Comparative Effectiveness of Tirzepatide with Dulaglutide or Semaglutide on Major Cardiovascular Events in Type 2 Diabetes and Cardiovascular Disease: Insights From Two Target Trial Emulation Studies

Objective: To evaluate the comparative effectiveness of dulaglutide or semaglutide with 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 non-fatal myocardial infarction, non-fatal stroke, or all-cause death. First, new users of tirzepatide and dulaglutide were 1:1 propensity score (PS) matched. Second, new users of tirzepatide and semaglutide were 1:1 PS matched. Incidence rates (IR) per 1,000 person-years and hazard ratios (HRs) were estimated. Results: After PS matching, 9,233 pairs of tirzepatide and dulaglutide initiators, and 25,266 pairs of tirzepatide and semaglutide initiators, were identified. Tirzepatide initiators experienced a lower rate of modified MACE versus dulaglutide initiators (IR, 31.3 versus 39.4, respectively; HR, 0.80 [95% CI, 0.65-0.99]), which appeared 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 hospitalizations when compared with dulaglutide. Rates of modified MACE were similar among tirzepatide and semaglutide initiators (IR, 23.7 versus 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 lower risk of modified MACE when compared with dulaglutide, driven by reductions in all-cause mortality. Risks of modified MACE appeared similar with tirzepatide and semaglutide.