Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov 8:e2521358.
doi: 10.1001/jama.2025.21358. Online ahead of print.

Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease: The PERMET Randomized Clinical Trial

Mary M McDermott  1 , Kathryn J Domanchuk  2 , Lu Tian  3 , Lihui Zhao  4 , Dongxue Zhang  2 , Lydia Bazzano  5 , Scott Berceli  6 , Michael H Criqui  7 , Luigi Ferrucci  8 , Jack M Guralnik  9 , Christiaan Leeuwenburgh  10 , Karen J Ho  11 , Ahmed Ismaeel  12 , Melina R Kibbe  13 , Claudia Korcarz  14 , Kate Kosmac  15 , Donald Lloyd-Jones  16 , Charlotte A Peterson  17 , James H Stein  14 , Robert Sufit  18 , John Wilkins  19 , Tamar S Polonsky  20
Affiliations

Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease: The PERMET Randomized Clinical Trial

Mary M McDermott et al. JAMA. .

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr McDermott reported grants from the National Heart, Lung, and Blood Institute, National Institute on Aging, and the American Heart Association (AHA) 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. Dr Korcarz reported grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Stein reported grants from the NIH during the conduct of the study. No other disclosures were reported.

References

    1. Polonsky TS, McDermott MM. Lower extremity peripheral artery disease without chronic limb threatening ischemia. JAMA. 2021;325(21):2188-2198. doi: 10.1001/jama.2021.2126 - DOI - PubMed
    1. Gornik HL, Aronow HD, Goodney PP, et al. ; Peer Review Committee Members . 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(24):e1313-e1410. doi: 10.1161/CIR.0000000000001251 - DOI - PubMed
    1. McDermott MM, Ferrucci L, Gonzalez-Freire M, et al. Skeletal muscle pathology in peripheral artery disease: A brief review. Arterioscler Thromb Vasc Biol. 2020;40(11):2577-2585. doi: 10.1161/ATVBAHA.120.313831 - DOI - PMC - PubMed
    1. Hamburg NM, Creager MA. Pathophysiology of intermittent claudication in peripheral artery disease. Circ J. 2017;81(3):281-289. doi: 10.1253/circj.CJ-16-1286 - DOI - PubMed
    1. White SH, McDermott MM, Sufit RL, et al. Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study. J Transl Med. 2016;14(1):284. doi: 10.1186/s12967-016-1030-6 - DOI - PMC - PubMed

Associated data