PMID-40169145 — STRIDE: Semaglutide and Walking Capacity in PAD + T2D

[DRAFT — authored 2026-04-18. Requires Medical Director review.]

Citation

Bonaca MP, Catarig AM, Houlind K, Ludvik B, Nordanstig J, Ramesh CK, Rasmussen S, Sourij H, Verma S, Badariotti G, Bengtsson O, Rasmussen SLS, Tandon N, Nanna MG, on behalf of the STRIDE Trial Investigators. 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. 2025;405(10489):1580-1593. doi: 10.1016/S0140-6736(25)00509-4. PMID: 40169145.

Study Design

Phase: 3b
Design: Multicenter, double-blind, randomized, placebo-controlled
Randomization: 1:1 to semaglutide 1.0 mg weekly SC or matching placebo
Duration: Treatment to 12 months; functional outcome at multiple timepoints
N: 792 participants
Setting: 112 outpatient clinics in North America, Asia, Europe
Period: October 2020 – July 2024

Population

Adults with type 2 diabetes and peripheral artery disease with intermittent claudication (Fontaine stage IIa)
Median age 68 years; 25% women; 68% White
Background standard medical management of PAD and T2D

Intervention

Semaglutide: 0.25 mg → 1.0 mg weekly SC (standard Ozempic titration)
Control: Matching placebo

Outcomes

Primary — Walking capacity improvement

Significantly improved maximum and pain-free walking distance in semaglutide arm vs. placebo
Improvement in WIQ (Walking Impairment Questionnaire) subscales
Quality-of-life (SF-36 physical function, EQ-5D) improvements

Secondary

HbA1c and body weight improvements consistent with class effect
Cardiovascular adverse events not differentially reported between arms
GI adverse events typical of class (nausea, diarrhea)

Key Findings

STRIDE is the first Phase 3 randomized trial to demonstrate functional benefit (walking capacity and quality-of-life) from a GLP-1 receptor agonist in a PAD-specific population with T2D. It establishes a new evidence-based indication for semaglutide beyond MACE reduction, kidney outcomes, and weight loss.

Clinical significance:

PAD with intermittent claudication is common in T2D; pharmacologic options for functional improvement have been limited
Semaglutide now has Phase 3 evidence supporting use for walking-capacity and health-related quality-of-life outcomes in this population
Mechanistically: benefit is likely multi-factorial — glycemic improvement, anti-inflammatory effect, weight loss, possibly direct vascular effects

Regulatory status: As of April 2026, the FDA has not updated semaglutide labels to add a PAD indication, but label expansion based on this trial is anticipated.

Limitations (Author-acknowledged)

Functional endpoint (walking distance) is not a hard cardiovascular outcome (MACE)
Single-dose (1 mg) studied — dose-response not characterized for PAD endpoint
Population restricted to Fontaine stage IIa (intermittent claudication); no data in more advanced PAD (critical limb ischemia)
12-month follow-up — longer-term durability of functional benefit not captured

Evidence Level

Level Ib (Oxford CEBM) — adequately-powered Phase 3 RCT with pre-specified primary functional endpoint.

PMID-40169145 – STRIDE Semaglutide PAD