The Metabolic Paradigm Shift in Gastroenterology and Hepatology: Clinical Applications of Incretin-Based Co-Agonists

: Background The global escalation of obesity and type 2 diabetes mellitus has driven a surge in gastrointestinal and hepatic pathologies, notably metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). Incretin hormones, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon, are pivotal regulators of the gut-liver-pancreas axis. Methods We synthesized recent clinical trial data and real-world evidence evaluating the efficacy and safety of incretin-based multi-receptor agonists in metabolic and gastrointestinal diseases. Results Advanced multi-agonists (e.g., tirzepatide, retatrutide, mazdutide) demonstrate unprecedented metabolic efficacy, achieving significant body weight reduction, preserving relative lean mass, and reversing metabolic syndrome. In hepatology, these agents fundamentally alter disease trajectories; semaglutide, tirzepatide, and survodutide achieve MASH resolution without worsening fibrosis. Emerging data also suggest GLP-1 receptor agonists significantly reduce colorectal cancer incidence and lower the risks of surgery and hospitalizations in patients with inflammatory bowel disease. However, therapy is associated with gastrointestinal dysmotility and an increased risk of cholelithiasis, requiring careful clinical and perioperative management. Furthermore, discontinuation of therapy leads to rapid weight regain and a complete reversal of cardiometabolic benefits. Conclusions Incretin multi-agonists represent a paradigm shift in gastroenterology and hepatology, offering definitive, disease-modifying interventions for the gut-liver axis. While highly effective, their chronic nature necessitates meticulous management of gastrointestinal tolerability and urgent health policy reforms to ensure long-term, equitable patient access.