Semaglutide vs. Tirzepatide for Heart Failure With Preserved Ejection Fraction in Obesity: Similar Outcomes in a Large Real-World Study

What the researchers found

After propensity score matching in 2,516 patients (1,258 per group), semaglutide and tirzepatide showed no significant difference in the composite of all-cause mortality and heart failure hospitalization over a median 24-week follow-up (HR 1.14, 95% CI 0.89–1.46, p=0.286). Individual components were also similar: all-cause death HR 1.24 (p=0.531) and HF hospitalization HR 1.10 (p=0.471). Results were consistent regardless of diabetes status.

Why it matters

While tirzepatide produces greater weight loss than semaglutide in general obesity populations, clinicians and patients with HFpEF need to know whether that translates into better heart outcomes. This large real-world comparison provides the first direct evidence that both drugs perform similarly for the outcomes that matter most — death and hospitalization — giving clinicians confidence that either option is reasonable for obese HFpEF patients.

How the study worked

Non-randomized, observational cohort study using electronic health records from the TriNetX Global Collaborative Research Network. Adults with obesity and HFpEF who started semaglutide or tirzepatide for the first time between November 2023 and May 2025 were identified. Propensity score matching was used to balance the groups (1,258 per arm). The primary endpoint was a composite of all-cause mortality and HF hospitalization.

What this study cannot tell us

This is an observational study, not a randomized trial, so residual confounding is possible despite propensity score matching. The median follow-up of only 24 weeks may be too short to detect differences that emerge over longer treatment. Electronic health records may have incomplete outcome capture. The study compared clinical events but did not assess weight loss, symptom improvement, or quality of life, where differences between the drugs might exist.

How to read the evidence

This is a large observational cohort study with propensity score matching, using real-world electronic health records from a global network. While it provides valuable comparative effectiveness data, it lacks the rigor of a randomized controlled trial and is subject to residual confounding.

When this study was published

Published in 2026 with data from November 2023 through May 2025, this is among the first real-world comparative analyses of these two drugs in HFpEF and is highly current.

The bigger picture

HFpEF is the most common form of heart failure and has been notoriously difficult to treat. The STEP-HFpEF and SUMMIT trials showed semaglutide and tirzepatide individually benefit these patients, but no head-to-head trial exists. This real-world study fills an important gap by showing comparable clinical outcomes, suggesting that drug selection in HFpEF can be guided by factors like cost, availability, side-effect profiles, and patient preference rather than assumed superiority of one peptide over the other.

Questions still open

• Would a longer follow-up period reveal outcome differences between semaglutide and tirzepatide in HFpEF, given that tirzepatide produces greater weight loss?
• Do semaglutide and tirzepatide differ in quality-of-life improvements, exercise capacity, or symptom burden in HFpEF even if hard clinical endpoints are similar?
• Would a dedicated randomized head-to-head trial in HFpEF patients show the same equivalence seen in this observational analysis?

Common questions

Read the original research

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

ESC heart failure, 13(1)

Citation

Monzo, Luca; Savarese, Gianluigi; Duarte, Kevin; Baudry, Guillaume; Petrie, Mark C; Girerd, Nicolas. (2026). Semaglutide vs tirzepatide in patients with obesity and HFpEF: a report from a global federated research network.. ESC heart failure, 13(1). https://doi.org/10.1093/eschf/xvag042