Comparative Effectiveness of Tirzepatide Versus Dulaglutide or Semaglutide on Major Cardiovascular Events in Type 2 Diabetes and Cardiovascular Disease: Insights From Two Target-Trial Emulations

OBJECTIVE To evaluate the comparative effectiveness of dulaglutide or semaglutide versus tirzepatide on cardiovascular outcomes in adults with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). RESEARCH DESIGN AND METHODS Two target trial emulations included commercially insured adults (June 2022–December 2024) with T2D and ASCVD who initiated subcutaneous tirzepatide, dulaglutide, or semaglutide. The primary outcome was modified major adverse cardiovascular events (MACE), defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause death. First, new users of tirzepatide and dulaglutide were propensity score (PS) matched one to one. Second, new users of tirzepatide and semaglutide were PS matched one to one. Incidence rates (IRs) per 1,000 person-years and hazard ratios (HRs) were estimated. RESULTS After PS matching, 9,233 pairs of tirzepatide or dulaglutide initiators and 25,266 pairs of tirzepatide or semaglutide initiators were identified. Tirzepatide initiators experienced a lower rate of modified MACE versus dulaglutide initiators (IR 31.3 vs. 39.4, respectively; HR 0.80 [95% CI 0.65–0.99]), which seemed to be driven by lower all-cause mortality among tirzepatide versus dulaglutide initiators (HR 0.60 [95% CI 0.43–0.83]). In post hoc analyses, tirzepatide was associated with lower rates of pneumonia-related hospitalization when compared with dulaglutide. Rates of modified MACE were similar among tirzepatide and semaglutide initiators (IR 23.7 vs. 23.2, respectively; HR 1.03 [95% CI 0.90–1.17]). CONCLUSIONS Among adults with T2D and ASCVD in routine care, tirzepatide was associated with a lower risk of modified MACE when compared with dulaglutide, driven by reduction in all-cause mortality. Risks of modified MACE seemed similar with tirzepatide and semaglutide.