Top

Published in:

Open Access 01-12-2016 | Research article

Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies

Authors: Ling Li, Sheyu Li, Jiali Liu, Ke Deng, Jason W. Busse, Per Olav Vandvik, Evelyn Wong, Zahra N. Sohani, Malgorzata M. Bala, Lorena P. Rios, German Malaga, Shanil Ebrahim, Jiantong Shen, Longhao Zhang, Pujing Zhao, Qunfei Chen, Yingqiang Wang, Gordon H. Guyatt, Xin Sun

Published in: BMC Cardiovascular Disorders | Issue 1/2016

Abstract

Background

The effect of glucagon-like peptide-1(GLP-1) receptor agonists on heart failure remains uncertain. We therefore conducted a systematic review to assess the possible impact of GLP-1 agonists on heart failure or hospitalization for heart failure in patients with type 2 diabetes.

Methods

We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov to identify randomized controlled trials (RCTs) and observational studies that addressed the effect of GLP-1 receptor agonists in adults with type 2 diabetes, and explicitly reported heart failure or hospitalization for heart failure. Two paired reviewers screened reports, collected data, and assessed the risk of bias. We pooled data from 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 observational studies (n = 111,029). Low quality evidence from 20 RCTs suggested, if anything, a lower incidence of heart failure between 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 cohort studies comparing GLP-1 agonists to alternative agents provided very low quality evidence that GLP-1 agonists do not increase the incidence of heart failure. One RCT provided moderate quality evidence that GLP-1 agonists were not associated with hospitalization for heart failure (lixisenatide vs placebo: 122/3,034 vs. 127/3,034; adjusted hazard 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 a case–control study provided very low quality evidence also suggesting no association (GLP-1 agonists vs. other anti-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 or hospitalization for heart failure among patients with type 2 diabetes.

Available only for authorised users

Aroda VR, Henry RR, Han J, Huang W, DeYoung MB, Darsow T, et al. Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin Ther. 2012;34(6):1247–58.e22.CrossRefPubMed

Liu FP, Dong JJ, Yang Q, Xue XZ, Ren ZF, Gan YZ, et al. Glucagon-like peptide 1 receptor agonist therapy is more efficacious than insulin glargine for poorly controlled type 2 diabetes: A systematic review and meta-analysis. J Diabetes. 2015;7(3):322–8.CrossRefPubMed

Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771.CrossRefPubMedPubMedCentral

Wu S, Sun F, Zhang Y, Yang Z, Hong T, Chen Y, et al. The cardiovascular effects of glucagon-like peptide-1 receptor agonists: a trial sequential analysis of randomized controlled trials. J Clin Pharm Ther. 2014;39(1):7–13.CrossRefPubMed

Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(1):38–47.CrossRefPubMed

Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–9.CrossRefPubMed

U.S. Food and Drug Administration. Saxagliptin (marketed as Onglyza and Kombiglyze XR): Drug Safety Communication - FDA to Review Heart Failure Risk. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm385471.htm. Accessed 27 Aug 2015.

Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.CrossRefPubMed

Wang KL, Liu CJ, Chao TF, Huang CM, Wu CH, Chen SJ, et al. Sitagliptin and the risk of hospitalization for heart failure: a population-based study. Int J Cardiol. 2014;177(1):86–90.CrossRefPubMed

10.

Weir DL, McAlister FA, Senthilselvan A, Minhas-Sandhu JK, Eurich DT. Sitagliptin use in patients with diabetes and heart failure: a population-based retrospective cohort study. JACC Heart Fail. 2014;2(6):573–82.CrossRefPubMed

11.

Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58(4):975–83.CrossRefPubMedPubMedCentral

12.

Chilton R, Wyatt J, Nandish S, Oliveros R, Lujan M. Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagonlike peptide-1-based therapies. Am J Med. 2011;124(1 Suppl):S35–53.CrossRefPubMed

13.

Drucker DJ, Goldfine AB. Cardiovascular safety and diabetes drug development. Lancet. 2011;377(9770):977–9.CrossRefPubMed

14.

Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109(8):962–5.CrossRefPubMed

15.

Bentley-Lewis R, Aguilar D, Riddle MC, Claggett B, Diaz R, Dickstein K, et al. Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J. 2015;169(5):631–8.e7.CrossRefPubMed

16.

Lewis EF, Evaluation of LIXisenatide in Acute Coronary Syndrome (ELIXA). European Society of Cardiology Congress 2015: Hot Line III - Diabetes mellitus/Pharmacology. Presented on August 31, 2015. http://congress365.escardio.org/Search-Results?vgnextkeyword=ELIXA#.VjsFJfnMVLA.

17.

Kannan S, Pantalone KM, Matsuda S, Wells BJ, Karafa M, Zimmerman RS. Risk of overall mortality and cardiovascular events in patients with type 2 diabetes on dual drug therapy including metformin: A large database study from the Cleveland Clinic. J Diabetes. 2015. doi:10.1111/753-0407.12301 [Epub ahead of print].PubMed

18.

Paul SK, Klein K, Maggs D, Best JH. The association of the treatment with glucagon-like peptide-1 receptor agonist exenatide or insulin with cardiovascular outcomes in patients with type 2 diabetes: a retrospective observational study. Cardiovasc Diabetol. 2015;14:10.CrossRefPubMedPubMedCentral

19.

Yu OH, Filion KB, Azoulay L, Patenaude V, Majdan A, Suissa S. Incretin-based drugs and the risk of congestive heart failure. Diabetes Care. 2015;38(2):277–84.CrossRefPubMed

20.

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.CrossRefPubMedPubMedCentral

21.

Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12.CrossRefPubMed

22.

Higgins JPT AD, Sterne JAC. Assessing risk of bias in included studies. In Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. Cochrane Collaboration, 2011.

23.

Guyatt GH, Busse JW. Modification of Cochrane Tool to assess risk of bias in randomized trials. http://distillercer.com/resources/. Accessed 06 Dec 2015

24.

Akl EA, Sun X, Busse JW, Johnston BC, Briel M, Mulla S, et al. Specific instructions for estimating unclearly reported blinding status in randomized trials were reliable and valid. J Clin Epidemiol. 2012;65(3):262–7.CrossRefPubMed

25.

Wells GA SB, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 25 Aug 2015

26.

Busse JW, Guyatt GH. Tool to Assess Risk of Bias in Cohort Studies. http://distillercer.com/resources/. Accessed 06 Dec 2015

27.

Busse JW, Guyatt GH. Tool to Assess Risk of Bias in Case-control Studies. http://distillercer.com/resources/. Accessed 06 Dec 2015

28.

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6.CrossRefPubMedPubMedCentral

29.

Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). J Clin Epidemiol. 2011;64(4):407–15.CrossRefPubMed

30.

Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence--imprecision. J Clin Epidemiol. 2011;64(12):1283–93.CrossRefPubMed

31.

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 7. Rating the quality of evidence--inconsistency. J Clin Epidemiol. 2011;64(12):1294–302.CrossRefPubMed

32.

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 8. Rating the quality of evidence--indirectness. J Clin Epidemiol. 2011;64(12):1303–10.CrossRefPubMed

33.

Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al. GRADE guidelines: 5. Rating the quality of evidence--publication bias. J Clin Epidemiol. 2011;64(12):1277–82.CrossRefPubMed

34.

Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P, et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011;64(12):1311–6.CrossRefPubMed

35.

Higgins JPT DJSsacdIHJ, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. Cochrane Collaboration, 2011.

36.

Bradburn MJ, Deeks JJ, Berlin JA, Russell LA. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26(1):53–77.CrossRefPubMed

37.

Higgins JPT DJ, Altman DG. Special topics in statistics. In Higgins JPT, Green S, (eds) Cochrane handbook for systematic reviews of interventions. Version 5.1.0. Cochrane Collaboration, 2011.

38.

Inagaki N, Atsumi Y, Oura T, Saito H, Imaoka T. Efficacy and Safety Profile of Exenatide Once Weekly Compared With Insulin Once Daily in Japanese Patients With Type 2 Diabetes Treated With Oral Antidiabetes Drug(s): Results From a 26-Week, Randomized, Open-Label, Parallel-Group, Multicenter, Noninferiority Study. Clin Ther. 2012;34(9):1892–908.e1.CrossRefPubMed

39.

AstraZeneca, Eli Lilly and Company. Study to evaluate the efficacy and safety of exenatide once-weekly injection compared to once-daily insulin in type 2 diabetes mellitus. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00935532.

40.

Novo Nordisk A/S. To evaluate the effect of liraglutide versus glimepiride (Amaryl®) on haemoglobin A1c (LEAD-3). National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00294723.

41.

Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473–81.CrossRefPubMed

42.

Novo Nordisk. To compare the effect of liraglutide when given together with metformin with the effect of metformin given alone and with the effect of glimepiride and metformin given together (LEAD-2). National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00318461.

43.

Nauck M, Frid A, Hermansen K, Thomsen AB, During M, Shah N, et al. Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study. Diabetes Obes Metab. 2013;15(3):204–12.CrossRefPubMed

44.

Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84–90.CrossRefPubMedPubMedCentral

45.

AstraZeneca, Eli Lilly and Company. A study comparing exenatide with basal insulin in achieving a target HbA1c with minimum weight gain in type 2 diabetes patients. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00360334.

46.

Novo Nordisk A/S. Effect of liraglutide or glimepiride added to metformin on blood glucose control in subjects with type 2 diabetes. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00614120.

47.

AstraZeneca, Eli Lilly and Company. Effect of exenatide on abdominal fat distribution in patients with type 2 diabetes pretreated with metformin. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00701935.

48.

GlaxoSmithKline. Efficacy and safety of albiglutide in treatment of type 2 diabetes. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00838903.

49.

Ahren B, Johnson SL, Stewart M, Cirkel DT, Yang F, Perry C, et al. HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin. Diabetes Care. 2014;37(8):2141–8.CrossRefPubMed

50.

GlaxoSmithKline. A study to determine the safety and efficacy of albiglutide in patients with type 2 diabetes. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00838916.

51.

Weissman PN, Carr MC, Ye J, Cirkel DT, Stewart M, Perry C, et al. HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia. 2014;57(12):2475–84.CrossRefPubMed

52.

GlaxoSmithKline. A study to determine the safety and efficacy of albiglutide in subjects with type 2 diabetes. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00839527.

53.

GlaxoSmithKline. Safety and efficacy study of albiglutide in type 2 diabetes. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00849017.

54.

GlaxoSmithKline. Safety and efficacy of albiglutide in type 2 diabetes. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00849056.

55.

University of Michigan, Amylin Pharmaceuticals, LLC, Eli Lilly and Company. Evaluation of exenatide in patients with diabetic neuropathy. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00855439.

56.

AstraZeneca; Eli Lilly and Company. A trial comparing two therapies: basal insulin/glargine, exenatide and metformin therapy (BET) or basal insulin/glargine, bolus insulin lispro and metformin therapy (BBT) in subjects with type 2 diabetes. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT00960661.

57.

Diamant M, Nauck MA, Shaginian R, Malone JK, Cleall S, Reaney M, et al. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care. 2014;37(10):2763–73.CrossRefPubMed

58.

Eli Lilly and Company. A Study in participants with type 2 diabetes mellitus (AWARD-1). National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT01064687.

59.

Eli Lilly and Company. A study in participants with type 2 diabetes mellitus (AWARD-2). National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT01075282.

60.

Eli Lilly and Company. A Study in participants with type 2 diabetes mellitus (AWARD-3). National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT01126580.

61.

Umpierrez G, Tofe Povedano S, Perez Manghi F, Shurzinske L, Pechtner V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014;37(8):2168–76.CrossRefPubMed

62.

Eli Lilly and Company. A study in participants with type 2 diabetes mellitus (AWARD-4). National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT01191268.

63.

Novo Nordisk A/S. Safety and efficacy of liraglutide in combination with an oad in subjects with type 2 diabetes insufficiently controlled on oad alone. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT01512108.

64.

Novo Nordisk A/S. Efficacy and safety of liraglutide versus placebo as add-on to existing diabetes medication in subjects with type 2 diabetes and moderate renal impairment. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT01620489.

65.

Pratley RE, Urosevic D, Boldrin M, Balena R. Efficacy and tolerability of taspoglutide versus pioglitazone in subjects with type 2 diabetes uncontrolled with sulphonylurea or sulphonylurea-metformin therapy: A randomized, double-blind study (T-emerge 6). Diabetes Obes Metab. 2013;15(3):234–40.CrossRefPubMed

66.

AstraZeneca, Eli Lilly and Company. Exenatide and Basal Insulins Use in the Real Setting: an Observational Study in Patients With Type 2 Diabetes. In: ClinicalTrials.gov [Internet]. National Library of Medicine (US), 2000. http://clinicaltrials.gov/show/NCT01060059.

67.

Thrainsdottir I, Malmberg K, Olsson A, Gutniak M, Ryden L. Initial experience with GLP-1 treatment on metabolic control and myocardial function in patients with type 2 diabetes mellitus and heart failure. Diab Vasc Dis Res. 2004;1(1):40–3.CrossRefPubMed

68.

Hattori A, Kawamura I, Yamada Y, Kanamori H, Aoyama T, Ushikoshi H, et al. Elevated plasma GLP-1 levels and enhanced expression of cardiac GLP-1 receptors as markers of left ventricular systolic dysfunction: a cross-sectional study. BMJ Open. 2013;3(9), e003201.CrossRefPubMedPubMedCentral

69.

Liu R, Li L, Chen Y, Yang M, Liu H, Yang G. Effects of glucagon-like peptide-1 agents on left ventricular function: systematic review and meta-analysis. Ann Med. 2014;46(8):664–71.CrossRefPubMed

70.

Sun F, Wu S, Guo S, Yu K, Yang Z, Li L, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: A systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110(1):26–37.CrossRefPubMed

Title: Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies
Authors: Ling Li
Sheyu Li
Jiali Liu
Ke Deng
Jason W. Busse
Per Olav Vandvik
Evelyn Wong
Zahra N. Sohani
Malgorzata M. Bala
Lorena P. Rios
German Malaga
Shanil Ebrahim
Jiantong Shen
Longhao Zhang
Pujing Zhao
Qunfei Chen
Yingqiang Wang
Gordon H. Guyatt
Xin Sun
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Cardiovascular Disorders / Issue 1/2016
Electronic ISSN: 1471-2261
DOI: https://doi.org/10.1186/s12872-016-0260-0

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The STEP trials

Springer Medicine

Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

Urine proteomics in the diagnosis of stable angina

Diastolic versus systolic ankle-brachial pressure index using ultrasound imaging & automated oscillometric measurement in diabetic patients with calcified and non-calcified lower limb arteries

Patients with HFpEF and HFrEF have different clinical characteristics but similar prognosis: a retrospective cohort study

Effects of non-supervised low intensity aerobic excise training on the microvascular endothelial function of patients with type 1 diabetes: a non-pharmacological interventional study

Effects of lifestyle intervention using patient-centered cognitive behavioral therapy among patients with cardio-metabolic syndrome: a randomized, controlled trial

Rationale and design of a randomised clinical trial for an extended cardiac rehabilitation programme using telemonitoring: the TeleCaRe study

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page