Superior Cardiorenal Protection With Tirzepatide Over Dulaglutide in Heart Failure With Preserved Ejection Fraction: A Large‐Scale Propensity Score–Matched Real‐World Analysis
Ibrahim Khalil, Md. Imran Hossain, Mst. Mahmuda Akter, Ferdous Wahid, Aizaz Anwar Khalid, Sunjida Amin Promi, Md. Abu Sayed, Mohd Turzo Rahman, Pallab SarkerABSTRACT
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.