Oral Semaglutide Shows 14% Reduction in MACE in Adults with T2D, ASCVD, and/or CKD: Topline Results from Phase 3 SOUL Trial
Novo Nordisk plans to file for regulatory approval this year of an expanded label for oral semaglutide, with an indication for reduction of MACE in high-risk adults with T2D.
Oral semaglutide (Rybelsus; Novo Nordisk) was associated with a reduction in major adverse cardiovascular events (MACE) of 14% in a population of high-risk adults with type 2 diabetes (T2D), established cardiovascular disease (CVD) and/or chronic kidney disease (CKD), according to a company announcement this morning.1
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In the topline findings from the SOUL CV outcomes trial (CVOT), all 3 components of the primary endpoint (CV death, nonfatal myocardial infarction or nonfatal stroke), contributed to the statistically significant and superior reduction in MACE for oral semaglutide compared to placebo.1
Oral semaglutide was approved in 2019 as the first oral glucagon like peptide-1 receptor agonist (GLP-1RA) to improve poorly controlled hyperglycemia in adults with T2D, as an adjunct to diet and exercise; Novo Nordisk was granted a label expansion in 2023 approving the medication as first-line treatment for the disease.2 Novo Nordisk plans to file for regulatory approval of a further label expansion to include the reduced risk of MACE, by the end of the year, according to the press release. The company will report full data from the SOUL trial at a scientific meeting in 2025.1
The randomized, double-blind SOUL (Semaglutide cardiOvascular oUtcomes; NCT03914326) phase 3 CVOT was launched in 2019, enrolling 9650 adults aged 50 years or older with T2D, CVD, and/or CKD.3 Participants were randomly assigned to receive oral semaglutide 14 mg once daily or placebo, both in addition to standard of care. The primary outcome was time from random assignment to first occurrence of MACE in the event-driven trial, with a target of 1225 first adjudication-confirmed MACEs.3
SOUL CVOT History
In 2022, based on findings from the SUSTAIN 6 trial with injectable semaglutide and “complemented” by further data from the registration program for oral semaglutide, including the PIONEER 6 study, the subcutaneous, but not the oral, formulation of semaglutide was granted a broader label to reduce the risk for CV death, MI, and stroke in adults with T2D and established CVD.3 The phase 3 PIONEER trial demonstrated the CV safety of oral semaglutide but was not powered to formally assess the medication’s CV efficacy. SOUL was designed specifically for this purpose.3
In Diabetes, Obesity, and Metabolism, in 2023, SOUL CVOT trial authors wrote that the evidence for the CV safety and efficacy of GLP-1RAs in individuals with T2D and elevated CV risk is both broad and deep, with at least 9 published CVOTs thus far. Those results are further supported by a wide-ranging meta-analysis of the trials that comprised a combined total of 60 080 participants. “The results from these trials have confirmed that the GLP-1RA class, as a group, has beneficial effects on CV, mortality and kidney outcomes in individuals with type 2 diabetes with or at high risk for CVD,” the investigators observed.3
"We are pleased to see that the results from SOUL demonstrate that oral semaglutide reduces the risk of cardiovascular events and that the benefits of oral semaglutide come on top of standard of care,” Martin Holst Lange, executive vice president and head of Development at Novo Nordisk, said in the press release. “Approximately one in three adults with type 2 diabetes also have cardiovascular disease; therefore, it is crucial to have therapies that can address both conditions.”1
The SOUL population comprised 71.1% men, predominantly White (68.9%) who had a mean age of 66.1 years and mean diabetes duration of 15.4 years. The cohort had a mean BMI of 31.3 and HbA1c of 8.0%. At the time participants were randomly assigned to treatment groups, 70.0% had coronary artery disease, 42.3% had CKD, 21.1% had cerebrovascular disease, and 15.7% had symptomatic peripheral arterial disease. Prevalent heart failure was reported in 23.0% of participants.3
