Metformin and Walking Performance in Non-Diabetic Peripheral Artery Disease: A Randomized Clinical Trial

Article Impact Level: HIGH
Data Quality: STRONG
Summary of  JAMA. https://doi.org/10.1001/jama.2025.21358 
Dr. Mary M. McDermott  et al.

Points

This randomized double blind clinical trial evaluated whether metformin could improve the six minute walk distance for two hundred two adults diagnosed with peripheral artery disease but without type two diabetes.
Researchers assigned ninety seven participants to receive daily metformin and one hundred five to the placebo group to measure mobility changes during a six month follow up period in four centers.
Results showed a negligible one meter difference between the metformin and placebo groups which failed to meet the minimum clinically important difference of eight to twenty meters for walking performance improvement.
The study found no significant improvements in secondary outcomes including maximal treadmill walking time or pain free walking time despite the known pleiotropic effects of the medication on vascular health.
Findings from this major clinical trial do not support the use of metformin to enhance mobility in non diabetic patients with peripheral artery disease who suffer from significant walking impairments

Summary

This randomized, double-blind clinical trial evaluated the efficacy of metformin in improving walking performance among 202 adults aged 50 and older with lower extremity peripheral artery disease (PAD) and without diabetes. Metformin’s activation of AMP-activated protein kinase and stimulation of endothelial nitric oxide synthase suggested potential for improving vascular health and mobility in this population. The study, conducted across four U.S. centers from 2017 to 2025, sought to address the critical need for effective therapies to mitigate the functional impairment and ischemic pain that characterize PAD.

Participants were randomized to receive either metformin (n=97) or placebo (n=105) for a 6-month period. The primary outcome was the 6-month change in 6-minute walk distance, with a predefined minimum clinically important difference (MCID) of 8 to 20 m. Secondary measures included maximal and pain-free treadmill walking times, Walking Impairment Questionnaire (WIQ) scores, and brachial artery flow-mediated dilation. All analyses were adjusted for site and baseline values to ensure statistical rigor, with final follow-up occurring in August 2025.

The results indicated that metformin did not improve walking distance compared with placebo at the 6-month follow-up. The difference in the 6-minute walk distance change between the two cohorts was negligible, totaling approximately 1 m. Both groups experienced a slight decline in mobility, and metformin demonstrated no significant effect on any secondary functional or vascular outcomes. Consequently, these findings do not support the off-label use of metformin for enhancing walking performance in patients with PAD who do not have diabetes.

Link to the article: https://jamanetwork.com/journals/jama/article-abstract/2841244#google_vignette

References

McDermott, M. M., Domanchuk, K. J., Tian, L., Zhao, L., Zhang, D., Bazzano, L., Berceli, S., Criqui, M. H., Ferrucci, L., Guralnik, J. M., Leeuwenburgh, C., Ho, K. J., Ismaeel, A., Kibbe, M. R., Korcarz, C., Kosmac, K., Lloyd-Jones, D., Peterson, C. A., Stein, J. H., … Polonsky, T. S. (2025). Metformin to improve walking performance in lower extremity peripheral artery disease: The permet randomized clinical trial. JAMA. https://doi.org/10.1001/jama.2025.21358