Cardiovascular outcomes of oral versus injectable semaglutide: a propensity-matched real-world cohort study

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