Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial.

Summary

In SOUL, oral semaglutide reduced MACE by 14% overall (HR 0.86; 95% CI 0.77–0.96). Benefits were consistent among participants with or without SGLT2 inhibitor therapy at baseline or during follow-up, and serious adverse events were similar, supporting the safety of combination therapy.

Key Findings

• Overall MACE reduction with oral semaglutide vs placebo: HR 0.86 (95% CI 0.77–0.96).
• Effect estimates were similar with baseline SGLT2i use (HR 0.89; 95% CI 0.71–1.11) and without (HR 0.84; 95% CI 0.74–0.95); no signal of harm with combination.
• Serious adverse events were comparable between groups, supporting safety of co-administration.

Clinical Implications

For T2D with ASCVD/CKD, oral semaglutide can be added to SGLT2i without compromising safety and with preserved CV benefit. Consider combination therapy to maximize cardiorenal protection.

Limitations

• Subgroup analyses may be underpowered; confidence intervals in SGLT2i users crossed 1.0.
• Not designed to detect interaction effects definitively; background therapies may vary over time.

Future Directions

Direct randomized trials testing combination therapy strategies (GLP-1RA plus SGLT2i) with renal and HF endpoints; mechanistic studies to delineate additive vs. independent pathways.