Oral semaglutide cut major cardiovascular events by 14% in SOUL trial

Oral semaglutide reduced major cardiovascular events by 14% in adults who have type 2 diabetes along with heart disease, kidney disease or both, according to full results from the SOUL trial presented March 29, 2025, at the American College of Cardiology's annual scientific session and published the same day in The New England Journal of Medicine ^[1][2][3].

Over a median follow-up of about four years, 12.0% of participants taking oral semaglutide had a primary endpoint event — cardiovascular death, a nonfatal heart attack or a nonfatal stroke — compared with 13.8% of those taking placebo (hazard ratio 0.86; 95% confidence interval 0.77 to 0.96) ^[1][2][3]. That works out to 3.1 events per 100 person-years on the drug versus 3.7 on placebo ^[3]. One account lists the P value as .0028 ^[1], while the journal abstract and the ACC trial summary list it as 0.006 ^[2][3].

How the trial was run

The phase 3 trial enrolled 9,650 adults and randomly assigned them one-to-one to once-daily oral semaglutide or placebo on top of standard care ^[2][3]. The dose started at 3 mg and was increased to 7 mg and then 14 mg ^[2]. To join, participants had to be 50 or older, have type 2 diabetes with an A1c between 6.5% and 10.0%, and have atherosclerotic cardiovascular disease, chronic kidney disease or both ^[2][3]. The average age was 66.1 years, and 28.9% of participants were women ^[2]. Follow-up averaged 47.5 months, with a median of 49.5 months ^[3]. AJMC reported the trial ran at 450 sites in 44 countries; the ACC summary says 444 sites in 33 countries ^[1][2]. The two write-ups also describe the primary composite slightly differently, with the journal abstract specifying cardiovascular death and the ACC summary listing all-cause death ^[2][3].

Researchers said a 26% reduction in nonfatal heart attacks was the main driver of the overall benefit. Nonfatal stroke fell 12% and cardiovascular death fell 7%, though those two components did not reach statistical significance on their own ^[1]. The confirmatory secondary outcomes — a five-point kidney disease composite, major limb events and serious adverse events — did not differ significantly between the two groups ^[1][2][3]. Benefits were consistent across subgroups including age, sex and other conditions, and nearly half of participants were also taking SGLT2 inhibitors, a class that showed no significant interaction with semaglutide ^[1].

Side effects and who stopped taking it

Serious adverse events were reported in 47.9% of the semaglutide group and 50.3% of the placebo group, and gastrointestinal disorders in 5.0% and 4.4%, respectively ^[3]. Nausea, constipation and diarrhea were among the most common complaints, and 20% to 30% of participants discontinued treatment — a rate that was similar in the drug and placebo groups, said Gina Lundberg, MD, a professor of medicine at Emory University ^[1]. Lundberg described the trial population as predominantly White and male and said more studies including women are needed; the trial also did not address cost ^[1]. She added that patients with the highest BMI and better kidney function appeared to do better ^[1].

Why it matters for patients

SOUL is described as the first trial showing that an oral GLP-1 receptor agonist lowers cardiovascular risk, which matters for people who are hesitant about injections. "We have many patients who are reticent or even resistant to using an injectable therapy," said Darren K. McGuire, MD, the University of Texas Southwestern cardiologist who presented the results ^[1].

The findings apply to a specific group: adults with type 2 diabetes plus established cardiovascular or kidney disease. Whether oral semaglutide protects the heart in people who take it without type 2 diabetes has not been reported in these results ^[1][2][3].

The absolute difference was modest — 1.8 percentage points — and roughly one in five to one in three participants stopped their assigned treatment, mostly because of gastrointestinal effects ^[1]. Cost is another factor the trial did not measure; Lundberg said "my patients can't benefit from a drug they can't afford" ^[1].

What happens next

No timeline for regulatory review or label changes based on SOUL has been announced. The trial is registered as NCT03914326 ^[3].