Cardiovascular outcomes across GLP-1/GIP agonists in a large, diverse real-world cohort: the INCRETIN-CV study

Background GLP-1 receptor agonists and dual GLP-1/GIP agonists reduce cardiovascular events in randomized trials, yet comparative effectiveness across agents and across cardiovascular (CV) endpoints in large real-world populations remains incompletely defined. Purpose To evaluate the association between GLP-1/GIP agonist use and major CV outcomes in a large, diverse real-world cohort, and to compare effectiveness across individual agents. Methods We analyzed 871,994 adults with type 2 diabetes or obesity identified from a large multi-hospital electronic health record database. The primary outcome was 3-point MACE (myocardial infarction [MI], stroke or coronary artery disease). Secondary outcomes included 2-point MACE (MI or stroke) and individual components (MI, stroke). Multivariable logistic regression adjusted for age, sex, race/ethnicity, baseline BMI, diabetes, hypertension, hyperlipidemia, CKD, and 25 medication classes. Results Among 871,994 adults with type 2 diabetes or obesity (mean age 51.5 ± 16.6 years), 44,746 (5.1%) received GLP-1/GIP agonists. The overall cohort was racially diverse, comprising 34.4% White, 15.8% African American, 0.5% Asian, 1.3% mixed race, 4.5% other race, and 42.3% unknown race. GLP-1 users had higher baseline BMI (35.6 ± 6.8 vs 33.9 ± 5.6 kg/m²), greater prevalence of hypertension (24.8% vs 16.4%), hyperlipidemia (27.1% vs 15.6%), and diabetes (59.2% vs 18.5%), all p<0.001. Baseline CAD prevalence was similar (2.8% vs 2.9%, p=0.42). GLP-1/GIP agonists use was associated with lower odds of 3-point MACE (OR 0.55, 95% CI 0.52–0.57), 2-point MACE (OR 0.61, 95% CI 0.57–0.64), MI (OR 0.66, 95% CI 0.59–0.74), and stroke (OR 0.70, 95% CI 0.64–0.76), all p<0.001. Drug-specific analyses demonstrated heterogeneity of effect (Figure). Tirzepatide showed the strongest associations with reduced 3-point MACE (OR 0.27, 95% CI 0.24–0.31) and 2-point MACE (OR 0.24, 95% CI 0.20–0.30), and was associated with reduced MI (OR 0.18, 95% CI 0.11–0.29) and stroke (OR 0.34, 95% CI 0.26–0.43), p<0.001 for all. Semaglutide demonstrated substantial protection for 3-point MACE (OR 0.43, 95% CI 0.40–0.46) and 2-point MACE (OR 0.45, 95% CI 0.41–0.50), and was associated with reduced MI (OR 0.48, 95% CI 0.40–0.59) and stroke (OR 0.50, 95% CI 0.43–0.57), p<0.001 for all. Dulaglutide showed modest benefit for 3-point MACE (OR 0.84, 95% CI 0.78–0.90, p<0.001) ,but was not significantly associated with MI or stroke. Liraglutide and exenatide did not demonstrate significant protective associations across CV outcomes. Conclusions In a large, racially diverse real-world cohort, GLP-1/GIP agonists were associated with significant reductions in CV and cerebrovascular outcomes, with differential effectiveness across agents. These findings support broad cardiometabolic benefit extending beyond trial settings and highlight potential heterogeneity within the incretin class.