# Improve PAD PERformance with METformin. The PERMET Trial

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $711,015

## Abstract

PROJECT SUMMARY
 Improve PAD PERformance with METformin: The PERMET Trial.
 Our work and that of others has established that people with lower extremity peripheral artery disease
(PAD) have greater functional impairment, faster functional decline, and increased rates of mobility loss
compared to people without PAD. However, few therapies are available that improve functioning or prevent
functional decline in people with PAD.
 Metformin is an inexpensive, widely available, well tolerated biguanide medication and the most
commonly prescribed drug for Type 2 diabetes mellitus worldwide. Recent pre-clinical and preliminary human
evidence suggest that metformin has previously unrecognized therapeutic properties. Therapeutic properties
of metformin in pre-clinical models that may benefit people with PAD include: calf skeletal muscle increases in
peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) (a major regulator of
mitochondrial biogenesis), calf skeletal muscle increases in mitochondrial protein expression and activity,
increases in capillary density in ischemic tissue, reductions in oxidative stress, increased autophagy (repair of
cellular damage), and improved endothelial function. These therapeutic properties target pathophysiologic
conditions present in PAD. Therefore, we hypothesize that metformin will improve lower extremity functioning
in people with PAD, by facilitating favorable changes in calf skeletal muscle and by increasing calf skeletal
muscle perfusion. No randomized clinical trials have studied whether metformin improves lower
extremity functioning in PAD. A definitive trial is needed.
 We propose a placebo controlled double-blind randomized clinical trial to establish whether metformin
(2,000 mgs daily) improves and/or prevents decline in walking performance in people with PAD. Participants
will be 212 people with PAD who do not have diabetes mellitus, since metformin is a first-line therapy for Type
2 diabetes. Our primary outcome is change in six-minute walk at 6-month follow-up. Secondary outcomes are
6-month changes in treadmill walking performance, brachial artery flow-mediated dilation, calf skeletal muscle
biopsy measures, patient-reported walking performance, and quality of life. Calf muscle outcomes consist of
changes in PGC-1α abundance, mitochondrial quantity, mitochondrial enzyme activity, capillary density,
reactive oxygen species (ROS)-induced tissue damage, and autophagy.
 If metformin improves functional performance and prevents functional decline in PAD, this widely
available, inexpensive, and well tolerated medication will have a major impact on preventing mobility loss and
improving quality of life in the large and growing number of people with PAD.

## Key facts

- **NIH application ID:** 9836865
- **Project number:** 5R01HL131771-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mary McGrae McDermott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $711,015
- **Award type:** 5
- **Project period:** 2016-12-09 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836865

## Citation

> US National Institutes of Health, RePORTER application 9836865, Improve PAD PERformance with METformin. The PERMET Trial (5R01HL131771-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9836865. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*