Semaglutide makes STRIDEs in peripheral artery disease

Patients with symptomatic peripheral artery disease (PAD) and type 2 diabetes (T2D) see notable improvements in their walking capacity and quality of life with once-weekly semaglutide injections in the phase 3b STRIDE study.

Over 52 weeks of treatment, the primary endpoint of median ratio to baseline in maximum walking distance was 13-percent greater with semaglutide than with placebo (estimated treatment ratio, 1.13, 95 percent confidence interval [CI], 1.06–1.21; p=0.0004). In absolute terms, semaglutide-treated patients walked a mean of 39.9-m (95 percent CI, 13.9–66.0) or a median of 26.4-m (95 percent CI, 11.8–40.9) more on a constant-load treadmill test compared with placebo-treated patients. [Lancet 2025;doi:10.1016/S0140-6736(25)00449-0]

Results for secondary and exploratory outcomes also favoured semaglutide. Compared with placebo-treated patients, those who received semaglutide had a significantly greater improvement in maximal walking distance at week 57 (estimated treatment ratio, 1.08; p=0.0380) and pain-free walking distance at week 52 (estimated treatment ratio, 1.11; p=0.0046).

The semaglutide group also had more favourable scores on the patient-reported peripheral artery disease-specific Vascular Quality of Life Questionnaire-6 (p=0.011) and the physical functioning domain of the Short Form Health Survey (p=0.013) than the placebo group at week 52.

Similarly, semaglutide was associated with significantly greater ankle brachial index improvement (estimated treatment ratio, 1.05; p=0.0037) and weight loss (estimated treatment difference, –4.1 kg; p<0.0001) compared with placebo at week 52.

Not an effect of weight loss

The positive effect of semaglutide on walking capacity was consistent across all major subgroups, including those with lower and high BMI (<28.6 and ≥28.6 kg/m²), reported first study author Dr Marc Bonaca from the University of Colorado School of Medicine in Aurora, Colorado, US.

Bonaca pointed out that the STRIDE population was not particularly obese, with more than a third of patients having a BMI of less than 27 kg/m². This suggests that the improvement in walking capacity was not a weight-loss effect, as evidenced by a very weak correlation between weight loss and maximal walking distance, he added. Although present, the correlation was “not sufficient to explain the magnitude of effect.”

“Coupled with only modest observed weight loss of 4.1 kg with semaglutide vs placebo and improvements in pain-free walking distance and ankle–brachial index, these data suggest a direct vascular benefit of semaglutide rather than benefits mediated solely by weight loss,” consistent with the exploratory data from SELECT, Bonaca said. [N Engl J Med 2023;389:2221-2232]

Tamping down inflammation

Overall, STRIDE provides important evidence on patients with symptomatic PAD, for which there are very few, if any, effective therapies, according to Bonaca. The findings demonstrate that semaglutide improves function, symptoms, quality of life, and haemodynamics, representing a significant advancement for clinicians in this field, he added.

The observed benefits may be attributed to the ability of GLP-1 RAs to suppress inflammation within the peripheral vasculature, according to Bonaca. This rationale is grounded in the known role of inflammation in claudication and the resulting ischaemia. [Circulation 2010;122:1862-1875]

Bonaca emphasized that this anti-inflammatory action of semaglutide differentiates the GLP1-RA drug from therapies such as cilostazol and other cardiometabolic drugs with cardiovascular benefit but without beneficial effects on symptoms in peripheral artery disease. [JAMA 2022;328:1302-1303; Circulation 1998;98:678-686]

“Semaglutide is the first drug we’ve ever had that makes people live longer and feel better and function better in PAD, and these are drugs that we can use tomorrow in our clinics on the basis of their approval for diabetes and other indications,” he said.

Clinically meaningful

In an accompanying commentary, Dr Joshua Beckman from the University of Texas Southwestern Medical Center in Dallas, Texas, and Dr Mark Creager from the Geisel School of Medicine at Dartmouth in Lebanon, New Hampshire, echoed Bonaca, saying that the STRIDE findings are a positive contribution to the ongoing effort to address the therapeutic needs of patients with PAD. [Lancet 2025;doi:10.1016/S0140-6736(25)00574-4]

Beckman and Creager emphasized that the effect of semaglutide on walking performance is clinically meaningful, especially within the context of the functional limitation in the STRIDE population. They drew attention to the fact that claudication in PAD results in a similar degree of functional limitation to that experienced by patients with New York Heart Association class III heart failure. [J Vasc Surg 2009;50:1391-1398]

Furthermore, the improvement in maximum walking distance observed in STRIDE was more than double than the mean gain of 14 m in 6-min walking distance reported among T2D patients with obesity-related heart failure with preserved ejection fraction in STEP HFpEF DM—a result already considered clinically relevant—despite STRIDE using a lower semaglutide dose, Beckman and Creager said. [N Engl J Med 2024;390:1394-1407]

“Moving forward, it will be important to establish whether semaglutide improves walking capacity in patients with peripheral artery disease but without diabetes, and also to evaluate its longer-term effects on major adverse limb events, such as progression to chronic limb threatening ischaemia and the need for revascularisation or amputation,” they added.

STRIDE population

A total of 792 patients (mean age 67 years, 25 percent women, 65 percent White) from 20 countries across North America, Asia, and Europe participated in the trial. These patients had intermittent claudication (Fontaine stage IIa, able to walk ≥200 m without pain on a flat treadmill). The median maximum walking distance and pain-free walking distance on a constant-load treadmill was 185.5 and 114.5 m, respectively, at baseline, which Bonaca noted to be significantly lower than a normal distance of more than 600–800 m.

Most patients had been living with diabetes for at least 10 years (61 percent). At baseline, the median BMI was 28.7 kg/m², the mean ankle-brachial index was 0.75, and the mean toe-brachial index was 0.48. Bonaca described the population as well-treated, with most patients using statins as background therapy.

Roughly a quarter (24 percent) of patients had a history of lower limb revascularization, 65 percent had moderate or severe limitations in walking, and 63 percent rated the effect of PAD on their health-related quality of life as moderate or severe.

The patients were randomly assigned to receive subcutaneous semaglutide injections at 1.0 mg once per week (n=396) or placebo (n=396) for 52 weeks.

Safety data showed six serious adverse events occurring in five (1 percent) patients in the semaglutide group and nine serious adverse events (AEs) in six (2 percent) patients in the placebo group. These AEs were deemed possibly or probably related to treatment, with the most frequent being serious gastrointestinal events. Serious AEs leading to permanent treatment discontinuation were documented in 11 (3 percent) patients in the semaglutide group and in 13 (3 percent) in the placebo group. Three and eight patients in the respective groups died due to serious AEs, none of which was treatment-related.