Cardiovascular outcomes, heart failure and mortality in type 2 diabetic patients treated with glucagon-like peptide 1 receptor agonists (GLP-1 RAs): A systematic review and meta-analysis of observational cohort studies

Abstract

Background: Cardiovascular outcomes trials (CVOTs) have assessed the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on major adverse cardiovascular events (MACE) and mortality in high cardiovascular (CV) risk populations. Observational research can provide complementary evidence about these effects in unselected populations.

Aim: To systematically review retrospective observational cohort studies conducted in electronic healthcare databases (EHDs) assessing GLP-1 RAs´ effects on MACE and/or hospitalisation for heart failure (HHF) and/or all-cause mortality in Type 2 diabetes mellitus (T2DM) patients.

Methods: We systematically searched studies meeting inclusion criteria, compared design, methods and population characteristics, assessed risk for bias and did a meta-analysis (MA) using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals).

Results: Sixteen studies included 285,436 T2DM patients exposed to GLP-1 RAs (exenatide bid, liraglutide, lixisenatide, long-acting exenatide), n ranged from 219 to 160,803 patients. Comparators included: no exposure, other antidiabetic medications (OADs), combined OADs, canagliflozin or multiple comparators. Ten studies estimated all-cause mortality, hazard ratios (HRs) ranged from 0.17 (95% CI 0.02-1.22) to 1.29 (95% CI 0.54-3.13). Thirteen studies assessed cardiovascular events and/or MACE; HRs ranged from 0.27 (95% CI 0.14-0.53) to 1.11 (95% CI 0.99-1.24). Eight studies assessed HHF, HRs ranged from 0.12 (95% CI 0.02-0.66) to 1.64 (95% CI 1.28-2.13). Excluding two studies because of temporal bias, we obtained pooled estimates for all-cause mortality: HR 0.63 (0.44-0.89), CV outcomes HR 0.84 (0.75-0.94) and HHF; HR 0.94 (0.78-1.14), (high between-study variability: I² = 83.35%; I² = 70.3%; and I² = 90.1%, respectively).

Conclusion: Pooled results of EHDs' studies assessing GLP-1 RAs effects favoured GLP-1 RAs for all-cause mortality and MACE while were neutral for HHF. Results should be interpreted cautiously because of studies' substantial heterogeneity and limitations of observational research.

Keywords: all-cause mortality; electronic healthcare databases; glucagon-like peptide-1 receptor agonists; hospitalisation for heart failure; major adverse cardiovascular outcomes; type 2 diabetes mellitus.