In nearly 100,000 real-world patients with cardiometabolic HFpEF, both semaglutide and tirzepatide reduced the risk of heart failure hospitalization or death by over 40% compared to sitagliptin, with no meaningful difference between the two drugs.
HR 0.58Semaglutide reduced heart failure hospitalization or death by 42% versus sitagliptin in 58,333 real-world HFpEF patients
What the researchers found
In expanded eligibility cohorts reflecting real clinical practice:
- Semaglutide vs sitagliptin (n=58,333): HR 0.58 (95% CI 0.51-0.65) — 42% risk reduction for heart failure hospitalization or all-cause mortality
- Tirzepatide vs sitagliptin (n=11,257): HR 0.42 (95% CI 0.31-0.57) — 58% risk reduction
- Tirzepatide vs semaglutide head-to-head (n=28,100): HR 0.86 (95% CI 0.70-1.06) — no statistically meaningful difference
Benchmarking analyses emulating the STEP-HFpEF DM and SUMMIT trials showed high agreement, validating the real-world study design. No substantially increased safety risks were identified.
Why it matters
HFpEF accounts for roughly half of all heart failure cases and has had few effective treatments until recently. While early randomized trials of semaglutide and tirzepatide showed promise, they were based on few clinical events. This study provides the first large-scale real-world evidence that these peptide drugs substantially reduce heart failure hospitalization and death — the outcomes that matter most to patients and clinicians. Published in JAMA, this is landmark evidence supporting GLP-1-based therapy for HFpEF.
How the study worked
Five cohort studies using national US healthcare claims data (2018-2024). Two studies emulated the STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) randomized trials as benchmarks. Three studies used expanded eligibility criteria to evaluate real-world effectiveness, including a head-to-head comparison. Sitagliptin served as a placebo proxy. Propensity score weighting adjusted for comprehensive pretreatment characteristics. Follow-up was up to 52 weeks. Negative control outcomes, secondary endpoints, subgroups, and sensitivity analyses were prespecified.
What this study cannot tell us
This is an observational study using insurance claims data, not a randomized controlled trial, so residual confounding is possible despite propensity score adjustment. Sitagliptin was used as a placebo proxy, which may introduce bias if sitagliptin itself has cardiac effects. Claims data may not capture all clinical details, and drug adherence cannot be verified. The tirzepatide cohort is smaller due to its more recent market entry. Follow-up was limited to 52 weeks.
How to read the evidence
This is a large observational cohort study published in JAMA, using rigorous trial-emulation methodology with propensity score weighting and prespecified sensitivity analyses. While not a randomized trial, the benchmarking against existing RCTs and the very large sample size provide high-quality real-world evidence.
When this study was published
Published in 2025 using data through 2024, this is among the most current evidence available on GLP-1-based therapies for HFpEF.
The bigger picture
This study is a pivotal piece of evidence in the expansion of GLP-1 receptor agonists beyond diabetes and obesity into cardiovascular medicine. Combined with the STEP-HFpEF and SUMMIT trial data, it builds a strong case for semaglutide and tirzepatide as standard treatments for cardiometabolic HFpEF. The finding that tirzepatide (a dual GIP/GLP-1 agonist) does not meaningfully outperform semaglutide (GLP-1 monoagonist) on hard outcomes suggests the GLP-1 pathway may be the primary driver of cardiac benefit.
Questions still open
- Will ongoing randomized trials confirm the >40% risk reduction for hard outcomes seen in this real-world data?
- Why does tirzepatide not meaningfully outperform semaglutide despite adding GIP receptor activation?
- Should GLP-1 receptor agonists become first-line therapy for all patients with cardiometabolic HFpEF?
Common questions
What does a hazard ratio of 0.58 mean in practical terms?
If tirzepatide didn't beat semaglutide, why would anyone choose it?
Read the original research
Semaglutide and Tirzepatide in Patients With Heart Failure With Preserved Ejection Fraction.
JAMA, 334(14), 1255-1266
Citation
Krüger, Nils; Schneeweiss, Sebastian; Fuse, Kenshiro; Matseyko, Sofiya; Sreedhara, Sushama Kattinakere; Hahn, Georg; Schunkert, Heribert; Wang, Shirley V. (2025). Semaglutide and Tirzepatide in Patients With Heart Failure With Preserved Ejection Fraction.. JAMA, 334(14), 1255-1266. https://doi.org/10.1001/jama.2025.14092