.20) 1.06 (0.89-1.27) 2.1.2. Sitagliptin Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.11 (0.69-1.78) 2.70 (2.11-3.46)* 1.09 (0.65-1.84) 0.98 (0.65-1.49) 1.06 (0.64-1.76) Cumulative duration Low 1.34 (0.79-2.26) 2.56 (1.87-3.51)* 1.33 (0.76-2.35) 1.27 (0.82-1.97) 1.36 (0.79-2.34) Medium 0.93 (0.52-1.69) 2.11 (1.52-2.93)* 0.69 (0.33-1.45) 1.14 (0.73-1.77) 0.93 (0.50-1.73) High 1.91 (1.28-2.85)* 2.61 (1.96-3.48)* 1.57 (0.97-2.52) 1.69 (1.19-2.39)* 1.85 (1.20-2.83)* Continuous 1.13 (1.04-1.23)* 1.23 (1.16-1.29)* 1.07 (0.97-1.19) 1.12 (1.04-1.20)* 1.13 (1.03-1.23)* Cumulative dose Low 1.30 (0.77-2.20) 2.47 (1.80-3.39)* 1.30 (0.74-2.29) 1.23 (0.79-1.91) 1.32 (0.77-2.27) 315 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 0.88 (0.47-1.64) 2.14 (1.54-2.99)* 0.61 (0.28-1.37) 1.13 (0.72-1.77) 0.87 (0.45-1.67) High 1.97 (1.33-2.92)* 2.64 (1.99-3.51)* 1.64 (1.03-2.61)* 1.72 (1.22-2.42)* 1.91 (1.26-2.91)* Continuous 1.13 (1.04-1.23)* 1.23 (1.16-1.30)* 1.07 (0.97-1.19) 1.12 (1.04-1.20)* 1.13 (1.04-1.24)* 2.2. GLP-1 receptor agonists Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.73 (0.33-1.63) 1.84 (1.23-2.75)* 0.76 (0.32-1.82) 0.71 (0.36-1.42) 0.79 (0.36-1.76) Cumulative duration Low 1.28 (0.53-3.07) 3.33 (2.17-5.10)* 0.64 (0.16-2.55) 1.43 (0.72-2.86) 1.09 (0.41-2.91) Medium 1.40 (0.63-3.12) 1.96 (1.14-3.38)* 1.45 (0.60-3.47) 1.02 (0.46-2.28) 1.52 (0.68-3.38) High 1.25 (0.60-2.63) 1.68 (0.98-2.90) 1.24 (0.56-2.77) 1.01 (0.50-2.02) 1.17 (0.52-2.60) Continuous 1.04 (0.85-1.28) 1.12 (0.97-1.29) 1.04 (0.84-1.29) 0.96 (0.79-1.18) 1.04 (0.83-1.28) Cumulative dose Low 1.22 (0.51-2.94) 3.30 (2.17-5.02)* 0.59 (0.15-2.35) 1.35 (0.67-2.70) 1.05 (0.40-2.81) Medium 2.01 (1.05-3.87)* 2.14 (1.27-3.62)* 2.20 (1.10-4.39)* 1.61 (0.87-3.00) 2.17 (1.13-4.16)* High 0.77 (0.29-2.04) 1.47 (0.81-2.66) 0.69 (0.22-2.13) 0.55 (0.21-1.47) 0.62 (0.20-1.93) Continuous 1.07 (0.46-2.51) 1.66 (1.14-2.43)* 1.14 (0.48-2.70) 0.81 (0.30-2.16) 1.08 (0.45-2.59) 3. SGLT-2 inhibitors Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.72 (1.16-2.54)* 3.07 (2.46-3.83)* 1.48 (0.91-2.42) 1.53 (1.07-2.19)* 1.77 (1.19-2.65)* Cumulative duration Low 0.66 (0.25-1.76) 3.38 (2.47-4.61)* 0.45 (0.11-1.81) 0.71 (0.32-1.58) 0.71 (0.27-1.89) Medium 1.61 (0.89-2.91) 2.71 (1.92-3.82)* 1.20 (0.54-2.67) 1.27 (0.72-2.24) 1.74 (0.96-3.14) High 2.22 (1.40-3.53)* 2.78 (1.97-3.92)* 1.86 (1.05-3.28)* 2.20 (1.47-3.29)* 2.12 (1.30-3.47)* Continuous 1.32 (1.14-1.52)* 1.46 (1.32-1.62)* 1.21 (1.01-1.45)* 1.29 (1.13-1.46)* 1.31 (1.13-1.53)* Cumulative dose Low 1.11 (0.53-2.34) 3.51 (2.60-4.74)* 0.88 (0.33-2.35) 1.02 (0.53-1.97) 1.20 (0.57-2.51) Medium 0.58 (0.22-1.55) 2.23 (1.53-3.26)* 0.60 (0.19-1.87) 0.64 (0.29-1.42) 0.47 (0.15-1.46) High 2.79 (1.84-4.25)* 3.12 (2.24-4.34)* 2.04 (1.18-3.52)* 2.54 (1.74-3.71)* 2.88 (1.87-4.42)* Continuous 1.24 (1.10-1.39)* 1.33 (1.23-1.44)* 1.16 (1.01-1.35)* 1.20 (1.08-1.34)* 1.23 (1.09-1.40)* 4. AGIs (i.e., acarbose) Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.91 (0.29-2.81) 2.36 (1.34-4.15)* 1.04 (0.34-3.24) 0.46 (0.19-1.10) 0.77 (0.19-3.08) Cumulative duration Low 1.19 (0.50-2.86) 2.99 (1.86-4.81)* 1.34 (0.56-3.21) 1.56 (1.04-2.35)* 1.20 (0.45-3.19) Medium 2.68 (1.48-4.84)* 3.01 (1.87-4.84)* 2.47 (1.29-4.74)* 1.49 (0.98-2.26) 2.81 (1.46-5.41)* High 1.23 (0.51-2.95) 1.71 (0.92-3.17) 1.37 (0.57-3.29) 1.05 (0.66-1.67) 1.31 (0.49-3.49) Continuous 1.04 (0.91-1.20) 1.08 (0.98-1.18) 1.05 (0.91-1.21) 1.02 (0.95-1.10) 1.00 (0.81-1.23) Cumulative dose Low 1.24 (0.52-2.98) 3.11 (1.93-5.01)* 1.38 (0.58-3.32) 1.59 (1.05-2.39)* 1.26 (0.47-3.35) Medium 2.53 (1.40-4.57)* 2.84 (1.76-4.57)* 2.33 (1.21-4.47)* 1.37 (0.89-2.11) 2.60 (1.35-4.99)* High 1.25 (0.52-3.01) 1.74 (0.94-3.23) 1.40 (0.58-3.37) 1.13 (0.72-1.77) 1.36 (0.51-3.61) Continuous 1.11 (0.92-1.33) 1.13 (0.98-1.30) 1.13 (0.94-1.35) 1.01 (0.90-1.13) 0.96 (0.67-1.39) 5. Insulin secretagogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.43 (1.25-1.64)* 4.10 (3.82-4.41)* 1.21 (1.04-1.42)* 1.09 (0.98-1.22) 1.48 (1.28-1.70)* Cumulative duration Low 1.32 (1.10-1.59)* 5.86 (5.41-6.33)* 1.14 (0.92-1.40) 1.14 (0.97-1.34) 1.38 (1.14-1.66)* Medium 1.64 (1.39-1.94)* 2.49 (2.20-2.81)* 1.24 (1.01-1.52)* 1.40 (1.22-1.60)* 1.69 (1.42-2.02)* High 1.51 (1.26-1.80)* 1.91 (1.66-2.20)* 1.39 (1.14-1.69)* 1.37 (1.22-1.54)* 1.48 (1.21-1.80)* Continuous 1.05 (1.04-1.07)* 1.08 (1.07-1.10)* 1.04 (1.02-1.06)* 1.03 (1.02-1.04)* 1.06 (1.04-1.08)* Cumulative dose Low 1.32 (1.11-1.58)* 5.18 (4.78-5.61)* 1.04 (0.85-1.29) 1.10 (0.94-1.29) 1.36 (1.13-1.63)* Medium 1.45 (1.22-1.73)* 2.68 (2.39-3.01)* 1.20 (0.98-1.47) 1.26 (1.10-1.45)* 1.53 (1.27-1.83)* High 1.74 (1.46-2.08)* 2.23 (1.94-2.56)* 1.60 (1.31-1.94)* 1.52 (1.35-1.71)* 1.72 (1.41-2.09)* Continuous 1.02 (1.02-1.03)* 1.03 (1.03-1.04)* 1.02 (1.01-1.03)* 1.02 (1.01-1.02)* 1.03 (1.02-1.03)* 5.1. Meglitinides Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.50 (0.63-3.59) 3.54 (2.20-5.69)* 1.67 (0.69-4.00) 1.07 (0.51-2.25) 1.37 (0.51-3.65) Cumulative duration Low 2.97 (1.60-5.52)* 4.34 (2.80-6.73)* 2.95 (1.53-5.67)* 2.73 (1.78-4.20)* 3.14 (1.64-6.04)* Medium 0.91 (0.30-2.84) 2.43 (1.34-4.38)* 1.02 (0.33-3.17) 1.10 (0.55-2.19) 1.07 (0.34-3.30) High 2.11 (1.10-4.06)* 2.39 (1.42-4.04)* 2.32 (1.21-4.46)* 1.40 (0.79-2.47) 1.66 (0.74-3.69) Continuous 1.10 (1.00-1.21) 1.10 (1.02-1.20)* 1.11 (1.01-1.22)* 1.06 (0.98-1.16) 1.05 (0.92-1.20) Cumulative dose Low 2.92 (1.62-5.27)* 4.48 (2.98-6.75)* 2.93 (1.58-5.45)* 2.44 (1.56-3.82)* 3.10 (1.67-5.76)* 316 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 0.57 (0.14-2.30) 1.45 (0.69-3.05) 0.64 (0.16-2.55) 1.06 (0.53-2.12) 0.67 (0.17-2.68) High 2.46 (1.28-4.73)* 2.97 (1.79-4.92)* 2.71 (1.41-5.22)* 1.72 (1.02-2.90)* 1.94 (0.87-4.33) Continuous 1.08 (1.03-1.13)* 1.08 (1.03-1.12)* 1.09 (1.04-1.14)* 1.05 (1.01-1.10)* 1.02 (0.90-1.15) 5.1.1. Repaglinide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.51 (0.63-3.62) 3.57 (2.22-5.74)* 1.68 (0.70-4.04) 1.08 (0.52-2.27) 1.38 (0.52-3.67) Cumulative duration Low 3.03 (1.63-5.63)* 4.43 (2.86-6.86)* 3.01 (1.57-5.79)* 2.79 (1.82-4.28)* 3.21 (1.67-6.17)* Medium 0.92 (0.30-2.86) 2.45 (1.36-4.42)* 1.03 (0.33-3.21) 1.11 (0.55-2.21) 1.08 (0.35-3.34) High 2.14 (1.11-4.12)* 2.42 (1.43-4.09)* 2.35 (1.22-4.52)* 1.42 (0.81-2.50) 1.67 (0.75-3.72) Continuous 1.10 (1.00-1.21) 1.10 (1.02-1.20)* 1.11 (1.01-1.22)* 1.06 (0.98-1.16) 1.05 (0.92-1.20) Cumulative dose Low 2.96 (1.64-5.35)* 4.55 (3.02-6.85)* 2.98 (1.60-5.54)* 2.45 (1.56-3.85)* 3.14 (1.69-5.84)* Medium 0.58 (0.15-2.34) 1.48 (0.71-3.10) 0.65 (0.16-2.60) 1.08 (0.54-2.16) 0.68 (0.17-2.72) High 2.49 (1.29-4.78)* 3.00 (1.80-4.97)* 2.74 (1.43-5.27)* 1.73 (1.03-2.93)* 1.96 (0.88-4.37) Continuous 1.08 (1.03-1.13)* 1.08 (1.03-1.12)* 1.09 (1.04-1.14)* 1.05 (1.01-1.10)* 1.02 (0.90-1.15) 5.2. Sulfonylureas Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.43 (1.25-1.64)* 4.13 (3.84-4.43)* 1.21 (1.03-1.41)* 1.10 (0.98-1.23) 1.48 (1.29-1.71)* Cumulative duration Low 1.36 (1.13-1.63)* 5.87 (5.43-6.35)* 1.18 (0.96-1.45) 1.15 (0.98-1.35) 1.41 (1.16-1.70)* Medium 1.60 (1.35-1.90)* 2.44 (2.16-2.77)* 1.18 (0.96-1.46) 1.38 (1.20-1.58)* 1.63 (1.36-1.95)* High 1.52 (1.27-1.82)* 1.92 (1.66-2.21)* 1.40 (1.15-1.70)* 1.38 (1.22-1.55)* 1.51 (1.24-1.84)* Continuous 1.05 (1.04-1.07)* 1.08 (1.07-1.10)* 1.04 (1.02-1.06)* 1.03 (1.02-1.04)* 1.06 (1.04-1.08)* Cumulative dose Low 1.35 (1.13-1.61)* 5.22 (4.81-5.66)* 1.07 (0.87-1.31) 1.10 (0.94-1.29) 1.37 (1.14-1.65)* Medium 1.45 (1.22-1.73)* 2.68 (2.39-3.01)* 1.19 (0.97-1.46) 1.27 (1.10-1.46)* 1.50 (1.25-1.81)* High 1.72 (1.44-2.06)* 2.20 (1.91-2.53)* 1.57 (1.29-1.91)* 1.51 (1.35-1.70)* 1.73 (1.43-2.11)* Continuous 1.02 (1.02-1.03)* 1.03 (1.03-1.04)* 1.02 (1.01-1.03)* 1.02 (1.01-1.02)* 1.03 (1.02-1.03)* 5.2.1. Gliclazide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.35 (1.11-1.64)* 3.75 (3.39-4.14)* 1.18 (0.94-1.48) 1.15 (0.97-1.36) 1.40 (1.15-1.72)* Cumulative duration Low 1.68 (1.29-2.18)* 5.78 (5.13-6.52)* 1.56 (1.16-2.09)* 1.49 (1.21-1.84)* 1.75 (1.34-2.29)* Medium 1.35 (1.03-1.77)* 2.95 (2.52-3.45)* 0.83 (0.57-1.21) 1.33 (1.08-1.64)* 1.33 (1.00-1.77) High 1.51 (1.19-1.93)* 1.85 (1.54-2.24)* 1.49 (1.15-1.92)* 1.38 (1.15-1.67)* 1.51 (1.17-1.95)* Continuous 1.06 (1.02-1.09)* 1.11 (1.09-1.13)* 1.04 (1.01-1.08)* 1.05 (1.02-1.07)* 1.06 (1.02-1.10)* Cumulative dose Low 1.49 (1.14-1.95)* 5.39 (4.78-6.07)* 1.35 (0.99-1.82) 1.36 (1.09-1.69)* 1.54 (1.17-2.03)* Medium 1.46 (1.13-1.89)* 2.88 (2.46-3.37)* 1.05 (0.75-1.45) 1.38 (1.13-1.69)* 1.45 (1.11-1.91)* High 1.57 (1.22-2.01)* 1.99 (1.65-2.40)* 1.48 (1.13-1.95)* 1.45 (1.20-1.75)* 1.56 (1.20-2.03)* Continuous 1.02 (1.01-1.03)* 1.03 (1.02-1.04)* 1.02 (1.01-1.03)* 1.01 (1.01-1.02)* 1.02 (1.01-1.03)* 5.2.2. Glyburide Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.50 (1.25-1.80)* 4.27 (3.89-4.69)* 1.25 (1.01-1.55)* 1.06 (0.92-1.23) 1.55 (1.28-1.89)* Cumulative duration Low 1.25 (1.02-1.54)* 4.47 (4.05-4.93)* 1.11 (0.88-1.40) 1.03 (0.86-1.23) 1.31 (1.05-1.62)* Medium 1.88 (1.56-2.27)* 2.66 (2.32-3.06)* 1.45 (1.16-1.81)* 1.45 (1.25-1.68)* 1.92 (1.57-2.34)* High 1.53 (1.23-1.89)* 1.80 (1.52-2.14)* 1.36 (1.07-1.72)* 1.40 (1.23-1.60)* 1.52 (1.20-1.93)* Continuous 1.06 (1.04-1.08)* 1.09 (1.07-1.10)* 1.04 (1.02-1.07)* 1.04 (1.02-1.05)* 1.07 (1.04-1.09)* Cumulative dose Low 1.26 (1.04-1.54)* 4.10 (3.72-4.52)* 1.06 (0.84-1.33) 1.06 (0.89-1.27) 1.28 (1.04-1.58)* Medium 1.68 (1.39-2.03)* 2.58 (2.25-2.95)* 1.42 (1.14-1.76)* 1.32 (1.14-1.54)* 1.74 (1.42-2.13)* High 1.81 (1.45-2.25)* 2.12 (1.78-2.53)* 1.53 (1.19-1.96)* 1.49 (1.31-1.70)* 1.85 (1.45-2.37)* Continuous 1.03 (1.02-1.05)* 1.04 (1.04-1.05)* 1.03 (1.01-1.04)* 1.02 (1.01-1.03)* 1.04 (1.03-1.05)* 6. Thiazolidinediones Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.94 (0.54-1.62) 2.91 (2.25-3.76)* 0.74 (0.38-1.41) 0.86 (0.59-1.26) 1.12 (0.65-1.92) Cumulative duration Low 1.43 (0.97-2.10) 3.31 (2.67-4.12)* 1.16 (0.74-1.82) 1.43 (1.09-1.86)* 1.59 (1.08-2.36)* Medium 1.67 (1.16-2.41)* 2.13 (1.62-2.81)* 1.34 (0.87-2.06) 1.29 (0.97-1.71) 1.84 (1.26-2.68)* High 1.90 (1.38-2.63)* 2.42 (1.90-3.08)* 1.50 (1.02-2.20)* 1.79 (1.43-2.24)* 2.05 (1.45-2.88)* Continuous 1.10 (1.05-1.15)* 1.14 (1.10-1.18)* 1.06 (1.00-1.12) 1.08 (1.05-1.12)* 1.12 (1.06-1.17)* Cumulative dose Low 1.36 (0.92-2.02) 3.28 (2.64-4.07)* 1.02 (0.64-1.65) 1.38 (1.05-1.82)* 1.51 (1.01-2.25)* 317 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 2.00 (1.44-2.78)* 2.38 (1.84-3.07)* 1.67 (1.15-2.44)* 1.57 (1.22-2.02)* 2.15 (1.53-3.03)* High 1.66 (1.17-2.37)* 2.22 (1.71-2.87)* 1.31 (0.86-2.00) 1.59 (1.25-2.01)* 1.83 (1.26-2.65)* Continuous 1.09 (1.04-1.14)* 1.12 (1.09-1.16)* 1.06 (1.00-1.12) 1.07 (1.04-1.10)* 1.10 (1.05-1.16)* 6.1. Pioglitazone Never 1.00 1.00 1.00 1.00 1.00 Ever use 0.78 (0.35-1.74) 2.40 (1.65-3.51)* 0.75 (0.31-1.79) 0.75 (0.42-1.32) 0.93 (0.42-2.07) Cumulative duration Low 0.96 (0.48-1.91) 2.57 (1.80-3.68)* 0.40 (0.13-1.24) 1.17 (0.75-1.81) 0.97 (0.46-2.04) Medium 1.54 (0.89-2.65) 2.02 (1.35-3.01)* 1.46 (0.81-2.63) 1.53 (1.05-2.23)* 1.41 (0.76-2.63) High 1.64 (1.01-2.68)* 2.25 (1.58-3.20)* 0.81 (0.39-1.70) 1.53 (1.08-2.18)* 1.71 (1.01-2.89)* Continuous 1.09 (1.01-1.17)* 1.12 (1.07-1.18)* 1.00 (0.89-1.11) 1.08 (1.03-1.14)* 1.10 (1.02-1.18)* Cumulative dose Low 0.95 (0.48-1.91) 2.66 (1.87-3.79)* 0.40 (0.13-1.23) 1.24 (0.81-1.90) 0.96 (0.46-2.02) Medium 1.95 (1.21-3.13)* 2.27 (1.56-3.29)* 1.67 (0.97-2.88) 1.83 (1.30-2.57)* 1.77 (1.03-3.04)* High 1.27 (0.72-2.24) 1.94 (1.32-2.86)* 0.60 (0.25-1.43) 1.20 (0.80-1.79) 1.40 (0.77-2.52) Continuous 1.07 (1.00-1.15) 1.10 (1.05-1.16)* 0.99 (0.89-1.10) 1.05 (1.00-1.11)* 1.08 (1.00-1.16) 6.2. Rosiglitazone Never 1.00 1.00 1.00 1.00 1.00 Ever use 1.08 (0.52-2.27) 3.40 (2.39-4.84)* 0.69 (0.26-1.85) 0.94 (0.57-1.56) 1.30 (0.62-2.73) Cumulative duration Low 1.43 (0.89-2.30) 3.14 (2.39-4.14)* 1.21 (0.70-2.09) 1.42 (1.03-1.96)* 1.67 (1.04-2.69)* Medium 1.81 (1.18-2.78)* 2.19 (1.57-3.05)* 1.53 (0.94-2.51) 1.53 (1.12-2.09)* 2.15 (1.40-3.30)* High 1.96 (1.31-2.92)* 2.44 (1.80-3.31)* 1.80 (1.16-2.79)* 1.68 (1.27-2.23)* 2.20 (1.45-3.34)* Continuous 1.13 (1.06-1.21)* 1.18 (1.13-1.24)* 1.11 (1.03-1.20)* 1.10 (1.05-1.16)* 1.16 (1.08-1.24)* Cumulative dose Low 1.41 (0.88-2.27) 3.05 (2.31-4.03)* 1.20 (0.69-2.06) 1.34 (0.96-1.87) 1.65 (1.03-2.66)* Medium 1.91 (1.27-2.88)* 2.28 (1.66-3.14)* 1.57 (0.98-2.53) 1.55 (1.14-2.11)* 2.24 (1.49-3.37)* High 1.88 (1.24-2.86)* 2.45 (1.79-3.34)* 1.79 (1.14-2.81)* 1.74 (1.32-2.30)* 2.13 (1.37-3.30)* Continuous 1.13 (1.06-1.20)* 1.17 (1.12-1.22)* 1.12 (1.04-1.20)* 1.10 (1.05-1.14)* 1.15 (1.08-1.22)* 7. Insulins and analogues Never 1.00 1.00 1.00 1.00 1.00 Ever use 2.84 (2.43-3.32)* 11.00 (10.21-11.84)* 2.48 (2.08-2.96)* 2.18 (1.96-2.42)* 2.87 (2.43-3.40)* Cumulative duration Low 2.66 (2.11-3.36)* 18.37 (16.97-19.88)* 2.01 (1.50-2.68)* 1.83 (1.49-2.25)* 2.83 (2.22-3.59)* Medium 3.06 (2.48-3.78)* 3.57 (2.99-4.26)* 2.72 (2.15-3.44)* 2.30 (1.97-2.69)* 2.98 (2.37-3.73)* High 2.18 (1.58-3.00)* 2.20 (1.64-2.94)* 2.25 (1.63-3.12)* 2.09 (1.79-2.43)* 2.31 (1.64-3.25)* Continuous 1.14 (1.11-1.18)* 1.16 (1.13-1.19)* 1.14 (1.10-1.17)* 1.08 (1.06-1.09)* 1.15 (1.11-1.19)* Cumulative dose Low 2.65 (2.11-3.33)* 17.76 (16.42-19.20)* 2.13 (1.62-2.80)* 1.83 (1.50-2.25)* 2.85 (2.26-3.60)* Medium 3.18 (2.57-3.92)* 3.34 (2.77-4.03)* 2.77 (2.19-3.50)* 2.29 (1.96-2.67)* 3.13 (2.50-3.93)* High 2.04 (1.46-2.85)* 1.99 (1.47-2.71)* 2.04 (1.45-2.88)* 2.11 (1.81-2.46)* 2.00 (1.38-2.90)* Continuous 1.04 (1.03-1.05)* 1.05 (1.04-1.05)* 1.04 (1.03-1.05)* 1.01 (1.01-1.01)* 1.04 (1.03-1.06)* 7.1. Basal insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 2.91 (2.48-3.41)* 10.85 (10.05-11.72)* 2.53 (2.11-3.03)* 2.20 (1.97-2.45)* 2.92 (2.46-3.47)* Cumulative duration Low 2.66 (2.09-3.38)* 18.06 (16.64-19.61)* 1.97 (1.46-2.66)* 1.83 (1.48-2.26)* 2.82 (2.20-3.61)* Medium 2.98 (2.40-3.71)* 3.58 (2.99-4.28)* 2.78 (2.19-3.52)* 2.30 (1.97-2.69)* 2.99 (2.37-3.77)* High 2.31 (1.69-3.16)* 2.24 (1.68-2.98)* 2.33 (1.70-3.21)* 2.10 (1.80-2.44)* 2.25 (1.59-3.18)* Continuous 1.16 (1.12-1.20)* 1.19 (1.15-1.22)* 1.16 (1.11-1.20)* 1.08 (1.07-1.10)* 1.17 (1.13-1.22)* Cumulative dose Low 2.69 (2.13-3.40)* 17.67 (16.30-19.16)* 2.10 (1.57-2.79)* 1.85 (1.50-2.28)* 2.85 (2.24-3.63)* Medium 3.01 (2.42-3.75)* 3.20 (2.64-3.88)* 2.75 (2.16-3.49)* 2.23 (1.91-2.62)* 2.98 (2.35-3.76)* High 2.21 (1.60-3.05)* 2.17 (1.61-2.92)* 2.22 (1.59-3.10)* 2.15 (1.85-2.50)* 2.19 (1.53-3.14)* Continuous 1.05 (1.04-1.06)* 1.05 (1.04-1.06)* 1.05 (1.04-1.06)* 1.04 (1.03-1.04)* 1.05 (1.04-1.07)* 7.2. Bolus insulins Never 1.00 1.00 1.00 1.00 1.00 Ever use 3.97 (3.15-5.01)* 13.73 (12.31-15.33)* 3.67 (2.85-4.72)* 2.71 (2.35-3.13)* 4.08 (3.19-5.23)* Cumulative duration Low 4.44 (3.39-5.82)* 17.43 (15.49-19.61)* 3.69 (2.69-5.05)* 3.28 (2.68-4.02)* 5.00 (3.80-6.56)* Medium 2.89 (2.03-4.11)* 4.61 (3.60-5.91)* 2.64 (1.80-3.88)* 1.97 (1.55-2.51)* 3.04 (2.10-4.40)* High 3.37 (2.19-5.17)* 3.13 (2.11-4.64)* 3.58 (2.33-5.50)* 2.38 (1.93-2.94)* 2.95 (1.78-4.91)* Continuous 1.24 (1.17-1.32)* 1.26 (1.20-1.32)* 1.24 (1.17-1.32)* 1.11 (1.08-1.14)* 1.24 (1.16-1.33)* Cumulative dose Low 4.16 (3.17-5.45)* 17.14 (15.28-19.24)* 3.38 (2.45-4.65)* 3.19 (2.62-3.90)* 4.69 (3.57-6.16)* 318 Exposure Model 1 Model 2 Model 3 Model 4 Model 5 Medium 2.94 (2.04-4.24)* 3.79 (2.85-5.05)* 2.85 (1.94-4.19)* 1.87 (1.46-2.40)* 3.20 (2.19-4.67)* High 3.64 (2.42-5.49)* 3.21 (2.18-4.71)* 3.69 (2.43-5.61)* 2.49 (2.02-3.07)* 3.12 (1.91-5.09)* Continuous 1.06 (1.04-1.09)* 1.07 (1.05-1.09)* 1.06 (1.04-1.09)* 1.04 (1.03-1.05)* 1.06 (1.04-1.09)* Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 1-year lag periods in the primary analysis. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 0-year lag periods. Model 3 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 1-year washout and 2-year lag periods. Model 4 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 0-year washout and 1-year lag periods. Model 5 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income with 2-year washout and 1-year lag periods. This table displays associations between all diabetes medications and pancreatic cancer. For a summary of selected medications with significant associations, please refer to Table 7-4. * denotes p<0.05. 319 Supplementary Table D-4. Associations between all diabetes medications and the risk of pancreatic cancer among people in the BCGP Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 1. Biguanides (i.e., metformin) Never 537,721 48 8.9 (6.7-11.8) 1.00 1.00 1.00 Ever use 8,443 Suppressed 47.4 (17.8-126.2) 1.29 (1.18-1.41)* 2.37 (0.85-6.64) 2.90 (0.99-8.48) Cumulative duration - trend 1.03 (1.02-1.04)* 1.11 (1.00-1.22)* 1.13 (1.02-1.25)* Cumulative dose - trend 1.04 (1.03-1.06)* 1.14 (1.03-1.26)* 1.16 (1.05-1.29)* 2. Incretin-based medicines Never 544,775 51 9.4 (7.1-12.3) 1.00 1.00 1.00 Ever use 1,389 Suppressed 72.0 (10.1-511.1) 1.08 (0.81-1.45) Not shown Not shown Cumulative duration - trend 1.08 (1.02-1.15)* 1.44 (1.09-1.88)* 1.55 (1.18-2.05)* Cumulative dose - trend 1.09 (1.02-1.17)* 1.52 (1.16-1.99)* 1.65 (1.26-2.17)* 2.1. DPP-4 inhibitors Never 545,345 51 9.4 (7.1-12.3) 1.00 1.00 1.00 Ever use 819 Suppressed 122.1 (17.2-866.8) 1.13 (0.82-1.55) Not shown Not shown Cumulative duration - trend 1.09 (1.02-1.17)* 1.53 (1.17-1.99)* 1.66 (1.26-2.18)* Cumulative dose - trend 1.09 (1.02-1.17)* 1.53 (1.17-2.00)* 1.66 (1.27-2.18)* 2.1.2. Sitagliptin Never 545,712 51 9.3 (7.1-12.3) 1.00 1.00 1.00 Ever use 452 Suppressed 221.2 (31.2-1570.6) 1.11 (0.69-1.78) Not shown Not shown Cumulative duration - trend 1.13 (1.04-1.23)* 1.59 (1.14-2.20)* 1.67 (1.21-2.30)* Cumulative dose - trend 1.13 (1.04-1.23)* 1.59 (1.15-2.20)* 1.67 (1.21-2.30)* 3. SGLT-2 inhibitors Never 545,638 51 9.3 (7.1-12.3) 1.00 1.00 1.00 Ever use 526 Suppressed 190.1 (26.8-1349.7) 1.72 (1.16-2.54)* Not shown Not shown Cumulative duration - trend 1.32 (1.14-1.52)* 2.10 (1.03-4.30)* 2.39 (1.15-4.93)* Cumulative dose - trend 1.24 (1.10-1.39)* 1.69 (1.01-2.83)* 1.85 (1.10-3.11)* 4. AGIs (i.e., acarbose) Never 546,085 51 9.3 (7.1-12.3) 1.00 1.00 1.00 Ever use 79 Suppressed 1265.8 (178.3-8986.5) 0.91 (0.29-2.81) Not shown Not shown Cumulative duration - trend 1.04 (0.91-1.20) 1.51 (1.01-2.27)* 1.40 (0.92-2.13) Cumulative dose - trend 1.11 (0.92-1.33) 1.75 (0.90-3.38) 1.77 (0.82-3.85) 5. Insulin secretagogues Never 543,809 50 9.2 (7.0-12.1) 1.00 1.00 1.00 Ever use 2,355 Suppressed 84.9 (21.2-339.6) 1.43 (1.25-1.64)* Not shown Not shown Cumulative duration - trend 1.05 (1.04-1.07)* 1.17 (1.03-1.33)* 1.20 (1.05-1.37)* Cumulative dose - trend 1.02 (1.02-1.03)* 1.07 (1.03-1.11)* 1.08 (1.04-1.13)* 5.2. Sulfonylureas Never 543,866 50 9.2 (7.0-12.1) 1.00 1.00 1.00 Ever use 2,298 Suppressed 87.0 (21.8-348.0) 1.43 (1.25-1.64)* Not shown Not shown Cumulative duration - trend 1.05 (1.04-1.07)* 1.17 (1.04-1.33)* 1.20 (1.05-1.37)* Cumulative dose - trend 1.02 (1.02-1.03)* 1.07 (1.03-1.11)* 1.08 (1.04-1.13)* 5.2.1. Gliclazide Never 544,845 51 9.4 (7.1-12.3) 1.00 1.00 1.00 Ever use 1,319 Suppressed 75.8 (10.7-538.2) 1.35 (1.11-1.64)* Not shown Not shown Cumulative duration - trend 1.06 (1.02-1.09)* 1.21 (1.06-1.38)* 1.29 (1.10-1.51)* 320 Exposure Person-years Events Incidence rate Model 1 Model 2 Model 3 Cumulative dose - trend 1.02 (1.01-1.03)* 1.07 (1.03-1.11)* 1.09 (1.05-1.14)* 6. Thiazolidinediones Never 545,633 51 9.3 (7.1-12.3) 1.00 1.00 1.00 Ever use 531 Suppressed 188.3 (26.5-1337.0) 0.94 (0.54-1.62) Not shown Not shown Cumulative duration - trend 1.10 (1.05-1.15)* 1.22 (0.93-1.61) 1.28 (0.96-1.69) Cumulative dose - trend 1.09 (1.04-1.14)* 1.13 (0.81-1.57) 1.18 (0.83-1.67) 6.1. Pioglitazone Never 545,943 51 9.3 (7.1-12.3) 1.00 1.00 1.00 Ever use 221 Suppressed 452.5 (63.7-3212.4) 0.78 (0.35-1.74) Not shown Not shown Cumulative duration - trend 1.09 (1.01-1.17)* 1.21 (0.80-1.84) 1.27 (0.82-1.97) Cumulative dose - trend 1.07 (1.00-1.15) 1.09 (0.65-1.83) 1.13 (0.66-1.96) 7. Insulins and analogues Never 544,673 50 9.2 (7.0-12.1) 1.00 1.00 1.00 Ever use 1,491 Suppressed 134.1 (33.5-536.4) 2.84 (2.43-3.32)* Not shown Not shown Cumulative duration - trend 1.14 (1.11-1.18)* 1.14 (0.77-1.69) 1.19 (0.80-1.77) Cumulative dose - trend 1.04 (1.03-1.05)* 1.04 (0.80-1.35) 1.07 (0.82-1.38) 7.1. Basal insulins Never 544,761 50 9.2 (7.0-12.1) 1.00 1.00 1.00 Ever use 1,403 Suppressed 142.6 (35.7-570.0) 2.91 (2.48-3.41)* Not shown Not shown Cumulative duration - trend 1.16 (1.12-1.20)* 1.20 (0.76-1.90) 1.27 (0.79-2.02) Cumulative dose - trend 1.05 (1.04-1.06)* 1.06 (0.79-1.42) 1.08 (0.81-1.45) 7.2. Bolus insulins Never 545,495 50 9.2 (6.9-12.1) 1.00 1.00 1.00 Ever use 669 Suppressed 299.0 (74.8-1195.4) 3.97 (3.15-5.01)* Not shown Not shown Cumulative duration - trend 1.24 (1.17-1.32)* 1.19 (0.40-3.51) 1.29 (0.44-3.79) Cumulative dose - trend 1.06 (1.04-1.09)* 1.06 (0.57-1.97) 1.11 (0.60-2.06) Incidence rate: per 100,000 person-years. Model 1 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile in the primary analysis using Population Data BC. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile in the BCGP subset. Model 3 further adjusted for sociodemographic and lifestyle-related factors: race/ethnicity, marital status, physical activity, education, individual-level income, fruit and vegetable consumption, alcohol consumption, smoking status, waist to hip ratio, and body mass index using the BCGP subset. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. Effect estimates denoted as “Not shown” have been omitted due to low number of events, which may result in unreliable estimates. This table displays associations between all diabetes medications and pancreatic cancer. For a summary of selected medications with significant associations, please refer to Table 7-5. * denotes p<0.05. 321 Supplementary Table D-5. Associations between all diabetes medications and the risk of pancreatic cancer morphological subtype: adenocarcinoma Exposure Person-years Events Incidence rate Model 1 Model 2 1. Biguanides (i.e., metformin) Never 50,067,218 6,525 13.0 (12.7-13.4) 1.00 1.00 Ever use 2,021,426 669 31.3 (28.6-34.2) 1.32 (1.20-1.45)* 1.24 (1.13-1.36)* Cumulative duration Low 736,609 175 23.8 (20.5-27.6) 1.18 (1.02-1.38)* 1.14 (0.98-1.33) Medium 720,912 268 37.2 (33.0-41.9) 1.60 (1.41-1.80)* 1.51 (1.34-1.71)* High 563,905 226 40.1 (35.2-45.7) 1.32 (1.16-1.51)* 1.22 (1.06-1.39)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.04)* Cumulative dose Low 761,186 184 24.2 (20.9-27.9) 1.13 (0.98-1.31) 1.09 (0.94-1.27) Medium 720,432 254 35.3 (31.2-39.9) 1.46 (1.29-1.65)* 1.38 (1.22-1.57)* High 539,808 231 42.8 (37.6-48.7) 1.54 (1.35-1.76)* 1.41 (1.23-1.61)* Continuous 1.05 (1.04-1.07)* 1.04 (1.03-1.06)* 2. Incretin-based medicines Never 51,846,234 7,114 13.7 (13.4-14.0) 1.00 1.00 Ever use 242,410 80 24.1 (17.7-32.7) 1.18 (0.87-1.60) 1.05 (0.77-1.42) Cumulative duration Low 76,647 25 32.6 (22.0-48.3) 1.75 (1.18-2.58)* 1.57 (1.06-2.32)* Medium 82,123 19 23.1 (14.8-36.3) 1.18 (0.75-1.85) 1.05 (0.67-1.64) High 83,640 36 43.0 (31.0-59.7) 1.81 (1.31-2.51)* 1.59 (1.15-2.21)* Continuous 1.11 (1.04-1.18)* 1.08 (1.01-1.15)* Cumulative dose Low 79,230 30 37.9 (26.5-54.2) 2.18 (1.52-3.12)* 1.95 (1.36-2.79)* Medium 80,356 18 22.4 (14.1-35.6) 1.10 (0.69-1.75) 0.98 (0.62-1.56) High 82,824 32 38.6 (27.3-54.6) 1.58 (1.12-2.24)* 1.39 (0.98-1.98) Continuous 1.12 (1.04-1.20)* 1.09 (1.01-1.17)* 2.1. DPP-4 inhibitors Never 51,896,422 7,126 13.7 (13.4-14.1) 1.00 1.00 Ever use 192,222 68 27.8 (20.1-38.6) 1.24 (0.89-1.72) 1.10 (0.80-1.53) Cumulative duration Low 63,002 23 36.5 (24.3-54.9) 1.74 (1.15-2.61)* 1.56 (1.03-2.34)* Medium 63,244 17 26.9 (16.7-43.2) 1.26 (0.78-2.02) 1.11 (0.69-1.79) High 65,976 28 42.4 (29.3-61.5) 1.68 (1.16-2.43)* 1.48 (1.02-2.14)* Continuous 1.12 (1.04-1.20)* 1.09 (1.01-1.17)* Cumulative dose Low 64,188 23 35.8 (23.8-53.9) 1.69 (1.13-2.55)* 1.52 (1.01-2.29)* Medium 61,937 15 24.2 (14.6-40.2) 1.13 (0.68-1.87) 1.00 (0.60-1.66) High 66,097 30 45.4 (31.7-64.9) 1.80 (1.26-2.58)* 1.59 (1.11-2.27)* Continuous 1.12 (1.04-1.20)* 1.09 (1.01-1.17)* 2.1.1. Linagliptin Never 52,023,970 7,171 13.8 (13.5-14.1) 1.00 1.00 Ever use 64,674 23 30.1 (18.2-50.0) 1.15 (0.69-1.91) 1.02 (0.61-1.69) Cumulative duration Low 19,887 Suppressed 25.1 (10.5-60.4) 1.04 (0.43-2.50) 0.92 (0.38-2.21) Medium 21,325 Suppressed 42.2 (22.0-81.1) 1.68 (0.87-3.22) 1.49 (0.78-2.86) High 23,462 Suppressed 38.4 (20.0-73.7) 1.33 (0.69-2.56) 1.18 (0.62-2.28) Continuous 1.10 (0.93-1.30) 1.06 (0.89-1.26) Cumulative dose Low 19,952 Suppressed 30.1 (13.5-66.9) 1.24 (0.56-2.77) 1.10 (0.49-2.45) Medium 21,425 Suppressed 37.3 (18.7-74.7) 1.49 (0.74-2.97) 1.31 (0.66-2.63) High 23,297 Suppressed 38.6 (20.1-74.2) 1.34 (0.70-2.58) 1.19 (0.62-2.29) Continuous 1.10 (0.93-1.30) 1.06 (0.89-1.26) 2.1.2. Sitagliptin Never 51,955,454 7,148 13.8 (13.4-14.1) 1.00 1.00 Ever use 133,190 46 24.4 (14.9-39.8) 1.24 (0.76-2.02) 1.11 (0.68-1.81) Cumulative duration Low 42,249 14 33.1 (19.6-56.0) 1.57 (0.93-2.66) 1.42 (0.84-2.39) Medium 47,499 10 21.1 (11.3-39.1) 1.01 (0.54-1.88) 0.90 (0.48-1.67) High 43,442 22 50.6 (33.3-76.9) 2.11 (1.39-3.21)* 1.85 (1.22-2.82)* Continuous 1.16 (1.06-1.26)* 1.12 (1.03-1.22)* Cumulative dose Low 43,259 14 32.4 (19.2-54.6) 1.53 (0.90-2.58) 1.38 (0.81-2.33) 322 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 45,625 Suppressed 19.7 (10.3-37.9) 0.95 (0.49-1.82) 0.84 (0.44-1.62) High 44,306 23 51.9 (34.5-78.1) 2.19 (1.46-3.30)* 1.92 (1.27-2.89)* Continuous 1.16 (1.06-1.26)* 1.13 (1.03-1.23)* 2.2. GLP-1 receptor agonists Never 52,013,587 7,179 13.8 (13.5-14.1) 1.00 1.00 Ever use 75,057 15 10.8 (4.5-25.8) 0.75 (0.31-1.81) 0.66 (0.28-1.59) Cumulative duration Low 23,429 Suppressed 8.5 (2.1-34.1) 0.62 (0.16-2.49) 0.56 (0.14-2.21) Medium 25,502 Suppressed 23.5 (10.6-52.4) 1.73 (0.78-3.85) 1.52 (0.69-3.39) High 26,126 Suppressed 26.8 (12.8-56.2) 1.56 (0.74-3.28) 1.35 (0.65-2.84) Continuous 1.10 (0.91-1.34) 1.06 (0.87-1.30) Cumulative dose Low 23,693 Suppressed 12.7 (4.1-39.3) 0.90 (0.29-2.78) 0.79 (0.26-2.46) Medium 25,629 Suppressed 31.2 (15.6-62.4) 2.22 (1.11-4.43)* 1.93 (0.97-3.87) High 25,735 Suppressed 15.5 (5.8-41.4) 0.95 (0.36-2.54) 0.83 (0.31-2.21) Continuous 1.22 (0.55-2.74) 1.09 (0.46-2.60) 3. SGLT-2 inhibitors Never 51,997,074 7,162 13.8 (13.5-14.1) 1.00 1.00 Ever use 91,570 32 36.0 (24.1-53.7) 2.10 (1.41-3.13)* 1.78 (1.19-2.65)* Cumulative duration Low 26,625 Suppressed 11.3 (3.6-34.9) 0.62 (0.20-1.91) 0.53 (0.17-1.64) Medium 30,375 11 36.2 (20.1-65.4) 2.02 (1.12-3.66)* 1.73 (0.96-3.13) High 34,570 18 52.1 (32.8-82.6) 2.83 (1.78-4.50)* 2.40 (1.51-3.82)* Continuous 1.43 (1.24-1.65)* 1.35 (1.17-1.56)* Cumulative dose Low 26,825 Suppressed 22.4 (10.0-49.8) 1.19 (0.53-2.64) 1.02 (0.46-2.28) Medium 30,296 Suppressed 13.2 (5.0-35.2) 0.73 (0.28-1.95) 0.63 (0.24-1.67) High 34,449 22 63.9 (42.0-97.0) 3.57 (2.35-5.43)* 3.02 (1.98-4.60)* Continuous 1.31 (1.17-1.47)* 1.26 (1.12-1.42)* 4. AGIs (i.e., acarbose) Never 52,043,873 7,174 13.8 (13.5-14.1) 1.00 1.00 Ever use 44,771 20 15.3 (3.8-61.2) 0.63 (0.16-2.52) 0.63 (0.16-2.51) Cumulative duration Low 16,863 Suppressed 29.7 (12.3-71.2) 1.28 (0.53-3.08) 1.25 (0.52-3.00) Medium 15,151 11 72.6 (40.2-131.1) 2.87 (1.59-5.19)* 2.79 (1.55-5.05)* High 12,757 Suppressed 31.4 (11.8-83.5) 1.06 (0.40-2.83) 1.02 (0.38-2.72) Continuous 1.04 (0.89-1.20) 1.03 (0.89-1.20) Cumulative dose Low 15,946 Suppressed 31.4 (13.1-75.3) 1.32 (0.55-3.17) 1.29 (0.54-3.11) Medium 16,084 11 68.4 (37.9-123.5) 2.72 (1.51-4.92)* 2.64 (1.46-4.77)* High 12,741 Suppressed 31.4 (11.8-83.6) 1.09 (0.41-2.90) 1.04 (0.39-2.78) Continuous 1.11 (0.91-1.34) 1.10 (0.90-1.33) 5. Insulin secretagogues Never 51,176,005 6,832 13.4 (13.0-13.7) 1.00 1.00 Ever use 912,639 362 36.4 (31.8-41.7) 1.49 (1.30-1.71)* 1.42 (1.23-1.63)* Cumulative duration Low 360,923 111 30.8 (25.5-37.0) 1.36 (1.13-1.64)* 1.32 (1.09-1.59)* Medium 315,845 132 41.8 (35.2-49.6) 1.72 (1.45-2.04)* 1.62 (1.37-1.93)* High 235,871 119 50.5 (42.2-60.4) 1.62 (1.36-1.95)* 1.50 (1.25-1.80)* Continuous 1.06 (1.05-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 372,575 121 32.5 (27.2-38.8) 1.36 (1.13-1.62)* 1.32 (1.10-1.58)* Medium 314,231 121 38.5 (32.2-46.0) 1.53 (1.28-1.83)* 1.44 (1.21-1.73)* High 225,833 120 53.1 (44.4-63.5) 1.89 (1.58-2.27)* 1.73 (1.45-2.08)* Continuous 1.03 (1.02-1.03)* 1.02 (1.02-1.03)* 5.1. Meglitinides Never 52,048,818 7,173 13.8 (13.5-14.1) 1.00 1.00 Ever use 39,826 21 36.7 (15.3-88.2) 1.61 (0.67-3.85) 1.56 (0.65-3.74) Cumulative duration Low 12,831 10 77.9 (41.9-144.8) 3.23 (1.74-6.01)* 3.10 (1.67-5.76)* Medium 13,013 Suppressed 23.1 (7.4-71.5) 1.00 (0.32-3.11) 0.96 (0.31-2.96) High 13,982 Suppressed 57.2 (28.6-114.4) 2.10 (1.05-4.21)* 1.96 (0.98-3.91) Continuous 1.10 (0.99-1.22) 1.08 (0.97-1.21) Cumulative dose Low 13,858 11 79.4 (44.0-143.3) 3.17 (1.75-5.72)* 3.04 (1.69-5.50)* 323 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 13,470 Suppressed 14.8 (3.7-59.4) 0.63 (0.16-2.50) 0.60 (0.15-2.40) High 12,498 Suppressed 64.0 (32.0-128.0) 2.48 (1.24-4.97)* 2.28 (1.14-4.57)* Continuous 1.07 (1.01-1.14)* 1.07 (1.00-1.13)* 5.1.1. Repaglinide Never 52,049,428 7,173 13.8 (13.5-14.1) 1.00 1.00 Ever use 39,216 21 37.1 (15.4-89.1) 1.62 (0.68-3.88) 1.57 (0.66-3.77) Cumulative duration Low 12,566 10 79.6 (42.8-147.9) 3.30 (1.78-6.14)* 3.16 (1.70-5.88)* Medium 12,873 Suppressed 23.3 (7.5-72.3) 1.01 (0.33-3.13) 0.96 (0.31-2.99) High 13,777 Suppressed 58.1 (29.0-116.1) 2.13 (1.07-4.27)* 1.98 (0.99-3.97) Continuous 1.10 (0.99-1.22) 1.09 (0.98-1.21) Cumulative dose Low 13,676 11 80.4 (44.5-145.2) 3.22 (1.78-5.81)* 3.09 (1.71-5.58)* Medium 13,159 Suppressed 15.2 (3.8-60.8) 0.64 (0.16-2.54) 0.61 (0.15-2.44) High 12,381 Suppressed 64.6 (32.3-129.2) 2.51 (1.25-5.02)* 2.31 (1.15-4.61)* Continuous 1.07 (1.01-1.14)* 1.07 (1.00-1.13)* 5.2. Sulfonylureas Never 51,188,413 6,836 13.4 (13.0-13.7) 1.00 1.00 Ever use 900,231 358 36.4 (31.7-41.7) 1.49 (1.29-1.71)* 1.41 (1.23-1.62)* Cumulative duration Low 359,009 114 31.8 (26.4-38.2) 1.40 (1.16-1.68)* 1.36 (1.13-1.63)* Medium 309,407 125 40.4 (33.9-48.1) 1.66 (1.39-1.98)* 1.57 (1.31-1.87)* High 231,815 119 51.3 (42.9-61.4) 1.65 (1.38-1.98)* 1.53 (1.28-1.83)* Continuous 1.06 (1.04-1.08)* 1.05 (1.04-1.07)* Cumulative dose Low 367,838 122 33.2 (27.8-39.6) 1.38 (1.16-1.65)* 1.34 (1.12-1.61)* Medium 309,412 118 38.1 (31.8-45.7) 1.51 (1.26-1.82)* 1.43 (1.19-1.71)* High 222,981 118 52.9 (44.2-63.4) 1.88 (1.57-2.26)* 1.73 (1.44-2.07)* Continuous 1.03 (1.02-1.03)* 1.02 (1.01-1.03)* 5.2.1. Gliclazide Never 51,695,028 7,025 13.6 (13.3-13.9) 1.00 1.00 Ever use 393,616 169 37.7 (30.9-46.0) 1.47 (1.21-1.80)* 1.36 (1.11-1.66)* Cumulative duration Low 126,908 55 43.3 (33.3-56.4) 1.85 (1.42-2.41)* 1.73 (1.32-2.25)* Medium 136,638 51 37.3 (28.4-49.1) 1.51 (1.15-1.99)* 1.39 (1.05-1.83)* High 130,070 63 48.4 (37.8-62.0) 1.64 (1.28-2.10)* 1.49 (1.16-1.91)* Continuous 1.07 (1.03-1.10)* 1.05 (1.02-1.09)* Cumulative dose Low 133,699 53 39.6 (30.3-51.9) 1.64 (1.25-2.14)* 1.53 (1.17-2.00)* Medium 136,394 57 41.8 (32.2-54.2) 1.64 (1.26-2.12)* 1.50 (1.16-1.95)* High 123,523 59 47.8 (37.0-61.6) 1.70 (1.31-2.19)* 1.54 (1.19-1.99)* Continuous 1.02 (1.01-1.03)* 1.02 (1.01-1.03)* 5.2.2. Glyburide Never 51,418,210 6,916 13.5 (13.1-13.8) 1.00 1.00 Ever use 670,434 278 36.0 (29.9-43.3) 1.51 (1.25-1.82)* 1.48 (1.23-1.79)* Cumulative duration Low 283,215 85 30.0 (24.3-37.1) 1.25 (1.01-1.55)* 1.22 (0.98-1.51) Medium 224,722 108 48.1 (39.8-58.0) 1.95 (1.61-2.36)* 1.87 (1.55-2.26)* High 162,497 85 52.3 (42.3-64.7) 1.67 (1.35-2.07)* 1.57 (1.26-1.94)* Continuous 1.07 (1.05-1.09)* 1.06 (1.04-1.09)* Cumulative dose Low 296,014 95 32.1 (26.2-39.2) 1.28 (1.05-1.57)* 1.25 (1.02-1.53)* Medium 230,574 102 44.2 (36.4-53.7) 1.72 (1.41-2.09)* 1.65 (1.35-2.00)* High 143,846 81 56.3 (45.3-70.0) 2.00 (1.61-2.49)* 1.86 (1.49-2.32)* Continuous 1.04 (1.03-1.05)* 1.03 (1.02-1.05)* 6. Thiazolidinediones Never 51,871,508 7,105 13.7 (13.4-14.0) 1.00 1.00 Ever use 217,136 89 16.6 (9.4-29.3) 0.92 (0.52-1.61) 0.90 (0.51-1.59) Cumulative duration Low 76,357 25 32.7 (22.1-48.5) 1.52 (1.03-2.25)* 1.44 (0.97-2.13) Medium 72,351 28 38.7 (26.7-56.1) 1.79 (1.24-2.60)* 1.69 (1.17-2.45)* High 68,428 36 52.6 (37.9-72.9) 2.12 (1.53-2.94)* 1.94 (1.40-2.70)* Continuous 1.12 (1.07-1.17)* 1.11 (1.05-1.16)* Cumulative dose Low 75,982 24 31.6 (21.2-47.1) 1.44 (0.97-2.15) 1.37 (0.92-2.04) 324 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 74,257 35 47.1 (33.8-65.6) 2.16 (1.55-3.01)* 2.04 (1.46-2.84)* High 66,897 30 44.8 (31.4-64.1) 1.85 (1.29-2.65)* 1.69 (1.18-2.42)* Continuous 1.11 (1.06-1.16)* 1.10 (1.05-1.15)* 6.1. Pioglitazone Never 51,987,564 7,157 13.8 (13.5-14.1) 1.00 1.00 Ever use 101,080 37 16.7 (7.5-37.2) 0.85 (0.38-1.88) 0.82 (0.37-1.82) Cumulative duration Low 33,963 Suppressed 23.6 (11.8-47.1) 1.06 (0.53-2.13) 1.00 (0.50-2.00) Medium 34,409 13 37.8 (21.9-65.1) 1.73 (1.00-2.98)* 1.61 (0.94-2.78) High 32,708 16 48.9 (30.0-79.8) 1.89 (1.16-3.08)* 1.72 (1.06-2.82)* Continuous 1.11 (1.04-1.19)* 1.10 (1.02-1.18)* Cumulative dose Low 33,724 Suppressed 23.7 (11.9-47.4) 1.06 (0.53-2.12) 1.00 (0.50-2.00) Medium 34,952 17 48.6 (30.2-78.2) 2.18 (1.36-3.51)* 2.04 (1.27-3.29)* High 32,404 12 37.0 (21.0-65.2) 1.47 (0.84-2.59) 1.34 (0.76-2.35) Continuous 1.09 (1.02-1.17)* 1.08 (1.01-1.15)* 6.2. Rosiglitazone Never 51,946,176 7,135 13.7 (13.4-14.1) 1.00 1.00 Ever use 142,468 59 15.9 (7.1-35.4) 0.95 (0.43-2.12) 0.97 (0.43-2.15) Cumulative duration Low 49,170 16 32.5 (19.9-53.1) 1.49 (0.91-2.43) 1.41 (0.86-2.30) Medium 48,028 20 41.6 (26.9-64.5) 1.92 (1.24-2.97)* 1.81 (1.17-2.80)* High 45,270 23 50.8 (33.8-76.5) 2.14 (1.42-3.22)* 1.97 (1.31-2.96)* Continuous 1.15 (1.08-1.24)* 1.14 (1.06-1.22)* Cumulative dose Low 49,567 16 32.3 (19.8-52.7) 1.47 (0.90-2.40) 1.39 (0.85-2.27) Medium 49,349 22 44.6 (29.4-67.7) 2.03 (1.34-3.08)* 1.92 (1.26-2.91)* High 43,552 21 48.2 (31.4-74.0) 2.05 (1.34-3.15)* 1.88 (1.23-2.89)* Continuous 1.15 (1.08-1.22)* 1.13 (1.06-1.20)* 7. Insulins and analogues Never 51,772,245 7,008 13.5 (13.2-13.9) 1.00 1.00 Ever use 316,399 186 66.3 (56.6-77.6) 3.12 (2.66-3.66)* 2.82 (2.40-3.31)* Cumulative duration Low 143,015 63 44.1 (34.4-56.4) 2.66 (2.08-3.41)* 2.48 (1.94-3.18)* Medium 113,499 86 75.8 (61.3-93.6) 3.44 (2.78-4.25)* 3.11 (2.51-3.85)* High 59,885 37 61.8 (44.8-85.3) 2.55 (1.84-3.52)* 2.24 (1.62-3.10)* Continuous 1.16 (1.13-1.20)* 1.14 (1.11-1.18)* Cumulative dose Low 146,186 67 45.8 (36.1-58.2) 2.68 (2.10-3.40)* 2.49 (1.96-3.17)* Medium 108,141 86 79.5 (64.4-98.2) 3.60 (2.91-4.46)* 3.26 (2.64-4.04)* High 62,072 33 53.2 (37.8-74.8) 2.32 (1.64-3.26)* 2.03 (1.44-2.86)* Continuous 1.05 (1.04-1.06)* 1.04 (1.03-1.06)* 7.1. Basal insulins Never 51,784,863 7,015 13.5 (13.2-13.9) 1.00 1.00 Ever use 303,781 179 67.8 (57.6-79.6) 3.21 (2.73-3.78)* 2.90 (2.46-3.42)* Cumulative duration Low 135,289 59 43.6 (33.8-56.3) 2.65 (2.05-3.42)* 2.46 (1.91-3.18)* Medium 109,417 81 74.0 (59.5-92.0) 3.39 (2.72-4.22)* 3.06 (2.46-3.82)* High 59,075 39 66.0 (48.2-90.4) 2.70 (1.97-3.70)* 2.38 (1.73-3.26)* Continuous 1.19 (1.14-1.23)* 1.16 (1.12-1.21)* Cumulative dose Low 136,909 63 46.0 (35.9-58.9) 2.71 (2.11-3.47)* 2.51 (1.96-3.22)* Medium 106,571 82 76.9 (62.0-95.5) 3.50 (2.82-4.35)* 3.17 (2.55-3.94)* High 60,301 34 56.4 (40.3-78.9) 2.44 (1.74-3.42)* 2.14 (1.53-3.01)* Continuous 1.06 (1.05-1.07)* 1.05 (1.04-1.06)* 7.2. Bolus insulins Never 51,947,122 7,092 13.7 (13.3-14.0) 1.00 1.00 Ever use 141,522 102 83.0 (65.7-105.0) 4.49 (3.55-5.68)* 4.03 (3.18-5.10)* Cumulative duration Low 68,567 51 74.4 (56.5-97.9) 4.86 (3.69-6.39)* 4.50 (3.42-5.93)* Medium 48,161 31 64.4 (45.3-91.5) 3.41 (2.40-4.85)* 3.05 (2.14-4.34)* High 24,794 20 80.7 (52.0-125.0) 3.90 (2.52-6.06)* 3.41 (2.20-5.29)* Continuous 1.27 (1.20-1.35)* 1.24 (1.17-1.32)* Cumulative dose Low 71,251 51 71.6 (54.4-94.2) 4.55 (3.46-5.99)* 4.21 (3.20-5.55)* 325 Exposure Person-years Events Incidence rate Model 1 Model 2 Medium 44,054 29 65.8 (45.7-94.7) 3.47 (2.41-4.99)* 3.11 (2.16-4.48)* High 26,217 22 83.9 (55.3-127.4) 4.26 (2.81-6.48)* 3.71 (2.44-5.63)* Continuous 1.07 (1.04-1.09)* 1.06 (1.04-1.09)* Incidence rate: per 100,000 person-years. Model 1 adjusted for age. Model 2 adjusted for age, sex at birth, birth cohort, health authority, and neighbourhood income quintile. Numbers less than 10 are suppressed, as per the confidentiality policies of the Population Data BC. This table displays associations between all diabetes medications and pancreatic adenocarcinoma. For a summary of selected medications with significant associations, please refer to Table 7-7. * denotes p<0.05.
Thesis/Dissertation
eng
Population and Public Health
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Murphy, Rachel Anne
Dummer, Trevor J. B.
Diabetes medication use and risk of breast, colorectal, and pancreatic cancer : a population-based cohort study
Text