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Review
. 2020 Mar 11;21(6):1907.
doi: 10.3390/ijms21061907.

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

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Free PMC article
Review

Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis

Yoshio Sumida et al. Int J Mol Sci. .
Free PMC article

Abstract

Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.

Keywords: dipeptidyl peptidase-4; fibroblast growth factor; gastrointestinal peptide; glucagon receptor; glucagon-like peptide 1; peroxisome proliferator-activated receptor; sodium glucose cotransporter.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Mechanisms of antidiabetic therapies for nonalcoholic steatohepatitis (NASH). GLP-1: glucagon-like peptide, DNL: de novo lipogenesis, TNFα: tumor necrosis factor α, FFA: free fatty acid, TG: triglyceride, KHK: ketohexokinase, GCGR: glucagon receptor, GPR: G-protein-coupled receptor, MPC: mitochondrial pyruvate carrier, SGLT: sodium-glucose cotransporter, TCA: tricarboxylic acid, ROS: reactive oxygen species, PPAR: peroxisome proliferator-activated receptor, FGF: fibroblast growth factor, CREBP: cAMP-response element-binding protein, FAO: fatty acid oxidation.
Figure 2
Figure 2
Sub-analyses of efficacy and safety of tirzepatide (TZP) in patients with type 2 diabetes: a randomized, placebo-controlled, and dulaglutide-controlled phase 2 trial [57]. * p < 0.05 change from baseline vs. Dulaglutide. # p < 0.05 change from baseline vs. placebo.
Figure 3
Figure 3
Drug pipelines of NASH “Combo”, including antidiabetic drugs. GLP-1RA: glucagon-like peptide receptor agonist, DPP-4: dipeptidyl peptidase-4, SGLT: sodium-glucose cotransporter, GIP: gastrointestinal peptide, GCGR: glucagon receptor, PPAR: peroxisome proliferator-activated receptor, FXR: farnesoid X receptor, FGF-21: fibroblast growth factor-21, CCR2/5: C-C motif chemokine receptor-2/5.

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