Review Article: GLP‐1 Receptor Agonists and Glucagon/GIP/GLP‐1 Receptor Dual or Triple Agonists—Mechanism of Action and Emerging Therapeutic Landscape in MASLD

ABSTRACT Background Metabolic dysfunction‐associated steatotic liver disease (MASLD) is primarily managed through diet and lifestyle modifications. However, these behavioural interventions alone may not achieve disease regression or remission, and maintaining long‐term adherence is challenging. Incretin mimetics and other gastrointestinal hormones targeting the pleiotropic pathophysiological pathways underlying MASLD have now emerged as promising disease‐modifying therapies. Aims This is a comprehensive review summarising the role of glucagon‐like peptide‐1 (GLP‐1) receptor agonists and glucagon/glucose‐dependent insulinotropic polypeptide (GIP)/GLP‐1 receptor dual or triple agonists in the treatment of metabolic dysfunction‐associated steatohepatitis (MASH). Methods Only clinical trials with endpoints assessed by liver histology were included for a robust evaluation of therapeutic efficacy. Results Recent evidence from phase 2 clinical trials for MASH demonstrated that pharmacological agents based on GLP‐1 receptor agonism are effective in improving disease activity. Additionally, tirzepatide and survodutide showed potential clinical benefits in reducing fibrosis. Other cardiometabolic benefits observed include weight loss and improvements in glycaemic control and lipid profile. Adherence to treatment may be limited by gastrointestinal side effects, though they were found to be generally mild to moderate in severity. An interim analysis of the semaglutide phase 3 trial confirmed its efficacy in improving steatohepatitis and demonstrated its potential to improve fibrosis. Conclusions GLP‐1 receptor agonists, alone or in combination with GIP and/or glucagon receptor agonists, represent promising, effective pharmacotherapies for the treatment of MASLD/MASH. Larger and longer‐duration clinical trials are needed to further evaluate the efficacy and safety of GIP receptor and glucagon receptor agonism.