The Next Frontier in Peripheral Artery Disease Treatment

This article was created with Dr. Chris DeGroat, a cardiologist at Cardiology Specialists of Birmingham, UAB St. Vincent’s. This article was edited by Elizabeth Hyska.

Peripheral artery disease (PAD) happens when blood vessels in your legs become narrowed or blocked, reducing blood flow. Progressive narrowing of the arteries supplying the lower extremities impairs skeletal muscle perfusion, leading to ischemia (lack of blood flow) and exertional limb discomfort. PAD is a major public health problem, affecting approximately 8 to 10 million individuals in the United States and more than 230 million worldwide.

The prevalence of PAD increases markedly with age. While uncommon in individuals 50 years or younger, it rises sharply after age 60 and exceeds 20% among those older than 80 years. Importantly, PAD is not an isolated limb disorder but rather a marker of diffuse atherosclerosis. Patients with PAD have a high burden of concomitant coronary artery disease (CAD) and experience a significantly increased (approximately 6×) risk of cardiovascular mortality compared with individuals without PAD. The disease frequently overlaps with traditional cardiometabolic risk factors, including:

• Type 2 diabetes mellitus
• Hypertension
• Tobacco use
• Dyslipidemia
• Obesity
• Sedentary lifestyle

Despite its prevalence and prognostic significance, PAD remains substantially underrecognized and undertreated. Up to half of patients have no symptoms, while a smaller proportion experience classic leg pain with walking, and 10–20% develop chronic limb-threatening ischemia, characterized by rest pain, nonhealing ulcers, or gangrene. Symptom severity is commonly categorized using the Fontaine classification, which ranges from asymptomatic disease to critical limb ischemia.

Diagnosis relies on a combination of clinical assessment and objective testing. A thorough history and physical examination are complemented by measurement of the ankle–brachial index (ABI), with values <0.9 indicating PAD. Advanced imaging modalities—including duplex Doppler ultrasound, computed tomography angiography (CTA), and invasive angiography—are used to define disease severity and guide revascularization strategies.

Current Treatment Landscape and Unmet Needs

The cornerstone of PAD management begins with lifestyle modification, including smoking cessation, dietary optimization, and structured exercise therapy. Medical therapy focuses on reducing cardiovascular and limb-related events. It includes:

• Antiplatelet agents like…
  • Aspirin
  • Clopidogrel
  • Low-dose rivaroxaban in combination with aspirin
  • Vorapaxar in select patients
• Cilostazol for relief of claudication (leg pain when walking) symptoms
• Aggressive risk factor modification like…
  • Statins
  • ACE inhibitors or ARBs
  • Optimized glycemic control

Endovascular and surgical interventions—such as angioplasty, stenting, and bypass surgery—are reserved for patients with lifestyle-limiting claudication or limb-threatening ischemia. Despite these strategies, PAD continues to carry a high morbidity burden, with approximately 150,000 lower-extremity amputations performed annually in the United States.

Notably, most existing therapies address downstream consequences of atherosclerosis rather than directly modifying the metabolic and inflammatory drivers of PAD progression. This gap highlights the need for novel, disease-modifying therapeutic approaches.

Emerging Role of GLP-1 Receptor Agonists in PAD

Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as potent cardiometabolic therapies, demonstrating benefits in glycemic control, weight reduction, blood pressure lowering, and cardiovascular risk reduction. Recent data suggest that these agents may also exert direct vasculoprotective effects, independent of their metabolic actions.

The STRIDE clinical trial provided important proof-of-concept evidence in PAD. In this randomized study, 792 patients with type 2 diabetes mellitus and intermittent claudication were enrolled, with 396 patients receiving semaglutide 1 mg weekly for 52 weeks. During this randomized trial, treatment with semaglutide resulted in a significant improvement in walking distance compared with placebo, supporting the hypothesis that GLP-1 receptor agonism may improve functional capacity in PAD.

Mechanistically, GLP-1 receptor agonists are postulated to improve vascular health through multiple pathways, with preclinical and emerging clinical evidence suggesting:

• Reduction of vascular inflammation
• Attenuation of intimal hyperplasia (thickening of blood vessel walls)
• Inhibition of smooth muscle cell proliferation
• Decreased plaque formation
• Improved endothelial function

These may collectively lead to enhanced tissue perfusion and reduced ischemia.

The Promise of Oral GLP-1 Receptor Agonists

Oral GLP-1 receptor agonist (Rybelsus) has been used primarily for managing type 2 diabetes mellitus and reducing the risk of major cardiovascular events. In December 2025, the FDA approved an oral version of semaglutide (Wegovy) for the treatment of obesity and overweight.

Recent advances have led to the development of investigational oral, non-peptide GLP-1 receptor agonists, including orforglipron, which has demonstrated robust reductions in HbA1c in adults with type 2 diabetes mellitus and significant weight loss in patients with overweight and obesity in phase 2 clinical trials. On April 1, 2026, Eli Lilly announced that the FDA had approved orforglipron.

Oral administration offers practical advantages over injectable therapies, including improved patient acceptance, adherence, and scalability—key considerations for a chronic disease such as PAD.

While GLP-1 receptor agonists represent a promising area of investigation, established therapies—including lifestyle modification, antiplatelet treatment, and risk factor management—remain the foundation of care, and treatment decisions should be individualized based on patient needs and preferences.

What You Can Do Now

If you have peripheral artery disease—or are at risk—there are practical steps you can take to improve blood flow and reduce complications now. The most important is to quit smoking, as it significantly damages blood vessels and accelerates disease progression. Regular walking exercise is also highly effective; walking until mild discomfort, resting, and repeating over time can help you walk farther with less pain.

Managing underlying conditions is key. Keep your blood sugar, blood pressure, and cholesterol under control with the help of your healthcare provider, and take prescribed medications such as antiplatelets or statins consistently. A heart-healthy diet—rich in fruits, vegetables, whole grains, lean proteins, and healthy fats—can further support vascular health.

It’s also important to monitor your feet and legs for any cuts or wounds that are slow to heal, as reduced circulation increases the risk of complications. Finally, don’t ignore symptoms like leg pain with walking or numbness—early evaluation and treatment can prevent more serious outcomes, including limb loss and cardiovascular events.

Future Directions

Researchers are beginning to explore new ways to treat PAD by targeting both metabolic health and blood vessel function. One promising approach involves oral GLP-1 medications, such as orforglipron, which are already being studied for diabetes and weight loss.

An ongoing large clinical trial aims to evaluate whether orforglipron can help people with PAD walk farther and improve their quality of life. If successful, this approach could offer a new way to treat PAD—not just by managing symptoms, but by addressing the underlying drivers of the disease.

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