Superior Cardiorenal Protection With Tirzepatide Over Dulaglutide in Heart Failure With Preserved Ejection Fraction: A Large‐Scale Propensity Score–Matched Real‐World Analysis

BACKGROUND: No direct head-to-head trials compare tirzepatide and dulaglutide in heart failure with preserved ejection fraction (HFpEF), though tirzepatide shows superior weight loss and potential cardiovascular benefits in recent trials like SURPASS-CVOT. METHODS: This retrospective, propensity score-matched cohort study used de-identified electronic health records from the TriNetX US Collaborative Network (as of December 2025). Adults ≥ 18 years with HFpEF (ICD-10: I50.3) initiating tirzepatide (n = 35 174) or dulaglutide (n = 52 999), without prior exposure to the comparator, were identified. One-to-one greedy nearest-neighbor matching (caliper 0.1) on demographics, comorbidities, medications, and laboratory/echocardiographic data produced balanced cohorts of 24 305 patients each. Kaplan-Meier and Cox proportional hazards models evaluated 1-year and 3-year risks of all-cause mortality, acute heart failure events, all-cause hospitalization, myocardial infarction, stroke, atrial fibrillation, MACE, MAKE, acute pancreatitis, and hypoglycemia. RESULTS: Post-matching, cohorts were well-balanced. Tirzepatide linked to lower 1-year risks of all-cause mortality (HR: 0.66, 95% CI: [0.59-0.74]), all-cause hospitalization (HR: 0.85, 95% CI: [0.82-0.88]), stroke (HR: 0.92, 95% CI: [0.87-0.97]), MACE (HR: 0.89, 95% [CI: 0.84-0.93]), MAKE (HR: 0.85, 95% CI: [0.79-0.91]), and acute pancreatitis (HR: 0.78, 95% CI: [0.63-0.96]). Benefits amplified at 3 years, especially mortality (HR: 0.60, [0.55-0.65]). Tirzepatide showed slightly higher 1-year atrial fibrillation risk (HR: 1.04, [1.00-1.07]). No differences in myocardial infarction or hypoglycemia. CONCLUSIONS: In this large real-world propensity-matched analysis, tirzepatide demonstrated superior reductions in mortality, hospitalizations, and cardiorenal outcomes versus dulaglutide in HFpEF patients, with a favorable safety profile.