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

May 14, 2025Alimentary pharmacology & therapeutics

How GLP-1 and Related Receptor Activators Work and Their Potential for Treating MASLD

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Abstract

Recent phase 2 clinical trials indicate that pharmacological agents targeting the GLP-1 receptor are effective in improving disease activity in metabolic dysfunction-associated steatohepatitis (MASH).

Tirzepatide and survodutide showed potential benefits in reducing liver fibrosis.
Treatment with GLP-1 receptor agonists is associated with weight loss and improvements in glycaemic control and lipid profiles.
Gastrointestinal side effects may limit adherence to treatment, but they are generally mild to moderate.
An interim analysis of the semaglutide phase 3 trial confirmed its efficacy in improving steatohepatitis and suggests potential for fibrosis improvement.
GLP-1 receptor agonists, especially in combination with GIP and/or glucagon receptor agonists, may be promising therapies for MASLD/MASH.

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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.

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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

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