Cardiovascular Outcomes in Semaglutide Versus Tirzepatide Users With Obesity and Atherosclerotic Disease: A Target Trial Emulation

AIMS: Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is approved for cardiovascular risk reduction in individuals with overweight or obesity and cardiovascular disease. Whether tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, has similar cardiovascular benefits remains unknown. The objective was to compare the effectiveness of semaglutide versus tirzepatide on the risk of major adverse cardiovascular events (MACE) in individuals with overweight or obesity and atherosclerotic cardiovascular disease (ASCVD) without diabetes. MATERIALS AND METHODS: This active comparator, new user study emulated a trial using national claims data from Komodo Health. Eligible individuals had a history of ASCVD and, within 1 year prior to initiation: BMI ≥ 27 with a diagnosis of overweight or obesity, continuous insurance coverage and no diabetes or contraindications. Prior GLP-1 receptor agonist or obesity medication users were excluded. The primary outcome was a composite of myocardial infarction, stroke, hospitalization for heart failure or unstable angina, coronary revascularization and mortality (revised 5-point MACE). Secondary outcomes included revised 3-point MACE and individual endpoints. Hazard ratios were estimated using Cox models with inverse probability weighting. RESULTS: There was a non-significant difference in risk of revised 5-point MACE (HR = 1.21, 95% CI: 0.99-1.51) or secondary outcomes between semaglutide and tirzepatide. Sensitivity analyses showed directionally consistent point estimates for revised 5-point MACE but highlighted sensitivity to decisions surrounding early events, off-label use, analytic approach and outcome definition. CONCLUSIONS: Among adults with overweight or obesity and ASCVD without diabetes, there was no significant difference in cardiovascular risk between semaglutide and tirzepatide.