Systematic Reviews
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Aug 27, 2023; 15(8): 1001-1012
Published online Aug 27, 2023. doi: 10.4254/wjh.v15.i8.1001
Emerging therapeutic options for non-alcoholic fatty liver disease: A systematic review
Jasmine Tidwell, Natalie Balassiano, Anjiya Shaikh, Mahmoud Nassar
Jasmine Tidwell, Anjiya Shaikh, Department of Internal Medicine, University of Connecticut, Farmington, CT 06032, United States
Natalie Balassiano, Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/NYC Health+Hospitals/Queens, New York, NY 11432, United States
Mahmoud Nassar, Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY 14221, United States
Author contributions: Tidwell J and Balassiano N performed the screening of articles, extraction of data and wrote the manuscript; Tidwell J and Shaikh A contributed to the results and discussion section; Nassar M contributed to editing, formatting and reviewing; All authors have read and approve the final manuscript.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
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: Mahmoud Nassar, MD, MSc, PhD, Doctor, Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, WNY 705 Maple Road, Williamsville, Buffalo, NY 14221, United States. dr.nassar@aucegypt.edu
Received: April 30, 2023
Peer-review started: April 30, 2023
First decision: June 7, 2023
Revised: June 18, 2023
Accepted: August 7, 2023
Article in press: August 7, 2023
Published online: August 27, 2023
Abstract
BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation. In the United States alone, annual medical costs are approximately 100 billion dollars. Unfortunately, there is no Federal Drug Administration (FDA)-approved medication for its treatment. However, various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD. It is valuable to have a compilation of the data available on their efficacy.

AIM

To assess the efficacy of cyclophilin inhibitors, fibroblast growth factor 21 analogs (FGF21), and dual and pan peroxisome proliferator-activated receptor (PPAR) agonists for treating NAFLD.

METHODS

A comprehensive literature search using keywords including cyclophilin inhibitor, FGF agonist, pan-PPAR agonists, dual-PPAR agonist, NAFLD, non-alcoholic steatohepatitis, and fatty liver was conducted on October 29, 2022, in PubMed, EMBASE, Cochrane Library, Scopus and Web of Science. Animal and human research, case reports, and published articles in English from all countries with patients aged 18 and above were included. Only articles with a National Institutes of Health (NIH) Quality Assessment score of five or higher out of eight points were included. Articles that were narrative or systematic reviews, abstracts, not in English, focused on patients under 18 years old, did not measure outcomes of interest, were inaccessible, or had a low NIH Quality Assessment score were excluded. Each article was screened by two independent researchers evaluating relevance and quality. Resources were scored based on the NIH Quality Assessment Score; then, pertinent data was extracted in a spreadsheet and descriptively analyzed.

RESULTS

Of the 681 records screened, 29 met the necessary criteria and were included in this review. These records included 12 human studies and 17 animal studies. Specifically, there were four studies on cyclophilin inhibitors, four on FGF agonists/analogs, eleven on pan-PPAR agonists, and ten on dual-PPAR agonists. Different investigational products were assessed: The most common cyclophilin inhibitor was NV556; FGF agonists and analogs was Efruxifermin; pan-PPAR agonists was Lanifibranor; and dual-PPAR agonists was Saroglitazar. All classes were found to be statistically efficacious for the treatment of NAFLD, with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan (P < 0.05).

CONCLUSION

The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes, as well as good safety profiles (P < 0.05). We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.

Keywords: Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Cyclophilin inhibitors, Fibroblast growth factor 21 analogs, Dual peroxisome proliferator-activated receptor agonists, Pan peroxisome proliferator-activated receptor agonists

Core Tip: Non-alcoholic fatty liver disease (NAFLD) has become a significant global health issue. There is no medication approved by the Federal Drug Administration for the treatment of NAFLD. However, there are several therapeutic classes currently being studied in clinical trials. In this systematic review, we analyze the scientific data of cyclophilin inhibitors, fibroblast growth factor 21 analogs, and dual and pan peroxisome proliferator-activated receptor agonists for the treatment of NAFLD.