{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T00:12:06Z","timestamp":1793059926010,"version":"4.5.0"},"reference-count":39,"publisher":"American Medical Association (AMA)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2026,2,3]]},"abstract":"\n Importance<\/jats:title>\n 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).<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To determine whether metformin improves 6-minute walk distance, compared with placebo, in people with PAD and without diabetes at 6-month follow-up.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Participants with PAD were randomized to receive either metformin (n\u2009=\u200997) or placebo (n\u2009=\u2009105) for 6 months.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 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: \u22125.4 m; placebo: 359.8 to 354.5 m, within-group change: \u22125.3 m, adjusted between-group difference: 1.1 m [95% CI, \u221216.3 to 18.6 m];\n P<\/jats:italic>\n \u2009=\u2009.90). 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).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT03054519<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2025.21358","type":"journal-article","created":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T16:30:19Z","timestamp":1762619419000},"page":"407","source":"Crossref","is-referenced-by-count":7,"title":["Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease"],"prefix":"10.1001","volume":"335","author":[{"given":"Mary M.","family":"McDermott","sequence":"first","affiliation":[{"name":"Department of Medicine and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn J.","family":"Domanchuk","sequence":"additional","affiliation":[{"name":"Department of Medicine, Northwestern 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