Study summary · research use only
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
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This review summarizes the roles of glucagon-like peptide-1 (GLP-1) receptor agonists and glucagon/GIP/GLP-1 dual or triple agonists in treating metabolic dysfunction-associated steatohepatitis (MASH), including only clinical trials with liver histology endpoints. The review reports that phase 2 clinical trials of GLP-1 receptor agonism were associated with improved disease activity, and that tirzepatide and survodutide showed potential benefits in reducing fibrosis, alongside weight loss and improved glycaemic control and lipid profile. Gastrointestinal side effects, generally mild to moderate, were noted as a limitation to adherence. An interim analysis of a phase 3 semaglutide trial reported improvement in steatohepatitis and potential to improve fibrosis. The authors call for larger, longer-duration trials.
Abstract
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. 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). Only clinical trials with endpoints assessed by liver histology were included for a robust evaluation of therapeutic efficacy. 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. 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.
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