Semaglutide, compared to placebo, significantly improved walking distance, symptoms and quality of life in participants with symptomatic peripheral artery disease (PAD) and type 2 diabetes (T2D), according to results of the STRIDE study presented at ACC.25 in Chicago and simultaneously published in The Lancet. Additionally, an oral formulation of semaglutide lowered the risk major adverse cardiovascular events by 14% in four years, with no change in safety profile compared to placebo, according to the SOUL study simultaneously published in the NEJM. Both studies were presented during Late-Breaking Clinical Trial sessions.

The double-blind STRIDE trial, conducted at 112 outpatient clinics in North America, Asia and Europe from October 2020 to July 2024, randomized 792 participants (median age 68 years, 25% women, 68% White) with T2D and PAD with intermittent claudication (Fontaine stage IIa) as well as an ankle-brachial index of ≤0.90 (mean 0.75) or toe-brachial index ≤0.70 (mean 0.48) to either once-weekly doses of subcutaneous semaglutide (n=396) or placebo (n=396) for 52 weeks. Among participants, 59% had a BMI <30 kg/m2, lower than many studies with semaglutide.

Testing was conducted on a constant-load treadmill with fixed speed (3.2 km/hr) and fixed inclination (12%) at baseline, 26, 52 and 57 weeks.

Results showed that patients taking semaglutide had a median improvement of 26 meters and an average improvement of 40 meters, representing a statistically significant 13% improvement at one year (estimated treatment ratio, 1.13; 95% CI, 1.06-1.21; p=0.0004).

The improvement in maximum walking difference after five weeks cessation, quality of life as measured by VascuQoL-6 and improvement in pain-free walking distance were all significantly greater in the semaglutide group.

Treatment-related adverse events occurred in 1% of the semaglutide group and 2% of the placebo group. No treatment-related deaths occurred, and the most frequent adverse events were gastrointestinal.

"Taken together, the data support semaglutide for people with PAD and [T2D] as a therapy that has cardiometabolic, cardiovascular and kidney benefits and improves function, symptoms and quality of life," said Marc P. Bonaca, MD, FACC, the study's lead author. "There is more work to be done to understand the mechanism of benefit as the population had a median BMI of 28.6 [kg/m2] 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 [T2D] could benefit and that should be investigated in future studies."

The first study of the cardiovascular benefits of an oral formulation of a GLP-1 agonist, the international multicenter SOUL study randomized 9,650 patients with T2D, a glycated hemoglobin level of 6.5-10%, atherosclerotic cardiovascular disease and/or chronic kidney disease to either once-daily oral semaglutide at a maximum dose of 14 mg or placebo in addition to standard care. In both arms, about 27% of participants were receiving SGLT2 inhibitors at baseline. The mean age of the patients was 66 years, about 29% were women and about 69% White.

Results showed that the composite primary endpoint of cardiovascular death, nonfatal myocardial infarction (MI) or stroke occurred in 12% of the semaglutide group and 13.8% of the placebo group over the mean 47.5 months of follow-up, translating to 3.1 and 3.7 events per 100 person-years, respectively, and a 14% relative risk reduction p=0.006).

Looking at the individual endpoints, nonfatal MI had the largest reduction at 26%, nonfatal stroke was reduced by 12% and cardiovascular death by 7% with semaglutide vs. placebo. No significant difference between the two arms was observed in outcomes related to kidney function.

Although the trial was not powered to compare treatment effect across subgroups, investigators noted there seemed to be a larger effect for the primary outcome among patients with glycated hemoglobin levels >8% and those in the Asia region.

Serious adverse events were reported in 47.9% of the semaglutide group and 50.3% in the placebo group (p=0.02). Gastrointestinal disorders were more common in the oral semaglutide group (5.0% vs. 4.4% in the placebo group), which investigators believe led to a higher rate of discontinuation of treatment in the semaglutide group.

By the end of the study, around half of participants were on SGLT2 inhibitors. "There's been a huge [open] question among clinicians about whether these drugs are complementary and whether we should use one or the other or both," said the study's first author, Darren K. McGuire, MD, FACC. "The results showed no significant difference in outcomes between patients who took SGLT-2 inhibitors, who were likely to have more advanced disease, and those who did not, suggesting that the drugs can be safely used together and are complementary in their ability to reduce cardiovascular risk."

"This study gives us confidence that people who are resistant or reluctant to take injections can still have an option for clinical benefit with [semaglutide] in the form of a tablet," McGuire added. Whether taken as a tablet or injection, "these drugs very rapidly reduce systemic inflammation."

Citations:

• 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. Lancet. Published online March 29, 2025. Doi: 10.1016/S0140-6736(25)00509-4
• McGuire DK, Marx N, Mulvagh S, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. NEJM. Published online March 29, 2025. Doi: 10.1056/NEJMoa2501006