Tirzepatide and the prevention of heart failure in obesity: a multi-center cohort study using the TriNetX database

Abstract Aims To evaluate whether tirzepatide use is associated with a reduced risk of new-onset heart failure (HF) in patients with obesity. Methods and results We conducted a retrospective cohort study using the TriNetX global database, identifying adults with obesity (body mass index >30 kg/m2) between January 2022 and June 2025. Patients prescribed tirzepatide were compared with matched controls not receiving the drug. Propensity score matching was applied to balance baseline characteristics. The primary outcome was incident HF within one year. Secondary outcomes included all-cause mortality, hospitalization, and major adverse cardiovascular events (MACEs). A total of 381 026 matched individuals (190 513 per group) were analyzed. Tirzepatide use was associated with a significantly lower risk of new-onset HF [hazard ratio (HR), 0.53; 95% confidence interval (CI), 0.50–0.56; P < 0.001], as well as reduced 1-year all-cause mortality (HR, 0.31), hospitalization (HR, 0.46), and MACEs (HR, 0.55), all P < 0.001. Subgroup analyses across age, sex, comorbidities, and medications showed consistent results. Negative control outcomes confirmed robustness. Conclusion Tirzepatide may reduce the risk of developing HF and improve cardiovascular outcomes in obese individuals. These findings highlight its potential role in HF prevention and warrant further prospective studies.