Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.

Summary

In the SOUL trial (n=9,650), oral semaglutide 14 mg daily reduced time-to-first MACE versus placebo over a median of 49.5 months (HR 0.86), with similar rates of serious adverse events and slightly more gastrointestinal events. Benefits were observed in patients with T2D and ASCVD and/or CKD.

Key Findings

• Primary MACE reduced with oral semaglutide vs placebo (HR 0.86; 95% CI 0.77–0.96).
• Serious adverse events were similar (47.9% vs 50.3%); gastrointestinal disorders slightly higher with semaglutide (5.0% vs 4.4%).
• Efficacy observed in a high-risk population with ASCVD and/or CKD over a long median follow-up of 49.5 months.

Clinical Implications

Consider oral semaglutide for high-risk T2D patients with ASCVD/CKD to reduce MACE, especially when injectables are impractical; monitor for mild GI events. This supports incorporating oral GLP-1RA into cardiometabolic risk reduction strategies.

Limitations

• Confirmatory secondary outcomes were not significantly different
• Generalizability limited to ≥50-year-old T2D patients with ASCVD/CKD and max 14 mg dose

Future Directions

Define responders, evaluate earlier use and combination with SGLT2i, and assess cost-effectiveness and adherence advantages of oral GLP-1RA in routine cardiometabolic care.