Metformin did not improve walking performance in adults with peripheral artery disease without diabetes, according to results from the PERMET trial.
The multicenter, double-blind randomized clinical trial enrolled 202 participants across 4 US sites between May 2017 and February 2025. At 6-month follow-up, there was no statistically significant difference in 6-minute walk distance between groups. Participants in the metformin group declined from 359 m to 353 m (−5 m), while the placebo group declined from 360 m to 355 m (−5 m), for an adjusted between-group difference of 1 m.
"Among people with PAD [peripheral artery disease] without diabetes, metformin did not improve 6-minute walk distance at 6-month follow-up compared with placebo," wrote lead study author Mary M. McDermott, MD, of Northwestern University Feinberg School of Medicine, and colleagues. "These results do not support metformin for improving walking performance in patients with PAD."
The trial included adults aged 50 years and older with an ankle-brachial index of 0.90 or less. The mean age was 70 years, 28% were female, and 39% were Black. Participants were randomized to metformin (n = 97) or placebo (n = 105) for 6 months, with adherence of 85% and 88%, respectively, based on pill counts. The mean metformin group dose was 1,322 mg while the mean placebo dose was 1,568 mg.
None of the secondary outcomes differed significantly between groups. Participants receiving metformin walked an average of 0.77 minutes less on the treadmill than those on placebo, while pain-free walking time was 0.66 minutes longer—neither reaching statistical significance.
Patient-reported outcomes also showed minimal differences. The Walking Impairment Questionnaire distance and speed scores were 4 and 5 points higher, respectively, in the metformin group, and the Short-Form 36 Physical Functioning score was only 1 point higher. Brachial artery flow-mediated dilation showed no change, with identical absolute values and less than 0.1% difference in percent change between groups.
The results contradicted earlier preclinical and small human studies suggesting benefit. In a nonrandomized clinical trial of 11 men with symptomatic PAD without diabetes, metformin improved lower extremity perfusion and increased mean maximal treadmill walking time from 3 minutes to 6 minutes. In a separate trial of 15 patients, a daily dose of 2,550 mg of metformin improved lower extremity blood flow 17% at 3 months and 40% at 6 months.
Serious adverse events occurred in 11% (n=25) in the metformin group and 13% (n=14) in the placebo group, most commonly cardiovascular events (3% metformin; 2% placebo). The most common nonserious adverse events were indigestion/stomach upset (65% metformin; 41% placebo) and headache (37% metformin; 50% placebo). Sixteen of 81 participants (20%) randomized to metformin discontinued study medication due to gastrointestinal adverse effects, compared with 9 of 94 (10%) randomized to placebo.
Of the 202 randomized participants, 179 (89%) completed the 6-month follow-up. The final follow-up occurred on August 19, 2025. Enrollment ended after 202 participants, or 95% of the targeted 212, were recruited due to funding limitations. The study was designed to provide 80% power to detect a minimum difference of 28 m in the 6-minute walk test between treatment groups.
The study was funded by the National Heart, Lung, and Blood Institute (R01-HL13110) and supported by the National Institute on Aging (intramural division).
Dr McDermott reported grants from the National Heart, Lung, and Blood Institute, National Institute on Aging, and the American Heart Association during the conduct of the study; intervention and placebo for a clinical trial from Mar, ACI Medical, ChromaDex, and ReserveAge; personal fees from Eli Lilly; and grants from Helixmith outside the submitted work.
Source: JAMA
