GLP-1 receptor agonists for cardiovascular outcomes with and without metformin. A systematic review and meta-analysis of cardiovascular outcomes trials.

AIMS: To explore the effect of background treatment with metformin on the efficacy of GLP-1 receptor agonists (GLP-1 RAs) on cardiovascular outcomes in type 2 diabetes. METHODS: We searched MEDLINE and EMBASE through May 5, 2021 for randomized, placebo-controlled, cardiovascular outcomes trials of GLP-1 RAs in patients with type 2 diabetes that reported cardiovascular or mortality outcomes by baseline metformin use. Main outcome was incidence of major adverse cardiovascular events (MACE). Other outcomes included the individual components of the primary composite outcome (myocardial infarction, stroke, cardiovascular death), all-cause mortality and hospitalization for heart failure. We pooled hazard ratios (HRs) with 95% confidence intervals (CIs) stratified by baseline use of metformin using random-effects meta-analysis. RESULTS: We included 4 trials (43,456 patients) assessing albiglutide, dulaglutide, exenatide once weekly and liraglutide. GLP-1 RAs reduced MACE by 13% (HR 0.87, 95% CI 0.82-0.93), an effect which was consistent in both subgroups (HR 0.91, 95% CI 0.85-0.97 and HR 0.80, 95% CI 0.72-0.90 with and without metformin, respectively). Presence of metformin at baseline did not affect the overall favorable effect of GLP-1 RAs both on cardiovascular and all-cause mortality. Finally, subgroup meta-analyses suggested that GLP-1 RAs had a neutral effect on stroke, myocardial infarction and hospitalization for heart failure, irrespective of metformin use at baseline. CONCLUSIONS: Subgroup analyses suggested that treatment with GLP-1 RAs has a beneficial effect on cardiovascular outcomes irrespective of baseline use of metformin. However, given the exploratory nature of subgroup analyses, these findings should be treated as hypothesis-generating rather than conclusive evidence.