September 16, 2025
3 min read
Key takeaways:
- HF with preserved ejection fraction is common among people with obesity and type 2 diabetes.
- New real-world data suggest semaglutide and tirzepatide may reduce risk for HF hospitalization and mortality.
Results of a new study support using semaglutide and tirzepatide to reduce risk in patients with cardiometabolic heart failure with preserved ejection fraction.
The study investigated the effectiveness and safety of semaglutide (Ozempic/Wegovy, Novo Nordisk) and tirzepatide (Mounjaro/Zepbound, Eli Lilly) in clinical practice among new users who had cardiometabolic HFpEF.
HF with preserved ejection fraction is common among people with obesity and type 2 diabetes. Image: Adobe Stock
“Patients who initiated semaglutide or tirzepatide had over a 40% lower risk of being hospitalized due to heart failure or all-cause mortality compared to sitagliptin, which served as a placebo proxy,” Nils Krüger, MD, research fellow in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School and also physician scientist at TUM University Hospital German Heart Centre in Munich, said during a presentation of the results at the recent European Society of Cardiology Congress.
Moreover, in a head-to-head comparison of semaglutide vs. tirzepatide, the researchers found no incremental benefits of tirzepatide compared with semaglutide.
“Our findings complement early results from small [randomized clinical trials] that support the use of both agents in patients with HFpEF,” Krüger said during the presentation.
Krüger and colleagues used data from three large U.S. insurance claims databases to emulate two previous randomized clinical trials of semaglutide and tirzepatide — STEP-HFpEF and SUMMIT — in new study populations; the database studies were approximately 19 times larger than the trials. STEP-HFpEF and SUMMIT showed improvement in symptoms for patients with obesity-related HFpEF, but the trials had several limitations, including small size, few clinical events and restrictive eligibility criteria, according to the researchers. They then expanded the eligibility criteria to examine effectiveness of semaglutide and tirzepatide in real-world populations treated in clinical practice, followed by a head-to-head comparison to determine whether one drug yielded greater benefit over the other. Krüger and colleagues conducted the current study with the aim to generate real-world evidence to complement the randomized trials.
The researchers analyzed real-world data from more than 90,000 HFpEF patients with obesity and type 2 diabetes. Across the treatment cohorts, the mean age ranged from 66 to 71 years, BMI ranged from 36 kg/m2 to 40 kg/m2 and about 54% were women. Four percent to 6% of patients had a history of HF hospitalization in the previous year.
The results were simultaneously published in JAMA.
Risk for the primary endpoint, which was a composite of hospitalization for HF or all-cause mortality, was substantially lower among patients who initiated semaglutide (HR = 0.58; 95% CI, 0.51-0.65) and tirzepatide (HR = 0.42; 95% CI, 0.31-0.57) compared with sitagliptin, according to the results.
Krüger said the researchers chose sitagliptin to use in place of placebo, as the glucose-lowering drug was previously shown to have a null effect on HF outcomes.
In the head-to-head comparison, tirzepatide showed no meaningfully lower risk for the primary endpoint compared with semaglutide (HR = 0.86; 95% CI, 0.7-1.06), according to the results.
The researchers also found substantially lower risk for a broader secondary endpoint that comprised hospitalization for HF, urgent visit requiring IV diuretics or all-cause mortality with initiators of semaglutide or tirzepatide.
“While tirzepatide has demonstrated greater benefits than semaglutide in other indications, in this study, only modest differences were observed for hospitalization for heart failure and mortality, which supports the use of either agent as an effective option,” the researchers wrote in JAMA.
Krüger also said, “This study exemplifies how real-world evidence can complement randomized clinical trials in a timely and rigorous fashion.”
References:
Sources/Disclosures
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Krüger N, et al. Late-breaking clinical science: Cardiometabolic medicine. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2025; Madrid (hybrid meeting).
Disclosures:
Krüger reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
