Comparative effectiveness of GLP-1 receptor agonists on cardiovascular outcomes among adults with type 2 diabetes and moderate cardiovascular risk: emulation of a target trial.

AIM: To compare the cardiovascular outcomes of glucagon-like peptide-1 receptor agonists (GLP-1RAs) among adults with type 2 diabetes mellitus (T2D) at moderate cardiovascular risk. METHODS: We emulated a target trial using claims data of adults with T2D at moderate cardiovascular risk who initiated dulaglutide, exenatide, liraglutide, or semaglutide between 01/01/2014-12/31/2021. Random treatment assignment was emulated by propensity scores and incorporated into inverse probability of treatment weighted (IPTW) Cox models. Outcomes were time to composite major adverse cardiovascular events (MACE: myocardial infarction, stroke, and all-cause mortality), expanded MACE (MACE, hospitalization for heart failure, and revascularization) and its components, and severe hypoglycemia. RESULTS: After IPTW, 35,572 patients initiated dulaglutide, 4376 initiated exenatide, 8843 initiated liraglutide, and 33,063 initiated semaglutide. Compared to dulaglutide, semaglutide was associated with lower risk of MACE (HR 0.85, 95CI % 0.78-0.93), expanded MACE (HR 0.92, 95CI % 0.87-0.96), all-cause mortality (HR 0.81, 95CI % 0.71-0.92), stroke (HR 0.82, 95CI % 0.70-0.97), and revascularization (HR 0.93, 95CI % 0.88-0.99), while liraglutide was associated with lower risk of MACE (HR 0.84, 95CI % 0.72-0.97) and all-cause mortality (HR 0.79, 95CI % 0.64-0.99). CONCLUSIONS: Among GLP-1RAs, semaglutide and liraglutide were associated with the greatest cardiovascular risk reduction in patients with T2D at moderate cardiovascular risk.