Cardiovascular and Cerebrovascular Outcomes Risk Reduction Associated With Semaglutide vs Tirzepatide

Background: Glucagon-like peptide-1 receptor agonists demonstrate cardiovascular benefits; however, head-to-head comparisons between semaglutide and tirzepatide remain limited. Objectives: Whether treatment effects differ by diabetes status is still limited in the current literature evidence. We compared cardiovascular outcomes between these agents stratified by type 2 diabetes status using target trial emulation approach. Methods: We conducted a target trial emulation study following TARGET framework of 217,920 adults initiating semaglutide or tirzepatide based on TriNetX Research Network Platform. Patients were stratified by diabetes status and matched 1:1 on baseline characteristics (type 2 diabetes: 48,507 pairs; nondiabetic: 60,453 pairs). Primary outcomes included atrial fibrillation, heart failure (HF), and acute myocardial infarction. Secondary outcomes included ischemic stroke/transient ischemic attack, hemorrhagic stroke, and peripheral artery disease. Follow-up extended to 3 years. Results: Tirzepatide was associated with a lower risk across all outcomes at 1 and 3 years. For HF at 1 year, risk ratios were 0.82 (95% CI: 0.78-0.86) in diabetic and 0.60 (0.55-0.65) in nondiabetic patients, with risk differences of 1.5% and 0.9%, respectively. Effect modification by diabetes status was significant for atrial fibrillation (P = 0.003), HF (P < 0.001), and acute myocardial infarction (P = 0.019) at 1 year. Risk reduction associations appeared to strengthen over the 3-year follow-up period. Conclusions: Tirzepatide was associated with more favorable risk reduction compared with semaglutide across multiple outcomes, with effect heterogeneity by diabetes status suggesting differential treatment associations across these populations.