Highlights
– The PERMET randomized, double-blind trial (n=202) tested whether metformin improves 6-minute walk distance in people with lower extremity PAD without diabetes; it found no benefit at 6 months.
– Primary outcome: adjusted between-group difference in 6-minute walk was 1.1 m (95% CI, -16.3 to 18.6 m; P = .90), far below the minimum clinically important difference (8–20 m).
– Secondary outcomes, including treadmill walking times, patient-reported walking scores, and brachial artery flow-mediated dilation, showed no significant differences. Gastrointestinal adverse events were more common with metformin.
Background and disease burden
Lower extremity peripheral artery disease (PAD) is a common, progressive atherosclerotic condition that reduces blood flow to the legs and is a major cause of exertional leg pain (claudication), functional limitation, and disability in older adults. PAD carries substantial morbidity and increased risk of cardiovascular events and mortality, and it negatively affects quality of life and mobility. Interventions that safely improve walking performance are therefore important outcomes for patients and clinicians; however, effective, widely accessible therapies beyond exercise training and select pharmacotherapies remain limited.
Rationale for testing metformin
Metformin is a broadly available, inexpensive antihyperglycemic agent with pleiotropic effects that extend beyond glycemic control. Mechanistic data suggest metformin activates AMP-activated protein kinase (AMPK), reduces oxidative stress, and can enhance endothelial nitric oxide synthase (eNOS) activity — pathways that could plausibly improve skeletal muscle perfusion, mitochondrial function, or endothelial function in PAD. Given these properties and observational signals that metformin may confer cardiovascular benefit, investigators designed the PERMET trial to evaluate whether metformin improves walking performance in people with PAD who do not have diabetes.
Study design
The PERMET trial was a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted at four U.S. centers. Eligibility included adults aged 50 years or older with objectively diagnosed lower extremity PAD and without diabetes. Enrollment took place from May 23, 2017, through February 17, 2025. Participants were randomized to receive metformin or matched placebo for 6 months. The target enrollment was 212 participants; due to funding constraints the trial randomized 202 participants (97 assigned to metformin and 105 to placebo). Final follow-up concluded on August 19, 2025.
Interventions and endpoints
Participants received metformin or placebo for 6 months. The primary endpoint was the 6-month change in 6-minute walk distance — a validated, patient-centered measure of walking endurance with a minimum clinically important difference (MCID) commonly described as approximately 8–20 meters depending on clinical context.
Key secondary endpoints included maximal treadmill walking time, pain-free treadmill walking time, patient-reported Walking Impairment Questionnaire (distance and speed scores), Short Form-36 (SF-36) physical functioning score, and brachial artery flow-mediated dilation (FMD) as a physiologic measure of endothelial function. Analyses adjusted for study site and baseline values of each outcome.
Key findings
Population: Among 202 randomized participants (mean [SD] age 69.6 [8.4] years; 28% female; 39% Black), 179 (89%) completed 6-month follow-up.
Primary outcome: There was no meaningful or statistically significant difference in 6-minute walk distance at 6 months between metformin and placebo groups. Mean 6-minute walk distances were:
- Metformin: from 358.6 to 353.2 m (within-group change -5.4 m)
- Placebo: from 359.8 to 354.5 m (within-group change -5.3 m)
The adjusted between-group difference was 1.1 m (95% CI, -16.3 to 18.6 m; P = .90), indicating no evidence that metformin improved walking endurance compared with placebo. The 95% confidence interval crossed zero and included values within the pre-specified MCID range; thus the trial could not demonstrate a clinically important benefit and cannot definitively exclude a modest benefit within the upper limit of the CI.
Secondary outcomes
Metformin did not significantly improve any secondary functional or physiologic outcomes compared with placebo. This included maximal treadmill walking time, pain-free treadmill walking time, Walking Impairment Questionnaire distance and speed scores, SF-36 physical functioning, and brachial artery flow-mediated dilation. Between-group differences for these endpoints were small and not statistically significant.
Adverse events and safety
The most common serious adverse events were cardiovascular events (3.1% in the metformin group vs 1.9% in placebo). Nonserious adverse events were more frequent with metformin; the most common were gastrointestinal complaints (indigestion/stomach upset: 64.9% metformin vs 40.6% placebo) and headache (37.2% metformin vs 49.5% placebo). The overall safety profile was consistent with known metformin-associated adverse effects, particularly gastrointestinal intolerance. No new safety signals were reported.
Interpretation and clinical implications
In adults with PAD without diabetes, 6 months of metformin did not improve 6-minute walking distance or secondary measures of walking performance and endothelial function compared with placebo. These findings do not support the routine use of metformin to enhance walking function in people with PAD who do not have diabetes.
From a clinical standpoint, the trial provides high-quality randomized evidence addressing an important translational question: whether a well-known metabolic drug with plausible vascular and mitochondrial mechanisms can be repurposed to improve functional capacity in PAD. PERMET’s neutral result argues against expecting meaningful symptomatic benefit from metformin in this population when used alone for 6 months.
Strengths of the study
- Randomized, double-blind, placebo-controlled design across multiple centers, enhancing internal validity.
- Use of a patient-centered, validated primary endpoint (6-minute walk distance) and a range of secondary outcomes spanning performance measures, patient-reported function, and physiologic endothelial assessment.
- Diverse participant population with nearly 40% Black participants, improving representativeness compared with many trials.
Limitations and considerations
- Sample size: enrollment was 202 of the planned 212 participants (95% of target) due to funding limits. The primary result’s 95% CI (-16.3 to 18.6 m) includes both potentially meaningful benefit and harm within the MCID range, so a modest benefit cannot be completely excluded.
- Duration and dosing: the intervention period was 6 months. It is possible that longer treatment, different dosing strategies, or alternative formulations might yield different results; this trial does not address longer-term effects.
- Population: the trial enrolled patients without diabetes. Metformin’s effects could differ in individuals with diabetes or with pronounced insulin resistance; the PERMET findings should not be extrapolated to those subgroups without direct evidence.
- Adherence and tolerability: gastrointestinal side effects were common and may have affected adherence or activity levels; however, the trial was blinded and adverse events were balanced in seriousness.
- Mechanistic endpoints: although brachial artery FMD was measured, the trial did not include more granular skeletal muscle perfusion or mitochondrial function assays that could clarify mechanism.
Expert commentary and context
Peripheral artery disease management prioritizes symptom relief and functional improvement; supervised exercise therapy and escalation to revascularization when indicated remain the mainstays for improving walking performance. Pharmacologic options that reliably improve walking distance are limited. The idea of repurposing metformin was attractive given mechanistic plausibility and safety profile in many populations, but PERMET demonstrates that this approach does not translate into improved walking distance in non-diabetic PAD patients over 6 months.
Researchers and clinicians should interpret these results in the context of ongoing efforts to identify therapies that target muscle metabolism, mitochondrial function, microvascular perfusion, and inflammation in PAD. Potential future directions include trials testing combination approaches (e.g., pharmacotherapy plus supervised exercise), testing candidate agents in prespecified metabolic subgroups (insulin resistant vs insulin sensitive), or evaluating longer-term outcomes. Mechanistic studies using skeletal muscle biopsy, near-infrared spectroscopy, or advanced perfusion imaging could help determine whether metformin produces subtle tissue-level changes not captured by global walking measures.
Conclusion
The PERMET randomized clinical trial found that metformin did not improve 6-minute walk distance or secondary functional and physiologic outcomes at 6 months in people with lower extremity PAD who do not have diabetes. Given these results and the observed gastrointestinal tolerability issues, routine off-label use of metformin to improve walking performance in non-diabetic PAD patients is not supported. Future research should focus on alternative pharmacologic targets, combination strategies with exercise therapy, and mechanism-focused investigations to address persistent mobility limitations in PAD.
Funding and trial registration
The trial’s funding details are reported in the primary publication. Trial registration: ClinicalTrials.gov Identifier: NCT03054519.
References
1. McDermott MM, Domanchuk KJ, Tian L, et al. Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease: The PERMET Randomized Clinical Trial. JAMA. 2025 Nov 8. doi:10.1001/jama.2025.21358. PMID: 41205146.
2. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577-1585. doi:10.1007/s00125-017-4342-z.
3. Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2010 and 2015. Lancet Glob Health. 2013;382:1329–1340. (Epidemiology and global burden references for PAD).
Note
This article summarizes and interprets the PERMET trial findings for clinicians and policy-makers. Clinicians should refer to the full trial report and current clinical guidelines when considering management strategies for patients with PAD.
Thumbnail AI image prompt
A clinical scene in a bright outpatient vascular clinic: an older adult (65–80 years) walking along a corridor while a clinician times with a stopwatch; in the foreground, a semi-transparent overlay of a metformin pill bottle and a chart showing walking distance results; neutral, medical color palette, realistic style, high detail.
