Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease

Importance: Lower extremity peripheral artery disease (PAD) is a disabling cardiovascular condition that impairs walking ability. Few effective therapies improve walking performance in people with PAD. Metformin is a widely available and inexpensive therapy for type 2 diabetes with pleiotropic effects that include activating AMP-activated protein kinase, reducing oxidative stress, and stimulating endothelial nitric oxide synthase (eNOS). Objective: To determine whether metformin improves 6-minute walk distance, compared with placebo, in people with PAD and without diabetes at 6-month follow-up. Design, Setting, and Participants: Randomized double-blind clinical trial involving 4 centers in the US. Enrollment began May 23, 2017, and ended on February 17, 2025, with 202 of the targeted 212 (95%) enrolled, due to funding limitations. Participants were adults aged 50 years and older with PAD. Final follow-up occurred August 19, 2025. Interventions: Participants with PAD were randomized to receive either metformin (n = 97) or placebo (n = 105) for 6 months. Main Outcomes and Measures: The primary outcome was 6-month change in 6-minute walk distance (minimum clinically important difference, 8 to 20 m). Secondary outcomes were maximal treadmill walking time, pain-free treadmill walking time, the Walking Impairment Questionnaire distance and speed scores, the Short-Form 36 physical functioning score, and brachial artery flow-mediated dilation. Results were adjusted for site and the baseline value for each outcome measure. Results: Of 202 randomized patients (mean [SD] age, 69.6 [8.4] years, 56 [28%] female, 79 [39%] Black), 179 (89%) completed 6-month follow-up. Metformin did not significantly improve 6-minute walk distance compared with placebo (metformin: 358.6 to 353.2 m, within-group change: -5.4 m; placebo: 359.8 to 354.5 m, within-group change: -5.3 m, adjusted between-group difference: 1.1 m [95% CI, -16.3 to 18.6 m]; P = .90). Compared with placebo, metformin did not significantly improve any secondary outcomes. The most common serious adverse events were cardiovascular events (3.1% for metformin and 1.9% for placebo). The most common nonserious adverse events were indigestion/stomach upset (64.9% for metformin and 40.6% for placebo) and headache (37.2% for metformin and 49.5% for placebo). Conclusions and Relevance: Among people with PAD without diabetes, metformin did not improve 6-minute walk distance at 6-month follow-up compared with placebo. These results do not support metformin for improving walking performance in patients with PAD. Trial Registration: ClinicalTrials.gov Identifier: NCT03054519.