Semaglutide improved walking distance in peripheral artery disease

Peripheral artery disease — narrowed arteries in the legs — is common, disabling and stubbornly resistant to drug treatment. Its signature symptom is intermittent claudication: cramping leg pain that forces people to stop walking after a short distance. Few medicines improve how far patients can actually walk. STRIDE, published in The Lancet, tested whether semaglutide, the GLP-1 drug best known for diabetes and weight loss, could move that needle in people who also have type 2 diabetes [s1].

It did — by a modest, statistically clear margin. The size of the effect, and the narrowness of the population studied, are where the care is needed in reading it.

What STRIDE did

STRIDE was a phase 3b, double-blind, randomised, placebo-controlled trial run at 112 outpatient sites in 20 countries across North America, Asia and Europe [s1]. It enrolled adults aged 18 and older with type 2 diabetes and peripheral artery disease with intermittent claudication — Fontaine stage IIa, meaning they could walk more than 200 m — and an ankle-brachial index of 0·90 or less or a toe-brachial index of 0·70 or less [s1]. Participants were randomly assigned 1:1 to subcutaneous semaglutide 1·0 mg once a week or placebo for 52 weeks [s1].

From 1363 patients screened between Oct 1, 2020, and July 12, 2024, 792 were randomly assigned to semaglutide (n=396) or placebo (n=396) [s1]. Of these, 195 (25%) were female and 597 (75%) male, with a median age of 68·0 years (IQR 61·0-73·0) [s1]. The primary endpoint was the ratio to baseline of the maximum walking distance at week 52, measured on a constant-load treadmill [s1]. The trial is registered as NCT04560998, is completed, and was funded by Novo Nordisk [s1][s2].

The numbers

At 52 weeks, the estimated median ratio to baseline in maximum walking distance was significantly greater on semaglutide than on placebo: 1·21 (IQR 0·95-1·55) versus 1·08 (IQR 0·86-1·36), an estimated treatment ratio of 1·13 (95% CI 1·06-1·21; p=0·0004) [s1]. In plain terms, the typical patient on semaglutide walked about 13% farther relative to placebo by the end of the year.

Safety was reassuring over the year. Six serious adverse events in five (1%) semaglutide participants and nine in six (2%) placebo participants were judged possibly or probably treatment related, the most frequent being serious gastrointestinal events — two events in two (1%) semaglutide patients and five events in three (1%) placebo patients [s1]. There were no treatment-related deaths [s1].

How much a 13% ratio is worth

A treatment ratio of 1·13 is a genuine, prespecified, significant improvement on a functional endpoint that almost nothing else reliably shifts — and that is the news [s1]. It is also a reminder to keep expectations proportionate. The measure is a ratio of walking distance to each patient's own baseline, not a fixed number of extra metres, and the placebo group improved too (a ratio of 1·08), as people often do on a treadmill test repeated after months of trial participation [s1]. The 13% figure is the gap between the two, not the full change a patient experiences.

Two boundaries on the finding matter. First, the trial enrolled only people who also had type 2 diabetes, and the investigators are explicit that future work is needed to test whether the benefit extends to peripheral artery disease without diabetes [s1]. Many people with claudication do not have diabetes, and STRIDE does not speak to them. Second, the trial was funded by the drug's manufacturer [s1] — routine for a registration-stage study, and a reason the mechanism of benefit and its reproducibility deserve independent follow-up, which the authors themselves call for [s1].

What STRIDE does not report is just as important as what it does. It measured walking capacity and symptoms over a year, not hard vascular outcomes such as amputation, revascularisation or limb events, and it was not designed to [s1]. Whether better treadmill performance translates into fewer of those outcomes is a separate question this trial cannot answer.

What to watch

STRIDE establishes semaglutide as the rare drug that improves walking capacity in symptomatic peripheral artery disease — in the specific group that also has type 2 diabetes, over 52 weeks, by a modest margin [s1]. The open questions are whether the effect holds in patients without diabetes, how it compares with supervised exercise therapy (the existing mainstay for claudication), and whether it changes the outcomes patients fear most. Those will need trials built to measure them.

This article is informational and does not constitute medical advice.

Sources

• [s1] Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial. The Lancet, 29 March 2025. https://doi.org/10.1016/S0140-6736(25)00509-4
• [s2] A Research Study to Compare a Medicine Called Semaglutide Against Placebo in People With Peripheral Arterial Disease and Type 2 Diabetes. ClinicalTrials.gov identifier NCT04560998, US National Library of Medicine. https://clinicaltrials.gov/study/NCT04560998