Real-World Cardiovascular Outcomes of Obesity Treatment With Tirzepatide Versus Semaglutide in Non-Diabetic Adults.

AIMS: Treatment of obesity with glucagon-like peptide-1 (GLP-1) receptor agonists improves cardiovascular outcomes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, achieves greater weight loss than GLP-1 receptor agonists alone; however, direct real-world comparisons of clinical outcomes are limited. MATERIALS AND METHODS: We conducted a retrospective, active-comparator, new-user cohort study using the TriNetX global federated electronic health record database. Adults (≥ 18 years) without diabetes who initiated tirzepatide or semaglutide for the treatment of obesity between November 2023 and August 2024 were included. Patients with recent atherosclerotic events, prior heart failure (HF), or crossovers to the comparator were excluded. The primary outcome was major cardiovascular events including all-cause death, acute coronary syndrome, stroke, or new-onset HF at 12 months. RESULTS: One-to-one propensity score matching yielded 35 336 pairs. Tirzepatide was associated with a lower incidence of the composite outcome compared with semaglutide (1.90% vs. 2.18%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.97; p = 0.01), driven by reduced new-onset HF (1.04% vs. 1.29%; HR, 0.79; 95% CI, 0.68-0.92; p = 0.002), including both HF with reduced and preserved ejection fraction. No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke. Mean weight loss was greater with tirzepatide (-9.8 kg vs. -8.0 kg; p < 0.001). Adverse event rates were comparable, with no new safety signals. CONCLUSIONS: In obese individuals without diabetes, tirzepatide was associated with a lower risk of cardiovascular events, especially incident HF, compared with semaglutide, with a similar safety profile.