Oral Semaglutide Cuts MACE Risk by 14% in High-Risk Adults: Daily Dose

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Patient Care brings primary care clinicians a lot of medical news every day—it’s easy to miss an important study. The Daily Dose provides a concise summary of one of the website's leading stories you may not have seen.

On March 31, 2025, we reported on a study published in the New England Journal of Medicine that assessed the cardiovascular efficacy of oral semaglutide (Rybelsus; Novo Nordisk) 14 mg in persons with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both.

The study

The phase 3b SOUL cardiovascular outcomes trial, initiated in 2019, enrolled 9650 participants aged 50 years and older with T2D, with HbA_1c ranging from 6.5% to 10.0%, and with known ASCVD, CKD, or both. Participants were randomized to receive once daily oral semaglutide or placebo, in addition to standard of care. The primary outcome was major adverse cardiovascular events (MACE; a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), assessed in a time-to-first-event analysis.

The findings

The study achieved its primary endpoint, demonstrating a 14% reduction in risk of MACE among participants in the oral semaglutide group compared to those in the placebo group.

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 =.006). 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 endpoints did not reach statistical significance on their own.

Safety data showed a lower incidence of serious adverse events (SAEs) among participants receiving oral semaglutide compared to those receiving placebo, primarily due to higher rates of cardiovascular events (17.8% with semaglutide 14 mg vs 19.8% with placebo) and infections (15.0% vs 16.5%, respectively).

Authors' comments

"Heart attacks and strokes are the leading causes of disability and death for people with type 2 diabetes, and there is a need for new, patient-centric treatments to help manage this risk. The proven cardiovascular benefit [of oral semaglutide] reflects a profound clinical impact for our patients who now have an oral option to improve health outcomes."

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