Review
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. May 27, 2024; 16(5): 731-750
Published online May 27, 2024. doi: 10.4254/wjh.v16.i5.731
Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease: Opportunities and challenges
Chencheng Xie, Naim Alkhouri, Mohamed A Elfeki
Chencheng Xie, Mohamed A Elfeki, Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, United States
Chencheng Xie, Department of Hepatology, Avera Mckennan University Hospital and Transplant Institute, Sioux Falls, SD 57105, United States
Naim Alkhouri, Department of Hepatology, Arizona Liver Health, Chandler, AZ 85712, United States
Mohamed A Elfeki, Department of Hepatology, Avera McKennan University Hospital and Transplant Institute, Sioux Falls, SD 57105, United States
Author contributions: Xie C conceptualized of the design of the review article, performed the literature review, wrote the initial draft of the introduction and pathophysiology sections, created the figures, and critically revised the manuscript for important intellectual content; Alkhouri N revised the manuscript critically and added important intellectual content; Elfeki MA conceptualized the design of the review article, performed the literature search and review, wrote the initial draft of the following sections: clinical trials and therapeutic effects of incretin and glucagon RAs, adverse effects, clinical practice implications, barriers to access, perioperative management, clinical trials and future perspective sections, created the tables, and revised the manuscript critically for important intellectual content.
Conflict-of-interest statement: Xie C and Elfeki MA have no conflicts of interest to disclose. Alkhouri N has the following disclosure: Reports grant/research support from 89Bio, Akero, Altimmune, Better Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Corcept, DSM, Galectin, Genentech, Genfit, Gilead, Hepagene, Healio, Intercept, Inventiva, Ionis, Madrigal, Merck, NGM, Noom, NorthSea, Novo Nordisk, Perspectum, Pfizer, Poxel, Viking, and Zydus; Speaker’s fees from AbbVie, Alexion, Echosens, Eisai, Exelixis, Gilead, Intercept, Perspectum, Salix, and Theratechnologies; Consultant for 89Bio, Altimmune, Boehringer Ingelheim, Echosens, Fibronostics, Gilead, Intercept, Madrigal, NorthSea, Novo Nordisk, Perspectum, Pfizer, and Zydus.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Mohamed A Elfeki, MD, MSc, Assistant Professor, Department of Internal Medicine, University of South Dakota Sanford School of Medicine, 1315 S Cliff Ave, Plaza 3, Suite 1200, Sioux Falls, SD 57105, United States. m_elfiky@hotmail.com
Received: December 30, 2023
Revised: February 18, 2024
Accepted: April 3, 2024
Published online: May 27, 2024
Processing time: 143 Days and 13.1 Hours
Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, paralleling the rising pandemic of obesity and type 2 diabetes. Due to the growing global health burden and complex pathogenesis of MASLD, a multifaceted and innovative therapeutic approach is needed. Incretin receptor agonists, which were initially developed for diabetes management, have emerged as promising candidates for MASLD treatment. This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists: glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic polypeptide receptor agonists, and glucagon receptor agonists. Incretins and glucagon directly or indirectly impact various organs, including the liver, brain, pancreas, gastrointestinal tract, and adipose tissue. Thus, these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis. Importantly, this study provides a summary of clinical trials analyzing the effectiveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function, hepatic steatosis, and intrahepatic inflammation. There are emerging challenges associated with the use of these medications in the real world, particularly adverse events, drug-drug interactions, and barriers to access, which are discussed in detail. Additionally, this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

Keywords: Metabolic dysfunction-associated steatotic liver disease; Metabolic dysfunction-associated steatohepatitis; Glucagon-like peptide-1; Glucose-dependent inulinotropic polypeptide; Glucagon; Incretin; Receptor agonist

Core Tip: In this review, we highlight the evolving role of incretin and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease. These agents showed promising potential for improving hepatic steatosis and metabolic dysfunction-associated steatohepatitis (MASH) with a clear benefit for associated cardiometabolic risk factors. However, its role in MASH-associated fibrosis remains unclear. Barriers to access due to limited supplies, cost, and lack of insurance coverage could be overcome through patent and regulatory reforms on drug-device combinations, which may allow for generic competitors of these agents to be available for patients at affordable prices.