The study was conducted across 4 U.S. medical centers, aimed to test whether metformin could enhance exercise capacity in non-diabetic PAD patients. This research cited the biological actions of metformin like activating AMP-activated protein kinase (AMPK), reducing oxidative stress, and stimulating endothelial nitric oxide synthase (eNOS) as mechanisms that might potentially improve blood vessel function and walking endurance.
From May 2017 to February 2025, a total of 202 participants aged 50 years and older were enrolled which represented 95% of the planned study population. The participants were randomly assigned to receive either metformin (n=97) or a placebo (n=105) for 6 months. Follow-up assessments were completed by 179 participants (89%) by August 2025.
The primary outcome measure was the change in 6-minute walk distance, which is a widely accepted test to evaluate functional walking ability in PAD patients. A clinically meaningful improvement would typically range between 8 to 20 meters.
However, results showed no significant difference between the two groups. The participants in the metformin group saw their average distance drop slightly from 358.6 meters to 353.2 meters, a decline of 5.4 meters. Those in the placebo group similarly declined from 359.8 meters to 354.5 meters, a 5.3-meter decrease.
The adjusted difference between the 2 groups was only 1.1 meters (95% confidence interval, −16.3 to 18.6 meters; P = .90), which indicated no statistically meaningful benefit from metformin. Secondary measures (treadmill walking times, Walking Impairment Questionnaire scores (for distance and speed), Short-Form 36 physical functioning score, and brachial artery flow-mediated dilation) showed no improvement with metformin use when compared to placebo.
In terms of safety, serious adverse events were uncommon and comparable between groups: 3.1% in the metformin arm versus 1.9% in the placebo arm, mostly due to cardiovascular incidents. The most frequent non-serious side effects included indigestion or stomach upset (65% for metformin vs. 41% for placebo) and headaches (37% vs. 50%). Overall, the findings clearly demonstrate that metformin does not enhance walking performance or vascular function in PAD patients without diabetes.
Source:
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: The PERMET randomized clinical trial. JAMA: The Journal of the American Medical Association. https://doi.org/10.1001/jama.2025.21358
Disclaimer: This website is primarily for healthcare professionals. The content here does not replace medical advice and should not be used as medical, diagnostic, endorsement, treatment, or prescription advice. Medical science evolves rapidly, and we strive to keep our information current. If you find any discrepancies, please contact us at corrections@medicaldialogues.in. Read our Correction Policy here. Nothing here should be used as a substitute for medical advice, diagnosis, or treatment. We do not endorse any healthcare advice that contradicts a physician's guidance. Use of this site is subject to our Terms of Use, Privacy Policy, and Advertisement Policy. For more details, read our Full Disclaimer here.
NOTE: Join us in combating medical misinformation. If you encounter a questionable health, medical, or medical education claim, email us at factcheck@medicaldialogues.in for evaluation.