GLP-1 Medicines and Peripheral Artery Disease: What the STRIDE Trial Showed About Walking Distance and Leg Pain

Can a GLP-1 medicine help peripheral artery disease? For people with type 2 diabetes whose calves cramp after a block or two, the answer from one large trial is a qualified yes. In STRIDE, published in The Lancet in 2025, semaglutide 1.0 mg once weekly let people walk further on a treadmill after 52 weeks than placebo did, and they could also walk further before the pain started.

Peripheral artery disease, or PAD, is narrowing of the arteries that feed the legs. It affects approximately 236 million people worldwide, according to a 2026 New England Journal of Medicine review by Mary McDermott, and it is diagnosed when the ankle-brachial index (blood pressure at the ankle divided by blood pressure at the arm) falls below 0.90. The classic symptom is intermittent claudication: aching or cramping in the calf, thigh or buttock that comes on with walking and eases with rest.

This article walks through what STRIDE tested, how big the walking gain was, who benefited, what happened with amputation and side effects, and what is still unknown, including whether any of it applies at lower doses.

Why does peripheral artery disease limit walking so much?

McDermott, New England Journal of Medicine, 2026

Narrowed leg arteries cannot raise blood flow enough when calf muscles start working, so the muscle runs short of oxygen and hurts. The effect on daily life is large. In the McDermott review, 3.3% of older people without PAD could not finish a 6-minute walk test without stopping to rest, compared with 18.1% of those with mild PAD and 52.0% of those with severe PAD.

Diabetes makes PAD harder to live with. The Diabetes Care analysis of STRIDE notes that PAD in type 2 diabetes is linked to greater functional impairment and higher rates of limb events and amputation, partly because disease below the knee in small vessels is more common.

Standard PAD care aims at two things: preventing heart attacks and strokes, and helping people walk further. The NEJM review lists statins, antiplatelet therapy, blood pressure below 130/80 mm Hg and semaglutide for cardiovascular protection, with SGLT2 inhibitors added in diabetes. For walking ability, supervised and structured home-based walking exercise both work. Our overview of GLP-1s and cardiovascular health covers the heart side of the picture.

What did the STRIDE trial test?

Bonaca and colleagues, The Lancet, 2025

STRIDE tested whether semaglutide improves walking in people with PAD and type 2 diabetes. It was a double-blind, placebo-controlled phase 3b trial run at 112 sites in 20 countries. Of 1363 people screened, 792 were randomised, 396 to semaglutide 1.0 mg once weekly and 396 to placebo, for 52 weeks.

Everyone had intermittent claudication at Fontaine stage IIa, meaning leg pain on walking but still able to walk more than 200 m, plus an ankle-brachial index of 0.90 or less or a toe-brachial index of 0.70 or less. According to the design paper, nobody had a planned artery procedure or was already taking a GLP-1 medicine.

The group was older and carried a lot of cardiovascular risk. Median age was 68.0 years, 75% were men, and median diabetes duration was 12 years. At baseline 25.6% smoked, 87.9% had high blood pressure and 42.7% had coronary heart disease. Mean BMI was 29.6, so many participants did not have obesity.

The main measure was maximum walking distance on a constant load treadmill set to 3.2 kph (2 mph) at a 12% incline, expressed as a ratio to each person's own starting distance. At the start, the median maximum walking distance was 186 m. The trial was funded by Novo Nordisk, which makes semaglutide.

How much further could people walk on semaglutide?

The STRIDE primary endpoint

About 13% further than on placebo. At week 52 the median ratio to baseline was 1.21 in the semaglutide group, meaning a typical participant walked 21% further than at the start, against 1.08 (8% further) on placebo. The estimated treatment ratio was 1.13 (95% CI 1.06 to 1.21), with p=0.0004.

In metres, a 2026 review in Deutsches Ärzteblatt by Kröger and colleagues described the result as a median prolongation of maximum walking distance by 26.4 m. Against a starting median of 186 m, that is modest. For someone who has to stop at every second shop window, a little extra distance before the pain forces a halt can still matter.

The placebo group improved too. That is normal in walking trials, partly because people get used to the treadmill test and partly because taking part in a trial tends to make people more active. The comparison between groups is what counts.

Did semaglutide reduce leg pain while walking?

Rasouli 2025 and Verma 2025

Yes, by the trial's measures. Pain-free walking distance, the distance covered before claudication starts, was a key secondary endpoint. In a Diabetes Care analysis led by Neda Rasouli, semaglutide increased pain-free walking distance with an estimated treatment ratio of 1.15 (95% CI 1.06 to 1.24) among people who kept taking the drug without rescue therapy.

Women and men benefited alike. A post hoc analysis in the Journal of the American College of Cardiology found 195 women (24.6%) in the trial, with baseline maximum walking distances of 187.3 m in women and 191.5 m in men. Improvement in maximum walking distance was consistent across sexes (P-interaction 0.65), as were pain-free walking distance and PAD-specific quality of life on the VascuQoL-6 questionnaire.

Is the walking benefit just from weight loss or better blood sugar?

Rasouli and colleagues, Diabetes Care, 2025

The subgroup data suggest not. The Rasouli analysis split STRIDE participants by diabetes duration, BMI and HbA1c. The estimated treatment ratio was 1.15 for diabetes under 10 years and 1.13 for 10 years or more, 1.12 for BMI under 30 and 1.16 for 30 or more, and 1.13 for HbA1c both under 7% and at 7% or above. None of the differences between subgroups was statistically significant.

BMI reduction correlated only weakly with walking improvement. The authors concluded that semaglutide improved walking in people without obesity and in those with well-controlled HbA1c, supporting effectiveness beyond weight or glycemic changes. The biological reason is not settled; the Lancet authors call for studies on mechanisms of benefit.

Background medicines did not change the picture. In STRIDE, 35.1% of participants used SGLT2 inhibitors and 31.7% used insulin, and effects were consistent across those groups. Our article on combining SGLT2 inhibitors with GLP-1s covers that pairing in more detail.

Who gained the most walking distance in metres?

Placebo-subtracted gains by subgroup

People with higher BMI and higher HbA1c gained more metres, even though the ratios were similar. In the Rasouli analysis, the placebo-subtracted gain in maximum walking distance was 22.5 m for BMI under 30 and 62.9 m for BMI 30 or more. By blood sugar, it was 27.4 m for HbA1c under 7% and 48.5 m for HbA1c 7% or above.

Ratios and metres tell slightly different stories because the starting distances differ. The interaction tests found no significant difference in relative benefit between these groups, so the safest reading is that semaglutide helped across the board, with absolute gains that varied.

Do GLP-1 medicines lower amputation risk in PAD?

Giugliano and colleagues, Diabetes, Obesity and Metabolism, 2026

That has not been shown in randomised trials. A 2026 meta-analysis by Giugliano and colleagues pooled seven studies (3 randomised trials and 4 cohorts) with 107,092 people who had type 2 diabetes and PAD. In two trials with 3592 participants, major adverse limb events or amputation did not differ between GLP-1 drugs and placebo.

The cohort data look more favourable. Four cohort studies with 104,292 people linked GLP-1 use to a lower risk of lower-limb amputation (RR 0.53), with the largest reductions for tirzepatide (55%) and semaglutide (54%). But heterogeneity was high (I² 85.96%) and the authors rated the certainty of that evidence as very low. People who get prescribed newer drugs may differ from those who do not in ways that matching cannot fully fix.

The same meta-analysis pooled two trials with 847 participants on walking distance and found a consistent benefit with liraglutide or semaglutide (HR 1.10, 95% CI 1.05 to 1.15), rated moderate certainty. Kröger and colleagues point out that no randomised trial of GLP-1 drugs or SGLT2 inhibitors has used amputation as its primary endpoint, so the limb-saving question is still open.

What side effects showed up in STRIDE?

Serious events, stomach symptoms and stopping the drug

Serious treatment-related problems were rare. Possibly or probably treatment-related serious adverse events occurred in five participants (1%) on semaglutide and six (2%) on placebo, most often gastrointestinal, and there were no treatment-related deaths.

Stomach and bowel symptoms were the familiar trade-off, and leaner people reported more of them. In the BMI under 30 subgroup, 25.1% had gastrointestinal disorders on semaglutide versus 4.6% on placebo. In the BMI 30 or more subgroup the figures were 12.7% and 8.2%. Most of these events were mild. Our guide to GLP-1 nausea and vomiting explains why these symptoms cluster early.

Slightly more people stopped semaglutide than placebo: 57 (14.4%) versus 44 (11.2%). Fewer needed rescue therapy on semaglutide, 10 (2.5%) versus 17 (4.3%).

Does this apply to people with PAD who do not have diabetes?

The gap the STRIDE authors flagged

Nobody knows yet. Every STRIDE participant had type 2 diabetes, and the Lancet authors list testing efficacy and safety in people with PAD who do not have type 2 diabetes as a research priority. The finding that benefit held at lower BMI and good HbA1c is encouraging, but it is still a finding inside a diabetic population.

Smoking is the other big PAD driver, and a quarter of STRIDE participants smoked. If quitting is on the list, our article on GLP-1 medicines and quitting smoking covers what the trials show about cravings and post-quit weight gain.

Does microdosing a GLP-1 help peripheral artery disease?

What the evidence can and cannot support

That has not been studied. STRIDE used semaglutide 1.0 mg once weekly, and none of the published STRIDE analyses report results at lower doses. There is no data on whether a microdose protocol changes walking distance, claudication pain or limb outcomes.

The weak link between weight loss and walking gains does not fill that gap. It suggests the benefit may not depend on how much weight someone loses, but it says nothing about how much drug is needed to get it.

The practical summary is narrow. In adults with type 2 diabetes and claudication, semaglutide 1.0 mg improved treadmill walking distance and pain-free walking over a year. Calf pain that comes on with walking and eases with rest deserves a proper PAD assessment, and supervised walking exercise remains a proven treatment alongside any medicine. Our guide to exercise on a GLP-1 protocol covers training while the appetite drops.

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