In people with heart failure that still pumps normally but also have obesity or diabetes, the drugs semaglutide and tirzepatide cut the chance of ending up in the hospital for heart failure or dying by more than 40% compared to a standard diabetes drug. Tirzepatide didn’t show any extra benefit over semaglutide, and both were safe in this real‑world study.

Heart failure with preserved ejection fraction (HFpEF) is a major cause of hospitalization, often occurring in patients with cardiometabolic comorbidities such as obesity and type 2 diabetes. Although early trials of semaglutide and tirzepatide have shown promising results in improving symptoms, those findings were based on few clinical events, leaving treatment recommendations uncertain. To evaluate the effectiveness and safety of semaglutide and tirzepatide in patients with cardiometabolic HFpEF in clinical practice. Five cohort studies using national US health care claims data from 2018 to 2024. Two cohort studies emulated the STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) trials to benchmark results. Eligibility criteria were then expanded to evaluate treatment effects in patients typically treated in clinical practice. Finally, a head-to-head comparison of tirzepatide and semaglutide was implemented. Follow-up was up to 52 weeks. New use of semaglutide, tirzepatide, or sitagliptin as a placebo proxy. The primary end point was a composite of hospitalization for heart failure or all-cause mortality. Negative control outcomes, secondary end points, subgroups, and sensitivity analyses were prespecified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by fitting proportional hazards models with propensity score weighting to adjust for a comprehensive set of pretreatment patient characteristics. Benchmarking of the 2 trial emulations demonstrated high agreement on all prespecified metrics. In analyses using expanded eligibility criteria, 58 333 patients were included in the semaglutide vs sitagliptin cohort, 11 257 for tirzepatide vs sitagliptin, and 28 100 for tirzepatide vs semaglutide. Initiators of semaglutide (HR, 0.58 [95% CI, 0.51-0.65]) and tirzepatide (HR, 0.42 [95% CI, 0.31-0.57]) had substantially lower risk of the primary end point compared with sitagliptin. Tirzepatide had no meaningfully lowered risk compared with semaglutide (HR, 0.86 [95% CI, 0.70-1.06]). Negative controls, secondary end points, subgroups, and sensitivity analyses showed consistent results. No substantially increased risk was observed for select safety end points. In patients with cardiometabolic HFpEF, semaglutide and tirzepatide showed more than 40% risk reduction for the composite of hospitalization for heart failure or all-cause mortality compared with a placebo proxy. Tirzepatide showed no meaningful benefit over semaglutide. ClinicalTrials.gov Identifiers: NCT06914102, NCT06914154, NCT06914141.