Tirzepatide Versus Semaglutide in Heart Failure With Preserved Ejection Fraction and Type 2 Diabetes: A Target Trial Emulation Study

OBJECTIVE To evaluate the comparative effectiveness of semaglutide and tirzepatide in individuals with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This target trial emulation study included adults with HFpEF and T2D who were initiating once-weekly tirzepatide or semaglutide (June 2022 to June 2025). The data were from two U.S.-based commercial claims databases. The coprimary outcomes were heart failure (HF) hospitalization and all-cause mortality. Between-group characteristics were balanced through propensity score–based fine stratification. Adjusted incidence rates (IRs) per 1,000 person-years and hazard ratios (HRs) were estimated. RESULTS After fine stratification weighting, the final cohort consisted of 37,183 patients (age, mean ± SD, 67 ± 10 years; 54% women) with HFpEF and T2D newly initiating either tirzepatide (n = 11,780) or semaglutide (n = 25,387). Over a median follow-up of 5.1 months, tirzepatide initiators experienced a lower rate of HF hospitalization when compared with semaglutide initiators (IR 19.7 vs. 25.5, respectively; HR 0.80 [95% CI 0.66–0.96]). No evidence of heterogeneity was observed across key subgroups defined by age, sex, BMI, and baseline use of medications for HF or other cardiovascular conditions. Rates of all-cause mortality between the exposure groups were similar (IR 20.5 vs. 19.5, respectively; HR 0.99 [95% CI 0.81–1.21]). Sensitivity analyses mimicking on-treatment and intention-to-treat approaches revealed similar findings for both coprimary outcomes. CONCLUSIONS Tirzepatide was associated with a lower rate of HF hospitalization but not all-cause mortality when compared with semaglutide in adults with HFpEF and T2D in routine care. These findings may inform treatment selection for individuals with HFpEF and T2D.