GLP-1 Receptor Agonists and the Diabetic Foot: Mechanisms, Clinical Evidence, and Practical Considerations

Diabetic foot ulcers (DFUs) are a major complication of diabetes and are associated with impaired healing, lower-extremity amputation, and substantial morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used in the management of type 2 diabetes and obesity, with emerging evidence suggesting potential effects on diabetic foot health beyond glycemic control. This review examines the mechanistic and clinical evidence linking GLP-1RA therapy to DFU development, healing, and lower-extremity outcomes. Experimental studies demonstrate anti-inflammatory and antioxidant effects, improved endothelial function and angiogenesis, enhanced cellular repair, and potential neuroprotective effects. Clinical studies further suggest favorable associations with incident DFU, lower-extremity amputation, wound-related complications, and mortality, although findings are not uniform and most evidence is observational. Emerging data also suggest potentially favorable postoperative outcomes in patients undergoing diabetic foot and lower-extremity procedures. Comparative studies across glucose-lowering therapies demonstrate heterogeneous findings and do not establish a consistent advantage of one drug class across diabetic foot outcomes. Substantial GLP-1RA-associated weight loss may be accompanied by reductions in lean mass and nutritional intake and may raise additional concerns regarding peripheral neuropathy, wound healing, and foot biomechanics. However, direct evidence linking GLP-1RAs to plantar fat-pad loss, altered plantar pressure, or impaired DFU healing is lacking. Overall, GLP-1RAs may offer benefits relevant to diabetic foot health, but prospective studies using validated wound-healing endpoints are needed to determine whether these therapies directly improve DFU healing and to clarify their role in diabetic foot management.