Oral Semaglutide Cuts Cardiovascular Risk by 14% in SOUL Trial

In a major breakthrough for cardiovascular care in patients with type 2 diabetes, the oral formulation of semaglutide reduced the risk of major cardiovascular events by 14% over an average follow-up of nearly 4 years, according to late-breaking results from the phase 3 SOUL trial.¹

These findings were presented Saturday, March 29, at the American College of Cardiology 2025 Annual Scientific Session (ACC.25). The study was funded by semaglutide manufacturer Novo Nordisk and published simultaneously in The New England Journal of Medicine.

This makes oral semaglutide the first and only oral glucagon-like peptide-1 (GLP-1) receptor agonist to demonstrate cardiovascular safety and efficacy. According to Darren K. McGuire, MD, MHSc, cardiologist and professor of medicine at University of Texas Southwestern Medical Center, who presented the results, this expands treatment access to patients who may be hesitant or unable to use injectable formulations.

Darren K. McGuire, MD, MHSc | Image credit: ACC

“Semaglutide originally came to market as a once weekly injectable, where it's now approved for use for the treatment of hyperglycemia and to reduce cardiovascular risk in people with type 2 diabetes,” McGuire said during an ACC.25 press conference.² “But as clinicians, we have many patients who are reticent or even resistant to using an injectable therapy.”

The randomized, double-blind trial enrolled 9650 patients with type 2 diabetes and either atherosclerotic cardiovascular disease or chronic kidney disease from 450 sites in 44 countries.¹ Participants were assigned to take either oral semaglutide once daily or placebo. The primary end point was the occurrence of major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Over a median 47.5 months of follow-up, MACE occurred in 12.0% of patients taking semaglutide compared with 13.8% in the placebo group (HR, 0.86; 95% CI, 0.77-0.96; P = .0028). According to the researchers, the nonfatal heart attack reduction of 26% was the primary driver of the benefit. Reductions in nonfatal stroke (12%) and cardiovascular death (7%) also contributed, though these individual end points did not reach statistical significance on their own.

During a press conference discussion of the findings, Gina Lundberg, MD, FACC, professor of medicine at Emory University, clinical director of the Emory Women’s Cardiovascular Health Center, and chair of the ACC Women in Cardiology Council, noted important subgroup findings.²

“It did seem that when you break down the individual groups, that the patients at higher risk, the ones with the highest BMI [body mass index] and the better eGFR [estimated glomerular filtration rate], actually did better long term,” she said.

However, she also acknowledged some notable limitations when translating these findings into clinical practice. “On the concerning side, it's a very diverse population that we take care of, and I believe that we need more studies that included more women,” Lundberg said, noting the predominantly White male trial enrollment. “And there was obviously nothing that has to do with cost, and my patients can't benefit from a drug they can't afford.”

Lundberg also mentioned the “concerning” discontinuation rate between 20% and 30%, which was similar between oral semaglutide and placebo. While adherence was high and the safety profile matched prior studies, some of the most common gastrointestinal adverse effects included nausea, constipation, and diarrhea. Lundberg said many of her patients cannot tolerate these adverse effects and would like to see this gastrointestinal effect improved with future treatments in this vein.

Still, semaglutide's benefits were consistent across subgroups, including age, sex, and comorbid conditions.¹ Nearly half of the participants were also on sodium-glucose co-transporter 2 inhibitors, another class of diabetes drugs with cardiovascular benefits. The results showed no significant interaction between the 2 therapies and, according to McGuire, may suggest these drugs can be safely used together to reduce cardiovascular risk.

“Safety is clearly there,” added Lundberg, “and I think we have one more thing in our tool kit for preventive strategies.”²

References

1. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. N Engl J Med. Published online March 29, 2025. doi:10.1056/NEJMoa2501006
2. Kovacs R, Batchelor W, Lundberg G, et al. Late-breaking clinical trials III. ACC Press Conference. Presented March 29, 2025.