ACC 2025: Semaglutide Significantly Improves Walking Distance, Symptoms, QOL for Individuals with PAD and Diabetes

New data presented at the American College of Cardiology 2025 Scientific Sessions demonstrate that the glucagon-like peptide 1 (GLP-1) agonist semaglutide (Wegovy, Ozempic; Novo Nordisk) improved maximal walking distance in individuals with symptomatic peripheral artery disease (PAD) and type 2 diabetes. According to investigators, the STRIDE trial was the first of its kind to evaluate the use of a GLP-1 agonist in PAD management.¹

PAD involved a build-up of fat and cholesterol in arteries | Image credit: Юля Бурмистрова | stock.adobe.com

“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,” explained Marc P. Bonaca, MD, MPH, lead author of the study.¹

PAD affects an estimated 12 million adults in the US and more than 200 million individuals worldwide. The condition occurs when there is a build-up of fat and cholesterol in arteries, most commonly in the legs. It is often associated with challenges walking and poor circulation, which can lead to non-healing wounds and limb loss.²

Individuals with PAD have a very high risk of serious complications, including acute limb ischemia. The last drug approved by the FDA for functional outcomes in PAD was cilostazol (Pletal; Otsuka Pharmaceutical Co), approved in 2000, highlighting the great need for newer, more efficacious therapies.^1,2

“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, so we really have limited options to improve function in PAD,” Bonaca 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.”¹

In the STRIDE trial, 792 participants with type 2 diabetes and early-stage symptomatic PAD were enrolled at 112 medical centers in 20 countries. Participants were an average of 67 years old, about 25% were women, and 67% were White. All were randomly assigned to receive semaglutide 1 mg or placebo for 1 year. Investigators assessed maximal walking distance on a treadmill at 2 miles per hour and a 12% grade. Function was assessed at baseline (median 186 meters), week 26, week 52, and week 57 (5 weeks after stopping treatment).^1,3

Overall, investigators found that 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 1 year.³

“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,” Bonaca said.¹

The results were further supported by confirmatory secondary end points which showed significant improvements in quality of life, including pain-free walking distance and sustained improvement in maximal walking distance 5 weeks after stopping therapy. Safety was similar to earlier trials, with non-serious gastrointestinal adverse effects the most reported among patients taking semaglutide.^1,3

Patients’ ankle brachial index, which measures blood flow in the legs, was significantly improved among individuals taking semaglutide compared with placebo. A post-hoc analysis examined time to rescue treatment (the need for revascularization due to worsening symptoms) or death, and found that these measures were also lower in the semaglutide group. Within 1 year of treatment, patients taking semaglutide saw a 54% reduction in their risk of dying or needing a medication or procedure to open blocked arteries in their legs compared with those receiving a placebo (14 patients vs 30 patients).¹

“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.”

REFERENCES

1. Bonaca MP. Semaglutide significantly improves walking distance, symptoms and qualityof life for people with PAD and diabetes. Presented at: American College of Cardiology 2025 Scientific Sessions. Chicago, IL. March 29, 2025.

2. Peripheral artery disease (PAD). Mayo Clinic. August 9, 2024. Accessed March 29, 2025. https://www.mayoclinic.org/diseases-conditions/peripheral-artery-disease/symptoms-causes/syc-20350557

3. Bonaca MP, Catarig AM, Houlind K, et al. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial. The Lancet. 2025. doi:10.1016/S0140-6736(25)00509-4