Comment on Ostrominski et al. 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

Abstract

We read with interest the report by Ostrominski et al. (1), which used two target-trial emulations to compare tirzepatide with dulaglutide or semaglutide among patients with type 2 diabetes and established atherosclerotic cardiovascular disease. The study is timely and carefully constructed. Our concern is not whether a statistical contrast was observed but what that contrast represents: superior cardiovascular protection, a mortality-driven composite outcome difference, or a real-world signal shaped by background therapy and censoring. Modified major adverse cardiovascular events (MACE) change the estimand. The primary outcome replaced cardiovascular death in conventional 3-point MACE with all-cause mortality. This substitution changes the estimand, not merely the label. Composite end points are most interpretable when their components are clinically coherent and move in a