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Nonalcoholic Fatty Liver Disease and Diabetes: Part II: Treatment

  • Kim, Kyung-Soo (Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Lee, Byung-Wan (Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kim, Yong Jin (Department of Surgery, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine) ;
  • Lee, Dae Ho (Division of Endocrinology and Metabolism, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine) ;
  • Cha, Bong-Soo (Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Park, Cheol-Young (Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine)
  • Received : 2019.02.19
  • Accepted : 2019.03.19
  • Published : 2019.04.30

Abstract

Nonalcoholic fatty liver disease (NAFLD) and diabetes are common metabolic disorders that are often comorbid conditions. Among many proposed treatments, weight reduction is the only approved option for NAFLD to date. However, it is not easy to maintain weight loss by lifestyle modification alone; pharmacological treatments are helpful in this regard. Although many drugs have been investigated, pioglitazone could be a first-line therapy in patients with NAFLD and diabetes. Many more drugs are currently being developed and investigated, and it is likely that combination strategies will be used for future treatment of NAFLD and diabetes. Attention should be paid to the management of NAFLD and diabetes and efforts should be made to intervene early and individualize treatment of NAFLD in patients with diabetes.

Keywords

References

  1. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, Bass NM; Nonalcoholic Steatohepatitis Clinical Research Network. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012;56:943-51. https://doi.org/10.1002/hep.25772
  2. Lomonaco R, Bril F, Portillo-Sanchez P, Ortiz-Lopez C, Orsak B, Biernacki D, Lo M, Suman A, Weber MH, Cusi K. Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care 2016;39:632-8. https://doi.org/10.2337/dc15-1876
  3. Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care 2017;40:419-30. https://doi.org/10.2337/dc16-1787
  4. Han E, Lee YH. Non-alcoholic fatty liver disease: the emerging burden in cardiometabolic and renal diseases. Diabetes Metab J 2017;41:430-7. https://doi.org/10.4093/dmj.2017.41.6.430
  5. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia 2016;59:1121-40. https://doi.org/10.1007/s00125-016-3902-y
  6. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67:328-57. https://doi.org/10.1002/hep.29367
  7. Lazo M, Solga SF, Horska A, Bonekamp S, Diehl AM, Brancati FL, Wagenknecht LE, Pi-Sunyer FX, Kahn SE, Clark JM; Fatty Liver Subgroup of the Look AHEAD Research Group. Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care 2010;33: 2156-63. https://doi.org/10.2337/dc10-0856
  8. Ikramuddin S, Korner J, Lee WJ, Connett JE, Inabnet WB, Billington CJ, Thomas AJ, Leslie DB, Chong K, Jeffery RW, Ahmed L, Vella A, Chuang LM, Bessler M, Sarr MG, Swain JM, Laqua P, Jensen MD, Bantle JP. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the diabetes surgery study randomized clinical trial. JAMA 2013;309:2240-9. https://doi.org/10.1001/jama.2013.5835
  9. Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Chalasani NP, Anstee QM, Kowdley KV, George J, Goodman ZD, Lindor K. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2018;68:361-71. https://doi.org/10.1002/hep.29724
  10. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005;54:603-8. https://doi.org/10.2337/diabetes.54.3.603
  11. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, Fava JL, Wing RR. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121-9. https://doi.org/10.1002/hep.23276
  12. Wong VW, Wong GL, Chan RS, Shu SS, Cheung BH, Li LS, Chim AM, Chan CK, Leung JK, Chu WC, Woo J, Chan HL. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J Hepatol 2018;69: 1349-56. https://doi.org/10.1016/j.jhep.2018.08.011
  13. Huang MA, Greenson JK, Chao C, Anderson L, Peterman D, Jacobson J, Emick D, Lok AS, Conjeevaram HS. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 2005;100:1072-81. https://doi.org/10.1111/j.1572-0241.2005.41334.x
  14. Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol 2012;56:255-66. https://doi.org/10.1016/j.jhep.2011.06.010
  15. Kleiner DE, Makhlouf HR. Histology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children. Clin Liver Dis 2016;20:293-312. https://doi.org/10.1016/j.cld.2015.10.011
  16. Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2008;6:1396-402. https://doi.org/10.1016/j.cgh.2008.08.012
  17. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, Diago M, Romero-Gomez M. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;14:367-78.
  18. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomized trials. Diabetologia 2012;55:885-904. https://doi.org/10.1007/s00125-011-2446-4
  19. Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015;313:2263-73. https://doi.org/10.1001/jama.2015.5370
  20. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ; American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterology. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142:1592-609. https://doi.org/10.1053/j.gastro.2012.04.001
  21. Tamura Y, Tanaka Y, Sato F, Choi JB, Watada H, Niwa M, Kinoshita J, Ooka A, Kumashiro N, Igarashi Y, Kyogoku S, Maehara T, Kawasumi M, Hirose T, Kawamori R. Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2005;90:3191-6. https://doi.org/10.1210/jc.2004-1959
  22. Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology 2009;136:1552-60. https://doi.org/10.1053/j.gastro.2009.01.048
  23. Haufe S, Engeli S, Kast P, Bohnke J, Utz W, Haas V, Hermsdorf M, Mahler A, Wiesner S, Birkenfeld AL, Sell H, Otto C, Mehling H, Luft FC, Eckel J, Schulz-Menger J, Boschmann M, Jordan J. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology 2011;53:1504-14. https://doi.org/10.1002/hep.24242
  24. Keating SE, Hackett DA, George J, Johnson NA. Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012;57:157-66. https://doi.org/10.1016/j.jhep.2012.02.023
  25. Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA 2001;286:1218-27. https://doi.org/10.1001/jama.286.10.1218
  26. Bacchi E, Negri C, Targher G, Faccioli N, Lanza M, Zoppini G, Zanolin E, Schena F, Bonora E, Moghetti P. Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial). Hepatology 2013;58:1287-95. https://doi.org/10.1002/hep.26393
  27. Johnson NA, Sachinwalla T, Walton DW, Smith K, Armstrong A, Thompson MW, George J. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 2009;50:1105-12. https://doi.org/10.1002/hep.23129
  28. Sung KC, Ryu S, Lee JY, Kim JY, Wild SH, Byrne CD. Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. J Hepatol 2016;65:791-7. https://doi.org/10.1016/j.jhep.2016.05.026
  29. Shah K, Stufflebam A, Hilton TN, Sinacore DR, Klein S, Villareal DT. Diet and exercise interventions reduce intrahepatic fat content and improve insulin sensitivity in obese older adults. Obesity (Silver Spring) 2009;17:2162-8. https://doi.org/10.1038/oby.2009.126
  30. Yoshimura E, Kumahara H, Tobina T, Matsuda T, Ayabe M, Kiyonaga A, Anzai K, Higaki Y, Tanaka H. Lifestyle intervention involving calorie restriction with or without aerobic exercise training improves liver fat in adults with visceral adiposity. J Obes 2014;2014:197216.
  31. Wu T, Gao X, Chen M, van Dam RM. Long-term effectiveness of diet-plus-exercise interventions vs. diet-only interventions for weight loss: a meta-analysis. Obes Rev 2009;10:313-23. https://doi.org/10.1111/j.1467-789X.2008.00547.x
  32. Rodriguez B, Torres DM, Harrison SA. Physical activity: an essential component of lifestyle modification in NAFLD. Nat Rev Gastroenterol Hepatol 2012;9:726-31. https://doi.org/10.1038/nrgastro.2012.200
  33. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388-402. https://doi.org/10.1016/j.jhep.2015.11.004
  34. Maruthur NM, Wang NY, Appel LJ. Lifestyle interventions reduce coronary heart disease risk: results from the PREMIER trial. Circulation 2009;119:2026-31. https://doi.org/10.1161/CIRCULATIONAHA.108.809491
  35. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. https://doi.org/10.1056/NEJMoa012512
  36. Stefan N, Fritsche A, Schick F, Haring HU. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol 2016;4:789-98. https://doi.org/10.1016/S2213-8587(16)00082-6
  37. Stefan N, Haring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol 2019;7:313-24. https://doi.org/10.1016/S2213-8587(18)30154-2
  38. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, David E, Rizzetto M, Marchesini G. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082-90. https://doi.org/10.1111/j.1572-0241.2005.41583.x
  39. Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, Modi A, Nagabhyru P, Sumner AE, Liang TJ, Hoofnagle JH. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2009;29:172-82. https://doi.org/10.1111/j.1365-2036.2008.03869.x
  40. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Unalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; Nonalcoholic Steatohepatitis Clinical Research Network. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;305:1659-68. https://doi.org/10.1001/jama.2011.520
  41. Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep 2013;1:57-64. https://doi.org/10.3892/br.2012.18
  42. Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010;52:79-104. https://doi.org/10.1002/hep.23623
  43. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297-307. https://doi.org/10.1056/NEJMoa060326
  44. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, Tio F, Hardies J, Darland C, Musi N, Webb A, Portillo-Sanchez P. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 2016;165:305-15. https://doi.org/10.7326/m15-1774
  45. Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, Orsak B, Tio F, Cusi K. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol 2018;16:558-66. https://doi.org/10.1016/j.cgh.2017.12.001
  46. Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med 2017;177:633-40. https://doi.org/10.1001/jamainternmed.2016.9607
  47. Choung S, Joung KH, You BR, Park SK, Kim HJ, Ku BJ. Treatment with lobeglitazone attenuates hepatic steatosis in diet-induced obese mice. PPAR Res 2018;2018:4292509. https://doi.org/10.1155/2018/4292509
  48. Lee YH, Kim JH, Kim SR, Jin HY, Rhee EJ, Cho YM, Lee BW. Lobeglitazone, a novel thiazolidinedione, improves non-alcoholic fatty liver disease in type 2 diabetes: its efficacy and predictive factors related to responsiveness. J Korean Med Sci 2017;32:60-9. https://doi.org/10.3346/jkms.2017.32.1.60
  49. Armstrong MJ, Houlihan DD, Rowe IA, Clausen WH, Elbrond B, Gough SC, Tomlinson JW, Newsome PN. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther 2013;37:234-42. https://doi.org/10.1111/apt.12149
  50. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K; LEAN trial team, Abouda G, Aldersley MA, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hubscher SG, Newsome PN. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387:679-90. https://doi.org/10.1016/S0140-6736(15)00803-X
  51. Shao N, Kuang HY, Hao M, Gao XY, Lin WJ, Zou W. Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes. Diabetes Metab Res Rev 2014;30:521-9. https://doi.org/10.1002/dmrr.2561
  52. Gluud LL, Knop FK, Vilsboll T. Effects of lixisenatide on elevated liver transaminases: systematic review with individual patient data meta-analysis of randomised controlled trials on patients with type 2 diabetes. BMJ Open 2014;4:e005325. https://doi.org/10.1136/bmjopen-2014-005325
  53. Iwasaki T, Yoneda M, Inamori M, Shirakawa J, Higurashi T, Maeda S, Terauchi Y, Nakajima A. Sitagliptin as a novel treatment agent for non-alcoholic Fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology 2011;58:2103-5.
  54. Yilmaz Y, Yonal O, Deyneli O, Celikel CA, Kalayci C, Duman DG. Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis. Acta Gastroenterol Belg 2012;75:240-4.
  55. Kato H, Nagai Y, Ohta A, Tenjin A, Nakamura Y, Tsukiyama H, Sasaki Y, Fukuda H, Ohshige T, Terashima Y, Sada Y, Kondo A, Sasaoka T, Tanaka Y. Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes. Diabetes Res Clin Pract 2015;109:199-205. https://doi.org/10.1016/j.diabres.2015.04.008
  56. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, Richards L, Salotti J, Bhatt A, Hooker J, Haufe W, Hooker C, Brenner DA, Sirlin CB, Loomba R. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol 2016;65:369-76. https://doi.org/10.1016/j.jhep.2016.04.021
  57. Fukuhara T, Hyogo H, Ochi H, Fujino H, Kan H, Naeshiro N, Honda Y, Miyaki D, Kawaoka T, Tsuge M, Hiramatsu A, Imamura M, Kawakami Y, Aikata H, Chayama K. Efficacy and safety of sitagliptin for the treatment of nonalcoholic fatty liver disease with type 2 diabetes mellitus. Hepatogastroenterology 2014;61:323-8.
  58. Macauley M, Hollingsworth KG, Smith FE, Thelwall PE, Al-Mrabeh A, Schweizer A, Foley JE, Taylor R. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab 2015;100: 1578-85. https://doi.org/10.1210/jc.2014-3794
  59. Choi DH, Jung CH, Mok JO, Kim CH, Kang SK, Kim BY. Effect of dapagliflozin on alanine aminotransferase improvement in type 2 diabetes mellitus with non-alcoholic fatty liver disease. Endocrinol Metab (Seoul) 2018;33:387-94. https://doi.org/10.3803/EnM.2018.33.3.387
  60. Shimizu M, Suzuki K, Kato K, Jojima T, Iijima T, Murohisa T, Iijima M, Takekawa H, Usui I, Hiraishi H, Aso Y. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab 2019;21:285-92. https://doi.org/10.1111/dom.13520
  61. Eriksson JW, Lundkvist P, Jansson PA, Johansson L, Kvarnstrom M, Moris L, Miliotis T, Forsberg GB, Riserus U, Lind L, Oscarsson J. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Diabetologia 2018;61:1923-34. https://doi.org/10.1007/s00125-018-4675-2
  62. Kurinami N, Sugiyama S, Yoshida A, Hieshima K, Miyamoto F, Kajiwara K, Jinnouch K, Jinnouchi T, Jinnouchi H. Dapagliflozin significantly reduced liver fat accumulation associated with a decrease in abdominal subcutaneous fat in patients with inadequately controlled type 2 diabetes mellitus. Diabetes Res Clin Pract 2018;142:254-63. https://doi.org/10.1016/j.diabres.2018.05.017
  63. Leiter LA, Forst T, Polidori D, Balis DA, Xie J, Sha S. Effect of canagliflozin on liver function tests in patients with type 2 diabetes. Diabetes Metab 2016;42:25-32. https://doi.org/10.1016/j.diabet.2015.10.003
  64. Li B, Wang Y, Ye Z, Yang H, Cui X, Wang Z, Liu L. Effects of canagliflozin on fatty liver indexes in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. J Pharm Pharm Sci 2018;21:222-35. https://doi.org/10.18433/jpps29831
  65. Inoue M, Hayashi A, Taguchi T, Arai R, Sasaki S, Takano K, Inoue Y, Shichiri M. Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease. J Diabetes Investig 2018 Nov 21 [Epub]. https://doi.org/10.1111/jdi.12980.
  66. Itani T, Ishihara T. Efficacy of canagliflozin against nonalcoholic fatty liver disease: a prospective cohort study. Obes Sci Pract 2018;4:477-82. https://doi.org/10.1002/osp4.294
  67. Sattar N, Fitchett D, Hantel S, George JT, Zinman B. Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME trial. Diabetologia 2018;61:2155-63. https://doi.org/10.1007/s00125-018-4702-3
  68. Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, Bansal B, Kaur P, Jevalikar G, Gill HK, Choudhary NS, Mithal A. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT Trial). Diabetes Care 2018; 41:1801-8. https://doi.org/10.2337/dc18-0165
  69. Miyake T, Yoshida S, Furukawa S, Sakai T, Tada F, Senba H, Yamamoto S, Koizumi Y, Yoshida O, Hirooka M, Kumagi T, Niiya T, Miyaoka H, Masanori A, Matsuura B, Hiasa Y. Ipragliflozin ameliorates liver damage in non-alcoholic fatty liver disease. Open Med (Wars) 2018;13:402-9. https://doi.org/10.1515/med-2018-0059
  70. Tabuchi H, Maegawa H, Tobe K, Nakamura I, Uno S. Effect of ipragliflozin on liver function in Japanese type 2 diabetes mellitus patients: a subgroup analysis of the STELLA-LONG TERM study (3-month interim results). Endocr J 2019;66:31-41. https://doi.org/10.1507/endocrj.EJ18-0217
  71. Ito D, Shimizu S, Inoue K, Saito D, Yanagisawa M, Inukai K, Akiyama Y, Morimoto Y, Noda M, Shimada A. Comparison of ipragliflozin and pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled trial. Diabetes Care 2017;40:1364-72. https://doi.org/10.2337/dc17-0518
  72. Shibuya T, Fushimi N, Kawai M, Yoshida Y, Hachiya H, Ito S, Kawai H, Ohashi N, Mori A. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective randomized controlled pilot study. Diabetes Obes Metab 2018;20:438-42. https://doi.org/10.1111/dom.13061
  73. Sumida Y, Murotani K, Saito M, Tamasawa A, Osonoi Y, Yoneda M, Osonoi T. Effect of luseogliflozin on hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective, single-arm trial (LEAD trial). Hepatol Res 2019;49:64-71. https://doi.org/10.1111/hepr.13236
  74. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362:1675-85. https://doi.org/10.1056/NEJMoa0907929
  75. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46. https://doi.org/10.7326/0003-4819-142-1-200501040-00110
  76. Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, Minasian LM, Ford LG, Parnes HL, Gaziano JM, Karp DD, Lieber MM, Walther PJ, Klotz L, Parsons JK, Chin JL, Darke AK, Lippman SM, Goodman GE, Meyskens FL Jr, Baker LH. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306:1549-56. https://doi.org/10.1001/jama.2011.1437
  77. Cusi K. Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Diabetologia 2016;59:1112-20. https://doi.org/10.1007/s00125-016-3952-1
  78. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol 2009;43:990-4. https://doi.org/10.1097/MCG.0b013e31819c392e
  79. Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, Soaft L, Hooker J, Kono Y, Bhatt A, Hernandez L, Nguyen P, Noureddin M, Haufe W, Hooker C, Yin M, Ehman R, Lin GY, Valasek MA, Brenner DA, Richards L; San Diego Integrated NAFLD Research Consortium (SINC). Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015;61:1239-50. https://doi.org/10.1002/hep.27647
  80. Fabbrini E, Mohammed BS, Korenblat KM, Magkos F, McCrea J, Patterson BW, Klein S. Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2010;95:2727-35. https://doi.org/10.1210/jc.2009-2622
  81. Dasarathy S, Dasarathy J, Khiyami A, Yerian L, Hawkins C, Sargent R, McCullough AJ. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol 2015;49:137-44. https://doi.org/10.1097/MCG.0000000000000099
  82. Neuman M, Angulo P, Malkiewicz I, Jorgensen R, Shear N, Dickson ER, Haber J, Katz G, Lindor K. Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis. J Gastroenterol Hepatol 2002;17:196-202. https://doi.org/10.1046/j.1440-1746.2002.02672.x
  83. Bellentani S. Immunomodulating and anti-apoptotic action of ursodeoxycholic acid: where are we and where should we go? Eur J Gastroenterol Hepatol 2005;17:137-40. https://doi.org/10.1097/00042737-200502000-00001
  84. Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakela J, McGill DB. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464-7. https://doi.org/10.1053/jhep.1996.v23.pm0008675165
  85. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, Helbling B, Steuerwald M, Zimmermann A; Swiss Association for the Study of the Liver. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006;4:1537-43. https://doi.org/10.1016/j.cgh.2006.09.025
  86. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770-8. https://doi.org/10.1002/hep.20092
  87. Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rossle M, Cordes HJ, Zeuzem S, Hein J, Berg T; NASH Study Group. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010;52:472-9. https://doi.org/10.1002/hep.23727
  88. Koppe SW, Sahai A, Malladi P, Whitington PF, Green RM. Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet. J Hepatol 2004;41:592-8. https://doi.org/10.1016/j.jhep.2004.06.030
  89. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, McCullough AJ. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011;54:1610-9. https://doi.org/10.1002/hep.24544
  90. Van Wagner LB, Koppe SW, Brunt EM, Gottstein J, Gardikiotes K, Green RM, Rinella ME. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol 2011;10:277-86. https://doi.org/10.1016/S1665-2681(19)31539-X
  91. Townsend SA, Newsome PN. Review article: new treatments in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2017;46:494-507. https://doi.org/10.1111/apt.14210
  92. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, Castelloe E, Dillon P, Pruzanski M, Shapiro D. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145:574-82. https://doi.org/10.1053/j.gastro.2013.05.042
  93. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385:956-65. https://doi.org/10.1016/S0140-6736(14)61933-4
  94. Cariou B, Hanf R, Lambert-Porcheron S, Zair Y, Sauvinet V, Noel B, Flet L, Vidal H, Staels B, Laville M. Dual peroxisome proliferator-activated receptor ${\alpha}/{\delta}$ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 2013;36:2923-30. https://doi.org/10.2337/dc12-2012
  95. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M, Boursier J, Abdelmalek M, Caldwell S, Drenth J, Anstee QM, Hum D, Hanf R, Roudot A, Megnien S, Staels B, Sanyal A; GOLDEN-505 Investigator Study Group. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-${\alpha}$ and -${\delta}$, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016;150:1147-59. https://doi.org/10.1053/j.gastro.2016.01.038
  96. Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, Chou HL, Hashiguchi T, Plato C, Poulin D, Richards T, Yoneyama H, Jenkins H, Wolfgang G, Friedman SL. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One 2016; 11:e0158156. https://doi.org/10.1371/journal.pone.0158156
  97. Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, Francque S, Farrell G, Kowdley KV, Craxi A, Simon K, Fischer L, Melchor-Khan L, Vest J, Wiens BL, Vig P, Seyedkazemi S, Goodman Z, Wong VW, Loomba R, Tacke F, Sanyal A, Lefebvre E. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 2018;67:1754-67. https://doi.org/10.1002/hep.29477
  98. Li JL, Wang QY, Luan HY, Kang ZC, Wang CB. Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha. J Biomed Sci 2012;19:32. https://doi.org/10.1186/1423-0127-19-32
  99. Malaguarnera M, Gargante MP, Russo C, Antic T, Vacante M, Malaguarnera M, Avitabile T, Li Volti G, Galvano F. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis. A randomized and controlled clinical trial. Am J Gastroenterol 2010;105:1338-45. https://doi.org/10.1038/ajg.2009.719
  100. Bae JC, Lee WY, Yoon KH, Park JY, Son HS, Han KA, Lee KW, Woo JT, Ju YC, Lee WJ, Cho YY, Lee MK. Improvement of nonalcoholic fatty liver disease with carnitine-orotate complex in type 2 diabetes (CORONA): a randomized controlled trial. Diabetes Care 2015;38:1245-52. https://doi.org/10.2337/dc14-2852
  101. Jani RH, Pai V, Jha P, Jariwala G, Mukhopadhyay S, Bhansali A, Joshi S. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI). Diabetes Technol Ther 2014;16: 63-71. https://doi.org/10.1089/dia.2013.0253
  102. Jain MR, Giri SR, Bhoi B, Trivedi C, Rath A, Rathod R, Ranvir R, Kadam S, Patel H, Swain P, Roy SS, Das N, Karmakar E, Wahli W, Patel PR. Dual $PPAR{\alpha}$/${\gamma}$ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int 2018;38:1084-94. https://doi.org/10.1111/liv.13634
  103. Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics. Metabolism 2019;92:82-97. https://doi.org/10.1016/j.metabol.2018.11.014
  104. Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, Leshno M, Blendis L, Halpern Z, Oren R. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2006;4:639-44. https://doi.org/10.1016/j.cgh.2006.02.004
  105. Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 2009;49:80-6. https://doi.org/10.1002/hep.22575
  106. Wang H, Wang L, Cheng Y, Xia Z, Liao Y, Cao J. Efficacy of orlistat in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep 2018;9:90-6.
  107. Tuccinardi D, Farr OM, Upadhyay J, Oussaada SM, Mathew H, Paschou SA, Perakakis N, Koniaris A, Kelesidis T, Mantzoros CS. Lorcaserin treatment decreases body weight and reduces cardiometabolic risk factors in obese adults: a six-month, randomized, placebo-controlled, double-blind clinical trial. Diabetes Obes Metab 2019 Feb 6 [Epub]. https://doi.org/10.1111/dom.13655.
  108. Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, Pigeyre M, Verkindt H, Dharancy S, Louvet A, Romon M, Pattou F. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009;137:532-40. https://doi.org/10.1053/j.gastro.2009.04.052
  109. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, Raverdy V, Leteurtre E, Dharancy S, Louvet A, Romon M, Duhamel A, Pattou F, Mathurin P. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015;149:379-88. https://doi.org/10.1053/j.gastro.2015.04.014
  110. Bower G, Toma T, Harling L, Jiao LR, Efthimiou E, Darzi A, Athanasiou T, Ashrafian H. Bariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histology. Obes Surg 2015;25:2280-9. https://doi.org/10.1007/s11695-015-1691-x
  111. Lee Y, Doumouras AG, Yu J, Brar K, Banfield L, Gmora S, Anvari M, Hong D. Complete resolution of nonalcoholic fatty liver disease after bariatric surgery: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2018 Oct 13 [Epub]. https://doi.org/10.1016/j.cgh.2018.10.017.
  112. Mosko JD, Nguyen GC. Increased perioperative mortality following bariatric surgery among patients with cirrhosis. Clin Gastroenterol Hepatol 2011;9:897-901. https://doi.org/10.1016/j.cgh.2011.07.007
  113. Jan A, Narwaria M, Mahawar KK. A systematic review of bariatric surgery in patients with liver cirrhosis. Obes Surg 2015; 25:1518-26. https://doi.org/10.1007/s11695-015-1727-2

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