Peripheral Artery Disease, Weight and GLP-1s: What the STRIDE Trial Found

Peripheral artery disease (PAD) is narrowing of the arteries that supply the legs, usually from the same fatty plaque that causes heart attacks. Its classic symptom is claudication: cramping or aching in the calf, thigh or buttock that comes on with walking and eases with rest. An estimated 237 million people aged 25 and older were living with it in 2015 ^[1]. In 2025 a large randomized trial called STRIDE showed that a GLP-1 drug, semaglutide, improves walking distance in people with PAD and type 2 diabetes ^[5]. This article covers what that trial found, how weight and diabetes relate to PAD, and where the evidence stops.

The honest summary

• Diabetes and smoking are the big risk factors. A global analysis named smoking, diabetes, high blood pressure and high cholesterol as the major risk factors for PAD ^[1]. Genetic studies suggest a higher BMI also raises the risk ^[2].
• Semaglutide improved walking in PAD with type 2 diabetes. In STRIDE, 792 people with claudication took semaglutide 1 mg weekly or placebo for a year. Maximum walking distance rose by a median of 21% with semaglutide versus 8% with placebo ^[5].
• The benefit did not depend on weight. Walking improved about equally in people with and without obesity, and weight change correlated only weakly with the gain ^[6].
• Limb outcomes are less certain. Observational studies link GLP-1 drugs to fewer amputations, but pooled randomized trials have not shown a significant difference in major limb events ^[8].
• The Ozempic label does not include PAD. As of its June 2026 version, the US label has no PAD indication and does not describe STRIDE ^[9].
• Supervised exercise is still the foundation. Exercise programs add roughly 80 to 120 meters of walking distance on average, supported by high-quality evidence ^[10].

Peripheral artery disease symptoms

PAD is measured with a simple test, the ankle-brachial index (ABI), which compares blood pressure at the ankle and the arm. An ABI of 0.90 or less is the standard definition used in population studies ^[1]. The typical symptom is claudication: a predictable ache or cramp in the leg muscles that starts after a certain walking distance and settles with rest. The most severe form, chronic limb-threatening ischemia, carries a real risk of limb loss ^[4]; it can show up as pain in the foot at rest or wounds on the toes or feet that heal slowly.

PAD matters beyond the legs. It is a sign of atherosclerosis elsewhere, and people with both diabetes and PAD carry a high risk of amputation, with five-year survival after amputation worse than for many cancers ^[4]. Leg pain at rest, a cold or pale foot, or a foot wound that will not heal needs prompt medical care. For wounds specifically, see GLP-1 drugs and diabetic foot ulcer healing.

How weight and diabetes relate to PAD

Diabetes

Diabetes increases the chance of developing PAD, speeds its progression and makes it more severe ^[4]. In the United States, amputation numbers overall have fallen, but rates among people with both diabetes and PAD have stayed flat or risen in high-risk groups, with the highest risk among rural residents, African American and Native American patients, and people with low incomes ^[4].

Body weight

The link between weight and PAD is more complicated than for heart disease. In a Mendelian randomization study of about 368,000 UK Biobank participants, which uses genetic variants to estimate cause and effect, a genetically higher BMI was associated with a higher risk of PAD, alongside heart failure, coronary artery disease and several other conditions ^[2].

Once PAD is established, the picture flips. A meta-analysis of 12 studies covering more than 5.7 million people found that people with PAD and obesity had a lower risk of death than those without obesity (HR 0.78), while underweight patients had a much higher risk (HR 1.72) ^[3]. This is the so-called obesity paradox. It does not mean extra weight protects the arteries: the authors noted the mechanisms are unclear and called for more evidence before setting weight targets for people with PAD ^[3].

What the STRIDE trial found

STRIDE was a double-blind trial at 112 sites in 20 countries ^[5]. It enrolled 792 adults with type 2 diabetes and early symptomatic PAD: claudication, able to walk more than 200 meters, and an ABI of 0.90 or less (or a low toe-brachial index). Their median age was 68 and 75% were men. Half took semaglutide 1 mg once a week and half took placebo for 52 weeks. The main outcome was the change in maximum walking distance on a treadmill set at a fixed speed and incline ^[5][6]. At the start, participants could walk about 190 meters before they had to stop ^[7].

In plain terms, people on semaglutide improved their walking distance by about 13% more than those on placebo ^[5]. Pain-free walking distance and PAD-specific quality of life, two of the key secondary outcomes, also improved ^[6]. Serious side effects judged related to treatment were uncommon in both groups, and there were no treatment-related deaths ^[5].

Was it the weight loss?

Probably not, or not mainly. Participants started with a median BMI of 28.7, so many did not have obesity ^[6]. Semaglutide lowered body weight by about 4.1 kg more than placebo over the year, yet the walking benefit was similar in people with a BMI under 30 (treatment ratio 1.12) and 30 or above (1.16), and similar across levels of blood sugar control ^[6]. The researchers found only a weak correlation between weight loss and walking gains and concluded the benefit appeared to go beyond weight or glucose changes ^[6]. A separate analysis found consistent results in women and men ^[7]. How semaglutide helps leg blood flow or muscle remains unknown, and the trial authors listed it as a question for future research ^[5].

Who STRIDE does not cover

Every STRIDE participant had type 2 diabetes. The trial authors stated that studies in people with PAD who do not have diabetes are still needed ^[5]. It also enrolled people with early claudication who could walk more than 200 meters, not people with rest pain or foot wounds, and it tested a single dose, 1 mg a week ^[5].

Do GLP-1 drugs prevent amputation?

The evidence here is weaker than for walking distance. A 2026 meta-analysis pooled the trials and cohort studies that looked at people with type 2 diabetes and PAD ^[8]. Two randomized trials with 847 participants showed better walking distance with liraglutide or semaglutide. But two randomized trials with 3,592 participants found no significant difference in major limb events or amputation between exenatide or semaglutide and placebo. Four observational cohort studies, covering over 104,000 people, linked GLP-1 drugs to about half the risk of amputation, but the certainty of that evidence was rated very low ^[8]. Observational studies can be skewed because people who are prescribed newer drugs often differ in health and access to care.

The large heart trials were built to measure heart attacks, strokes and deaths, not leg outcomes. The SUSTAIN 6 cardiovascular outcomes trial of Ozempic, for example, included people with PAD, but they made up only 13.7% of participants ^[9]. For heart outcomes in people without diabetes, see the SELECT trial.

What the Ozempic label says about PAD

The current US prescribing information for Ozempic (DailyMed version published June 2026) lists three uses: improving blood sugar control in adults with type 2 diabetes, reducing the risk of major cardiovascular events in adults with type 2 diabetes and established cardiovascular disease, and reducing kidney and cardiovascular risks in adults with type 2 diabetes and chronic kidney disease ^[9]. It does not list PAD or improved walking as an indication, and it does not describe the STRIDE trial. The only mention of PAD is in the description of the SUSTAIN 6 trial population:

In the trial 453 patients (13.7%) had peripheral artery disease.

— Ozempic prescribing information, Section 14 (DailyMed, June 2026)

PAD was one of the conditions that qualified people for SUSTAIN 6, the trial behind the label's cardiovascular indication ^[9], so for someone with type 2 diabetes and PAD that indication may still be relevant. Whether and how to use semaglutide is a decision to make with your clinician, who can weigh STRIDE alongside your other conditions and medicines.

Exercise therapy: the treatment with the deepest evidence

Walking through the pain, in a structured way, is the most studied treatment for claudication. A Cochrane review of 32 trials with 1,835 participants found that exercise programs improved pain-free walking distance by about 82 meters and maximum walking distance by about 120 meters compared with usual care or placebo, with high-quality evidence and benefits lasting up to two years ^[10]. Exercise did not change the ABI, and the trials were too small to show effects on amputation or death ^[10].

Supervision matters. A second Cochrane review of 21 trials and 1,400 participants found that supervised exercise therapy, usually three sessions a week, added roughly 210 meters of maximum walking distance compared with walking advice alone and about 120 meters compared with home-based programs at three months ^[11]. Adherence to supervised programs was about 80%. STRIDE compared semaglutide with placebo, not with exercise, so there is no head-to-head comparison, and its results do not suggest a GLP-1 drug should replace an exercise program. For general aerobic training, see zone 2 cardio and weight loss.

Does losing weight help PAD?

Weight loss improves several drivers of PAD, including blood sugar, blood pressure and cholesterol, but direct evidence on PAD outcomes is limited and observational. In a US national hospital database, people who had previously had bariatric surgery were hospitalized for PAD at about half the rate of people with a BMI of 35 or more who had not (0.10% versus 0.21%) ^[12]. The groups differed in many ways, and after adjustment only length of stay and cost remained clearly different, so the authors called for prospective studies ^[12].

The obesity paradox adds a note of caution. Because underweight people with PAD have a higher risk of death ^[3], unplanned or very rapid weight loss is worth raising with a clinician, and keeping up a walking program while losing weight protects the fitness that matters most for claudication.

Practical guidance

• Get calf pain on walking checked. PAD is diagnosed with a simple ankle-brachial index test ^[1].
• Ask about supervised exercise therapy. It has the strongest evidence for walking distance ^[11].
• Stop smoking. It is one of the major risk factors for PAD ^[1].
• If you have type 2 diabetes, ask whether semaglutide fits. STRIDE showed better walking distance at the 1 mg dose ^[5].
• Do not expect a GLP-1 drug to prevent amputation on its own. Randomized evidence on limb events is not conclusive ^[8].
• Avoid unplanned or extreme weight loss. Underweight people with PAD have higher mortality ^[3].
• Treat rest pain, cold feet or non-healing wounds as urgent. These suggest advanced disease.