Pharmacoepidemiology
Target Trial Emulation of Semaglutide vs Tirzepatide on Cardiovascular Outcomes in Patients with Obesity and Established CVD Rafeya Raquib* Rafeya Raquib Raquib Raquib Raquib Boston University
Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the dual glucose-dependent insulinotropic polypeptide and GLP-1 RA tirzepatide have shown cardiovascular benefits in patients with diabetes. Recently, semaglutide was indicated for cardiovascular risk management in patients without diabetes. 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 5-point and 3-point MACE risk in new users of semaglutide and tirzepatide with obesity and CVD but without diabetes from Komodo Health (11/8/2023-5/31/2025). We used a per-protocol approach over 18 months of follow-up, censoring those with ≥90 day-gaps in supply or treatment switching. We applied inverse probability of treatment weights (IPTW) and inverse probability of censoring weights (IPCW). We estimated hazard ratios from weighted Cox proportional hazards models and incidence rate differences from weighted Kaplan-Meier curves with 1,000 bootstrap samples.
Results: We identified 6,903 new users of semaglutide and 6,937 new users of tirzepatide. Semaglutide users tended to be older, have more comorbidities, and were more likely to have commercial insurance, but balance was achieved after weighting. Risk of 5-point MACE was 18% higher in semaglutide compared to tirzepatide users (HR=1.18, 95% CI: 1.09 to 1.3), while risk of 3-point MACE did not differ (HR=1.09, 95% CI: 0.94 to 1.27).
Conclusions: MACE risk was lower for tirzepatide compared to semaglutide in those with obesity and CVD but without diabetes. Given the proven cardiovascular benefit of semaglutide compared to placebo from clinical trials, these findings suggest tirzepatide can be a promising alternative treatment option. Future research should confirm these results, which may have implications for expanding the indication of tirzepatide.
