Localized Injection of Semaglutide, a GLP-1 Agonist, for Hyperinsulinemia-Induced Lymphatic Dysfunction A Novel Therapeutic Strategy for Lymphedema Treatment

Lymphedema, traditionally considered a secondary complication of lymphatic damage, may have a deeper, metabolic etiology tied to chronic hyperinsulinemia and insulin resistance. This emerging hypothesis posits that prolonged hyperinsulinemia drives lymphatic endothelial cell (LEC) dysfunction, initiating inflammation, oxidative stress, and structural damage that culminates in impaired lymphatic drainage. Insulin resistance disrupts the PI3K/Akt signaling pathway, which is vital for lymphangiogenesis and endothelial health, further exacerbating lymphatic vessel integrity. Recent clinical evidence underscores the therapeutic potential of GLP-1 receptor agonists (GLP-1RAs), known for their insulin-sensitizing and anti-inflammatory properties. Notably, cases of breast cancer-related lymphedema have shown marked improvements following GLP-1RA treatment, with significant reductions in limb volume and restoration of lymphatic function. These observations suggest a dual mechanism by which GLP-1RAs address both the metabolic and vascular components of lymphedema, positioning them as a promising therapeutic avenue for lymphedema driven by insulin resistance. This review delves into the molecular pathophysiology of lymphedema in the context of metabolic dysfunction and explores the role of GLP-1RAs as an innovative treatment strategy.