Study underscores the direct vascular effects of this class of drugs, researchers say
AURORA, CO / ACCESS Newswire / March 29, 2025 / A novel study of a semaglutide, a glucagon-like peptide-1 (GLP-1) agonist used to treat type 2 diabetes, obesity and cardiovascular disease, semaglutide was found to significantly improve maximal walking distance in people with symptomatic peripheral artery disease (PAD) and type 2 diabetes, meeting the study's primary endpoint. The STRIDE Trial, presented at the American College of Cardiology's Annual Scientific Session (ACC.25), is the first to evaluate any GLP-1 agonist in PAD for this outcome. 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. People taking semaglutide also saw significant improvements in both symptoms and quality of life compared with those taking a placebo. Dr. Marc Bonaca, Executive Director of CPC presented the results and concluded, "We have the first new treatment for PAD symptoms in 25 years."
PAD affects an estimated 12 million U.S. adults and over 200 million people worldwide. PAD happens 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.
"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," said 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, adding that the last drug approved by the FDA for improving functional outcomes in PAD was cilostazol in 2000, so there is a huge unmet need.
"The only drug we have available is contraindicated in people with heart failure, has no benefits beyond improvement in symptoms, and causes a lot of side effects and, so overall it's used in less than 10% of people and so we really have limited options to improve function in PAD," he said. "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."
For this randomized, placebo-controlled, double-blind trial, called STRIDE, 792 people with type 2 diabetes and early-stage symptomatic PAD were enrolled at 112 medical centers in 20 countries. Patients (67 years old on average, about 25% women, 67% white) were randomized 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 (5 weeks after stopping treatment). The Colorado Prevention Center (CPC), affiliated with the University of Colorado School of Medicine, supported the treadmill endpoint through its core lab services.
"Despite the fact that people were recruited on the basis of reporting early-stage PAD 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 median and mean improvements in walking distance compared to placebo of 26 meters and 39.9 meters respectively, giving a statistically significant improvement in the ratio of change from baseline to week 52 of 1.13 (p=0.0004). "To put that into context, we usually think an increase in walking distance of 10 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), symptoms represented by pain-free walking distance, and sustained improvement in maximal walking distance 5 weeks after stopping therapy. Safety was shown to be similar to what was seen in earlier trials with semaglutide, with non-serious gastrointestinal side effects the most commonly reported side effects.
Patients' ankle brachial index, a measure of blood flow in the legs, was also 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 with semaglutide. 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 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.," said Bonaca, "There is more work to be done to understand the mechanism of benefit as the population had a median BMI of 28.6 and the relationship between the outcome and weight loss was very weak. This coupled with the increase in ABI 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 diabetes. In addition, there were fewer U.S. patients because revascularization is so common and that patients who had these procedures were excluded. As a result, there was also less diversity and very few Black patients.
This study was funded by Novo Nordisk. It was simultaneously published online in The Lancet at the time of presentation.
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Dr. Marc P. Bonaca can be reached by media at info@cpcmed.org or 303-860-9900.
Dr. Marc Bonaca will present the study, "The Effect Of Once-weekly Subcutaneous Semaglutide On Functional Capacity In People With Type 2 Diabetes And Peripheral Artery Disease: Primary Results From The Phase 3b, Randomized, Placebo-controlled, Double Blind Stride Trial," on March 29, 2025, at 9:30 a.m. CT in Chicago at the American College of Cardiology Meeting.
CPC Clinical Research, an ARO affiliated with the University of Colorado, is conducting the study in collaboration with Novo Nordisk.
CPC press contact: info@cpcmed.org
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SOURCE: CPC
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