GLP-1 RAs Linked to Lower Mortality, Amputation Risk in Patients With PAD and Type 2 Diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were associated with significantly lower rates of death, hospitalization, amputation, and revascularization procedures among patients with type 2 diabetes and peripheral artery disease (PAD), according to a new study published in the Journal of the American Heart Association.¹

PAD, which is caused by narrowed arteries that restrict blood flow to the legs, affects more than 236 million people worldwide and is roughly twice as common among individuals with diabetes. Although statins, antiplatelet therapy, and cilostazol remain standard options for reducing cardiovascular risk in PAD, treatments that directly address limb-related outcomes have been limited.¹

Real-World Data From a Large Matched Cohort

Investigators used the TriNetX platform to identify adults with type 2 diabetes and PAD who received either a GLP-1 RA or metformin between 2010 and 2025. After propensity score matching for demographics, comorbidities, and medication use, researchers compared 2133 patients per group over a 5-year follow-up period.¹

Patients who were treated with a GLP-1 RA had an approximate 26% lower risk of death, a 13% lower risk of hospitalization, and reductions of up to 48% and 36% in amputation and revascularization risk, respectively, compared with patients treated with metformin. Rates of myocardial infarction, stroke, and major kidney events were similar between the 2 groups.¹

Benefits Most Pronounced in Severe Disease

The association between GLP-1 RA use and improved outcomes was strongest among patients with chronic limb-threatening ischemia—the most advanced form of PAD—as well as those with obesity. Investigators noted that obesity and advanced PAD share underlying mechanisms, including inflammation, impaired blood vessel function, and insulin resistance, that GLP-1 RAs may help address.^1,2

Joshua J. Joseph, MD, MPH, an American Heart Association volunteer expert who was not involved in the study, said the findings raise questions for future research, including whether reduced inflammation drives the observed benefits and whether GLP-1 RAs could help patients with PAD who do not have type 2 diabetes.^1,2

Consistent With Randomized Trial Findings

The results build on data from the STRIDE trial (NCT04560998), a randomized, placebo-controlled phase 3b study that found semaglutide (Ozempic, Wegovy, Rybelsus; Novo Nordisk) improved walking distance and quality of life in patients with PAD and type 2 diabetes over 52 weeks. Because STRIDE was not designed to evaluate outcomes such as mortality or amputation, the new TriNetX analysis offers additional insight into longer-term, hard clinical end points using a larger, real-world population.^1,3

Study author Aravinda Nanjundappa, MD, an interventional cardiologist at the Cleveland Clinic, said the findings support considering GLP-1 RAs for patients with PAD given the condition's limited treatment options. The study's authors noted that although propensity matching balanced baseline characteristics across cohorts, the retrospective design cannot establish cause and effect, and unmeasured factors such as medication adherence or socioeconomic status may have influenced results.^1,2

Implications for Pharmacists

For pharmacists managing patients with type 2 diabetes, the findings may add another consideration when reviewing regimens for patients who also have PAD, particularly those with more severe limb involvement or obesity. As GLP-1 RAs continue to be studied across cardiometabolic and vascular conditions, pharmacists may be positioned to help identify appropriate candidates and counsel patients on the broader potential benefits of these therapies beyond glycemic control.

REFERENCES

1. Rosenzveig A, Tefera L, Agrawal A, et al. Long-term outcomes of glucagon-like peptide-1 receptor agonists in patients with peripheral artery disease and type 2 diabetes. J Am Heart Assoc. Published online July 1, 2026. doi:10.1161/JAHA.125.045664

2. American Heart Association. Can GLP-1 medications improve health in people with type 2 diabetes and PAD? News release. July 1, 2026. Accessed July 7, 2026. https://www.eurekalert.org/news-releases/1133696

3. Bonaca MP, Catarig AM, Houlind K, et al; STRIDE Trial Investigators. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial. Lancet. 2025;405(10489):1580-1593. doi:10.1016/S0140-6736(25)00509-4

4. Song P, Rudan D, Zhu Y, Fowkes FJI, Rahimi K, Fowkes FGR, Rudan I. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health. 2019;7(8):e1020-e1030. doi:10.1016/S2214-109X(19)30255-4