Research Summary

Oral Semaglutide Reduces Cardiovascular Events for High-Risk Patients With Type 2 Diabetes

Anthony Calabro, MA

Key Highlights

  • Oral semaglutide reduced the incidence of major adverse cardiovascular events by 14% compared with placebo.
  • Benefits were achieved in patients with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both.
  • Serious adverse event rates were similar between treatment and placebo groups.
  • Gastrointestinal disorders occurred slightly more often in the semaglutide group.

In a large, event-driven cardiovascular outcomes trial, oral semaglutide was shown to significantly reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes who also had atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both. Over a median follow-up of 49.5 months, the incidence of MACE was lower in the semaglutide group compared with placebo, without an associated rise in serious adverse events.

Given the established cardiovascular safety of oral semaglutide, this trial aimed to assess its cardiovascular efficacy in a particularly high-risk population—those with both type 2 diabetes and either ASCVD, CKD, or both. These patients are at heightened risk for cardiovascular complications, and determining whether oral semaglutide provides meaningful cardiovascular protection was a key clinical question.

In this double-blind, placebo-controlled superiority trial (SOUL; NCT03914326), 9650 participants 50 years of age or older with type 2 diabetes (HbA1c 6.5-10.0%) and coexisting ASCVD, CKD, or both were randomized to receive either once-daily oral semaglutide (up to 14 mg) or placebo, in addition to standard care. The primary outcome was time to first occurrence of a composite MACE endpoint, including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Primary outcome events occurred in 12.0% of the semaglutide group (579 of 4825; 3.1 events per 100 person-years) compared with 13.8% of the placebo group (668 of 4825; 3.7 events per 100 person-years), yielding a hazard ratio of 0.86 (95% CI, 0.77-0.96; P = .006). Confirmatory secondary outcomes related to kidney disease did not differ significantly. Serious adverse events were reported in 47.9% of the semaglutide group and 50.3% of the placebo group. Gastrointestinal disorders occurred slightly more frequently with semaglutide (5.0%) than with placebo (4.4%).

“Among persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, the use of oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events than placebo, without an increase in the incidence of serious adverse events,” the authors concluded.

Reference
McGuire DK, Marx N, Mulvagh SL, et al; for the SOUL Study Group. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. N Engl J Med. 2025;392(20):2001–2012. doi:10.1056/NEJMoa2501006.