Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2022; 28(35): 5129-5140
Published online Sep 21, 2022. doi: 10.3748/wjg.v28.i35.5129
Combination strategies for pharmacologic treatment of non-alcoholic steatohepatitis
Jaspreet Suri, Sebastian Borja, Joseph K Lim
Jaspreet Suri, Department of Gastroenterology, Norwalk Hospital, Norwalk, CT 06856, United States
Sebastian Borja, Department of Internal Medicine, Norwalk Hospital, Norwalk, CT 06850, United States
Joseph K Lim, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, United States
Author contributions: Suri J was responsible for background data review, writing, editing and final review of the manuscript; Borja S was responsible for background data review and writing of the manuscript; Lim JK was responsible for writing, editing and final review of the manuscript.
Conflict-of-interest statement: Suri J, None; Borja S, None; Lim JK, research contract (to Yale University) from Allergan, Celgene, Genfit, Intercept, Pfizer, Viking.
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:
Corresponding author: Joseph K Lim, MD, Professor, Section of Digestive Diseases, Yale University School of Medicine, Yale Liver Center, 333 Cedar Street, LMP 1080, New Haven, CT 06520, United States.
Received: June 24, 2022
Peer-review started: June 24, 2022
First decision: July 11, 2022
Revised: July 26, 2022
Accepted: August 25, 2022
Article in press: August 25, 2022
Published online: September 21, 2022

Non-alcoholic steatohepatitis (NASH) is defined as hepatic steatosis, inflammation, and hepatocyte injury with or without fibrosis. It has emerged as the second leading indication for liver transplantation with a rising death rate in the non-transplantable population. While there are many drugs in evaluation, currently no approved therapies are on the market for this condition. Given this importance, the Food and Drug Administration has provided formal guidance regarding drug development for stopping or reversing NASH or NASH associated fibrosis. The complex pathogenesis of NASH and its bidirectional relationship with metabolic syndrome has highlighted multiple drugs of interest that address metabolic, inflammatory, and fibrotic factors. A few promising liver specific targets include farnesoid X receptor agonists and peroxisome proliferator-activated receptor agonists. Previously studied drug classes such as glucagon-like peptide-1 analogs or sodium/glucose transport protein 2 inhibitors have also demonstrated ability to improve hepatic steatosis. Here we discuss current rationale, scientific work, and preliminary data in combining multiple drugs for the purposes of a multimodal attack on the pathogenesis of NASH. We highlight multiple Phase 2 and Phase 3 studies that demonstrate the potential to achieve a response rate higher than previously assessed monotherapies for this condition. Ultimately, one of these combination strategies may rise above in its safety and efficacy to become a part of a standardized approach to NASH.

Keywords: Non-alcoholic steatohepatitis, Fatty liver, Combination treatment, Drug therapy, Pharmacologic treatment, Clinical trials

Core Tip: Multimodal combination approaches targeting two or more molecular pathways contributing to steatohepatitis and liver fibrosis are needed to augment efficacy of novel investigational drug regimens to achieve non-alcoholic steatohepatitis (NASH) resolution and NASH fibrosis improvement.