Comparison of Semaglutide or Dulaglutide Versus Empagliflozin for Risk for Death and Cardiovascular Outcomes Among Patients With Type 2 Diabetes : Two Target Trial Emulation Studies.

BACKGROUND: Reduction of premature death and adverse cardiovascular outcomes is a key goal in type 2 diabetes management. OBJECTIVE: To compare mortality and cardiovascular event risks in patients treated with semaglutide versus empagliflozin and, secondarily, dulaglutide versus empagliflozin. DESIGN: Target trial emulation studies from observational data comparing semaglutide- or dulaglutide-treated patients with propensity score-matched patients treated with empagliflozin. SETTING: Health care system of 703 academic and community clinical practices. PARTICIPANTS: Patients aged 45 years or older with type 2 diabetes treated from 1 January 2019 to 31 December 2024 with semaglutide, dulaglutide, or empagliflozin. INTERVENTION: Initial treatment with semaglutide, dulaglutide, or empagliflozin. At baseline, concomitant treatment with other diabetes medication was permitted, excluding other glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter-2 inhibitors. MEASUREMENTS: A composite of death, myocardial infarction (MI), or stroke was the primary outcome, and secondary composite outcomes included death or MI, MI or stroke, and individual cardiac events. RESULTS: Patients treated with semaglutide ( = 7899) versus empagliflozin ( = 7899) were followed for a median of 2.2 years; the respective rates of the composite of death, MI, or stroke were 3.7% versus 4.5% at 2 years and 5.9% versus 6.9% at 3 years. Corresponding incidence rates for the composite outcome were 20.99 versus 23.56 per 1000 person-years, with a hazard ratio (HR) of 0.89 (95% CI, 0.78 to 1.02). The HRs for the individual outcomes were 0.97 (CI, 0.81 to 1.15) for death, 0.85 (CI, 0.68 to 1.05) for MI, and 0.62 (CI, 0.43 to 0.89) for stroke. Risks for dulaglutide- and empagliflozin-treated patients were similar for the composite outcome (HR, 1.03 [CI, 0.90 to 1.16]) and for death, MI, and stroke separately. LIMITATION: Observational study design, lack of data on cause-specific mortality, and residual confounding. CONCLUSION: Semaglutide treatment seems to confer some advantage over empagliflozin. This advantage was not observed for dulaglutide. PRIMARY FUNDING SOURCE: American Heart Association.