New study confirms benefits of GLP-1 drugs in patients with PAD

GLP-1 receptor agonists can reduce the risk of deaths, amputations and hospitalizations among people with Type 2 diabetes who also have peripheral artery disease (PAD), according to research published recently in the Journal of the American Heart Association.

“Our findings indicate these medications may improve long-term health for people with PAD, in addition to managing blood sugar and weight loss,” said author Aravinda Nanjundappa, M.D., an interventional cardiologist in the invasive & interventional cardiology section in the Robert and Suzanne Tomisich Department of Cardiovascular Medicine at the Cleveland Clinic in Cleveland.

Peripheral artery disease results in the narrowing or blockage of the vessels in the legs. Both men and women can be affected; African Americans have an increased risk of PAD. Older age, smoking, diabetes and high triglycerides increase the risk of PAD. Approximately 6.5 million people age 40 and older in the United States have PAD, according to the CDC.

In this study, researchers reviewed the health records for more than 2,000 adults with Type 2 diabetes and PAD in the TriNetX platform from January 2010 through January 2025. They wanted to assess the records of patients with both conditions who had either been prescribed a GLP-1 or metformin. They excluded patients with recent cardiovascular events, end‐stage renal disease, or prior amputations.

Researchers compared adults who were prescribed GLP1-RAs at least five times during the study period with a comparison group who had no record of GLP1-RA prescriptions. The comparison group had to have had at least five prescriptions for metformin. Outcomes included mortality, myocardial infarction, hospitalization, stroke, revascularization, amputations, dialysis, major adverse cardiovascular events, and kidney events.

They found that there was a positive impact of GLP-1 drugs on overall health compared with patients who took metformin, which is the most widely prescribed medication for people with Type 2 diabetes. Compared with people taking metformin, patients taking GLP-1s had:

• a 26% reduction in all causes of death;
• a 13% reduction in hospitalizations;
• up to a 48% reduction in amputations; and
• about 36% reduction in the need for procedures to open clogged arteries.

The rates of heart attack, stroke, and serious kidney events were similar between both groups.

Researchers noted that the link between GLP1-RAs and medical benefits was strongest among participants with severe PAD, including chronic limb-threatening ischemia and those with a body mass index of 30 or higher.

“Obesity and PAD, including chronic limb-threatening ischemia, are linked to increased inflammation, poor blood vessel function, insulin resistance, oxidative stress, and faster hardening of the arteries,” study coauthor Akiva Rosenzveig, M.D., a cardiology fellow at the Cleveland Clinic, said in a news release. “These results indicate GLP1-RAs can help reduce inflammation, improve blood vessel function and manage blood sugar levels.”

Related: Semaglutide Improves CV Function, Walk Distance in PAD | ACC 2025

A previous study (STRIDE) that was presented at the American College of Cardiology Scientific Sessions in March 2025 and published in The Lancet found that semaglutide significantly improved cardiovascular function and walking endurance, along with other quality-of-life measures, after one year in people with PAD and Type 2 diabetes.

Researchers from the Journal of the American Heart Association study said their results support earlier and more routine initiation of GLP‐1 receptor agonists in patients with peripheral artery disease and diabetes.

Researchers said one limitation of the study was that they could not prove cause and effect. Additionally, electronic health records may have diagnostic coding errors that would impact the results of the analysis.

The study was supported by a grant from the Cleveland Clinic Heart, Vascular, and Thoracic Institute.