HFpEF, a condition frequently associated with obesity and type 2 diabetes, remains one of the leading causes of hospital admissions and carries a significant health burden. While prior small-scale clinical trials suggested that GLP-1 receptor agonists such as semaglutide and the dual GIP/GLP-1 receptor agonist tirzepatide may improve symptoms, the evidence was limited by a low number of clinical events. The present large-scale investigation aimed to provide real-world insights into their effectiveness and safety.
The research, led by Nils Krüger from the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, utilized U.S. health care claims data from 2018 to 2024. Five cohort studies were conducted, two of which mirrored the STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) trials to validate outcomes. The analysis was further extended to broader patient groups typically encountered in clinical practice.
In total, the study evaluated 58,333 patients in the semaglutide versus sitagliptin group, 11,257 in the tirzepatide versus sitagliptin group, and 28,100 in a direct comparison of tirzepatide with semaglutide.
The study led to the following findings:
- Patients starting semaglutide had a 42% lower risk of hospitalization for heart failure or death from any cause compared with those on sitagliptin (HR, 0.58).
- Tirzepatide use was linked to a 58% reduction in the same risk outcomes compared with sitagliptin (HR, 0.42).
- Direct comparison between tirzepatide and semaglutide showed no significant difference in outcomes (HR, 0.86).
- Results were consistent across subgroup analyses, secondary outcomes, and sensitivity checks, strengthening the reliability of the findings.
- Neither semaglutide nor tirzepatide was associated with a major increase in adverse events, supporting their safety in this patient population.
The study concluded that semaglutide and tirzepatide substantially reduced the combined risk of hospitalization for heart failure or all-cause mortality compared with sitagliptin, which was used as a placebo proxy given its lack of influence on heart failure outcomes. These findings provide much-needed real-world evidence to complement prior trial data and support the therapeutic role of these agents in cardiometabolic HFpEF.
Despite its strengths, the authors acknowledged several limitations. As treatment allocation was not randomized, residual confounding could not be fully ruled out, though the large effect size makes this less likely to explain the outcomes. Medication adherence was inferred from pharmacy records rather than direct monitoring, and data on symptom improvement and ejection fraction relied on claims-based algorithms. Additionally, the study assumed sitagliptin to be a neutral comparator, an assumption supported by prior research.
"Overall, the real-world analysis strengthens the case for semaglutide and tirzepatide as beneficial options in managing HFpEF in patients with obesity and type 2 diabetes. However, further randomized trials and longer-term follow-up may be needed to confirm the durability of benefits and refine treatment strategies," the authors wrote.
Reference:
Krüger N, Schneeweiss S, Fuse K, et al. Semaglutide and Tirzepatide in Patients With Heart Failure With Preserved Ejection Fraction. JAMA. Published online August 31, 2025. doi:10.1001/jama.2025.14092
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