Cardiovascular outcomes of glucagon-like peptide-1 receptor agonists: A systematic review

Abstract Purpose To identify and evaluate cardiovascular outcome trials for glucagon-like peptide-1 receptor agonists (GLP1RAs) in various patient populations, including those with or without type 2 diabetes (T2D). Summary A systematic search of MEDLINE identified 12 cardiovascular outcome-based randomized controlled trials: 10 in patients with T2D, one in patients with overweight/obesity and atherosclerotic cardiovascular disease (ASCVD) but not T2D, and one in patients with obesity and heart failure with preserved ejection fraction (HFpEF). Most trials had a low risk of bias. The GLP1RA was administered as a weekly subcutaneous injection in 8 trials, and 2 trials used once-daily oral semaglutide. Follow-up ranged from 1.2 to 5.4 years. GLP1RA therapy showed a consistent reduction in major adverse cardiovascular events (MACE) in patients with T2D. The effect on cardiovascular and all-cause death was less certain. Individually, only liraglutide demonstrated a reduction in MACE, cardiovascular death, and all-cause death. In patients with overweight/obesity and ASCVD (but without T2D), weekly subcutaneous semaglutide lowered the risk of MACE but not cardiovascular death. In patients with obesity and HFpEF (with or without T2D), tirzepatide lowered the occurrence of the composite endpoint of adverse heart failure events and cardiovascular death. Discontinuation of GLP1RA therapy due to gastrointestinal adverse events was common across the trials. Conclusion These data support the use of GLP1RAs to lower MACE in patients with T2D. A cardiovascular benefit with GLP1RA therapy was also observed in 2 additional patient populations: those with overweight/obesity and ASCVD but without T2D and those with obesity and HFpEF with or without T2D.