Cardiovascular and Cerebrovascular Outcomes Risk Reduction Associated With Semaglutide vs Tirzepatide: A Target Trial Emulation.

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.