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Beneficial Effect of Anti-Diabetic Drugs for Nonalcoholic Fatty Liver Disease

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Beneficial Effect of Anti-Diabetic Drugs for Nonalcoholic Fatty Liver Disease pISSN 2287-2728 eISSN 2287-285X https://doi.org/10.3350/cmh.2020.0137 Review Clinical and Molecular Hepatology 2020;26:430-443 Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease Kyung-Soo Kim1 and Byung-Wan Lee2 1Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam; 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder and is associated with various metabolic diseases, including type 2 diabetes mellitus. There are no approved drugs for NAFLD, and the only approved treatment option is weight reduction. As insulin resistance plays an important role in the development of NAFLD, many anti- diabetic drugs have been evaluated for the treatment of NAFLD. Improvement of liver enzymes has been demonstrated by many anti-diabetic drugs, but histological assessment still remains insufficient. Pioglitazone could become the first- line therapy for T2DM patients with NAFLD, based on evidence of histological improvement in patients with biopsy- proven nonalcoholic steatohepatitis (NASH). Liraglutide, another promising alternative, is not yet recommended in patients with NAFLD/NASH due to limited evidence. Therefore, well-designed randomized controlled trials should be performed in the near future to demonstrate if and how anti-diabetic drugs can play a role in the treatment of NAFLD. (Clin Mol Hepatol 2020;26:430-443) Keywords: Anti-diabetic drug; Diabetes mellitus; Metabolic diseases; Non-alcoholic fatty liver disease; Treatment INTRODUCTION hepatitis (NASH), advanced fibrosis, and hepatocellular carcinoma (HCC). NAFLD is the fastest growing cause of HCC in liver trans- Nonalcoholic fatty liver disease (NAFLD) is associated with liver- plant candidates,1 and it is projected that NAFLD is becoming the related morbidity, including progression to nonalcoholic steato- leading cause of liver transplantation.2 NAFLD can be coexistent Abbreviations: Corresponding author : Byung-Wan Lee ALT, alanine aminotransferase; AMPK, adenosine monophosphate-activated Division of Endocrinology and Metabolism, Department of Internal protein kinase; AST, aspartate aminotransferase; AWARD, Assessment of Weekly Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Administration of LY2189265 (dulaglutide) in Diabetes; BMI, body mass index; Seodaemun-gu, Seoul 03722, Korea CV, cardiovascular; DEAN, Dapagliflozin Efficacy and Action in NASH; DPP- Tel: +82-2-2228-1938, Fax: +82-2-393-6884 4, dipeptidyl peptidase-4; E-LIFT, Effect of Empagliflozin on Liver Fat Content E-mail: [email protected] in Patients With Type 2 Diabetes; EFFECT-II, Effects of Omega-3 Carboxylic Acids and Dapagliflozin on Liver Fat Content in Diabetic Patients; EMPA- https://orcid.org/0000-0002-9899-4992 REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RAs, GLP-1 receptor agonists; GLP-1, glucagon-like peptide-1; HCC, hepatocellular carcinoma; LEAD, Liraglutide Effect and Action in Diabetes; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; PDFF, proton density fat fraction; PIVENS, Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH; PPAR-γ, peroxisome proliferator-activated receptor-γ; RCTs, randomized controlled trials; SGLT2, sodium-glucose cotransporter 2; T2DM, type 2 diabetes mellitus; TNF, tumor necrosis factor; TZDs, thiazolidinediones Editor: Silvia Sookoian, University of Buenos Aires, Argentina Received : Jun. 22, 2020 / Revised : Jun. 29, 2020 / Accepted : Jun. 30, 2020 Copyright © 2020 by Korean Association for the Study of the Liver This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Kyung-Soo Kim, et al. Anti-diabetic drugs for NAFLD with type 2 diabetes mellitus (T2DM), and this combination re- progression to NASH, advanced fibrosis, cirrhosis, and even HCC,7-9 sults in the undesirable consequence of cardiovascular (CV) independently of liver enzymes.10,11 Studies on South Korean pa- events, which underscores the need for lifestyle modification in tients with T2DM who underwent ultrasonography in a university the management of NAFLD regardless of diabetes.3,4 NAFLD is the and a private clinic-based diabetes care facility showed 63.3% one of the most common liver disorders, affecting approximately and 72.7% prevalence of NAFLD, respectively.12,13 A recent meta- 20–40% of the population worldwide, with different burdens ac- analysis reported that the global prevalence of NAFLD and NASH cording to age, sex, ethnicity, and diagnostic tools.5,6 The pres- among patients with T2DM is 55.5% and 37.3%, respectively.14 ence of diabetes is closely associated with the severity of NAFLD, The European Association for the Study of the Liver, the European Increased hepatic glucose production Metformin Decreased glucose uptake Thiazolidinediones Increased lipolysis and reduced glucose uptake Sulforylureas /meglitinides Impaired insulin secretion DPP-4 inhibitors Increased glucagon secretion Hyperglycemia GLP1-RAs Increased rate of glucose absorption α-glucosidase inhibitors Increased glucagon resbsorption SGLT2 inhibitors Figure 1. Mechanism of action and effects of anti-diabetic drugs on glucose metabolism. DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT2, sodium-glucose cotransporter 2. 431 http://www.e-cmh.org https://doi.org/10.3350/cmh.2020.0137 Volume_26 Number_4 October 2020 Association for the Study of Diabetes, and the European Associa- phate depletion21 or autophagy activation.22 In a pilot study of tion for the Study of Obesity, in their joint clinical practice guide- 20 non-diabetic patients with NAFLD, metformin treatment for lines for the management of NAFLD recommend screening for 4 months reduced liver enzymes and improved insulin sensitivity NAFLD in T2DM patients and vice versa.15 Although weight reduc- and liver volume as detected by ultrasound.23 However, among tion is the cornerstone of therapy among the various treatments well-designed randomized controlled trials (RCTs), the TONIC trial, for NAFLD,16 pharmacotherapy should be administered since suffi- which recruited 173 non-diabetic patients aged 8–17 years with cient weight reduction can be difficult to achieve and maintain. In biopsy-proven NAFLD and persistent increase in ALT, did not dem- subjects with T2DM and NAFLD, management with anti-diabetic onstrate reduced ALT level and improved liver histology with met- drugs is more effective than lifestyle modification in controlling formin compared to placebo.24 To date, meta-analyses have glucose level (Fig. 1). Moreover, lifestyle changes, together with shown that metformin could improve liver function, insulin resis- anti-diabetic medications, are likely to have an additive effect on tance, and body mass index (BMI) to some extent, but does not reducing the risk factors associated with CV diseases, decreasing impact histological response in NAFLD patients.25-27 In this regard, hepatic fat accumulation, and delaying progression to NASH and current guidelines do not recommend metformin for treating fibrosis. Although there is no approved drug of choice for manag- NASH in adult patients.15,28 Despite the lack of known benefits to ing NAFLD, many anti-diabetic drugs have been tested in patients treat NAFLD, metformin aids in reducing CV risks related to dia- with NAFLD due to the shared epidemiological and pathophysio- betes. Furthermore, a meta-analysis of case-control studies found logical features between NAFLD and T2DM. The aim of this re- that metformin use was associated with a reduced risk of HCC, view is to summarize the beneficial effects of anti-diabetic drugs which is the final sequence of NAFLD, and it may be a relevant for NAFLD. factor in preventing HCC in diabetic patients.29 Based on these studies, metformin could be beneficial for NAFLD patients with T2DM. METFORMIN Metformin has been derived from the guanidine-rich Galega of- THIAZOLIDINEDIONES ficinalis (goat’s rue or French lilac), and is a kind of general insulin sensitizer.17 Although its molecular mechanisms of action are com- Thiazolidinediones (TZDs) are peroxisome proliferator-activated plex and not completely understood, metformin has been shown receptor-γ (PPAR-γ) agonists that act as insulin sensitizers on adi- to act via both adenosine monophosphate-activated protein ki- pose tissue, muscle, and liver. TZDs improve insulin and glucose nase (AMPK)-dependent and AMPK-independent mechanisms, by parameters, modulate adipose tissue distribution while decreasing the inhibition of mitochondrial respiration but also perhaps by the visceral fat and increasing subcutaneous fat, and reduce lipotoxic- inhibition of mitochondrial glycerophosphate dehydrogenase and ity in the liver. In addition, TZDs have demonstrated anti-inflam- a mechanism involving lysosomes at the molecular level (Table 1).18 matory and antioxidant properties. Physiologically, metformin reduces
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