VIENNA — Oral semaglutide showed similar reductions in cardiovascular events in patients with type 2 diabetes (T2D) and cardiovascular or chronic kidney disease with and without peripheral artery disease (PAD), according to a new SOUL trial subanalysis. Overall, however, patients without PAD experienced the most benefit.

Major adverse limb events (MALE), including both acute limb ischemia and chronic limb ischemia, were also lower in patients treated with oral semaglutide than placebo, regardless of whether patients had PAD or not.

“PAD is common and significantly increases risk of cardiovascular and limb events, yet [it] is an under-recognized comorbidity in patients with type 2 diabetes,” said Matthew Cavender, MD, interventional cardiologist at the University of North Carolina at Chapel Hill, who presented the data at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting.

“Therapeutic options that reduce cardiovascular and limb events are limited, and there’s an urgent need for novel strategies to improve outcomes in this vulnerable population,” he said.

The SOUL trial was a large, double-blind, cardiovascular outcomes study enrolling 9650 adults with T2D and either established cardiovascular or chronic kidney disease. The primary endpoint was three-point major adverse cardiovascular events (MACEs). Initial results presented earlier this year, as reported by Medscape Medical News, showed a 14% reduction in MACE with oral semaglutide compared with placebo (hazard ratio [HR], 0.86; P = .006) after a mean of 49.5 months of follow-up.

Given the high burden of PAD in patients with T2D and its link to MALE, investigators conducted a prespecified subanalysis to examine whether oral semaglutide’s benefits extended to this high-risk subgroup.

“Limb events carry high morbidity and mortality, with up to 50% 1-year mortality in critical limb ischemia,” said Cavender, highlighting the importance of these results.

Of the total trial population, 18% had PAD at baseline, most with coexisting vascular disease in other areas (70% coronary and 24% cerebrovascular). These patients were older (mean age, 67 years), predominantly men (71%), and carried a heavy burden of comorbidities, including chronic kidney disease (25%), prior myocardial infarction or stroke (45%), and heart failure (34%).

Baseline medications reflected aggressive risk management, with 87% on lipid-lowering therapy, 82% on antiplatelets, 74% on metformin, and 23% on SGLT2 inhibitors.

Semaglutide Effect Not Modified by PAD Status

In patients without PAD, oral semaglutide significantly reduced the three-point MACE composite (HR, 0.82; 95% CI, 0.72-0.93; P = .002) compared with placebo. In those with PAD, the HR was 0.97 (95% CI, 0.76-1.24; P = .79).

“The interaction P value of 0.22 suggested no modification of semaglutide’s effect by PAD status,” remarked Cavender.

Expanded analyses including hospitalization for unstable angina or revascularization showed consistent trends with a HR of 0.83 (95% CI, 0.74-0.93; P = .002) in patients without PAD, and a HR of 0.88 (95% CI, 0.69-1.11; P = .27) in patients with PAD (P interaction = .67).

Again, said Cavender, this suggested “no effect modification of the presence or absence of PAD with oral semaglutide.”

In patients with PAD, who had a high morbidity and mortality risk, the risk for cardiovascular death had an HR of 0.93 (95% CI, 0.67-1.28; P = .64); for those without PAD, the HR was also 0.93 (95% CI, 0.77-1.11; P = .41).

As for limb events, MALE were significantly reduced with oral semaglutide (HR, 0.71; 95% CI, 0.52-0.96; P = .03) compared with placebo, with similar HRs in patients with PAD at 0.70 (95% CI, 0.47-1.03; P = .07) and without PAD at 0.69 (95% CI, 0.42-1.12; P = .14). 

Patients with PAD had a much higher incidence of MALE than those without, but the effects of semaglutide were similar in both groups, said Cavender.

Statistical Uncertainty

Commenting on the findings, Ildiko Lingvay, MD, endocrinologist at UT Southwestern Medical Center, Dallas, said she welcomed the PAD-focused subanalysis but expressed caution in interpretation.

Looking at graphs of the results of MACE in patients with PAD (HR, 0.97 for oral semaglutide vs placebo), she said, “The lines crisscross a lot, so I hesitate to call this a positive finding in PAD. This makes sense clinically because these patients have very advanced disease, so they are probably beyond modifying disease scores at this stage.”

The MALE results are interesting, she added, but again cautioned, “We are applying Cox proportional hazards when the hazards are not proportional, so it doesn’t quite work. I don’t know what to make of these data.”

The SOUL trial was sponsored by Novo Nordisk, the manufacturer of semaglutide.

Cavender reported receiving research support from Amgen, Boehringer Ingelheim, Cleerly, Janssen Pharmaceuticals, Novo Nordisk, Novartis, Silence Therapeutics, and Massachusetts General Hospital/Patient-Centered Outcomes Research Institute; he also reported receiving consulting fees from AbbVie, AOP Pharmaceuticals, Bayer, Corcept Therapeutics, Faraday Pharmaceuticals, New Amsterdam Pharma Co., and Novo Nordisk. 

Lingvay reported serving as a consultant to AbbVie, Altimmune, Amgen, Alveus Therapeutics, Antag Therapeutics, AstraZeneca, Bayer, Betagenon AB, Bioio Inc., Biomea Fusion, Boehringer Ingelheim, Carmot Therapeutics, Cytoki Pharma, Eli Lilly and Company, Intercept Pharmaceuticals, Janssen/Johnson & Johnson, Juvena Therapeutics, Keros Therapeutics, Novo Nordisk, PharmaVentures Ltd., Pfizer, Regeneron, Roche, Sanofi, Shionogi and Company, Source BioScience Limited, Structure Therapeutics, Target RWE, Terns Pharma, The Communication Group, WebMD, and Zealand Pharma. She also reported receiving research support from Boehringer Ingelheim, Novo Nordisk, and Sanofi.