ESC Congress 2026 Abstract · Oct 26, 2026
Cardiovascular outcomes of oral versus injectable semaglutide: a propensity-matched real-world cohort study
By Hicks J, Mouawad C, Thaker V et al.
Introduction: Patients with type 2 diabetes represent a population at high risk of atherosclerotic cardiovascular disease (ASCVD) despite advances in glucose-lowering therapy. The landmark SUSTAIN-6 and SOUL trials demonstrated that injectable and oral glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events (MACE) in this population, respectively. However, oral formulations of GLP-1 RAs have different pharmacokinetics profiles and require stringent fasting windows for administration, introducing variability in absorption that may impact real-world long-term cardiovascular outcomes. Whether oral formulations confer cardiovascular protection comparable to injectable formulations of GLP-1 Ras in routine clinical practice remains unexplored. Purpose: As both formulations are increasingly prescribed in clinical practice, this retrospective, multicenter study aims to compare MACE reduction between oral and injectable formulations of GLP-1 RAs. Methods: We utilized the TriNetX research network and identified 50,511 adults aged 40-75 years who initiated oral or injectable GLP-1 RAs between January 2019 and January 2023 and had no previous exposure to GLP-1 RAs or history of MACE. Propensity score analysis incorporating AHA PREVENT cardiac risk factors and 1:1 matching was performed. Following propensity matching, primary endpoints included first myocardial infarction, stroke, and new diagnosis of heart failure, over a three-year follow-up period. Risk differences were calculated, and Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% confidence intervals. Results: Propensity matching yielded two well-matched cohorts (n=50,511) with mean age 56 years, (62% White, 57% women). Over three years of follow-up, initiation of oral GLP-1 RAs was not associated with statistically significant differences in the risk of individual cardiovascular outcomes including first myocardial infarction (hazard ratio [HR] 1.07, 95% CI 0.99-1.17, p=0.612), stroke (HR 1.00, 95% CI 0.91-1.1, p=0.689) or heart failure diagnosis (HR 1.00, 95% CI 0.94-1.06, p=0.903) compared with injectable semaglutide. Conclusions: Oral and injectable semaglutide are associated with comparable three-year risks of myocardial infarction, stroke, and heart failure. These results indicate that differences in pharmacokinetic profiles may not translate to detectable differences in real-world cardiovascular outcomes. These findings provide reassurance regarding cardiovascular outcomes with oral formulations and support their use as a practical alternative in appropriate patients.3-year CV outcomes