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Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and… Li, Ling; Li, Sheyu; Liu, Jiali; Deng, Ke; Busse, Jason W; Vandvik, Per O; Wong, Evelyn; Sohani, Zahra N; Bala, Malgorzata M; Rios, Lorena P; Malaga, German; Ebrahim, Shanil; Shen, Jiantong; Zhang, Longhao; Zhao, Pujing; Chen, Qunfei; Wang, Yingqiang; Guyatt, Gordon H; Sun, Xin May 11, 2016

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RESEARCH ARTICLE Open AccessGlucagon-like peptide-1 receptor agonistsand heart failure in type 2 diabetes:systematic review and meta-analysis ofrandomized and observational studiesLing Li1, Sheyu Li2, Jiali Liu1, Ke Deng3, Jason W. Busse4,5,6, Per Olav Vandvik7,8, Evelyn Wong9, Zahra N. Sohani4,10,Malgorzata M. Bala11,12, Lorena P. Rios13, German Malaga14, Shanil Ebrahim4,5,15,16, Jiantong Shen1,Longhao Zhang1, Pujing Zhao1, Qunfei Chen17, Yingqiang Wang18, Gordon H. Guyatt4,19 and Xin Sun1*AbstractBackground: The effect of glucagon-like peptide-1(GLP-1) receptor agonists on heart failure remains uncertain. Wetherefore conducted a systematic review to assess the possible impact of GLP-1 agonists on heart failure orhospitalization for heart failure in patients with type 2 diabetes.Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) andClinicalTrials.gov to identify randomized controlled trials (RCTs) and observational studies that addressed theeffect of GLP-1 receptor agonists in adults with type 2 diabetes, and explicitly reported heart failure or hospitalizationfor heart failure. Two paired reviewers screened reports, collected data, and assessed the risk of bias. We pooled datafrom RCTs and observational studies separately, and used the GRADE approach to rate the quality of evidence.Results: We identified 25 studies that were eligible for our review; 21 RCTs (n = 18,270) and 4 observationalstudies (n = 111,029). Low quality evidence from 20 RCTs suggested, if anything, a lower incidence of heart failurebetween GLP-1 agonists versus control (17/7,441 vs. 19/4,317; odds ratio (OR) 0.62, 95 % confidence interval (CI)0.31 to 1.22; risk difference (RD) 19 fewer, 95 % CI 34 fewer to 11 more per 1000 over 5 years). Three cohortstudies comparing GLP-1 agonists to alternative agents provided very low quality evidence that GLP-1 agonistsdo not increase the incidence of heart failure. One RCT provided moderate quality evidence that GLP-1 agonistswere not associated with hospitalization for heart failure (lixisenatide vs placebo: 122/3,034 vs. 127/3,034; adjustedhazard ratio 0.96, 95 % CI 0.75 to 1.23; RD 4 fewer, 95 % CI 25 fewer to 23 more per 1000 over 5 years) and acase–control study provided very low quality evidence also suggesting no association (GLP-1 agonists vs. otheranti-hyperglycemic drugs: 1118 cases and 17,626 controls, adjusted OR 0.67, 95 % CI 0.32 to 1.42).Conclusions: The current evidence suggests that GLP-1 agonists do not increase the risk of heart failure orhospitalization for heart failure among patients with type 2 diabetes.Keywords: Glucagon-like peptide-1 receptor, Heart failure, Type 2 diabetes, Systematic review, Meta-analysis* Correspondence: sunx79@hotmail.com1Chinese Evidence-based Medicine Center, West China Hospital, SichuanUniversity, 37 GuoXue Xiang, Chengdu 610041, Sichuan, ChinaFull list of author information is available at the end of the article© 2016 Li et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 InternationalLicense (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in anymedium, provided you give appropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Li et al. BMC Cardiovascular Disorders  (2016) 16:91 DOI 10.1186/s12872-016-0260-0BackgroundGlucagon-like peptide-1 (GLP-1) receptor agonists are arelatively new class of incretin-based agents for the treat-ment of type 2 diabetes mellitus that lower blood glucose[1, 2], reduce body weight [3], and possibly reduce cardio-vascular risk compared to placebo [4, 5]. The AmericanDiabetes Association and the European Association forthe Study of Diabetes recommend GLP-1 agonists as asecond-line treatment option for type 2 diabetes [6].In 2014, the US Food and Drug Administration raisedconcerns regarding heart failure risk with one dipepti-dyl peptidase-4 (DPP-4) inhibitor, saxagliptin [7]. Theseconcerns followed publication of studies that reportedincreased risk of hospitalization for heart failure in pa-tients using DPP-4 inhibitors [8–10]. These observa-tions raise the possibility that GLP-1 agonists, whichshare a similar pharmacological mechanism with DPP-4inhibitors, might also cause heart failure.Animal studies have shown that the GLP-1 agonistliraglutide can activate cytoprotective pathways in theheart, and improve outcomes after experimental myo-cardial infarction in mice [11]. Early clinical studies alsosuggested that GLP-1 agonists have positive effects oncardiovascular biomarkers, such as high-sensitivity C-reactive protein and plasminogen activator inhibitor-1[12, 13], and improve regional and overall left ventricu-lar function in patients with acute myocardial infarctionand severe systolic dysfunction after successful primaryangioplasty [14].Clinical trial results often, however, prove inconsistentwith laboratory and surrogate outcome studies, andemerging randomized trials and observational studieshave, reported inconsistent results [15–19]. We there-fore undertook a systematic review to address the effectof GLP-1 agonists on heart failure or hospitalization forheart failure in patients with type 2 diabetes.MethodsWe followed the PRISMA and MOOSE guidelines for con-ducting and reporting systematic reviews and meta-analysesof randomized controlled trials (RCTs) and observationalstudies [20, 21].Data sources and search strategyWe searched MEDLINE, EMBASE, and the CochraneCentral Register of Controlled Trials (CENTRAL) frominception to 25 June, 2015. We used both MeSH andfree text terms to identify relevant articles. An informa-tion expert (DP) developed each database-specific searchstrategy (Additional file 1). We also searched Clinical-Trials.gov as well as conference abstracts published bythe American Diabetes Association, European Associationfor the Study of Diabetes, and European Society of Cardi-ology for additional eligible studies and trial information.Eligibility criteriaWe included RCTs, cohort studies, or case–controlstudies that compared GLP-1 agonists against placebo,lifestyle modification, or active anti-hyperglycemic medica-tion in adult type 2 diabetes patients, reported ≥ 12 weeksfollow-up data (not applicable to case–control studies),and explicitly reported the outcome of heart failure orhospitalization for heart failure.Study selectionPaired reviewers, trained in research methods, inde-pendently screened titles/abstracts and then full textsfor eligibility, assessed risk of bias, and collected datafrom each included study, using pilot-tested standard-ized forms with corresponding detailed instructions.Any disagreement between the two reviewers was re-solved through discussion or adjudication by a third re-viewer (XS).Risk of bias and quality of evidence assessmentWe assessed the risk of bias of RCTs according to modi-fied version of the Cochrane Collaboration’s tool [22, 23]in which the response options are "probably yes" and"probably no" instead of "unclear"; the approach hasshown to be reliable and valid for blinding [24]. Theitems include randomization sequence generation; allo-cation concealment; blinding of participants, caregivers,outcome assessors (i.e., heart failure or hospitalizationfor heart failure), and outcome adjudicators; prognosticbalance between treatment groups; and incomplete out-come data.We used a modified version of the Newcastle – OttawaQuality Assessment Scale [25–27] for assessing risk ofbias of observational studies. Specifically, we removed twoitems “representativeness of the exposed cohort” and “wasfollow-up long enough for outcomes to occur” that wejudge related to applicability, and added two items - ascer-tainment of type 2 diabetes and adjustment for potentialconfounding factors. We planned to assess for risk of pub-lication bias, but were unable to do so due to low powerof the relevant tests in the presence of low events rates.We rated the quality of evidence for heart failure andhospitalization for heart failure as high, moderate, low,or very low using the Grading of Recommendations As-sessment, Development and Evaluation (GRADE) meth-odology [28–34].Data extractionWe collected the following information from each eli-gible studies: study characteristics (e.g., author name,year of publication, study design, sample size, lengthof follow-up), patient characteristics (e.g., gender, age,diabetes duration, body mass index (BMI), baselineHbA1c level), interventions (e.g., details of GLP-1Li et al. BMC Cardiovascular Disorders  (2016) 16:91 Page 2 of 14agonists therapy and control group), and outcomes(number of events and patients included for analysesin each group, as well as adjusted data if available).For trials with multiple reports, we collated all datainto a single study [35]; for trials with reports bothfrom ClincialTrials.gov and journal publications, wecarefully checked the data for consistency; for trialsreporting outcome data of multiple follow up points,we used the data with longest follow up. For observa-tional studies, we also collected information on datasource, methods used to control confounding, and re-ported adjustment factors.Statistical analysisWe analyzed RCTs and observational studies separately.We did not combine the outcomes of heart failure andhospitalization for heart failure, as hospitalization for heartfailure is likely more serious and of greater importance topatients than heart failure not requiring hospitalization.We assessed statistical heterogeneity with the Cochranchi-square test and I-squared statistic. We used Peto’smethod to pool data from RCTs [36, 37] using randomeffects models and reported pooled Peto odds ratios(ORs) and associated 95 % confidence intervals (CIs).We conducted four a priori subgroup analyses to exploreheterogeneity associated with our pooled estimates: (1)type of control (placebo vs. active treatment), (2) lengthof follow up (52 weeks or shorter vs. over 52 weeks), (3)mode of therapy (GLP-1 agonists monotherapy vs. add-on/combination therapy), and (4) individual GLP-1 ago-nists agents (different GLP-1 agonists agents vs. control).We also carried out sensitivity analyses to explore therobustness of our findings using different effect mea-sures, pooling methods, and statistical models.We pooled adjusted estimates of heart failure fromcohort studies using random effects model due to sig-nificant variations in the comparison and patient popu-lations among eligible studies.EthicsEthical approval was not necessary as this study is a Sys-tematic Review and Meta-Analysis.ResultsStudy selectionOur literature search yielded 11,441 reports; 821 werepotentially eligible after title and abstract screening,and 25 studies proved eligible after full text screening.These included 21 RCTs involving 18,270 patients from30 reports [15, 16, 38–65] and four observational stud-ies [17–19, 66] involving 111,029 patients (three cohortstudies and one nested case–control study) (Fig. 1).Evidence from randomized controlled trialsRCTs reporting heart failureTwenty trials reported on heart failure; 18 (80 %) weremulti-center studies, and 18 (90 %) were clearly labeledas phase III trials. These trials enrolled 46 to 1,091 pa-tients (total 12,199); the mean age of patients ranged52.9 to 67.2 years old, mean BMI 25.6 to 33.3 kg/m2,mean baseline HbA1c 7.6 to 8.5 %, mean FPG 7.1 to10.0 mmol/L, and mean or median duration of diabeteswas 2.6 to 11.5 years (Table 1). Five used GLP-1 ago-nists as monotherapy, 15 as add-on or combinationtherapy (Table 2). The length of follow-up ranged from16 to 164 weeks (median 52; 10 trials followed patientsfor > 52 weeks).All the trials reported industry funding; 18 were iden-tified from ClinicalTrials.gov, of which 12 had no corre-sponding journal publications. Because of the limitedinformation provided in the trial registry, we were un-able to adequately assess the risk of bias for these 12trials. Additional file 2 presents the details of the as-sessment for risk of bias. The baseline demographicsand clinical characteristics of patients in each includedtrials were generally balanced between groups. Theoverall risk bias of eligible RCTs was moderate.Twenty trials reported 36 heart failure events in11,758 patients using at least one medication (rawevent rate 0.3 %). The pooling of those trials showed nostatistically significant difference in the risk of heartfailure between GLP-1 agonists treatment and control(17/7,441 in GLP-1 agonists and 19/4,317 control; OR0.62, 95 % CI 0.31 to 1.22, I-square = 0 %; risk differ-ence (RD) 19 fewer, 95 % CI 34 fewer to 11 more per1000 over 5 years) (Fig. 2). We rated the quality of evi-dence as low because of risk of bias and imprecision(Table 3).Subgroup analysis by type of control (interaction p =0.79), mode of therapy (interaction p = 0.84) and lengthof follow up (interaction p = 0.64) showed no differen-tial treatment effects (Additional files 3, 4, 5 and 6).The subgroup analysis of heart failure risk by individualGLP-1 agonists agents suggested a possibility of differen-tial treatment effect across individual agents (interactionp = 0.07), with liraglutide associated with a non-significantincreased risk for heart failure (OR 4.85, 95 % CI 0.75 to31.36); this finding was however based on a limited num-ber of events (five in total) and characterized with verywide confidence interval.Sensitivity analysis using alternative effect measures,statistical methods, and analysis models did not showimportant changes in pooled effects.Trials reporting hospitalization for heart failureThe Evaluation of LIXisenatide in Acute Coronary Syn-drome (ELIXA) trial, designed to assess the cardiovascularLi et al. BMC Cardiovascular Disorders  (2016) 16:91 Page 3 of 14safety of lixisenatide, reported hospitalization for heartfailure [15, 16] (Table 1). The ELIXA trial randomized6,068 patients with type 2 diabetes and a recent acutecoronary syndrome to lixisenatide or placebo, with amedian of follow up of 2.1 years. In this trial, 122 pa-tients were hospitalized for heart failure among 3,034patients taking lixisenatide (4.0 %) and 127 in 3034 pa-tients taking placebo (4.2 %), and no statistically signifi-cant difference was present between the groups (hazardratio (HR) 0.96, 95 % CI 0.75 to 1.23; RD 4 fewer, 95 %CI 25 fewer to 23 more per 1000 over 5 years). The trialauthors' subgroup analysis by type of history of heartfailure showed no differential treatment effects (lixise-natide vs. placebo: patients with history of heart failure:HR 0.93, 95%CI 0.66 to 1.30; patients with no history ofheart failure: HR 0.97, 95 % CI 0.67 to 1.40). We ratedthe quality of evidence as moderate (Table 3).Evidence from observational studiesStudies reporting heart failureThree cohort studies [17, 18, 66] reported heart fail-ure. Of these, one prospectively designed study [66]examined exenatide versus basal insulin; the other two[17, 18] – retrospective in design - assessed GLP-1 ag-onists versus sulfonylureas, and exenatide or exenatideplus insulin versus insulin (Tables 4 and 5). The sam-ple sizes ranged from 882 to 39,225, and length of fol-low up ranged from 1 to 4 years. The mean age rangedfrom 58.28 to 62.5 years, BMI 32.6 to 35.3 kg/m2, andmean baseline HbA1c 7.9 to 8.9 %.The three studies used electronic heath records orclaims data for their analyses. Type 2 diabetes patientswere ascertained by specialists in outpatient setting inthe prospective cohort study [66]; the other two retro-spective cohort study [17, 18] did not explicitly state thePotentially eligible reports accessed for full text screening (n=821)Duplicates (n=2749)Excluded studies (n=787)Improper study design (n=50)Inappropriate comparisons (n=121)Follow-up less than12 weeks (n=11)Not type 2 diabetes mellitus patients (n=7)No heart failure outcome clearly and explicitly reported (n=596)Data from a same electronic database (n=2)Records identified through database searches (n=11106)Studies included in the review (n= 25)21 RCTs reported in 30 reports (10 journals reports, 19 trial registry reports,and 1 conference abstract)4 observational studies (3 cohort studies and 1 nested case-control studies; 3 journals reports, 1 trial registry report)Records screened (n=8692)Records excluded after title and abstract screening (n=7871)Additional records identified from ClinicalTrials.gov (n=329),and conference website (n=6)Fig. 1 Flow chart of article selectionLi et al. BMC Cardiovascular Disorders  (2016) 16:91 Page 4 of 14ascertainment of type 2 diabetes. None of these studiesmentioned the ascertainment of exposure to GLP-1agonist agents and other confounding variables. Onlyone study [17] demonstrated that outcome of interestwas not present at start of study, and mentioned themethod used to assess the outcome of interest. TwoTable 1 Baseline characteristics of included randomized controlled trialsStudy InternationalstudyNumber ofcountriesinvolvedNumberof studysitesStudyphaseTotal numberof patientsrandomizedLength offollow up(weeks)Male(n,%)Meanage(years)Mean BMI(kg/m2)MeanHbA1c(%)Mean FPG(mmol/L)Meandiabetesduration(years)Trials reporting heart failureInagaki 2012[38, 39]No 1 NR III 427 26 290(67.9)56.8 26.1 8.5 NR 9.0NCT002947232010 [40, 41]Yes 2 138 III 746 104 371(49.7)53.0 33.1 8.3 9.4 5.4NCT003184612010 [42–44]Yes 21 170 III 1091 104 635(58.2)56.7 31.0 8.4 10.0 7.6NCT003603342009 [45]No 1 35 III 235 26 160(68.4)56.6 NR NR NR 6.0NCT006141202010 [46]Yes 3 51 III 929 16 514(55.3)53.3 25.6 NR NR 7.5NCT007019352013 [47]Yes 2 17 II 80 26 42(52.5)58.1 NR NR NR NRNCT008389032014 [48, 49]Yes 10 289 III 1049 164 482(47.6)54.5 32.6 8.1 9.2 6.0NCT008389162014 [50, 51]Yes 4 222 III 779 164 418(56.1)55.5 33.1 8.3 9.5 8.8NCT008395272014 [52]Yes 9 358 III 685 164 353(53.2)55.2 NR NR NR NRNCT008490172014 [53]Yes 3 262 III 309 164 166(55.1)52.9 NR NR NR NRNCT008490562014 [54]Yes 6 331 III 310 156 180(59.8)55.0 NR NR NR NRNCT008554392015 [55]No 1 1 NR 46 82 26(56.5)53.0 NR NR NR NRNCT009606612013 [56, 57]Yes 17 108 III 637 30 261(51.2)59.5 32.5 8.2 7.1 11.5aNCT010646872015 [58]Yes 3 89 III 978 26 570(58.4)55.7 33.2 8.1 9.0 8.8NCT010752822015 [59]Yes 20 78 III 810 78 353(51.3)56.7 31.6 8.1 9.1 9.1NCT011265802015 [60, 61]Yes 19 91 III 807 56 353(43.7)55.6 33.3 7.6 9.0 2.6NCT011912682014 [62]Yes 16 101 III 884 52 473(53.5)59.4 32.5 8.5 NR 12.7NCT015121082014 [63]No 1 36 III 363 52 262(72.8)59.5 NR 8.1 8.8 NRNCT016204892014 [64]Yes 6 50 III 277 26 140(50.5)67.2 NR NR NR NRPratley2013 [65]Yes 17 130 III 760 24 362(48.9)56.4 32.7 8.3 10.0 8.8Trials reporting hospitalization for heart failureBentley-Lewis2015 (ELIXA)[15, 16]Yes 49 NR III 6068 108b 4207(69.3)60.3 30.2 7.7 8.2 9.3BMI body mass index, FPG fasting plasma glucose, NR not reportedamedian diabetes duration (years); bmedian follow up time (weeks)Li et al. BMC Cardiovascular Disorders  (2016) 16:91 Page 5 of 14studies [18, 19] used advanced statistical model to con-trol for the influence of confounding factors. Overall,the risk of bias associated with these studies was moder-ate to high (Additional file 7).All three studies reported raw data, for a total of 2,868heart failures among 53,292 patients (raw event rate 5.4 %);two retrospective cohort studies [17, 18] reported adjustedeffect estimates (Tables 5 and 6). The prospective cohortstudy [66], enrolling 882 patients with one year follow-up,found that two patients (2/438) in the basal insulin hadheart failure events and no patients (0/444) in exenatidegroup. One retrospective cohort study [17], including13,185 patients and with a median follow-up of four years,reported that GLP-1 agonists were associated with a non-significant increase in heart failure versus sulfonylureas(adjusted HR 1.10, 95 % CI 0.99 to 1.22). The other retro-spective cohort study [18], involving 39,225 patients andwith a median follow-up of 3.5 years, found that both exe-natide and exenatide plus insulin were associated with alower risk of heart failure versus insulin alone (adjustedHR 0.34, 95 % CI 0.22 to 0.52; adjusted HR 0.40, 95 % CI0.32 to 0.50, respectively, Fig. 3). Using GRADE, we ratedthe quality of evidence in the included studies as very low,due to risk of bias, indirectness and heterogeneity inaddition to the inherent risk for confounding associatedwith observational studies.Studies reporting hospitalization for heart failureOne nested case–control study [19] assessed with GLP-1agonists versus other oral anti-hyperglycemic drugsTable 2 Intervention tested and event rates in randomized controlled trialsStudy Medications used across groups Incretin Control Duration oftreatment(weeks)Type Events Type EventsTrials reporting heart failureInagaki 2012 [38, 39] BG or BG + TZD Exenatide 1/215 Insulin glargine 0/212 26NCT00294723 2010 [40, 41] None Liraglutide 1/497 Glimepiride 0/248 104NCT00318461 2010 [42–44] Metformin Liraglutide 1/724 Placebo 0/121 104Liraglutide 1/724 Glimepiride 0/242NCT00360334 2009 [45] OADs Exenatide 0/118 Insulin glargine 1/116 26NCT00614120 2010 [46] Merformin Liraglutide 1/697 Glimepiride 0/231 16NCT00701935 2013 [47] None Exenatide 0/43 Placebo 1/37 26NCT00838903 2014 [48, 49] Metformin Albiglutide 2/302 Placebo 0/101 156Albiglutide 2/302 Glimepiride 1/307NCT00838916 2014 [50, 51] Metformin ± SU Albiglutide 2/504 Insulin glargine 2/241 156NCT00839527 2014 [52] Metformin + glimepiride Albiglutide 0/271 Placebo 1/115 164Albiglutide 0/271 Pioglitazone 4/277NCT00849017 2014 [53] None Albiglutide 1/200 Placebo 2/101 164NCT00849056 2014 [54] Pioglitazone ±Metformin Albiglutide 0/150 Placebo 1/151 156NCT00855439 2015 [55] Other diabetes medications Exenatide 1/22 Glargine 1/24 78NCT00960661 2013 [56, 57] Insulin glargine +metformin Exenatide 0/315 Insulin lispro 1/312 30NCT01064687 2015 [58] Metformin and pioglitazone Dulaglutide 1/559 Placebo 0/141 26Exenatide 0/278 Placebo 0/141NCT01075282 2015 [59] Metformin and glimepiride Dulaglutide 3/545 Insulin glargine 1/262 78NCT01126580 2015 [60, 61] None Dulaglutide 1/539 Metformin 0/268 52NCT01191268 2014 [62] Insulin lispro Dulaglutide 0/588 Insulin glargine 1/296 52NCT01512108 2014 [63] None Liraglutide 1/240 Additional OAD 0/120 52NCT01620489 2014 [64] OAD and/or insulin Liraglutide 1/140 Placebo 0/137 26Pratley 2013 [65] SU ±metformin Taspoglutide 0/494 Pioglitazone 2/257 24Trials reporting hospitalization for heart failureBentley-Lewis 2015 (ELIXA) [15, 16] Metformin, SU, glinide, TZD, insulin,metformin and SU, insulin and OADs,or other diabetes medicationsLixisenatide 122/3034 Placebo 127/3034 100BG biguanide, TZD thiazolidinedione, OADs oral antidiabetic drugs, SU sulfonylureaLi et al. BMC Cardiovascular Disorders  (2016) 16:91 Page 6 of 14(Tables 4 and 5). This study included 57,737 patients,with a mean age of 61.6 years and mean duration of dia-betes 2.3 years. The methodological details regarding thecontrol for bias are provided in Additional file 8. Thisstudy included 1118 cases and 17,626 matched controlsand found that, compared to the use of other anti-hyperglycemic drugs, GLP-1agonists were not associatedwith increased risk of hospitalization for congestiveheart failure (adjusted OR 0.67, 95 % CI 0.32 to 1.42).Using GRADE, we rated the quality of evidence as verylow, due to risk of bias and imprecision in addition tothe inherent risk for confounding associated with obser-vational studies.DiscussionMain findingsOur pooled analysis of 20 RCTs addressing use of GLP-1agonists for type 2 diabetes found moderate quality evi-dence suggesting no increase in heart failure. The onlyRCT provided high quality evidence that lixisenatide didnot increase the risk of hospitalization due to heart fail-ure. Though the four observational studies provide onlyvery low quality evidence, their results are consistentwith those from the randomized trials.Strengths and limitationsWe are the first to systematically review the evidence re-garding GLP-1 agonists for type 2 diabetes and risk ofheart failure. Our study has several strengths. First, weused rigorous methods to systematically identify bothrandomized and observational studies that reported datato inform this issue, including a large number of trialsthat were not published in journals. Second, we carefullychecked the data reported in ClinicalTrials.gov and jour-nal publications for consistency to ensure accuracy ofthe data. Third, we analysed the data on heart failureand hospitalization for heart failure separately, becausethose outcomes are likely to be of different importanceto patients. Fourth, we used the GRADE approach to as-sess the quality of evidence on an outcome-by-outcomebasis.Our study also has limitations. First, the available evi-dence is not strength to give definitive answer for thisquestion, since the included RCTs reported few heartfailure events and the follow-up was not enough forheart failure to occur, and much findings came from ob-servational studies of very low quality evidence. Second,we have included some observational studies at moder-ate to high risk of bias. This has made the inferenceabout the effects of GLP-1 agonists challenging. Third,the diversity of observational studies also made our ana-lysis of the evidence difficult. One retrospective cohortstudy [18], assessing exenatide and/or insulin on heartfailure outcome, included patients with heart failure atbaseline, and the proportion of patients with history ofheart failure was higher in the insulin group (3.2 %) thanin the exenatide group (1.7 %) and exenatide + insulingroup (2.4 %), which made the finding from this studybiased.Other researchesOurs is the first systematic review addressing the impactof GLP-1 agonists on heart failure. There is some evi-dence from human studies that GLP-1 agonists mightprovide protection against heart failure: preliminarystudy [67] showed that GLP-1 treatment might have atrend towards improvement of cardiac function in type 2diabetes patients with stable heart failure; intrinsic GLP-1 expression has been shown to compensatorily upregu-late in patients with left heart failure [68]; and GLP-1Fig. 2 Risk of heart failure in patients who received GLP-1 agonists versus control from randomized controlled trialsLi et al. BMC Cardiovascular Disorders  (2016) 16:91 Page 7 of 14Table 3 GRADE evidence profile of glucagon-like peptide-1 receptor agonists and risk of heart failure in type 2 diabetesQuality assessment Summary of findings Quality ofevidenceStudy event rates Relative risk(95 % CI)Anticipated absoluteeffects (5-year time frame)No of participants(studies)Follow-up timeRisk of bias Inconsistency Indirectness Imprecision PublicationbiasWith control With GLP-1agonistsRisk withcontrolRisk difference withGLP-1 agonists(95 % CI)Heart failure11758(20)16-164 weeksSeriouslimitation dueto risk ofbiasaNo seriouslimitationsNo seriouslimitationsSerious limitation,confidence intervalincludes importantbenefit and harmUndetected 19/4317(0.44 %)17/7441(0.23 %)OR 0.62(0.31 to 1.22)50 per1000b19 fewer per 1000(34 fewer to 11 more)⊕⊕ ΟΟLow due torisk of bias andimprecisionHospitalization for heart failure6068(1)2.1 yearsNo seriouslimitationsNo seriouslimitationsNo seriouslimitationsSerious limitation,confidence intervalincludes importantbenefit and harmUndetected 127/30344.2 %122/30344 %HR 0.96(0.75 to 1.23)100 per1000c4 fewer per 1000(25 fewer to 23 more)⊕⊕⊕ΟModerate dueto imprecisionGLP-1 glucagon-like peptide-1aSeveral trials probably had risk of bias on random sequence generation, allocation concealment and blinding (Additional file 2), and the follow up (median of 52 weeks) was not long enough for heart failure to occurin patients with low risk of cardiovascular diseasebBaseline risk estimate for heart failure in a 5-year time frame comes from the control arm of the cohort study we identified to best represent our target population (Kannan 2015 [17]), with 528 events of heart failurein 13,185 participants (4.0 %) at four year follow up across control and intervention armcBaseline risk estimate for hospitalization for heart failure in 5-year time frame comes from the control arm of the only included ELIXA trial [16] we identified to best represent our target population with 127 events in3034 participants (42 per 1000) over a 2.1 year follow up period, in the absence of observational studies providing more credible baseline risk estimatesLietal.BMCCardiovascularDisorders (2016) 16:91 Page8of14Table 4 Characteristics of included observational studiesStudy Study design DatasourceCountriesinvolvedFunding TotalnumberofpatientsFollowup(years)Male(n, %)Meanage(years)Mean BMI(kg/m2)MeanHbA1c (%)Mean FPG(mmol/L)Mean diabetesduration (years)CVD at baselineStudies reporting heart failureNCT010600592013 [66]Prospectivecohort studyRealworlddataItaly Privatefor-profitfunding882 1 493(55.9)62.5 NR 8.9 NR NR NRKannan 2015 [17]a Retrospectivecohort studyElectronichealthrecordsU.S. Nofunding13,185 4b 7827(54.6)60.6 32.6c NR NR NR Included patients hadno history of CVD orcongestive heart failureat baselinePaul 2015 [18] Retrospectivecohort studyClaimsdataU.S. NR 39,225 3.5b 18093(46.1)58.2 35.3 7.9 NR 1.3 Included patients hadCVD or no CVD atbaselineStudies reporting hospitalization for heart failureYu 2015 [19]a Nested case–control studyElectronicmedicalrecordsUK Publicfunding57,737 NA 32795(56.8)61.6 NR NR NR 2.3 Included patients hadCVD or no CVD atbaselineaThese two studies accessed incretin agents (both glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) and the risk of heart failure, so the data above were the characteristics of totalpatients includedBMI body mass index, FPG fasting plasma glucose, CVD cardiovascular disease, NR not reported, NA not applicablebmedian follow-up (years);cMedian BMI (kg/m2)Lietal.BMCCardiovascularDisorders (2016) 16:91 Page9of14Table 5 Exposures, outcomes, and results of observational studiesStudy Exposure ofinterestControl group Number ofevents or casesTotal numberof analyzedpatientsAdjusted estimates(95 % CI)Adjusted covariateStudies reporting heart failureKannan 2015[17]GPL-1 agonists(combined withmetformine)Sulfonylureas(combined withmetformine)528a 13,185 (55,110person years)aHR 1.10 (0.99 to 1.22) Age, sex, race, BMI, number ofencounters, median householdincome, smoking status, systolicand diastolic blood pressure,hypertension, dyslipidemia,cerebral vascular event,presence of neuropathy,retinopathy, dementia, chronicobstructive pulmonary disease,cancer, atrial fibrillation, anti-hypertensive medications, lipidlowering agents, anti-plateletagents and propensity for beingon metformin and sulfonylureasat baseline, lipid profile, esti-mated glomerular filtration ratePaul 2015[18]Exenatide/exenatide+ insulinInsulin 2338 39,225 Exenatide vs insulin:HR 0.34 (0.22, 0.52)Exenatide + insulin vs insulin:HR 0.40 (0.32, 0.50)Without previous CVD:Exenatide vs insulin:HR 0.34 (0.22, 0.52)Exenatide + insulin vs insulin:HR 0.40 (0.32, 0.50)Without previous CVD& renal diseases:Exenatide vs insulin:HR 0.32 (0.21, 0.50)Exenatide + insulin vs insulin:HR 0.35 (0.28, 0.45)Gender, ethnicity, age at thestart of cohort, BMI, HbA1c,systolic and diastolic bloodpressure on the index date,history of cardiovascular disease,any renal disease prior to indexdate or during follow-up, use ofmetformin, sulfonylurea, cardio-protective medications or anti-hypertensive medications, andthe duration of diabetesNCT010600592013 [66]Exenatide Basal insulin 2 882 NR NRStudies reporting hospitalization for heart failureYu 2015 [19] GLP-1 agonists(exenatide andliraglutide, aloneor incombinationwith otherantidiabetic drugs)Other oralantidiabeticdrugs1,118a 18,744a OR 0.67 (0.32 to 1.42) Sex, BMI, excessive alcohol use,smoking status, HbA1c level,comorbidities (neuropathy,renal disease, retinopathy,atrial fibrillation, cancer [otherthan nonmelanoma skincancer], chronic obstructivepulmonary disease, coronaryartery disease, dyslipidemia,hypertension, previousmyocardial infarction, peripheralarteriopathy, previous coronaryrevascularization, peripheralvascular disease, and previousstroke), number of prescriptions,number of physician visits, anduse of the following drugs inthe year prior to cohort entry:angiotensin convertingenzyme inhibitors, angiotensinreceptor blockers, β-blockers,calcium channel blockers,diuretics, fibrates, statins, as-pirin, and other nonsteroidalanti-inflammatory drugsaThese two studies accessed incretin agents and the risk of heart failure, and the data of events/cases and total number of analyzed patients regarding glucagon-likepeptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors were not reported separately, so the data above were the data of total study patientsCI confidence interval, NR not reported, HR hazard ratio, OR odds ratio, CVD cardiovascular disease, BMI body mass indexLi et al. BMC Cardiovascular Disorders  (2016) 16:91 Page 10 of 14agonists are also shown to be associated with a modest in-crease of ejection fraction in diabetic patients [69]. A recentmeta-analysis of RCTs [70] found that GLP-1 agonists wereassociated with a modest reduction in blood pressure and aslight increase in heart rate. These biological studies suggestthat GLP-1 agonists might, if anything, reduce the inci-dence of heart failure. Though results of RCTs fail to showthis decrease, confidence intervals do not exclude the possi-bility of a modest reduction.ConclusionsThe current evidence suggests that GLP-1 agonists donot increase the risk of heart failure or hospitalizationfor heart failure. The current body of evidence, however,is not definitive. More carefully designed, conducted, ad-equately powered trials and observational studies arewarranted to confirm the effects of GLP-1 agonists onincidence of heart failure and hospitalization for heartfailure. Future studies should also examine whether theTable 6 Risk of heart failure or hospitalization for heart failure among patients with type 2 diabetes receiving glucagon-like peptide-1receptor agonists treatmentComparison Number of studies(Events or cases,patients)GLP-1 agonists(events/patients)Control(events/patients)Effect Estimate(95%CI)Cardiovascular morbiditiesat baseline1. Heart failureRandomized controlled trialsGLP-1 agonists vs. control 20 (36, 11758) 17/7441 19/4317 Pooled OR 0.62(0.31 to 1.22)Typically without CVDat baselineCohort studiesGLP-1 agonists vs. SU 1 (528, 13185) NR NR Adjusted HR 1.10(0.99 to 1.22)No history of CVD orcongestive heart failureat baselineExenatide vs. insulinExenatide + insulin vs. insulin1 (2338, 39225) 49/2804195/78702094/285512094/28551Adjusted HR 0.34(0.22, 0.52)Adjusted HR 0.40(0.32, 0.50)With or without CVDat baselineExenatide vs. basal insulin 1 (2, 882) 0/444 2/438 Unadjusted OR 0.13(0.01 to 2.13)NR2. Hospitalization for heart failureRandomized controlled trialsLixisenatide vs. placebo 1 (249, 6068) 122/3034 127/3034 Pooled Adjusted HR0.96 (0.75, 1.23)Acute coronary syndromeNested case–control studiesGLP-1 agonists vs. other OADs 1 (1118, 18744) Adjusted OR 0.67(0.32 to 1.42)With or without CVDat baselineGLP-1 glucagon-like peptide-1, CVD cardiovascular disease, SU sulfonylurea, OR odds ratio, HR hazard ratio, NR not reported, OADs oral antidiabetic drugsFig. 3 Risk of heart failure in patients who received GLP-1 agonists versus control based on adjusted data of observational studiesLi et al. BMC Cardiovascular Disorders  (2016) 16:91 Page 11 of 14effects of GLP-1 agonists on heart failure are affected bypatient's baseline risk of cardiovascular disease.Availability of data and materialsThe datasets supporting the conclusions of this articleare included within the article and its additional files.Additional filesAdditional file 1: Search strategies. (DOC 35 kb)Additional file 2: Risk of bias of included randomized controlled trials.(DOC 78 kb)Additional file 3: Subgroup analysis of heart failure risk by type ofcontrol based on raw data of randomized controlled trials. (DOC 47 kb)Additional file 4: Subgroup analysis of heart failure risk by mode oftherapy based on raw data of randomized controlled trials. (DOC 45 kb)Additional file 5: Subgroup analysis of heart failure risk by length offollow up based on raw data of randomized controlled trials. (DOC 45 kb)Additional file 6: Subgroup analysis of heart failure risk by individualGLP-1 agonists agents based on raw data of randomized controlled trials.(DOC 55 kb)Additional file 7: Risk of bias of included cohort studies. (DOC 55 kb)Additional file 8: Risk of bias of included case–control studies. (DOC 52 kb)AbbreviationsBMI: body mass index; CENTRAL: the Cochrane Central Register of ControlledTrials; CI: confidence interval; DPP-4: dipeptidyl peptidase-4; ELIXA: Evaluation ofLIXisenatide in Acute Coronary Syndrome; FPG: fasting plasma glucose; GLP-1: glucagon-like peptide-1; GRADE: Grading of Recommendations Assessment,Development and Evaluation; HbA1c: glycated haemoglobin; HR: hazard ratio;MOOSE: Meta-analysis Of Observational Studies in Epidemiology; OR: odds ratio;PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses;RCTs: randomized controlled trials; RD: risk difference.Competing interestsThis study was supported by National Natural Science Foundation of China(Grant No. 71573183), “Thousand Youth Talents Plan” of China (Grant No:D1024002) and Sichuan Province, and Young Investigator Award, SichuanUniversity (Grant No: 2013SCU04A37). These funders had no role in the studydesign, writing of the manuscript, or decision to submit this or futuremanuscripts for publication. SL is funded by the National Natural ScienceFoundation of China (Grant No. 81400811 and 21534008). JWB is funded bya New Investigator Award from the Canadian Institutes of Health Researchand Canadian Chiropractic Research Foundation. ZNS is funded by theCanadian Diabetes Association. SE is funded by MITACS Elevate andRestracomp Postdoctoral Awards.Authors’ contributorsXS and SL conceived the study. XS acquired the funding. XS and LL had fullaccess to all of the data in the study, and take responsibility for the integrityof the data and the accuracy of the data analysis. XS and LL designed thestudy. XS and LL developed and tested the data collection forms. LL, JL, KD,JWB, POV, EW, ZNS, MMB, LPR, GM, SE, JS, LZ, PZ, QC and YW acquired thedata. LL and XS conducted the analysis and interpreted the data. LL and XSdrafted the manuscript. LL, XS, SL, JWB, POV, GHG, JL, KD, EW, ZNS, MMB,LPR, GM, SE, JS, LZ, PZ, QC and YW critically revised the manuscript. XS is theguarantor. All authors read and approved the final manuscript.AcknowledgementsThe authors would like to thank Daphne Plaut for developing the searchstrategy and conducting the initial literature search.Author details1Chinese Evidence-based Medicine Center, West China Hospital, SichuanUniversity, 37 GuoXue Xiang, Chengdu 610041, Sichuan, China. 2Departmentof Endocrinology and Metabolism, West China Hospital, Sichuan University,Chengdu, Sichuan, China. 3West China school of Pharmacy, SichuanUniversity, Chengdu, Sichuan, China. 4Department of Clinical Epidemiologyand Biostatistics, McMaster University, Hamilton, ON, Canada. 5Department ofAnesthesia, McMaster University, Hamilton, ON, Canada. 6The Michael G.DeGroote Institute for Pain Research and Care, McMaster University,Hamilton, ON, Canada. 7Norwegian Knowledge Centre for the HealthServices, Oslo, Norway. 8Department of Medicine, Innlandet Hospital Trust,Gjøvik, Norway. 9Department of Medicine, University of British Columbia,Vancouver, BC, Canada. 10Faculty of Medicine, University of Toronto, 1 King’sCollege Circle, Toronto, ON, Canada. 11Department of Hygiene and Dietetics,Jagiellonian University Medical College, Krakow, Poland. 12Systematic ReviewsUnit-Polish Cochrane Branch, Jagiellonian University Medical College, Krakow,Poland. 13Internal Medicine Unit, Hospital Clinico FUSAT, Rancagua, Chile.14Department of Medicine, Universidad Peruana Cayetano Heredia, Lima,Peru. 15Stanford Prevention Research Center, Department of Medicine,Stanford University, Stanford, USA. 16Department of Anaesthesia & PainMedicine, The Hospital for Sick Children, Toronto, ON, Canada. 17The SecondHospital of Lanzhou University, Lanzhou, China. 18Department of MedicalAdministration, 363 Hospital, Chengdu, Sichuan, China. 19Department ofMedicine, McMaster University, Hamilton, ON, Canada.Received: 9 February 2016 Accepted: 29 April 2016References1. 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