A diabetes medication widely used to improve heart health did not help people with peripheral artery disease (PAD) walk farther or easier, according to a major clinical trial published in JAMA. The study tested metformin—an inexpensive, well-known drug—in 202 adults with PAD who did not have diabetes, hoping it might ease the painful leg symptoms that make walking difficult for millions of Americans. What Is Peripheral Artery Disease and Why Does It Matter? Peripheral artery disease affects approximately 12 million adults in the U.S. and impacts blood flow to the legs, making walking painful and difficult. The condition develops when fatty plaque builds up inside arteries, narrowing blood vessels and restricting blood flow to the lower extremities. Over 200 million people worldwide live with PAD, particularly older adults and those with diabetes, smoking history, or chronic kidney disease. PAD is serious because it's linked to higher risks of heart attack and stroke. In advanced cases, the condition can progress to chronic limb-threatening ischemia (CLTI), which carries a high risk of limb loss and even death if not treated promptly. Despite its prevalence, few treatments effectively improve walking performance in these patients. Why Researchers Thought Metformin Might Work? Metformin has been shown to improve blood vessel health and reduce oxidative stress—damage caused by harmful molecules in the body. These properties led scientists to believe the drug might benefit PAD patients, even those without diabetes. "Walking exercise is first-line therapy, but walking exercise is difficult because people get ischemic pain when they walk for exercise," said Dr. Mary McDermott, the Jeremiah Stamler Professor of Medicine in the Division of General Internal Medicine at Northwestern University and first author of the study. "There is one FDA-approved medication, but it's not very effective and it's associated with side effects". What Did the Clinical Trial Show? Researchers conducted the study at four U.S. medical centers, enrolling 202 adults with PAD. Participants were randomly assigned to take either metformin or a placebo for six months. The primary outcome was the change in distance walked during a six-minute test, a standard way to assess mobility in PAD patients. The results were clear: metformin did not make a difference. Both groups walked a shorter distance after six months, and the difference between metformin and placebo was negligible—just about one meter. This finding was disappointing but important, as it ruled out metformin as a viable treatment option for PAD patients without diabetes. What Are the Risk Factors for Peripheral Artery Disease? Understanding who is at highest risk for PAD can help with early detection and prevention. Several factors increase the likelihood of developing this condition: - Smoking: The strongest modifiable risk factor, increasing PAD risk fourfold and significantly contributing to disease severity - Diabetes: A major risk factor that accelerates atherosclerosis and arterial narrowing - Age: Adults 65 years and older have higher incidence rates, with PAD affecting as many as one in five people over 70 - Hypertension: High blood pressure damages artery walls and promotes plaque buildup - High cholesterol: Elevated LDL (low-density lipoprotein) cholesterol accelerates atherosclerosis - Chronic kidney disease: Impaired kidney function increases cardiovascular and vascular disease risk - Obesity and sedentary lifestyle: Excess weight and lack of physical activity worsen vascular health - Family history: A personal or family history of PAD, heart disease, or stroke increases risk What Happens Next in PAD Research? Although metformin did not work, researchers are not giving up on finding effective treatments. "Based on the results of this clinical trial, we do not intend to continue studying metformin for peripheral artery disease," said Dr. McDermott. "However, we have some preliminary evidence that cocoa flavanols and nicotinamide riboside both improved walking difficulty in peripheral artery disease, and we have some ongoing work that we expect will definitively establish the effects of those treatments". These emerging compounds represent a new direction for PAD treatment research. Cocoa flavanols—natural compounds found in chocolate and cocoa—have been studied for their potential to improve blood vessel function. Nicotinamide riboside is a form of vitamin B3 that may support cellular energy production and vascular health. Both show promise in early studies, though more research is needed to confirm their effectiveness. How to Manage Peripheral Artery Disease Today While researchers continue searching for new medications, current treatment approaches focus on managing symptoms and slowing disease progression: - Supervised exercise therapy: Walking programs under medical supervision remain the first-line treatment, helping patients gradually build walking distance and improve circulation - Risk factor modification: Controlling blood pressure, cholesterol, and blood sugar levels; quitting smoking; and maintaining a healthy weight are essential to slow disease progression - Medications: Antiplatelet drugs like aspirin, statins for cholesterol management, and blood pressure medications help reduce cardiovascular complications - Revascularization procedures: In advanced cases, doctors may recommend surgery or catheter-based interventions to restore blood flow to affected limbs The study was supported by funding from the National Heart, Blood and Lung Institute (NHLBI) and Northwestern University. For patients living with PAD, the takeaway is clear: while metformin won't help, working closely with healthcare providers on exercise, lifestyle changes, and medication management remains the best current approach to managing this serious condition.
