GLP-1s Reduced Adverse Heart Failure Events by 40% in Patients With HFpEF

Patients with heart failure with preserved ejection fraction (HFpEF) who initiated semaglutide or tirzepatide saw a 40% risk reduction in combined hospitalization for HF or all-cause mortality, a new study published in JAMA reported.¹

HFpEF is increasingly prevalent among individuals with obesity, and recent clinical trials like the Emulation of the STEP-HFpEF DM Heart Failure Trial in Healthcare Claims Data (STEP-HFpEF; NCT06914102) and the Emulation of the SUMMIT Heart Failure Trial in Healthcare Claims Data (DUP-SUMMIT; NCT06914154) provide evidence supporting the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in improving some of the functional capacity and symptoms among patients with obesity. However, these randomized trials were limited in study population size, thus encouraging researchers to collect and evaluate real-world evidence to complement previous findings on the effectiveness and safety of GLP-1 RAs in patients with HFpEF.^1,2

The new study published in JAMA used 3 US claims data sources, all of which contained longitudinal patient-level information, including demographics, diagnoses, procedures, and outpatient prescription medications.¹ The eligibility criteria required patients to have at least 12 months of continuous enrollment in addition to other criteria emulating the STEP-HFpEF and SUMMIT clinical trials and created 5 active-comparator, new-user cohort studies. The cohorts were semaglutide vs sitagliptin, tirzepatide vs sitagliptin, tirzepatide vs semaglutide, and 2 additional cohorts based on data and eligibility expansion to reflect routine clinical populations. Sitagliptin served as a placebo proxy in the study, and its effect was similar to that seen in previous research, in which it had no effect on HF events.

“Because regulatory agencies and guideline committees have emphasized the need for further evidence for major clinical outcomes in heart failure, these findings were first benchmarked against results from the STEP-HFpEF DM and SUMMIT trials,” the study authors explained.

The study population consisted of 1,670,792 individuals who had initiated semaglutide, tirzepatide, or sitagliptin, of whom only 21,151 met the trial eligibility criteria emulating that of the STEP-HFpEF trial. Moreover, 58,333 were included in the semaglutide vs sitagliptin cohort under the expanded eligibility criteria. For the tirzepatide vs sitagliptin cohort, 3173 patients met the trial criteria emulating that of the SUMMIT trial, and 11,257 were included under expanded eligibility. The semaglutide vs tirzepatide cohort consisted of 28,000 patients. The mean age across all of the cohorts ranged from 66.7 to 70.8 years; 53.3% to 54.7% were female; the mean body mass index ranged from 36.6 to 40.2 among patients with available data, and a history of HF hospitalization in the past 12 months was present in 4.1% to 5.8% of patients.

GLP-1 RA Efficacy in Patients with HFpEF

Researchers found that initiation of semaglutide or tirzepatide was associated with a significantly lower risk of the composite outcome of hospitalization for heart failure or all-cause mortality compared with sitagliptin. Specifically, patients starting semaglutide had a 42% reduction (HR, 0.58; 95% CI, 0.51-0.65), and those starting tirzepatide had a 58% reduction (HR, 0.42; 95% CI, 0.31-0.57) in the primary composite end point. In a direct head-to-head comparison, tirzepatide showed no meaningful benefit over semaglutide (HR, 0.86; 95% CI, 0.70-1.06), indicating similar effectiveness between these drugs. Both treatments also reduced broader secondary endpoints, including urgent visits and additional HF-related events, with no significant safety concerns identified.

“These observations suggest semaglutide may rapidly improve disease trajectory through cardiometabolic mechanisms independent of weight loss, although the underlying pathophysiology requires further investigation,” the study authors wrote. “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 study was limited by its nonrandomized design, leaving potential for unmeasured confounding despite propensity score adjustment. Medication use was inferred from dispensing records rather than adherence data, and HF symptoms and EF were assessed using claims-based algorithms rather than standardized clinical measures. Finally, the use of sitagliptin as a placebo proxy relies on prior evidence but still represents an assumption that could influence the interpretation of results.

“This stepwise approach anchored in trial evidence strengthens confidence in the validity and applicability of the current results, reinforcing the role of GLP-1–based therapies beyond previously established benefits in the evolving management of cardiometabolic HFpEF,” the study authors concluded.

References

1. 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

2. Patel R, Kokori E, Olatunji G, et al. Therapeutic potential of GLP-1 receptor agonists in heart failure with preserved ejection fraction (HFpEF) in obese patients. Curr Heart Fail Rep. 2025;22(1):17. doi:10.1007/s11897-025-00704-1