The Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) trial demonstrated cardiovascular benefits of semaglutide in patients with obesity without diabetes; however, the real-world effect across multiple GLP-1 receptor agonist (GLP-1 RA) agents in patients with established atherosclerotic cardiovascular disease (ASCVD) and overweight or obesity without diabetes mellitus remains unknown. We conducted a target trial emulation using data from the TriNetX US Collaborative Network (January 1, 2010-December 1, 2025) in adults aged ≥45 years with established ASCVD (history of myocardial infarction, stroke, or coronary or peripheral revascularization), BMI ≥27 kg/m², and without type 2 diabetes. New initiation of any GLP-1 RA (liraglutide, semaglutide, dulaglutide, or exenatide) was compared with no GLP-1 RA use. The primary outcome was all-cause mortality; secondary outcomes were acute myocardial infarction, stroke, and heart failure hospitalization over 5 years, analyzed using Cox proportional hazards and Fine-Gray subdistribution hazard models to account for the competing risk of death. Among 14,844 propensity-matched patients without diabetes (7,422 per group; median age 63 [IQR 55-71] years; 64% women), GLP-1 RA use was associated with lower all-cause mortality (HR 0.68; 95% CI 0.53-0.88; P=.003), acute myocardial infarction (sHR 0.63; 95% CI 0.41-0.98; P=.040), and heart failure hospitalization (sHR 0.61; 95% CI 0.39-0.95; P=.028); no significant association was observed for stroke (sHR 0.76; 95% CI 0.52-1.10; P=.146). Findings were consistent in landmark and age subgroup analyses; a sensitivity analysis including patients with diabetes (N=31,910 matched pairs) showed similar associations. In conclusion, these real-world findings are broadly directionally consistent with the SELECT trial and provide complementary observational evidence across multiple GLP-1 RA agents in patients with established ASCVD and overweight or obesity without diabetes mellitus, though causal inference cannot be established from observational data alone.
