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Review
. 2018 Mar;53(3):362-376.
doi: 10.1007/s00535-017-1415-1. Epub 2017 Dec 16.

Current and future pharmacological therapies for NAFLD/NASH

Yoshio Sumida  1 , Masashi Yoneda  2
Affiliations
Review

Current and future pharmacological therapies for NAFLD/NASH

Yoshio Sumida et al. J Gastroenterol. 2018 Mar.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation. Medications in this approach include modulation of peroxisome proliferator-activator receptors (e.g., pemafibrate, elafibranor), medications targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21 analogues. A second target is oxidative stress, inflammation, and apoptosis. This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and emricasan (an irreversible caspase inhibitor). A third target is intestinal microbiomes and metabolic endotoxemia. Several agents are in ongoing trials, including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics). The final target is hepatic fibrosis, which is strongly associated with all-cause or liver-related mortality in NASH. Antifibrotic agents are a cysteine-cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC) and galectin 3 antagonist. Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases.

Keywords: Diabetes; GLP-1 receptor agonist; Hepatic fibrosis; NASH; SGLT2 inhibitor.

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Conflict of interest statement

Authors must indicate whether or not they have/had a financial relationship (within the last 3 years) with any organization that sponsored the research. They should also confirm that they have full control of all primary data and that they agree to allow the journal to review their data if requested.

Figures

Fig. 1
Fig. 1
Fibrosis stage-based treatment algorithm for NASH/NAFLD
Fig. 2
Fig. 2
Targets of upcoming therapies for NASH/NAFLD
Fig. 3
Fig. 3
PPAR agonists for NASH/NAFLD
Fig. 4
Fig. 4
Milestones in the treatment of NASH are “ABC”??
Fig. 5
Fig. 5
Variety of stakeholders in the treatment of NASH/NAFLD
Fig. 6
Fig. 6
NASH drug pipelines
See this image and copyright information in PMC

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