SOUL Findings Highlight Cardiovascular Benefits Beyond Glycemic Control With Oral GLP-1

New data presented at the American College of Cardiology 2025 Annual Scientific Session found that patients with type 2 diabetes taking an oral formulation of the glucagon-like peptide-1 (GLP-1) agonist semaglutide were 14% less likely to experience cardiovascular death, heart attack, or stroke over an average follow-up of 4 years compared with placebo. The SOUL (NCT03914326) clinical trial is the first to assess the cardiovascular benefits of an oral GLP-1 inhibitor, building on its effectiveness aligns with injectable formulations.

In an interview at ACC.25, SOUL investigator John B. Buse, MD, PhD, a professor at the University of North Carolina School of Medicine and director of the Diabetes Care Center, discussed how these findings could expand access to the drug, particularly for patients hesitant to use injections. He underscored that these findings go beyond mere numbers of glycemic control and into aspects of cardiovascular health that patients and physicians care most about.

This transcript has been lightly edited; captions were auto-generated.

Transcript

Can you discuss how semaglutide benefited patients with type 2 diabetes and atherosclerotic cardiovascular disease or chronic kidney disease in the SOUL trial and how these results relate to previous cardiovascular outcomes trials?

The patient population in the SOUL trial were patients with atherosclerotic cardiovascular disease or chronic kidney disease, or both, in the setting of type 2 diabetes, and therefore, the population of interest here in your question is exactly the population that we studied. With oral semaglutide, there was a 14% reduction in the primary end point—a reduction in heart attack, stroke, and cardiovascular death—which is identical to the 14% reduction that's been seen overall with the other clinical trials. I think it's a direct extension from the prior work that the cardiovascular benefit that we have expected from semaglutide in prior studies, or is re-demonstrated with this oral product, and that creates new opportunities for patients that have been reluctant to take injected products, and for providers that are sort of unfamiliar with the training that needs to go along with how to instruct patients to take injected medication. So, it reduces the barriers and increases opportunities for patients who may benefit from oral semaglutide.

What implications do the SOUL data present for future treatment with GLP-1 receptor agonists in this patient population?

Patients with type 2 diabetes are at high risk for cardiovascular disease, namely people who have prior atherosclerotic cardiovascular disease, and patients with chronic kidney disease are at high risk for having cardiovascular disease. They often also have uncontrolled diabetes, and they may have problems with their weight and blood pressure. We have known for a long time that semaglutide improves glycemic control, improves weight, lowers blood pressure. Sometimes, that's not quite compelling enough for patients. It's a pretty compelling story, though. Now, adding to it that it reduces the risk of heart attack, stroke, and cardiovascular death allows for a whole different kind of conversation with patients about what benefits they’re looking for.

Some patients with a personal or family history of heart disease are primarily concerned about heart disease. Many patients are extremely concerned about stroke as an outcome for which we don't have a lot of treatments that reduce the incidence of stroke, and since most people with diabetes when they die, die of atherosclerotic cardiovascular disease, again, many patients are quite concerned about their risk of early mortality. I do think it allows for a different layer of conversation. This is not just about controlling numbers that people may not care that much about—the risk factors for cardiovascular disease, but most people do care about their cardiovascular health. They see it as a threat to their survival.

Reference

Klein H. Oral semaglutide cuts cardiovascular risk by 14% in SOUL trial. The American Journal of Managed Care^®. March 29, 2025. Accessed March 30, 2025. https://www.ajmc.com/view/oral-semaglutide-cuts-cardiovascular-risk-by-14-in-soul-trial