Oral Semaglutide Lowers Risk of MACE 14% in High-Risk Adults: Final Phase 3 SOUL Trial Readout
ACC.25. The results seen with the only oral GLP-1 mimetic reflect "a profound clinical impact" for adults at high risk for MACE who are averse to injectable therapy.
Oral semaglutide (Rybelsus; Novo Nordisk) 14 mg, demonstrated a significant 14% reduction in major adverse cardiovascular events (MACE) compared with placebo in adults with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD), according to full results from the phase 3b SOUL cardiovascular outcomes trial. The late-breaking findings were presented at the American College of Cardiology's Annual Scientific Session in Chicago.1
The trial results, simultaneously published in the New England Journal of Medicine,2 showed risk reduction across all components of the primary composite endpoint, which included CV death, nonfatal myocardial infarction, and nonfatal stroke. This CV benefit was observed on top of standard CV and T2D care, according to the study.2
Based on the outcomes, Novo Nordisk submitted an application for a label expansion for semaglutide tablets 14 mg which has been accepted for review by the US FDA and the US FDA, with a decision expected in 2025, the company said.1
The multicenter international SOUL trial, initiated in 2019, enrolled 9,650 participants aged 50 years and older with T2D, with HbA1c 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.2
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.2
"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," Darren McGuire, MD, distinguished chair in cardiovascular science and teaching professor of medicine at UT Southwestern and SOUL steering committee co-chair, said in the company announcement. "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."1
Safety data from the trial 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), according to the results. No new safety signals were identified, and the overall safety profile was consistent with previous semaglutide trials.2
A key secondary analysis of the data published simultaneously indicated that oral semaglutide reduced the risk of MACE independently of baseline use of SGLT2 inhibitors, suggesting similar benefits regardless of concomitant SGLT2i use during the trial.2
“These data...reinforce the comprehensive set of health benefits of semaglutide, making it a strong option for healthcare professionals addressing the spectrum of metabolic and cardiovascular health..." Martin Holst Lange, Novo Nordisk executive vice president for development, stated.1
Semaglutide 14 mg is currently the only approved oral GLP-1 receptor agonist and is indicated for the treatment of adults with insufficiently controlled T2D as an adjunct to diet and exercise.1
Nearly one in three adults with type 2 diabetes have cardiovascular disease, which represents part of a broader spectrum of cardiometabolic conditions that collectively constitute the leading cause of death globally.3
