Beyond intestinal failure: Expanding therapeutic frontiers of glucagon-like peptide-2 in gastrointestinal disease

Short bowel syndrome represents a severe form of intestinal failure characterized by malabsorption and dependence on parenteral nutrition (PN). Advances in gut hormone research have positioned glucagon-like peptide-2 (GLP-2) and its analogues as key pharmacologic agents promoting intestinal adaptation and reducing PN dependence. This minireview summarizes current evidence on the mechanisms, clinical efficacy, and expanding therapeutic applications of GLP-2 analogues, with emphasis on emerging agents such as glepaglutide and their safety profiles. GLP-2, a 33-amino acid peptide secreted by enteroendocrine L cells, enhances mucosal growth, nutrient absorption, and intestinal barrier integrity through activation of cyclic adenosine monophosphate-dependent and insulin-like growth factor-1-mediated pathways. Clinical trials have demonstrated that teduglutide and newer long-acting analogues such as glepaglutide significantly increase plasma citrulline levels, reduce fecal output, and decrease PN requirements while improving hepatic function and quality of life. Additionally, preclinical and clinical data support GLP-2's anti-inflammatory effects in inflammatory bowel disease and its potential to mitigate intestinal failure-associated liver disease. Although current evidence indicates low neoplastic risk, long-term safety monitoring remains essential. GLP-2 analogues represent a paradigm shift in short bowel syndrome management, transforming care from supportive nutrition to regenerative therapy. Ongoing studies exploring novel formulations, broader indications, and precision medicine approaches will further refine their clinical integration and maximize therapeutic benefit.