Semaglutide Shows Benefits for PAD Across T2D Subgroups

CHICAGO — Use of the GLP-1 receptor agonist semaglutide improved walking capability in patients with peripheral arterial disease (PAD) and type 2 diabetes (T2D), regardless of duration of diabetes, BMI, or glycemic control, a post-hoc analysis of phase 3 double-blind randomized STRIDE showed.

“PAD remains a recalcitrant problem in people living with diabetes. We need solutions for improving quality of life and preventing limb loss” said senior study author Subodh Verma, MD, PhD, a cardiovascular surgeon and professor of medicine at the University of Toronto, Canada, here at the American Diabetes Association (ADA) 85th Scientific Sessions, where the results were presented. The data was simultaneously published online in Diabetes Care.

About 230 million people globally — and up to a third of those with diabetes — have PAD, which is why the ADA recommends using ankle-brachial index testing in individuals with T2D who are over 65 and meet certain criteria. 

The STRIDE Study

STRIDE was conducted at 112 sites in 20 countries, enrolling 792 patients aged 18 years and older with T2D and PAD with intermittent claudication and reduced ankle-brachial or toe-brachial index. The median age was 68 years, the mean diabetes duration was 13.3 years, and 195 (25%) participants were female and 597 (75%) were male.

Patients were randomized to subcutaneous semaglutide 1 mg per week for 52 weeks (n = 396) or to placebo (n = 396).

The primary analysis of the trial, presented at the American College of Cardiology Scientific Session 2025 in March, showed that semaglutide significantly improved walking distance, pain, and quality of life in patients with symptomatic PAD and T2D. 

It was also associated with reductions in disease progression and use of rescue therapy and improvement in ankle-brachial index.

At baseline, trial participants could walk a maximum of 184 m, and the pain-free walking distance was 119 m. Two-thirds of the individuals said PAD moderately-to-severely impacted quality of life.

At week 52, patients taking once-weekly semaglutide had a roughly 40-m improvement in maximum walking distance, and a 30-m improvement in pain-free walking distance on a treadmill with a fixed speed of 3.2 kph (2.3 mph) and fixed inclination of 12%, when compared with placebo.

For the current analysis, the researchers stratified the participants by baseline T2D characteristics. The mean BMI was 29.6; 41% had a BMI > 30, and 44% had A1C < 7%. Only a third used insulin and a third used an SGLT2 inhibitor.

Their analysis showed no meaningful distinction between the subgroups for improvement in either maximum walking distance or pain-free walking distance, said lead author Neda Rasouli, MD, professor of medicine at the University of Colorado Anschutz Medical Campus, Aurora, at the meeting. 

The estimated treatment ratio favored semaglutide regardless of diabetes duration, BMI, A1C, or medication used, she added.

These findings support semaglutide’s “consistent efficacy and safety profile across the spectrum of type 2 diabetes, including those who are non-obese and have well-controlled diabetes,” she concluded.

Vascular Medications

“This was a really important study,” said Kim Eagle, MD, the Albion Walter Hewlett professor of internal medicine at the University of Michigan, when asked to comment by Medscape Medical News. Eagle said that while the additional 40 m of walking distance might not seem huge, it could be meaningful for a golfer, for instance, who could walk that much further to their ball, without a golf cart. 

“We’re still learning about the effects of GLP-1s,” said Eagle, who is also director of the Frankel Cardiovascular Center at the University of Michigan. “They clearly affect vascular function,” he said, adding that the effects in PAD would be expected for the entire class.

“The thesis here is that these are vascular medications,” said Verma, noting in a briefing with reporters that patients had an improvement in hemodynamics. 

The improvement is not driven by changes in weight or A1C, he added. 

Given the results of STRIDE and the post-hoc analysis, “I would suggest that it should be strongly considered by our patients living with PAD and diabetes as a strategy to not only improve MACE outcomes, but to also improve functional outcomes in PAD,” said Verma.

Eagle noted, however, that clinicians often face barriers in prescribing GLP-1s. “We’re basically scrambling to see what’s covered by patients’ insurance,” he said.

Verma and his co-authors said that more research is needed to understand if semaglutide’s benefits extend to people with PAD who do not have diabetes.

The study was funded by Novo Nordisk A/S. Rasouli reported receiving consultation fees and/or research funding from Novo Nordisk, Eli Lilly, Sanofi and SomaLogic. Verma disclosed research grants and/or speaking fees from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, HLS Therapeutics, Anthos, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S&L Solutions Event Management, and Sanofi. Eagle reported no relevant conflicts. 

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in many health and science publications, including Smithsonian.com. You can find her on X @aliciaault and on Bluesky @aliciaault.bsky.social.