STRIDE: Semaglutide Improves Functional Outcomes in Peripheral Artery Disease

Data from the phase 3b STRIDE trial suggest semaglutide 1.0 mg (Ozempic) could be on track to become the first therapy in more than 2 decades to earn a nod for improving functional outcomes in peripheral artery disease (PAD).

Billed as a first-of-its kind trial assessing the use of a GLP-1 receptor agonist to manage PAD in patients with type 2 diabetes, results, which were presented at the American College of Cardiology (ACC) 2025 Annual Scientific Sessions, indicate the use of semaglutide was associated with improvements in maximal walking distance, quality of life, and ankle-brachial index.

“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,” said principal investigator Marc Bonaca, MD, MPH, professor of medicine and director of vascular research at the University of Colorado School of Medicine in Aurora, Colorado. “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.”

In recent years, semaglutide has taken on a lead role in revolutionizing the role of GLP-1 receptor agonists in care. Though much of the focus on semaglutide has focused on semaglutide 2.4 mg (Wegovy) for weight loss, recent trials focusing on semaglutide (Ozempic) in patients with diabetes have also made waves. Since initial approval in 2017, semaglutide received subsequent approvals for cardiovascular risk reduction in adults with type 2 diabetes and known heart disease in 2020 and 5 years later, based on the FLOW trial, the agent received an expanded indication to reduce risk of worsening kidney disease and cardiovascular death in chronic kidney disease and type 2 diabetes.1,2,3

Funded by Novo Nordisk, STRIDE was launched in 2020 as a double-blind, randomized, placebo-controlled trial done at 112 outpatient clinical trial sites in 20 countries in North America, Asia, and Europe. The trial enrolled patients aged 18 years and older with type 2 diabetes and PAD meeting Fontaine stage IIa criteria and an ankle-brachial index of less than or equal to 0.90 or toe–brachial index of less than or equal to 0.70. The primary outcome of interest for the study was the ratio from baseline of the maximum walking distance at week 52, which was measured on a constant load treadmill.1,2,3

A total of 1363 patients underwent screening for eligibility. Of these, 792 underwent randomization in a 1:1 ratio to placebo or semaglutide for 52 weeks, with 396 assigned placebo and 396 assigned semaglutide. The overall cohort included in the study had a median age of 68.0 (IQR, 61.0 to 73.0), median BMI of 28.7 kg/m² (IQR, 25.6 to 33.0), 75% were male, and 68% were White. Baseline assessment of disease information indicated 61% had a duration of diabetes 10 years or longer and 59% had a BMI of less than 30 kg/m².1

Per trial protocol, semaglutide was administered in a dose-escalating manner, with 0.25 mg from week 1 to week 4, 0.5 mg from week 5 to week 8 and 1.0 mg from week 9 to week 52. Additionally, participants took part in assessments of adherence, dispense medication, and outcome and safety events at 4, 8, 12, 26, 49, 52, and 57 weeks, with functional testing carried out at baseline, 26, 52, and 57 weeks.1

Upon analysis, week 52 results indicated the estimated median ratio to baseline in maximum walking distance was significantly greater in the semaglutide group than the placebo group (1.21 [IQR, 0.95 to 1.55] vs 1.08 [0.86 to 1.36]; estimated treatment ratio [ETR], 1.13 [95% CI, 1.06 to 1.21]; P=.0004). When assessing secondary confirmatory outcomes, results suggested the median maximum walking distance improved with semaglutide (ratio to baseline, 1.16; 95% CI, 0.92 to 1.48) compared with placebo (1.10; 95% CI, 0.87 to 1.40), with an ETR of 1.08 (95% CI, 1.00 to 1.16; P = 0.038) at week 57.1

Further analysis of confirmatory secondary outcomes indicated the median VascuQoL-6 total score at week 52 demonstrated a greater improvement with semaglutide (2.0 [IQR, 0.0 to 4.0]) relative to placebo (1.0 [IQR, –1.0 to 4.0]), with an estimated treatment difference of 1.00 (95% CI, 0.48 to 1.52; P=.011). Additionally, the median pain-free walking distance at week 52 increased more with semaglutide (ratio to baseline, 1.21; 95% CI, 0.92 to 1.52) than with placebo (1.10; 95% CI, 0.86 to 1.44), yielding an ETR of 1.11 (95% CI, 1.03 t 1.20; P = 0.0046).1

Analysis of safety indicated serious adverse events considered possibly or probably treatment-related occurred in 1% of the semaglutide group and 2% of the placebo group. Investigators pointed out the most frequently reported serious adverse events were gastrointestinal in nature, with 2 events in 2 participants (1%) in the semaglutide group and 5 events in 3 participants (1%) in the placebo group. Additionally, investigators highlighted there were no treatment-related deaths were reported.1

“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,” Bonaca said.2

References:

1. Bonaca MP, Catarig A, Houlind K. 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. Published online March 29, 2025. doi: 10.1016/S0140-6736(25)00509-4

2. American College of Cardiology. Semaglutide Significantly Improves Walking Distance, Symptoms and Quality of Life for People with PAD and Diabetes. American College of Cardiology. Published March 29, 2025. Accessed March 29, 2025. https://accmedia.org/wp-content/uploads/2025/02/Bonaca_STRIDE_LBCTI_Release.pdf.

3. Brooks A. FDA Approves Semaglutide (Ozempic) for Type 2 Diabetes, Chronic Kidney Disease. HCP Live. Published January 28, 2025. Accessed March 29, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-ozempic-type-2-diabetes-chronic-kidney-disease.