Heart failure with preserved ejection fraction (HFpEF) represents a significant clinical challenge, particularly among patients with obesity and type 2 diabetes, where cardiometabolic factors exacerbate disease progression. While glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists like tirzepatide have demonstrated symptomatic improvements in preliminary trials, evidence on hard clinical endpoints such as hospitalization and mortality remains limited due to small event numbers. The objective of this study is to assess the real-world effectiveness and safety of semaglutide and tirzepatide in reducing heart failure hospitalization or all-cause mortality in patients with cardiometabolic HFpEF, including trial emulation and head-to-head comparisons.
This observational study comprised five cohort analyses using national US health care claims databases spanning 2018 to 2024. Two cohorts emulated the STEP-HFpEF DM trial for semaglutide (n=58,333 in expanded analysis) and the SUMMIT trial for tirzepatide (n=11,257), benchmarking against original trial metrics for validity. Eligibility was broadened to reflect typical clinical populations, and a direct comparison of tirzepatide versus semaglutide (n=28,100) was conducted. Follow-up extended up to 52 weeks, with propensity score weighting applied to balance over 100 pretreatment covariates, including demographics, comorbidities, and medication use. Initiation of semaglutide, tirzepatide, or sitagliptin (as a placebo proxy for non-GLP-1 glucose-lowering therapy).
The primary composite endpoint was hospitalization for heart failure or all-cause mortality. Secondary endpoints included individual components, all-cause hospitalization, and safety events (e.g., gastrointestinal adverse effects). Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from Cox proportional hazards models. In expanded cohorts, semaglutide initiators had a 42% lower risk of the primary endpoint versus sitagliptin (HR, 0.58; 95% CI, 0.51-0.65), while tirzepatide showed a 58% reduction (HR, 0.42; 95% CI, 0.31-0.57). No substantial difference was observed between tirzepatide and semaglutide (HR, 0.86; 95% CI, 0.70-1.06). Subgroup analyses (e.g., by obesity class, diabetes duration) and sensitivity tests confirmed robustness. Safety profiles were favorable, with no elevated risks for prespecified adverse events.
Semaglutide and tirzepatide significantly reduce major adverse outcomes in cardiometabolic HFpEF, with comparable efficacy between agents. These real-world data bolster trial findings and inform broader clinical application, though randomized trials are needed for confirmation.
