Semaglutide improves maximal walking distance in people with symptomatic PAD and Type 2 diabetes

Semaglutide, a glucagon-like peptide 1 (GLP-1) agonist, significantly improved maximal walking distance in people with symptomatic peripheral artery disease (PAD) and Type 2 diabetes in the first-of-its kind trial to evaluate the use of a GLP-1 agonist to manage PAD. In addition to improvements in walking ability and function, people taking semaglutide also saw significant improvements in both symptoms and quality of life compared with those taking a placebo.

PAD, which affects an estimated 12 million U.S. adults and over 200 million people worldwide, occurs when there is a build-up of fat and cholesterol, most commonly in the arteries of the legs. It's often associated with difficulty walking and poor circulation that can lead to non-healing wounds and a high rate of limb loss. People with PAD are at very high risk for serious complications, including acute limb ischemia—similar to a heart attack or stroke of the leg—that can lead to limb amputation or death if not treated quickly. The last drug approved by the U.S. Food and Drug Administration for improving functional outcomes in PAD was cilostazol in 2000.

Even at very early stages of PAD, people can't walk well, but they often don't know it's PAD. They may say, 'I've just slowed down,' 'I'm getting older,' or 'I have arthritis,' but they're actually severely functionally impaired and they often will self-limit what they are doing. The only drug we have available and is guideline recommended for symptoms is contraindicated in people with heart failure, has no benefits beyond improvement in symptoms and causes a lot of side effects, so overall it's used in less than 10% of people and so we really have limited options to improve function in PAD. The issue is that as PAD progresses, patients go on to get revascularization procedures to open arteries and become at high risk for adverse cardiovascular and limb events."

Marc P. Bonaca, MD, MPH, professor of medicine and director of vascular research at the University of Colorado School of Medicine in Aurora, Colorado, and the study's lead author

GLP-1 agonists are a class of medication currently used to treat Type 2 diabetes, obesity, kidney disease, cardiovascular disease including atherosclerotic vascular disease and heart failure. In the trial called STRIDE, 792 people with Type 2 diabetes and early-stage symptomatic PAD were enrolled at 112 medical centers in 20 countries. Participants were on average 67 years old, about 25% were women and 67% were White. All were randomly assigned to receive semaglutide (1 mg) or placebo for one year (52 weeks). Researchers assessed maximal walking distance—the maximum distance that patients were able to walk on a treadmill at 2 miles per hour at a 12% grade (similar to walking up a moderate hill). Function was assessed at baseline (median maximal walk distance was 186 meters), week 26, week 52 (primary endpoint) and week 57 (five weeks after stopping treatment).

"Despite the fact that people were recruited on the basis of reporting early-stage PAD, we observed that they were actually severely impaired and could only walk about one-tenth of a mile with symptom onset significantly earlier," Bonaca said. "We saw that the drug clearly worked. There was a clear early benefit at six months that continued to increase at one year."

Overall, patients in the semaglutide arm had a median improvement in walking distance of 26 meters and an average improvement of 40 meters, representing a statistically significant 13% improvement at one year.

"To put that into context, we usually think an increase in walking distance of 10 meters to 20 meters is clinically important in PAD, so this exceeded those expectations," he said.

The results were further supported by confirmatory secondary endpoints showing significant improvements in quality of life (as measured by the Vascular Quality of Life Questionnaire-6 score), including pain-free walking distance and sustained improvement in maximal walking distance at five weeks after stopping therapy. Safety was similar to earlier trials, with non-serious gastrointestinal side effects the most reported side effect among patients taking semaglutide.

Patients' ankle brachial index, a measure of blood flow in the legs, was significantly improved among those taking semaglutide compared with placebo. A post-hoc analysis looking at time to rescue treatment (the need for revascularization due to worsening symptoms) or death was also lower. Within one-year of treatment, patients taking semaglutide had a 54% reduction in their risk of dying or needing a medication or procedure to open blocked arteries in their legs due to worsening symptoms compared with those receiving a placebo (14 patients vs. 30 patients).

"Taken together, the data support semaglutide for people with PAD and Type 2 diabetes mellitus as a therapy that has cardiometabolic, cardiovascular and kidney benefits and improves function, symptoms and quality of life," Bonaca said. "There is more work to be done to understand the mechanism of benefit as the population had a median [body mass index] of 28.6 and the relationship between the outcome and weight loss was very weak. This coupled with the increase in ankle brachial index really suggests a direct vascular effect. This also raises the question of whether patients with PAD and without Type 2 diabetes mellitus could benefit and that should be investigated in future studies."

The study was limited in that it was only in patients who also had Type 2 diabetes. In addition, approximately 14% of the study population was enrolled in North America, while 57% were enrolled in Europe and 29% in Asia. As a result, there were few Black patients.

This study was funded by Novo Nordisk. It was simultaneously published online in The Lancet at the time of presentation.