Key results and new insights from the Stride trials, as well as the evolutionary role of GLP-1 receptor agonist (RA) therapy in type 2 diabetes (T2D) and peripheral arterial disease (PAD) were discussed in a science session in Chicago during the symposium of the American Diabetes Association (ADA) symposium.
Common comorbidities
The T2D and the pads are not strangers to each other. Patients with T2D are twice as likely to develop PAD compared to the general population. PAD has been shown to be the most common early symptoms of cardiovascular disease of T2D. Furthermore, patients with complications of diabetes are more afraid of amputation and infection than death.
However, PAD is not recognized by T2D. Only about 20% of patients presenting with classic symptoms of intermittent cloudization (IC). PAD can also have insidious onset. Patients experience functional decline and slow leg discomfort. This is often not recognized as PAD by medical professionals or patients.
T2D and PAD have an increased incidence and share many risk factors, including obesity. A recent systematic literature review examining the epidemiology of T2D and the burden of PAD found that 12.5%-22% of T2D patients had a comorbidity pad. Furthermore, patients with T2D and PAD are at a very high risk of major lower extremity complications and major adverse cardiovascular events, including all-cause and cardiovascular mortality. Naturally, PAD was associated with reduced quality of life and significant medical use and costs.
In particular, the ADA 2025 medical criteria for diabetes recommends screening for PAD using an ankle arm index (ABI) tests in patients with diabetic patients age 65 and older, microvascular disease, or PAD diagnosis alters management. Pad screening should also be considered in patients with diabetes for more than 10 years and at high cardiovascular risk.
PAD in T2D is often experienced with surgical interventions because it tends to affect the distal vasculature (i.e., symptomatic vessels). These lesions are less compatible with traditional revascularization procedures such as anterior femoral lobe bypass and stent placement. Unfortunately, this situation often leaves patients with symptoms and almost surgical options that debilitate T2D and PAD.
Many international medical guidelines have class I recommendations for examining SGLT2 inhibitors and GLP-1 RAS in patients with T2D and atherosclerotic cardiovascular disease, although not specifically PAD. The only class recommended for PAD is cilostazole, which is intended to improve symptoms of claudysis. Cilostazol is a phosphodiesterase 3 inhibitor that promotes vasodilation and increases blood flow, and may improve IC symptoms (but not cardiovascular outcome). A recent review of Cochrane found that cilostazol provides a 40 m improvement in absolute cloudization distance. From my clinical experience, cilostazole is often inadmissible (headaches and diarrhea are common). It is contraindicated in heart failure, and this occurs frequently with pads.
Stride Results
The Randomized Controlled Stride Trial was published in the Lancet in May 2025 to investigate the effects of subcutaneous semaglutide (1 mg per week) and standard care. Essentially, Stride laid the foundation for a paradigm shift in the way GLP-1 RAS is used for symptomatic pads.
The study recruited 792 patients with T2D and Fontaine stage IIA pads. Fontaine Stage IIA is an early stage symptomatic pad, where patients experience IC symptoms after walking more than 200 m. The average ABI was below 0.9 for all participants. The normal ABI is usually 0.90-1.30, indicating normal blood flow to the lower limbs. A quarter of participants were female, with a median age of 68 years. Obesity was not a standard for research enrollment. 35% of participants had a BMI <27. The main findings of the study were the maximum walking distance after 52 weeks compared to baseline.
Stride achieved its main results. Subcutaneous semaglutide was associated with a significant increase in maximum walking distance (an improvement of 40 m at a 12% slope, which corresponds to an improvement of 80 m on flat surfaces). This improvement was related to cilostazole and, importantly, confirmed clinical significance. The researchers also observed significant improvements in symptoms and quality of life, as evidenced by improvements in the Vascuqol questionnaire. In particular, the reported improvement in ABI and disease progression confirm the vascular benefits of semaglutide. Encouraged, the clinical benefits continued five weeks after halting semaglutide therapy. The treatment safety profile was consistent with previous semaglutide trials, with no unexpected safety findings manifested.
New data presented and published simultaneously in diabetes care confirmed that the effect of semaglutide on maximum walking distance was consistent regardless of T2D characteristics. The advantages were independent of baseline diabetes duration, BMI, HBA1C, or simultaneous use of sodium/glucose cotransporter 2 inhibitors or insulin. Functional benefits do not appear to correlate with weight loss or improvement in blood glucose, highlighting the vascular benefits of semaglutide in reducing atherosclerosis, possibly through anti-inflammatory effects.
In conclusion, Stride increases the suite of recognized cardiometabolic and renal benefits of semaglutide by adding walking ability, quality of life, and disease progression in patients with T2D and PAD. In my year as a junior doctor, my vascular consultant was constantly reminded me of the core management of the pad with five words: “Stop smoking and keep walking.” While this is the cornerstone of management 25 years from now, Semaglutide is now well positioned as a basic therapy to improve the quality and quantity of life in patients with T2D and PAD.
Fernando is a general practitioner near Edinburgh, Scotland, and has a professional interest in diabetes. Cardiovascular disease, kidney disease, metabolic disease; and medical education.
