Novo Nordisk's semaglutide improved walking distance in peripheral artery disease trial

Novo Nordisk's once-weekly semaglutide 1 mg injection improved maximum walking distance by 13% compared with placebo in adults with type 2 diabetes and symptomatic peripheral artery disease (PAD), according to results from the STRIDE trial presented March 29, 2025, at the American College of Cardiology's annual meeting in Chicago and published the same day in The Lancet ^[1][3][4].

STRIDE is a phase 3b, double-blind, placebo-controlled trial that enrolled 792 adults at 112 outpatient sites in 20 countries across North America, Asia and Europe between October 2020 and July 2024. Half received semaglutide 1.0 mg under the skin once a week for 52 weeks; the other half received placebo. Participants had type 2 diabetes and early-stage symptomatic PAD with walking-induced leg pain, an ankle-brachial index of 0.90 or less or a toe-brachial index of 0.70 or less, and could walk more than 200 meters without pain but no more than 600 meters at maximum on a treadmill test ^[1][4]. Median age was 68, and 25% of participants were women ^[4]. The median baseline maximum walking distance was 185 meters ^[2].

The main measure was the ratio of maximum walking distance at week 52 compared with the start of the trial, tested on a constant-load treadmill. The ratio was 1.21 with semaglutide versus 1.08 with placebo, an estimated treatment ratio of 1.13 (95% CI 1.06-1.21; p=0.0004) ^[4]. In absolute terms, that was a median treatment difference of 26.4 meters, or about 87 feet, measured on a 12% incline ^[3]. MedPage Today reported the same result as a 21% improvement in walking ability with semaglutide against 8% with placebo ^[2].

All confirmatory secondary endpoints favored semaglutide, including pain-free walking distance (estimated treatment ratio 1.11; 95% CI 1.03-1.20; p=0.0046) and the Vascular Quality of Life Questionnaire-6 (estimated treatment difference 1.00; 95% CI 0.48-1.52; p=0.011) ^[1][3]. The trial was funded by Novo Nordisk ^[2][4].

Serious adverse events occurred in 19% of the semaglutide group and 20% of the placebo group. Serious events that were possibly or probably related to treatment occurred in 1% and 2%, respectively, most often gastrointestinal. There were no treatment-related deaths, though deaths from any cause occurred in 3 participants (1%) taking semaglutide and 8 (2%) taking placebo ^[3][4]. Serious adverse events led to permanent discontinuation in 2.8% of the semaglutide group and 3.3% of the placebo group ^[3], while MedPage Today reported that 14% of semaglutide participants and 11% of placebo participants stopped their assigned treatment for any reason ^[2]. An exploratory analysis found a combined rate of rescue therapy or death of 4% with semaglutide versus 8% with placebo (hazard ratio 0.46; 95% CI 0.24-0.85), a finding the researchers said needs confirmation ^[2].

Limitations: STRIDE did not include people who have PAD without type 2 diabetes ^[2][4], and low numbers of limb events meant the trial could not assess effects on major adverse limb events ^[2]. Lead investigator Marc Bonaca said at an ACC press conference, "We haven't had a new therapy for function in PAD in 25 years" ^[2].

Why it matters for patients

PAD affects roughly 12 million people in the United States, and about one in four of them also has type 2 diabetes ^[3]. The condition narrows the arteries in the legs and can make even short walks difficult, which affects quality of life ^[3]. Current drug options for walking are limited: cilostazol is the only guideline-recommended therapy for walking, has no proven cardiovascular benefit and is used infrequently because of side effects ^[2]. Cardiologist Chiadi Ndumele, who was not involved in the trial, called the quality-of-life improvement important for patients ^[2].

Semaglutide is not approved to improve walking. Ozempic is currently indicated to lower blood sugar in adults with type 2 diabetes, to reduce the risk of major cardiovascular events in adults with type 2 diabetes and known heart disease, and to reduce the risk of kidney disease worsening in adults with type 2 diabetes and chronic kidney disease ^[3]. Whether insurers would cover the drug for a walking indication, and at what cost to patients, has not been disclosed. Whether the benefit extends to people with PAD who do not have diabetes is also not yet known.

What happens next

Novo Nordisk has submitted a label extension application to the FDA based on STRIDE, and the company says a decision is anticipated in 2025 ^[3][6]. The trial authors wrote that future studies should examine how semaglutide produces the benefit and test it in people with PAD who do not have type 2 diabetes ^[4].