The role of GLP-1 in the pathophysiology and treatment of sepsis: a narrative review.

Background: Sepsis remains a leading cause of morbidity and mortality in critically ill patients, often complicated by sepsis-induced myopathy (SIM), systemic inflammation, and multiorgan dysfunction. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for the treatment of type 2 diabetes, have demonstrated pleiotropic effects that may be beneficial in the septic context. Objective: This review aims to explore the significance of GLP-1 receptors in the sepsis mechanism, as well as the therapeutic potential of GLP-1RAs in sepsis treatment, with a particular emphasis on their role in modulating inflammation, improving metabolic and endothelial function, and mitigating systemic inflammatory response syndrome (SIRS). Methods: A comprehensive synthesis of preclinical and clinical studies was conducted, focusing on the cellular mechanisms and systemic outcomes of GLP-1RA therapy in various models of sepsis and critical illness. Results: GLP-1RAs attenuate inflammation by suppressing NF-κB and p38 MAPK pathways, reduce oxidative stress, enhance insulin sensitivity, and promote mitochondrial and endothelial stability. In skeletal muscle, they downregulate atrophy-associated genes (MuRF1, MAFbx) and upregulate myogenic factors (MyoD, MyoG), thereby improving perfusion and energy metabolism. Central GLP-1R signaling plays a crucial role in neuroimmune modulation and organ protection. Notably, these agents also increase adiponectin levels, which may further contribute to vascular integrity and anti-inflammatory effects during sepsis. Conclusion: GLP-1RAs represent a novel and multifaceted therapeutic strategy for sepsis and its complications. They show promise as adjunctive therapy in sepsis due to their anti-inflammatory, antioxidant, and endothelial-protective actions. Experimental and limited clinical data suggest improved organ function and survival, but further human studies are needed to confirm efficacy, safety, and optimal treatment strategies.