Abstract
Background/Objectives: Diabetic foot disease is one of the most severe and disabling complications of type 2 diabetes mellitus, resulting from the interaction between peripheral neuropathy, peripheral arterial disease, and infection. It is associated with a high risk of ulceration, lower-limb amputation, hospitalisation, and mortality, and is currently recognised as a marker of advanced systemic vascular disease. Although glucagon-like peptide-1 receptor agonists have demonstrated robust cardiometabolic benefits, their potential impact on diabetic foot disease outcomes remains insufficiently explored. Methods: This narrative review critically synthesises clinical, experimental, and translational evidence evaluating the association between glucagon-like peptide-1 receptor agonist therapy and diabetic foot disease-related outcomes. A comprehensive literature search was conducted in PubMed and related databases, focusing on studies published over the last decade that assessed diabetic peripheral neuropathy, foot ulceration, amputations, hospitalisations, and mechanistic pathways potentially linking glucagon-like peptide-1 receptor agonists to diabetic foot pathophysiology. Results: Available observational studies and population-based analyses suggest that glucagon-like peptide-1 receptor agonist treatment is associated with a reduced incidence of diabetic foot ulcers, lower-limb amputations, and related hospitalisations. Experimental and translational data provide biological plausibility for these findings, demonstrating neuroprotective effects, attenuation of neuroinflammation, and improvement of endothelial function and microvascular perfusion, as well as modulation of inflammatory and reparative pathways involved in wound healing. These pleiotropic actions extend beyond glycaemic control and may influence the natural history of diabetic foot disease. Conclusions: Glucagon-like peptide-1 receptor agonists emerge as promising therapeutic agents with potential benefits in the prevention and progression of diabetic foot disease. Their integrated neurovascular and immunometabolic effects may contribute to improved clinical outcomes and a reduced healthcare burden. Prospective studies and dedicated clinical trials are warranted to confirm these associations and to define the role of glucagon-like peptide-1 receptor agonists in the multidisciplinary management of diabetic foot disease.