Semaglutide Shows Major Benefits in PAD: STRIDE

Semaglutide, a GLP-1 agonist, has shown convincing benefits in yet another population: patients with peripheral arterial disease (PAD).

In the STRIDE trial, the drug significantly improved walking distance, symptoms like pain, and quality of life in patients with symptomatic PAD and type 2 diabetes. It was also associated with a reduction in disease progression and the use of rescue therapy and an improvement in ankle brachial index scores.

“Semaglutide is the first drug to reduce cardiovascular and kidney outcomes, improve walking capacity in a clinically meaningful way, and show benefits in symptoms and related quality of life in this really difficult-to-treat population,” said lead investigator, Marc Bonaca, MD, from the University of Colorado Anschutz Medical Campus in Aurora.

“So, we have a new drug for peripheral artery disease,” he said when he presented the STRIDE results at the American College of Cardiology (ACC) Scientific Session 2025 in Chicago.

“Semaglutide should be prioritized for this population,” the authors of the study assert in The Lancet, where the findings were simultaneously published online. 

STRIDE is a “practice and guideline-changing trial,” said Joshua Beckman, MD, from the University of Texas Southwestern Medical Center in Dallas. “In concert with the cardiovascular benefits previously shown with semaglutide, we now have in one agent a medication that will make people feel better and live longer.”

“I cannot tell you, as a vascular physician, how hard it is to explain to patients that we are treating their legs to reduce the risk of a heart attack. It is really easy, however, to tell people that you want to give them medication so they can feel better and walk better. That is where this medication comes in and will make a huge difference,” he pointed out.

PAD and Diabetes: A Particular Clinical Challenge 

PAD is a prevalent and morbid manifestation of atherosclerotic vascular disease, estimated to affect more than 230 million individuals globally, Bonaca explained during his presentation. It is the most frequent first manifestation of cardiovascular disease in patients with diabetes.

“The combination of diabetes and PAD is a particular clinical challenge,” in patients who have “small vessel disease below the knee, often resulting in pain and severely limited walking distances, and we have few interventional and therapeutic options,” he said.

Although SGLT2 inhibitors and GLP-1 inhibitors are indicated in the PAD guidelines for patients with diabetes, neither class is prioritized because, until now, they have not shown PAD-specific benefits.

“In fact, it’s been a quarter of a century since the last drug — cilostazol — was approved for functional impairment in PAD. This agent is not used commonly, as it has a poor tolerability profile and no other cardiovascular benefits and is contraindicated in heart failure,” he pointed out.

The pathobiology of PAD is complex. “There are multiple drivers of risk: inflammation, cardiometabolic risk, smoking, and vascular dysfunction,” Bonaca said. “This leads to microvascular disease and progressive functional decline, which then is a vicious cycle, causing more inflammation and sedentary lifestyle, promoting progression of disease.” 

GLP-1 agonists have been shown to have a broad range of benefits in patients with diabetes, including anti-inflammatory effects, cardiometabolic benefits, and reductions in cardiovascular and kidney complications, he added. One trial showed a reduction in amputation related to diabetic foot ulcer, prompting the idea that these drugs could be of benefit to patients with PAD.

In the STRIDE trial, conducted in 20 countries in North America, Europe, and Asia, 792 patients with type 2 diabetes and PAD with intermittent claudication were randomized to subcutaneous semaglutide 1 mg per week for 52 weeks or placebo.

“While the trial recruited patients with early-stage symptomatic PAD, when measured objectively, these patients were severely disabled,” Bonaca reported. “The maximum walking distance was 185 meters on a 12% incline treadmill, and significantly less if defined as pain free. The overwhelming majority had noted a limitation in their walking ability, with two thirds rating that as moderate or severe.”

Baseline characteristics showed that patients had a lower body mass index (BMI) than in other trials of GLP-1 agonists (median, 28 kg/m²), and two thirds of patients were either former smokers or current smokers. At baseline, the geometric mean of low-density lipoprotein was 69 mg/dL and there was high use of indicated medications; more than 80% of patients were taking statins and the overwhelming majority were taking an anti-platelet drug or an anticoagulant.

The primary endpoint was the ratio to baseline of the maximum walking distance at week 52, measured on a constant-load treadmill with a 12% incline, which was significantly better in the semaglutide group than in the placebo group (1.21 vs 1.08; estimated treatment ratio, 1.13; P =.0004).

“In absolute terms, in this cohort that can walk about 185 meters, the median difference was 26 meters. And the mean improvement in walking distance in the semaglutide group was approximately 40 meters,” Bonaca reported.

An improvement of 20 meters on a flat surface would be considered clinically meaningful, “and this result is double that on a 12% grade,” he explained.

The benefits of semaglutide were consistent regardless of age, sex, or A1c, even in patients with a normal BMI.

“As expected, semaglutide patients lost weight — about 4 kg — and while there was a weak relationship between change in weight and maximum walking distance in both groups, this was not sufficient to explain the magnitude of the benefit seen with semaglutide,” Bonaca said.

Secondary outcomes were also improved with semaglutide, including pain-free walking distance, symptoms, and quality of life, and there was a significant improvement in ankle brachial index.

Although the trial was not powered to evaluate clinical outcomes, an exploratory post hoc analysis showed that a composite of rescue therapy and all-cause death was halved in the semaglutide group (4% vs 8%), with similar findings for the composite of rescue therapy — such as revascularization, all-cause death, and major adverse limb events.

In terms of safety, serious adverse events occurred in about 20% of patients in each group, as expected. There were more gastrointestinal side effects and cases of decreased appetite, but there were no unexpected imbalances, and there were no imbalances for serious adverse events, such as pancreatitis. Overall, the safety profile was consistent with what we know about semaglutide.

“Important Benefit”

“It is not well understood how much even what we describe as mild claudication limits patients with PAD,” Beckman said during a discussion of the trial. However, “physical component scores show that they feel as poorly as patients with New York Heart Association class III heart failure. Only being able to walk 100 meters is a horrendous result, and any improvement is an important one.”

The benefit with semaglutide is important. “While an improvement in walking distance of 40 meters doesn’t sound like a lot, it is a lot,” Beckman said, adding that in a recent trial, patients with heart failure and diabetes were “ecstatic” with an improvement of 14 meters. 

These results raise interesting mechanistic questions. “This is the first drug I am aware of that has increased ankle brachial index. We didn’t really think that was possible,” he pointed out.

The findings, combined with other data showing an increase in peripheral perfusion with a different GLP-1 agonist in PAD patients, suggest that these drugs may have both macrovascular and microvascular benefits, he said.

“This is a practice-changing trial,” echoed Kim Eagle, MD, from the University of Michigan School of Public Health in Ann Arbor. “I’m struck by the rescue rate being reduced by 50% and I bet, as you follow these patients out to years 2 and 3, it’s going to be even more magnificent.”

Eagle noted that these drugs change how patients eat and may change how people approach the use of alcohol, and asked whether there is any evidence that they change how patients use tobacco.

PAD is a multifactorial disease and smoking is believed to play a key role in the pathology. “It is possible that, over time, lower rates of smoking in the semaglutide group may have contributed to the benefit, although we saw the benefit as early as 6 months, and I suspect that wasn’t the primary driver, but it may be part of the multifactorial benefit that we observed,” Bonaca said.

What About Patients With PAD and No Diabetes?

In the future, could these drugs be used in patients with PAD who do not have diabetes or obesity, asked Harlan Krumholz, MD, from the Yale School of Medicine in New Haven, Connecticut, who chaired the session.

In the STRIDE trial, walking distance was still improved with semaglutide in patients with a normal BMI, said Beckman.

“We also saw the ankle brachial index go up, and I think these are some of the strongest data that really support a direct vascular benefit. So, I think this is a vascular drug. And while this study was restricted to patients with diabetes, I hope future work will investigate a broader vascular population,” he added.