THE MANAGEMENT of cardiovascular disease (CVD) and chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D) presents significant clinical challenges. Treatments such as glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose co-transporter-2 inhibitors (SGLT2i), have demonstrated beneficial effects on cardiovascular outcomes in T2D patients. However, the impact of combining these therapies remains under-researched. The SOUL trial (NCT03914326), investigated the effects of oral semaglutide on major adverse cardiovascular events (MACE) in patients with T2D, with or without the use of SGLT2i. A key finding was that oral semaglutide significantly reduced MACE risk, regardless of concomitant SGLT2i use.
The trial randomised 9650 participants with T2D and atherosclerotic CVD or CKD to receive oral semaglutide or placebo. Participants were further divided based on their baseline use of SGLT2i (SGLT2i users n=2596 and SGLT2i non-users n=7054). The primary endpoint of the study was the time to the first MACE, which included cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Safety was also assessed, with a focus on the incidence of serious adverse events. The study followed participants for a mean duration of 47.5±10.9 months.
Results showed that oral semaglutide reduced the risk of MACE by 14% compared to placebo (hazard ratio [HR] 0.86; 95% CI: 0.77–0.96). When analysed by baseline SGLT2i use, the reduction in MACE events was consistent. In those using SGLT2i at baseline, 11.0% (143 of 1296) of participants taking semaglutide experienced MACE, compared to 12.2% (158 of 1300) in the placebo group (HR 0.89; 95% CI: 0.71–1.11). In those not using SGLT2i at baseline, 12.4% (436 of 3529) semaglutide-treated participants experienced MACE, compared to 14.5% (510 of 3525) placebo-treated participants (HR 0.84; 95% CI: 0.74–0.95). These findings were not affected by whether SGLT2i was used during the trial, suggesting the benefits of oral semaglutide were independent of SGLT2i treatment. The safety profiles were similar between groups, with no significant differences in adverse events.
In conclusion, the SOUL trial highlights that oral semaglutide reduces cardiovascular risk in T2D patients, regardless of concurrent SGLT2i use. This combination therapy appears to be both effective and safe. However, the study’s limitations include the absence of long-term data on renal outcomes and the lack of further subgroup analyses. Despite these limitations, these results are promising for clinical practice, particularly in tailoring treatment for patients with T2D and cardiovascular comorbidities.
Reference
Marx N et al. Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial. Circulation. 2025:DOI: 10.1161/CIRCULATIONAHA.125.074545.
