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Results from the Phase III SOUL trial (NCT03914326) published by The New England Journal of Medicine show that treatment with daily oral semaglutide produced a significant reduction in the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both.1,2 Oral semaglutide demonstrated cardiovascular benefits that are consistent with injectable semaglutide and other glucagon-like peptide-1 (GLP-1) receptor agonists, according to the study authors.
“The effect of oral semaglutide with respect to cardiovascular outcomes appeared to be consistent across age-based subgroups and consistent with the effect observed in trials of injectable semaglutide, although direct comparisons cannot be made outside the context of a comparative-effectiveness trial,” the study authors wrote. “The effect of oral semaglutide with respect to the primary outcome appeared to be larger among participants with glycated hemoglobin levels higher than 8% than among those with lower glycated hemoglobin levels and also appeared to be larger among participants in certain regions (particularly Asia).”1
Semaglutide was initially approved in June 2021 for chronic weight management in those with obesity or overweight and at least one weight-related condition, including high blood pressure, type 2 diabetes, or high cholesterol, in addition to diet and increased exercise.3
Semaglutide has been approved by the FDA in both long-acting injectable (Wegovy and Ozempic) and daily oral tablet (Rybelsus) formulations. In March 2024, Wegovy was approved by the FDA to reduce the risk of MACE in adults with known heart disease and with obesity or overweight, in addition to a reduced calorie diet and increased physical activity.4
The double-blind, placebo-controlled, event-driven SOUL superiority trial enrolled 9650 patients aged 50 years or older with type 2 diabetes and a glycated hemoglobin level of 6.5 to 10.0%, and known ASCVD, CKD, or both. Patients were randomly assigned in a 1:1 ratio to receive once-daily oral semaglutide (n = 4825) with a maximal dose of 14 mg or placebo (n = 4825), as well as standard care. The trial’s primary endpoint was MACE as assessed in a time-to-first-event analysis, with confirmatory secondary endpoints that included major kidney disease events.
Over a mean (±SD) follow-up of 47.5±10.9 months, and median follow-up of 49.5 months, a primary-outcome event was reported in 12.0% of patients (incidence, 3.1 events per 100 person-years) administered oral semaglutide compared to 13.8% of patients (incidence, 3.7 events per 100 person-years) administered placebo (hazard ratio, 0.86; 95% confidence interval, 0.77 to 0.96; P=0.006).
Findings for the confirmatory secondary endpoint did not show a significant difference between both cohorts. In terms of safety, serious adverse events were reported by 47.9% of patients in the oral semaglutide cohort compared to 50.3% of patients in the placebo cohort. Gastrointestinal disorders occurred in 5.0% of patients in the oral semaglutide cohort compared to 4.4% of patients in the placebo cohort.
“Oral semaglutide was associated with a significantly lower risk of [MACE] than placebo, with a hazard ratio of 0.86 (corresponding to a relative risk reduction of 14%), among persons with type 2 diabetes and [ASCVD], [CKD], or both,” the study authors concluded. “These results show a cardiovascular benefit of oral semaglutide and are consistent with results reported for injectable semaglutide and other GLP-1 receptor agonists with established cardiovascular efficacy.”1
References
1. McGuire D., et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med 2025. Published March 29, 2025. DOI: 10.1056/NEJMoa2501006.
2. A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL). ClinicalTrials.gov. Updated March 25, 2025. Accessed April 2, 2025. https://clinicaltrials.gov/study/NCT03914326
3. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA. News release. June 4, 2021. Accessed April 2, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
4. Wegovy® receives FDA approval for cardiovascular risk reduction in adults with known heart disease and overweight or obesity. Novo Nordisk. News release. March 8, 2024. Accessed April 2, 2025. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=167031