Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease
Mary Mcdermott, Kathryn Domanchuk, Lü Tian, Lihui Zhao, Dongxue Zhang, Lydia Bazzano, Scott A. Berceli, Michael H Criqui, Luigi Ferrucci, J. Guralnik, Christiaan Leeuwenburgh, Karen J. Ho, Ahmed Ismaeel, Melina R. Kibbe, Claudia E. Korcarz, Kate Kosmac, Donald M. Lloyd‐Jones, Charlotte A. Peterson, James H. Stein, Robert Sufit, John T. Wilkins, Tamar S. Polonsky
Abstract
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.