Semaglutide vs tirzepatide in patients with obesity and HFpEF: a report from a global federated research network

BACKGROUND AND AIMS: Semaglutide and tirzepatide have been shown to reduce body weight, improve health status, and lower rates of clinical events in patients with obesity and heart failure with preserved ejection fraction (HFpEF). Although recent data suggest that tirzepatide leads to greater weight loss compared to semaglutide in non-HF populations, it remains uncertain whether these different drugs might result in different clinical event rates. This study aims to compare the rates of clinical outcomes for semaglutide vs tirzepatide in patients with obesity and HFpEF. METHODS: In this non-randomized, observational cohort study, adults with obesity and a concurrent diagnosis of HFpEF who initiated treatment with semaglutide or tirzepatide for the first time between November 2023 and May 2025 were identified using electronic health record data from the TriNetX Global Collaborative Research Network. The primary endpoint was a composite of all-cause mortality and HF hospitalization, evaluated after propensity score matching (PSM). RESULTS: Among 3983 patients meeting the study criteria (semaglutide, 2719; tirzepatide, 1264), 1258 remained in each group after PSM (mean age 66 years, 41% male, 77% White, mean body mass index 42 kg/m², 63% with diabetes). Over a median follow-up of 24 weeks, semaglutide and tirzepatide were associated with a similar risk of the primary composite endpoint (HR 1.14 [95% CI, 0.89-1.46]; P = .286), and of its individual components (all-cause death: HR 1.24 [95% CI, 0.63-2.44]; P = .531; HF hospitalization: HR 1.10 [95% CI, 0.85-1.43]; P = .471), irrespective of diabetes status. CONCLUSIONS: In this real-world analysis, no difference was observed between semaglutide and tirzepatide in terms of clinical outcomes among patients with obesity and HFpEF.