Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Outcomes in Patients With Atherosclerotic Cardiovascular Disease and Obesity Without Diabetes.

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 glucagon-like peptide-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, to 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 [interquartile range 55 to 71] years; 64% women), GLP-1 RA use was associated with lower all-cause mortality (hazard ratio [HR] 0.68; 95% CI 0.53 to 0.88; p = 0.003), acute myocardial infarction (subdistribution HR [sHR] 0.63; 95% CI 0.41 to 0.98; p = 0.040), and heart failure hospitalization (sHR 0.61; 95% CI 0.39 to 0.95; p = 0.028); no significant association was observed for stroke (sHR 0.76; 95% CI 0.52 to 1.10; p = 0.146). 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.