Introduction: The Quest for Functional Improvement in PAD
Lower extremity peripheral artery disease (PAD) remains a significant global health burden, characterized by atherosclerotic narrowing of the arteries supplying the legs. Beyond the risk of major adverse cardiovascular and limb events, the hallmark of PAD is functional impairment. Patients frequently experience claudication or asymptomatic walking limitations that lead to a sedentary lifestyle, muscle atrophy, and a precipitous decline in quality of life. Despite the prevalence of the condition, pharmacological options to improve walking performance are remarkably limited. Currently, only cilostazol is FDA-approved for symptomatic improvement, yet its use is often curtailed by side effects such as headache and palpitations, and its efficacy is modest at best.
Against this backdrop, researchers have looked toward repurposed therapies. Metformin, a cornerstone in the management of type 2 diabetes, emerged as a promising candidate. Beyond its glucose-lowering effects, metformin exhibits pleiotropic properties that are theoretically beneficial in the context of PAD. These include the activation of AMP-activated protein kinase (AMPK), reduction of oxidative stress, and the potential stimulation of endothelial nitric oxide synthase (eNOS). The PERMET (Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease) randomized clinical trial was designed to rigorously test whether these mechanistic potentials could translate into tangible clinical benefits for patients with PAD who do not have diabetes.
Highlights of the PERMET Trial
No Significant Functional Benefit
Metformin did not significantly improve the 6-minute walk distance compared with placebo over a 6-month period. The adjusted between-group difference was a negligible 1.1 meters, well below the minimum clinically important difference of 8 to 20 meters.
Consistent Lack of Secondary Efficacy
Secondary outcomes, including maximal treadmill walking time and brachial artery flow-mediated dilation, showed no significant improvement with metformin therapy.
Gastrointestinal Tolerability Issues
While serious adverse events were balanced between groups, nonserious gastrointestinal events, specifically indigestion and stomach upset, were significantly more common in the metformin group (64.9%) compared to the placebo group (40.6%).
Study Design and Methodology
The PERMET trial was a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted across four centers in the United States. The study targeted adults aged 50 years and older with a confirmed diagnosis of PAD, defined by an ankle-brachial index (ABI) of 0.90 or less or other objective evidence of arterial disease. Importantly, the trial excluded patients with diabetes to isolate the potential vascular and muscular effects of metformin from its glycemic control properties.
Participants were randomized in a 1:1 ratio to receive either metformin (titrated up to 2000 mg daily) or a matching placebo for six months. The primary endpoint was the change in the 6-minute walk distance from baseline to the 6-month follow-up. This metric is widely regarded as a robust and clinically relevant measure of functional capacity in PAD populations. Secondary endpoints included treadmill-based assessments (maximal and pain-free walking time), patient-reported outcomes via the Walking Impairment Questionnaire (WIQ) and the Short-Form 36 (SF-36) physical functioning score, and physiological measures such as brachial artery flow-mediated dilation to assess endothelial function.
Detailed Results and Data Analysis
A total of 202 participants were enrolled (mean age 69.6 years; 28% female; 39% Black). Of these, 179 completed the 6-month follow-up. The analysis was conducted on an intention-to-treat basis, adjusted for site and baseline values.
Primary Outcome: 6-Minute Walk Distance
The results for the primary outcome were definitive. In the metformin group, the mean 6-minute walk distance changed from 358.6 meters at baseline to 353.2 meters at six months (a within-group decrease of 5.4 meters). In the placebo group, the distance changed from 359.8 meters to 354.5 meters (a within-group decrease of 5.3 meters). The adjusted between-group difference was 1.1 meters (95% CI, -16.3 to 18.6 meters; P = .90). This result clearly failed to meet the threshold for clinical significance.
Secondary Outcomes and Physiological Measures
The lack of efficacy extended to all secondary measures. Maximal treadmill walking time, which provides a more controlled assessment of absolute exercise capacity, showed no benefit for metformin. Similarly, flow-mediated dilation, a surrogate for systemic endothelial health, did not improve, suggesting that metformin’s purported effects on eNOS did not translate into measurable vascular changes in this cohort. Patient-reported scores on the WIQ and SF-36 also remained stagnant, reinforcing the objective findings.
Safety and Adverse Events
Safety data indicated that metformin was associated with a higher burden of nonserious adverse events. Specifically, 64.9% of the metformin group reported indigestion or stomach upset, compared to 40.6% in the placebo group. Headache was also common, though slightly more frequent in the placebo group (49.5% vs 37.2%). Serious adverse events, primarily cardiovascular in nature, occurred at low and comparable rates (3.1% for metformin and 1.9% for placebo).
Expert Commentary: Why Did Metformin Fail?
The neutral results of the PERMET trial are disappointing but provide crucial evidence for clinical practice. Several factors may explain why the theoretical benefits of metformin did not manifest in patients with PAD. First, the biological pathway—AMPK activation—may not be the primary driver of functional limitation in non-diabetic PAD. While metformin improves insulin sensitivity and metabolic efficiency in skeletal muscle, the limiting factor in PAD is primarily macrovascular obstruction and microvascular rarefaction, which may be less responsive to metformin’s mechanism of action.
Second, the duration of the study (6 months) might have been insufficient to observe structural changes in the vasculature or muscle fiber types, although previous studies on exercise and other pharmacotherapies have shown changes within this timeframe. Finally, the high incidence of gastrointestinal side effects might have impacted overall physical activity levels or adherence, although the trial reported reasonable completion rates.
It is also worth noting that the trial did not reach its full enrollment target of 212 due to funding limitations. However, given the near-identical performance of both groups and the narrow confidence intervals around the primary endpoint, it is highly unlikely that a slightly larger sample size would have altered the statistical or clinical conclusion.
Conclusion and Clinical Implications
The PERMET trial provides high-quality evidence that metformin does not improve walking performance in patients with PAD who do not have diabetes. These findings suggest that metformin should not be prescribed for the specific purpose of improving functional capacity in this population. For clinicians, the focus for PAD management should remain on established therapies: supervised exercise programs, smoking cessation, intensive lipid-lowering therapy, and antiplatelet agents. While the search for effective pharmacotherapy to improve walking distance continues, metformin can be crossed off the list of potential candidates for non-diabetic PAD patients.
Funding and Registration
The study was funded by the National Heart, Lung, and Blood Institute (NHLBI). 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. 2026;335(5):407-415. doi:10.1001/jama.2025.21358
2. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease. Circulation. 2017;135(12):e686-e725.
3. Hiatt WR, Armstrong EJ, Larson CJ, Brass EP. Improvements in limb kinetics and functional capacity in response to exercise and pharmacological therapies in PAD. Vascular Medicine. 2015;20(4):363-372.
