Diabetes Metab J.  2020 Oct;44(5):640-657. 10.4093/dmj.2020.0115.

Nonalcoholic Fatty Liver Disease: A Drug Revolution Is Coming

• Jeong SW

• KMID: 2513026
• DOI: http://doi.org/10.4093/dmj.2020.0115

Abstract

The worldwide prevalence of non-alcoholic fatty liver disease is around 25%, and that of nonalcoholic steatohepatitis (NASH) ranges from 1.5% to 6.45%. Patients with NASH, especially those with fibrosis, are at higher risk for adverse outcomes such as cirrhosis and liver-related mortality. Although vitamin E, pioglitazone, and liraglutide improved liver histology in randomized trials, there are currently no Food and Drug Administration-approved drugs for NASH. Five pharmacologic agents—obeticholic acid, elafibranor, cenicriviroc, resmetirom, and aramchol—are being evaluated in large, histology-based phase 3 trials. Within 2 to 4 years, new and effective drugs for the treatment of NASH are expected. Additionally, many phase 2 trials are ongoing for various agents. Based on the results of phase 2 and 3 trials, combination treatments are also being investigated. Future treatment strategies will comprise drug combinations and precision medicine based on the different phenotypes of NASH and treatment response of the individual patient.

Keyword

Drug therapy, combination; Fibrosis; Non-alcoholic fatty liver disease; Precision medicine; Therapeutics

Figure

• 

  Fig. 1. Mechanism of action for nonalcoholic steatohepatitis treatment. OCA, obeticholic acid; HDL, high density lipoprotein; LDL, low density lipoprotein; SGLT2, sodium glucose cotransporter 2; FXR, farnesoid X receptor; THR-β, thyroid hormone receptor-β; LDL-R, low density lipoprotein receptor; SR-B1, scavenger receptor class B type 1; SREBP-2, sterol regulatory element-binding proteins-2; CYP7A1, cholesterol 7α-hydroxylase; SREBP-1c, sterol regulatory element binding protein-1c; ACC-1, acetyl-coenzyme A carboxylase-1; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; PPAR, peroxisome proliferator-activated receptor; LXRα, liver X receptor α; SHP, small heterodimer partner; ERK1/2, extracellular signal-regulated kinase 1/2; FGFR4, fibroblast growth factor receptor 4; FoxO1, forkhead box protein O1; CREB, cAMP response element-binding protein; FGF, fibroblast growth factor; FAO, fatty acid β-oxidation; CoA, coenzyme A; TCA, tricarboxylic acid; MPC, mitochondrial pyruvate carrier; TG, triglyceride; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6.

• 

  Fig. 2. The classification of phase 2,3 trials based on mechanism of action in nonalcoholic steatohepatitis (NASH) treatment. FXR, farnesoid X receptor; FGF, fibroblast growth factor; PPAR, peroxisome proliferator-activated receptor; SGLT2, sodium glucose cotransporter 2; GLP-1 RA, glucagon-like peptide-1 receptor agonist; MPC, mitochondrial pyruvate carrier; SCD1, stearoylCoA desaturase 1; ACC, acetyl-coenzyme A carboxylase; THR-β, thyroid hormone receptor-β.

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