GLP-1 drugs reduce deaths and amputations in patients with diabetes and PAD

GLP-1 drugs reduce deaths and amputations in patients with diabetes and PAD

New research indicates that GLP-1 receptor agonists (GLP-1 RA) medications can reduce the number of hospitalizations, amputations, and deaths among adults living with Type 2 diabetes and peripheral artery disease (PAD), a condition characterized by narrowed leg arteries.

The findings, published July 1, 2026, in the Journal of the American Heart Association, suggest these medications provide benefits beyond the traditional management of weight loss and blood sugar. According to study author Aravinda Nanjundappa, M.D., an interventional cardiologist at the Cleveland Clinic, clinicians should consider prescribing GLP-1s because PAD currently has limited treatment options, particularly for high-risk patients suffering from severe circulation problems in their legs.

Comparative Benefits and High-Risk Patients

Researchers analyzed health records for more than 2,000 adults with Type 2 diabetes and PAD. The study compared the outcomes of those taking GLP-1 RAs against a comparison group of participants who had received at least 5 metformin prescriptions and no GLP-1 RA prescriptions during the study period.

The analysis found that the positive impact of GLP-1 RAs on overall health surpassed that of metformin, the most commonly prescribed medication for Type 2 diabetes, across most categories. These medical benefits were most pronounced among participants with a body mass index of 30 or higher and those with severe PAD, including chronic limb-threatening ischemia.

Study coauthor Akiva Rosenzveig, M.D., a cardiology fellow at the Cleveland Clinic, noted that obesity and chronic limb-threatening ischemia are linked to oxidative stress, insulin resistance, poor blood vessel function, increased inflammation, and the faster hardening of arteries. Rosenzveig stated that the results indicate GLP-1 RAs can manage blood sugar levels, improve blood vessel function, and help reduce inflammation.

Improving Walking Distance and Function

Separate research presented at ACC.25 on March 29, 2025, focused on the specific GLP-1 agonist semaglutide. The STRIDE trial, which enrolled 792 people with Type 2 diabetes and early-stage symptomatic PAD across 20 countries, found that semaglutide significantly improved maximal walking distance compared to a placebo.

Participants in the semaglutide arm showed an average improvement in walking distance of 40 meters, and a median improvement of 26 meters, representing a 13% improvement at one year. Marc P. Bonaca, MD, MPH, the study's lead author from the University of Colorado School of Medicine, noted that an increase of 10 to 20 meters is typically considered clinically important in PAD, meaning these results exceeded expectations.

Additional findings from the STRIDE trial include:

• A 54% reduction in the risk of death or the need for a procedure or medication to open blocked leg arteries due to worsening symptoms (14 patients vs. 30 patients).
• Significant improvements in quality of life and pain-free walking distance.
• Improved ankle brachial index, which measures blood flow in the legs.
• Sustained improvement in maximal walking distance five weeks after stopping therapy.

Bonaca suggested that the increase in the ankle brachial index and the weak relationship between the outcome and weight loss—given the population had a median body mass index of 28.6—point to a direct vascular effect.

Clinical Context and Future Directions

The scale of these health issues is significant in the U.S. According to the American Heart Association’s 2026 Heart Disease and Stroke Statistics, an estimated 29.5 million adults (10.6%) were diagnosed with Type 2 diabetes between 2021 and 2023. PAD affects approximately 12.5 million Americans aged 40 or older, while globally, the condition affects over 200 million people.

Before the emergence of these findings, the last drug approved by the U.S. Food and Drug Administration to improve functional outcomes in PAD was cilostazol in 2000. Bonaca stated that the only guideline-recommended drug for symptoms is contraindicated for those with heart failure, causes many side effects, and is used in less than 10% of people.

Despite the positive data, experts call for more evidence. Joshua J. Joseph, M.D., M.P.H., an American Heart Association volunteer expert, stated that more research is needed to confirm these findings and determine the exact underlying mechanisms, such as whether the benefits are driven by reduced inflammation.

Both the STRIDE trial and the Cleveland Clinic research raise a critical question for future study: whether GLP-1 RAs could benefit people with PAD who do not have Type 2 diabetes.