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

Summary

In a 9,650-patient, event-driven RCT (median 49.5 months), once-daily oral semaglutide 14 mg reduced major adverse cardiovascular events versus placebo (HR 0.86) in adults with type 2 diabetes and ASCVD, CKD, or both, without increasing serious adverse events. Kidney composite outcomes were not significantly different.

Key Findings

• Major adverse cardiovascular events were lower with oral semaglutide versus placebo (HR 0.86; 95% CI 0.77–0.96).
• Serious adverse events were similar between groups (47.9% vs 50.3%); GI disorders were slightly higher with semaglutide (5.0% vs 4.4%).
• Confirmatory secondary kidney outcomes did not differ significantly between groups.
• Median follow-up was 49.5 months in an event-driven, double-blind, placebo-controlled trial of 9,650 participants.

Clinical Implications

For high-risk T2D with ASCVD and/or CKD, oral semaglutide offers a once-daily, oral alternative for CV risk reduction. Clinicians can consider it where injectables are not feasible, while monitoring GI tolerability.

Limitations

• No significant benefit on confirmatory secondary kidney composite outcomes
• Dose limited to maximal 14 mg; generalizability to other doses or populations may vary

Future Directions

Evaluate differential benefits across kidney function strata and compare oral versus injectable GLP-1 agents on renal and heart failure outcomes; implementation studies on adherence and access to oral incretins.