TY - JOUR

T1 - Localized Semaglutide Injection for Hyperinsulinemia-Induced Lymphatic Dysfunction: A Narrative Review Proposing a Promising Metabolic Perspective for Lymphedema Therapy

AU - Akl, Maher Monir

AU - Ahmed, Amr

N1 - Akl M. M., Ahmed A. Localized Semaglutide Injection for Hyperinsulinemia-Induced Lymphatic Dysfunction: A Narrative Review Proposing a Promising Metabolic Perspective for Lymphedema Therapy / M. M. Akl, A. Ahmed // Advanced Pharmaceutical Bulletin. - 2025. - Т. 15. № 3. - С. 499-505. DOI 10.34172/apb.025.43911

PY - 2025/9/4

Y1 - 2025/9/4

N2 - Lymphedema, traditionally viewed as a mechanical consequence of lymphatic obstruction, is increasingly recognized as a complex disorder rooted in metabolic dysfunction, particularly insulin resistance and chronic hyperinsulinemia. This paradigm-shifting hypothesis redefines lymphedema as a vascular complication driven by systemic metabolic stress, where prolonged hyperinsulinemia impairs lymphatic endothelial cell (LEC) function, triggering inflammation, oxidative stress, and structural damage. Insulin resistance disrupts the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, critical for lymphangiogenesis and endothelial integrity, leading to compromised lymphatic drainage. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), exacerbate this dysfunction by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and promoting reactive oxygen species (ROS) production, while advanced glycation end products (AGEs) engaging RAGE amplify fibrosis and endothelial apoptosis. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as liraglutide and semaglutide, offer a revolutionary therapeutic approach by addressing both metabolic and vascular components of lymphedema. By enhancing PI3K/AKT signaling, GLP-1RAs restore insulin sensitivity, mitigate hyperinsulinemia, and suppress inflammatory pathways (NF-κB, TLR4). Their activation of VEGF-C/VEGFR-3 and endothelial nitric oxide synthase (eNOS)/NO pathways promotes lymphangiogenesis and reduces ROS-induced damage, enhancing lymphatic vessel repair. Clinical evidence, including a 2024 case report, demonstrates significant reductions in limb volume (from 10.3% to 3.4%) and restored lymphatic function in breast cancer-related lymphedema following GLP-1RA therapy. Localized administration optimizes therapeutic outcomes by targeting lymphatic endothelial cells, minimizing systemic side effects. This narrative review synthesizes lymphedema’s metabolic pathophysiology, proposes localized semaglutide as a novel therapy, and suggests experimental protocols to advance lymphedema management.

AB - Lymphedema, traditionally viewed as a mechanical consequence of lymphatic obstruction, is increasingly recognized as a complex disorder rooted in metabolic dysfunction, particularly insulin resistance and chronic hyperinsulinemia. This paradigm-shifting hypothesis redefines lymphedema as a vascular complication driven by systemic metabolic stress, where prolonged hyperinsulinemia impairs lymphatic endothelial cell (LEC) function, triggering inflammation, oxidative stress, and structural damage. Insulin resistance disrupts the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, critical for lymphangiogenesis and endothelial integrity, leading to compromised lymphatic drainage. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), exacerbate this dysfunction by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and promoting reactive oxygen species (ROS) production, while advanced glycation end products (AGEs) engaging RAGE amplify fibrosis and endothelial apoptosis. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as liraglutide and semaglutide, offer a revolutionary therapeutic approach by addressing both metabolic and vascular components of lymphedema. By enhancing PI3K/AKT signaling, GLP-1RAs restore insulin sensitivity, mitigate hyperinsulinemia, and suppress inflammatory pathways (NF-κB, TLR4). Their activation of VEGF-C/VEGFR-3 and endothelial nitric oxide synthase (eNOS)/NO pathways promotes lymphangiogenesis and reduces ROS-induced damage, enhancing lymphatic vessel repair. Clinical evidence, including a 2024 case report, demonstrates significant reductions in limb volume (from 10.3% to 3.4%) and restored lymphatic function in breast cancer-related lymphedema following GLP-1RA therapy. Localized administration optimizes therapeutic outcomes by targeting lymphatic endothelial cells, minimizing systemic side effects. This narrative review synthesizes lymphedema’s metabolic pathophysiology, proposes localized semaglutide as a novel therapy, and suggests experimental protocols to advance lymphedema management.

KW - Lymphedema

KW - Insulin resistance

KW - GLP-1 receptor agonists

KW - Lymphangiogenesis

KW - Metabolic dysfunction

KW - Vascular inflammation

UR - https://www.mendeley.com/catalogue/9936b475-b6a9-3f66-9e2e-2ed7e5f560f7/

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105020318361&origin=inward

U2 - 10.34172/apb.025.43911

DO - 10.34172/apb.025.43911

M3 - Article

VL - 15

SP - 499

EP - 505

JO - Advanced Pharmaceutical Bulletin

JF - Advanced Pharmaceutical Bulletin

SN - 2228-5881

IS - 3

ER -