A recent study published in JAMA indicates that patients with heart failure with preserved ejection fraction (HFpEF) who were treated with either semaglutide or tirzepatide experienced a 40% reduction in the combined risk of hospitalization for heart failure or death from any cause.

HFpEF is becoming increasingly common, especially among individuals with obesity. Recent clinical trials, including 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), suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can improve functional capacity and alleviate symptoms in obese patients. However,due to the limited size of these randomized trials,researchers have been gathering and analyzing real-world data to further assess the effectiveness and safety of GLP-1 RAs in HFpEF patients.

The JAMA study utilized data from three US claims databases, which included longitudinal patient-level information such as demographics, diagnoses, procedures, and prescriptions. To ensure comparability with the STEP-HFpEF and SUMMIT trials, eligibility criteria included at least 12 months of continuous enrollment.The study comprised five active-comparator, new-user cohort studies: semaglutide vs sitagliptin, tirzepatide vs sitagliptin, tirzepatide vs semaglutide, and two additional cohorts with expanded eligibility criteria to reflect routine clinical populations. Sitagliptin was used as a placebo proxy, with its effect mirroring previous research showing no impact on HF events.

According to the study authors,”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 included 1,670,792 individuals who started semaglutide, tirzepatide, or sitagliptin. Of these, 21,151 met the trial eligibility criteria emulating the STEP-HFpEF trial, and 58,333 were included in the semaglutide vs sitagliptin cohort under the expanded criteria. In the tirzepatide vs sitagliptin cohort,3173 patients met the SUMMIT trial criteria,and 11,257 were included under expanded eligibility. The semaglutide vs tirzepatide cohort consisted of 28,000 patients. The mean age across 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, and 4.1% to 5.8% had a history of HF hospitalization in the past year.

GLP-1 RA Efficacy in hfpef Patients

“These observations suggest semaglutide may rapidly improve disease trajectory through cardiometabolic mechanisms independent of weight loss…”

The researchers discovered that starting semaglutide or tirzepatide was linked to a considerably lower risk of the composite outcome of heart failure hospitalization or death from any cause, compared to sitagliptin.Patients initiating semaglutide experienced a 42% reduction (HR, 0.58; 95% CI, 0.51-0.65), while those starting tirzepatide had a 58% reduction (HR, 0.42; 95% CI, 0.31-0.57) in the primary composite endpoint. A direct comparison showed no significant difference between tirzepatide and semaglutide (HR, 0.86; 95% CI, 0.70-1.06), suggesting similar effectiveness. Both treatments also reduced secondary endpoints, including urgent visits and additional HF-related events, without raising significant safety concerns.

The study authors noted, “these observations suggest semaglutide may rapidly improve disease trajectory through cardiometabolic mechanisms independent of weight loss, even though the underlying pathophysiology requires further inquiry. 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.”

Limitations of the study include its nonrandomized design, which could introduce unmeasured confounding despite propensity score adjustment. Medication use was based on dispensing records rather than adherence data, and HF symptoms and EF were assessed using claims-based algorithms rather of standardized clinical measures. Additionally, the use of sitagliptin as a placebo proxy relies on prior evidence but remains an assumption that could affect the interpretation of the results.

The study authors concluded, “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.”