GLP-1-based therapies and limb outcomes in PAD: a systematic review and meta-analysis of real-world studies

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the dual incretin agonist tirzepatide have demonstrated cardiometabolic benefits in cardiovascular outcome trials, but their effects on limb outcomes in peripheral artery disease (PAD) remain unclear. This study evaluated whether GLP-1-based therapies reduce the risk of major adverse limb events (MALE), major adverse cardiovascular events (MACE), and mortality in real-world PAD populations.

A systematic search of MEDLINE, Embase, Cochrane CENTRAL, Scopus, and grey literature identified comparative real-world studies of GLP-1-based therapies in adults with PAD.

Six studies including over 240,000 patients were analyzed. GLP-1-based therapies were associated with a significant reduction in MALE (HR 0.59, 95% CI 0.39-0.90), although heterogeneity was substantial. A significant reduction in MACE was also observed (HR 0.67, 95% CI 0.53-0.85), with greater consistency in diabetic populations. Stroke was significantly reduced (HR 0.75, 95% CI 0.63-0.89), demonstrating consistent effects across studies. Myocardial infarction and all-cause mortality were also significantly reduced, although with greater variability in effect magnitude.

In real-world PAD populations, GLP-1-based therapies are associated with meaningful reductions in both limb and cardiovascular outcomes. These findings support a vascular protective profile, particularly for stroke and MACE in more homogeneous populations such as patients with diabetes.