Comparative Effectiveness of Semaglutide and Tirzepatide on Cardiovascular Outcomes

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide have shown cardiovascular benefits in patients with diabetes. More recently, the indication for semaglutide was extended to cardiovascular risk management in patients without diabetes. However, direct comparative evidence on cardiovascular protection between semaglutide and tirzepatide in patients with obesity but without diabetes remains limited. Methods: We used an active comparator, new user design, and target trial emulation framework to compare the risk of 5-point MACE and 3-point MACE in new users of semaglutide and tirzepatide with obesity and established cardiovascular disease but without diabetes, identified from Komodo Health between November 8 th , 2023, and May 31 st , 2025. We used a per-protocol approach over 18 months of follow-up and censored patients who had a ≥90 day-gap in treatment supply or switched treatments. We created inverse probability of treatment weights (IPTW) to adjust for confounding and inverse probability of censoring weights (IPCW) to account for informative censoring. We estimated hazard ratios from weighted Cox proportional hazards models and incidence rate differences from weighted Kaplan-Meier survival curves, bootsrapped over 1,000 samples for robust confidence intervals. Results: We identified 6,903 new users of semaglutide and 6,937 new users of tirzepatide. Prior to weighting, semaglutide users tended to be older, have more comorbidities, and were more likely to have commercial insurance than Medicare or Medicaid, but balance was achieved after applying IPTW and IPCW weights. The risk of 5-point MACE was 18% higher in semaglutide users compared to tirzepatide users (HR=1.18, 95% CI: 1.09 to 1.31). The risk of 3-point MACE was not significantly different between treatment groups (HR=1.09, 95% CI: 0.94 to 1.27). Conclusions: The risk of cardiovascular events was lower for tirzepatide compared to semaglutide in initiators with obesity and a history of cardiovascular disease but without diabetes. Given the proven cardiovascular benefit of semaglutide compared to placebo from clinical trials in a similar population, these findings suggest that tirzepatide can be a promising alternative treatment option. Future research should confirm these results, which may have implications for expanding the indication of tirzepatide to include cardiovascular risk management.