Common Diabetes Drug Fails to Improve Walking Ability in Peripheral Artery Disease Patients Without Diabetes

A widely used and inexpensive diabetes medication has failed to deliver benefits for people living with peripheral artery disease (PAD) who do not have diabetes. According to results from a large U.S. clinical trial published in the Journal of the American Medical Association (JAMA), the drug metformin did not help patients walk farther or improve their physical function, despite earlier hopes that it might.

Peripheral artery disease is a common and serious circulatory condition in which narrowed arteries reduce blood flow to the limbs, most often the legs. This reduced blood supply can cause pain, cramping, and fatigue while walking, making even short distances difficult. In the United States alone, PAD affects an estimated 12 million adults, and it is strongly associated with a higher risk of heart attack, stroke, and cardiovascular death.

Because PAD is so prevalent and disabling, researchers have long searched for treatments that can improve patients’ ability to walk and remain physically active. Unfortunately, options are limited. Supervised walking exercise is considered the first-line therapy, but many patients struggle with it because walking itself triggers ischemic leg pain. There is currently only one FDA-approved medication aimed at improving walking performance in PAD, and it offers modest benefits while also causing side effects.

Against this backdrop, researchers turned their attention to metformin.

Why Metformin Was Considered a Promising Candidate

Metformin is one of the most commonly prescribed drugs in the world for type 2 diabetes. Beyond its glucose-lowering effects, metformin has been shown in previous studies to improve blood vessel function, reduce oxidative stress, and activate pathways involved in cellular energy regulation. These properties led scientists to believe that metformin might also help people with PAD, even if they did not have diabetes.

The idea was straightforward: if metformin could improve vascular health and reduce inflammation, it might increase blood flow to the legs and make walking less painful or more efficient. Given the drug’s long history of use, low cost, and relatively well-understood safety profile, it appeared to be an attractive option worth testing in a rigorous clinical trial.

Inside the Clinical Trial

The study, formally titled “Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease,” was conducted across four medical centers in the United States. A total of 202 adults with diagnosed PAD were enrolled. Importantly, none of the participants had diabetes, allowing researchers to isolate metformin’s effects on PAD rather than its blood sugar–lowering properties.

Participants were randomly assigned to receive either metformin or a placebo for a period of six months. The trial was designed as a randomized, double-blind, placebo-controlled study, which is considered the gold standard for clinical research. Neither the participants nor the researchers knew who was receiving the drug or the placebo until the study was completed.

The primary outcome measured was the change in distance walked during the six-minute walk test, a widely used and clinically meaningful assessment of mobility and endurance. In this test, patients are asked to walk as far as they can in six minutes, and the total distance is recorded. This measure is particularly relevant for PAD because it reflects real-world walking ability rather than performance on specialized exercise equipment.

Clear and Disappointing Results

After six months, the results were unambiguous. Metformin did not improve walking performance.

Participants in both the metformin group and the placebo group actually walked shorter distances at the end of the study compared to their baseline performance. The difference between the two groups was negligible—approximately one meter, a change that is neither statistically significant nor clinically meaningful.

In other words, taking metformin did not help patients with PAD walk farther, longer, or more comfortably than taking a placebo.

The researchers also looked at several secondary outcomes, including treadmill walking performance, patient-reported walking ability, physical functioning scores, and measures of blood vessel health. Once again, no meaningful differences were found between the metformin and placebo groups.

Side Effects and Safety Findings

From a safety standpoint, metformin performed largely as expected. Serious adverse events, including cardiovascular events, occurred at similar rates in both groups. However, non-serious side effects, particularly gastrointestinal symptoms such as stomach upset and indigestion, were more common among those taking metformin. This aligns with what is already known about the drug’s side effect profile.

While these side effects were generally manageable, they further reduce the appeal of metformin as a potential treatment for PAD, especially given its lack of benefit in improving mobility.

What This Means for PAD Treatment

The findings are significant because they provide a clear answer to an important clinical question. Despite strong theoretical reasons to believe metformin might help, the trial showed that it does not improve walking ability in PAD patients without diabetes.

As a result, the researchers have stated that they do not plan to continue studying metformin as a treatment for PAD-related walking impairment. This allows future research efforts to focus on other, potentially more promising therapies.

Exploring Other Potential Treatments

While metformin did not deliver the hoped-for results, the research team is not giving up. They have reported preliminary evidence suggesting that other interventions may hold promise. Among the treatments currently being explored are cocoa flavanols, which have been linked to improved vascular function, and nicotinamide riboside, a compound involved in cellular energy metabolism.

Ongoing and future studies aim to determine whether these or other therapies can meaningfully improve walking performance and quality of life for people living with PAD.

Understanding Peripheral Artery Disease Better

Peripheral artery disease is often underdiagnosed and undertreated, despite its serious consequences. Many people mistake PAD symptoms for normal aging or arthritis, delaying diagnosis and intervention. Beyond walking difficulty, PAD is a marker of widespread atherosclerosis, meaning patients often have blockages in other arteries as well.

Managing PAD typically involves a combination of lifestyle changes, such as smoking cessation and exercise, medications to control cholesterol and blood pressure, and in some cases surgical or endovascular procedures to restore blood flow. Improving walking ability remains one of the most challenging aspects of care, which is why studies like this one are so important—even when the results are negative.

Why Negative Results Still Matter

Although disappointing, this trial provides valuable clarity. Knowing what does not work is just as important as discovering what does. By ruling out metformin as an effective therapy for PAD-related walking impairment in non-diabetic patients, clinicians and researchers can avoid unnecessary treatments and focus their energy on better solutions.

For patients, the study reinforces the importance of evidence-based care and ongoing research aimed at improving daily function, not just managing risk factors.

Research paper:
https://jamanetwork.com/journals/jama/article-abstract/2841244