Diabetic foot ulcers (DFUs) represent a clinically burdensome and pathophysiologically distinct complication of diabetes mellitus, marked by persistent inflammation, dysregulated immune signaling, impaired angiogenesis, and delayed re-epithelialization. Despite adherence to standardized wound care protocols, DFUs remain recalcitrant to healing, contributing to high rates of recurrence, infection, and lower extremity amputation. Although established in glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exert pleiotropic immunomodulatory and regenerative effects relevant to cutaneous repair. This narrative review summarizes mechanistic insights derived from in vitro and animal models through which GLP-1 RA may suppress TNF-α and NF-κB signaling; activate adenosine monophosphate-activated protein kinase and phosphoinositide 3-kinase/protein kinase B pathways; and promote keratinocyte migration, endothelial progenitor cell function, and macrophage polarization toward reparative phenotypes. Additional mechanisms include restoration of neutrophil antimicrobial function, modulation of matrix remodeling, and upregulation of angiogenic mediators such as VEGFR-2 and HIF-1α. Preclinical findings suggest that these agents may address key barriers to wound healing. While preliminary findings are promising, clinical trials comparing GLP-1 RA therapy with standard of care are needed. Although still investigational, the topical formulation could expand therapeutic applicability if supported by additional clinical evidence. Given their immunomodulatory and tissue-regenerative properties, GLP-1 RAs may represent an adjunctive therapy for DFUs.
