Oral semaglutide reduces CV risk in T2D patients

Once-daily treatment with oral semaglutide, a GLP-1* receptor agonist, significantly reduced the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD), according to the SOUL** trial presented at ACC.25.

“Semaglutide originally came to market as a once-weekly injectable where it's now approved for use for the treatment of hyperglycaemia and to reduce CV risk in people with T2D,” said lead author Dr Darren McGuire from the University of Texas Southwestern Medical Center in Dallas, Texas, US. “But as clinicians, we have many patients and even clinician prescribers who are reticent, or even resistant, to using injectable therapies.”

“This study gives us confidence that people who are resistant or reluctant to take injections can still have an option for clinical benefit with this medication in the form of a tablet,” he added. “Whether you take it in tablet or injection, these drugs very rapidly reduce systemic inflammation.”

The phase IIIb SOUL trial included 9,650 patients (mean age 66.1 years, 28.9 percent female) with T2D who had a mean HbA_1C level of 8 percent and a mean BMI of 31 kg/m². Majority of the participants had a history of CV disease, such as coronary artery disease (70.7 percent), heart failure (23.1 percent), cerebrovascular disease (21.2 percent), and peripheral artery disease (15.7 percent), while almost half of the participants had a history of CKD (42.4 percent). [N Engl J Med 2025;doi:10.1056/NEJMoa2501006]

Participants were randomized in a 1:1 ratio to receive either once-daily oral semaglutide at a maximal dose of 14 mg or placebo (n=4,825 in each group) in addition to standard care. The primary outcome was MACE (defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) as assessed in a time-to-first-event analysis, followed by hierarchical testing of confirmatory secondary outcomes that included major kidney disease events.

At a median follow-up of 49.5 months, the primary-outcome event occurred in 12 percent of patients treated with semaglutide compared with 13.8 percent of those treated with placebo (3.1 vs 3.7 events per 100 person-years). This corresponded to a relative risk reduction of 14 percent (hazard ratio [HR], 0.86; one-sided p=0.0028), showing superiority of semaglutide over placebo. [McGuire, et al, ACC.25]

The treatment effect of semaglutide appeared consistent regardless of sex, age, BMI, HbA_1c, eGFR, region, or with or without background SGLT2 inhibitor use.

With regard to the confirmatory secondary endpoints, the five-point major kidney disease events, comprising CV-related death, kidney-related death, a persistent ≥50 percent eGFR reduction, a persistent eGFR <15 mL/min/1.73 m², or chronic kidney replacement therapy, did not differ significantly between the treatment groups (HR, 0.91; one-sided p=0.0967).

This result indicated that statistical superiority was missing, so all subsequent data will be regarded as exploratory, McGuire noted.

In terms of safety, serious adverse events occurred at a lower rate in the semaglutide group vs the placebo group (47.9 percent vs 50.3 percent; p=0.03), with cardiac disorders (17.8 percent vs 19.8 percent) and infections or infestations (15 percent vs 16.5 percent) being the most common events.

However, gastrointestinal disorders occurred more frequently with semaglutide than with placebo (5 percent vs 4.4 percent).

“Nevertheless, the overall safety profile of oral semaglutide in SOUL was similar to that observed in previous clinical trials with semaglutide, and no new safety signals were found,” said McGuire. “The trial results add to the favourable benefit-risk profile of oral semaglutide in this population.”

“Overall, oral semaglutide was superior to placebo in reducing the incidence of three-point MACE in people with T2D and ASCVD and/or CKD,” McGuire concluded, who added that “oral semaglutide is the first and only oral GLP-1 receptor agonist with proven CV benefits.”