Research presented at the American Diabetes Association (ADA) 2025 scientific session (20–23 June, Chicago, USA) has shown that oral semaglutide offers a cardiovascular benefit for individuals with type 2 diabetes, by lowering their risk for major adverse cardiovascular events (MACE).
Semaglutide is typically administered via an injection, but it is thought that delivering the anti-diabetes orally medication may improve adherence and support earlier initiation of therapy—broadening access to cardiovascular protection for patients who might otherwise delay or avoid treatment due to reluctance toward injectables.
The double-blind, placebo-controlled, event-driven superiority SOUL trial included 9,650 participants who were 50 years of age or older. All had type 2 diabetes with an A1C level between 6.5% and 10%, meaning elevated blood glucose, and had either known atherosclerotic cardiovascular disease, chronic kidney disease, or both.
Participants were randomly assigned to receive either once-daily oral semaglutide (maximum dose of 14mg) or a placebo, in addition to standard care. The primary outcome was MACE (a composite of death from cardiovascular causes, non-fatal myocardial infarction, or nonfatal stroke), assessed in a time-to-first-event analysis.
The confirmatory secondary outcomes included major kidney disease events (a five-point composite outcome). The mean (±SD) follow-up was 47.5±10.9 months, and the median follow-up was 49.5 months.
Initial results were published in the New England Journal of Medicine in March showing a 14% reduction in MACE. A primary-outcome event occurred in 579 of the 4,825 participants (12.0%; incidence, 3.1 events per 100 person-years) in the oral semaglutide group, as compared with 668 of the 4,825 participants (13.8%; incidence, 3.7 events per 100 person-years) in the placebo group (hazard ratio, 0.86; 95% confidence interval, 0.77 to 0.96; P=0.006).
The results for the confirmatory secondary outcomes did not differ significantly between the two groups. The incidence of serious adverse events was 47.9% in the oral semaglutide group and 50.3% in the placebo group and the incidence of gastrointestinal disorders was 5% and 4.4%, respectively. The new results will expand on these findings.
“When treating patients with type 2 diabetes, it’s also important to address dangerous comorbidities such as lowering the risk of heart disease,” said Darren K McGuire (UT Southwestern Medical Center, Dallas, Texas) and lead author of the study. “Our findings indicate that oral semaglutide could be a promising option in need of treatment for diabetes and cardiovascular risk.”
Looking ahead, the researchers will look to implement findings in a real-world setting to better inform clinical next steps.
STRIDE: Semaglutide in PAD
Elsewhere, attendees also heard the findings of a new analysis from the STRIDE trial demonstrating the potential vascular benefits of semaglutide in patients with peripheral artery disease (PAD) and type 2 diabetes, including improvement in symptoms, quality of life, and disease progression in patients.
STRIDE is a phase 3, multinational, double-blind, randomised clinical trial conducted at 112 outpatient clinical trial sites in 20 countries in North America, Asia, and Europe.
Researchers enrolled 792 patients aged 18 years and older with type 2 diabetes and PAD with intermittent claudication and reduced ankle-brachial or toe-brachial index.
Patients were randomly assigned to receive either semaglutide (n=396) or placebo (n=396) over a 52-week period to assess the impact on walking capacity, symptoms, and quality of life. The median age was 68 years, and 195 (25%) participants were female and 597 (75%) were male.
The sub-analysis builds on results previously presented at the American College of Cardiology (ACC) 2025 scientific session (29–31 March, Chicago, USA) and published in The Lancet, demonstrating that semaglutide significantly improved walking outcomes in people with PAD and diabetes, enhanced quality of life, and reduced the risk of disease progression by 54%.
At week 52, the estimated median ratio to baseline in maximum walking distance was 1.21 in the semaglutide group compared to 1.08 in the placebo group. Semaglutide was well tolerated, with no treatment-related deaths and a low rate of serious adverse events (1%), consistent with its known safety profile.
The analyses from STRIDE presented new and critical information on the benefits of semaglutide, which were observed independent of baseline levels of A1C, duration of diabetes, or intensity of diabetes, ADA said in a press release. Furthermore, the benefits were seen across all body mass index BMI categories and regardless of the treatment with SGLT2 inhibitors.
“These findings indicate that clinicians can now recognise semaglutide as a vascular protective medication, with benefits that extend beyond lowering weight or A1C,” said Subodh Verma (University of Toronto, Toronto, Canada), senior author of the STRIDE trial. “The totality of data now suggest that in people with diabetes, semaglutide favourably affects the pipes [atherosclerosis], pump [heart failure], filter [kidney outcomes]. And, in patients with PAD, these new data provide robust evidence that semaglutide is a therapy to improve their function, quality of life, and progression of disease.”
The study authors indicate that further research is warranted to understand whether these benefits extend to individuals with PAD who do not have diabetes.
