Advertisement

Long-term luseogliflozin therapy improves histological activity of non-alcoholic steatohepatitis accompanied by type 2 diabetes mellitus

  • Naoyuki Fujimori
  • Naoki TanakaEmail author
  • Takefumi Kimura
  • Kenji Sano
  • Akira Horiuchi
  • Naoyuki Kato
  • Yoshiyuki Takahashi
  • Naoya Kuribayashi
  • Ayumi Sugiura
  • Tomoo Yamazaki
  • Satoru Joshita
  • Takeji Umemura
  • Akihiro Matsumoto
  • Eiji Tanaka
Case Report
  • 25 Downloads

Abstract

A 60-year-old Japanese woman was referred to our hospital for further examination of persistent liver dysfunction. She had been suffering from type 2 diabetes mellitus since the age of 50 years. Her hemoglobin A1c (HbA1c) value was as high as 7.8% despite treatment with dipeptidyl peptidase-4 inhibitor, metformin, and sulfonylurea. After excluding viral hepatitis, alcohol or drug-induced liver injury, and autoimmune liver diseases, liver histology evidence of macrovesicular steatosis, hepatocyte ballooning, and pericellular fibrosis confirmed a diagnosis of non-alcoholic steatohepatitis (NASH). Luseogliflozin (2.5 mg/day), a sodium–glucose cotransporter 2 inhibitor (SGLT2I), was co-administered to strengthen glycemic control. Liver enzymes and HbA1c gradually improved without any adverse events. A second liver biopsy at 15 months after luseogliflozin commencement revealed improvements in steatosis, fibrosis, and overall histological activity score. This case demonstrates that long-term luseogliflozin may be a good therapeutic option for diabetic NAFLD/NASH patients. The merits of persistent SGLT2I administration for NAFLD/NASH patients warrant validation in future studies.

Keywords

Luseogliflozin Sodium–glucose cotransporter 2 inhibitor Non-alcoholic steatohepatitis Non-alcoholic fatty liver disease Fibrosis 

Notes

Acknowledgements

We appreciate Mr. Trevor Ralph for his English editorial assistance and Mr. Yukihiro Mizusawa and Ms. Yukari Mashimo (Asama Nanroku Komoro Medical Center) for their invaluable instruction of ultrasonography imaging.

Compliance with ethical standards

Conflict of interest

Fujimori N, Kimura T, and Tanaka N received a research grant from Taisho Pharmaceutical Co., Ltd. Tanaka N received lecture fees from Taisho Pharmaceutical Co., Ltd.

Human rights

All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

Informed consent was obtained from the patient.

References

  1. 1.
    Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol. 2018;69:896–904.CrossRefGoogle Scholar
  2. 2.
    Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–90.CrossRefGoogle Scholar
  3. 3.
    Eguchi Y, Hyogo H, Ono M, et al. Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol. 2012;47:586–95.CrossRefGoogle Scholar
  4. 4.
    Tanaka N, Kimura T, Fujimori N, et al. Current status, problems, and perspectives of non-alcoholic fatty liver disease research. World J Gastroenterol. 2019;25:163–77.CrossRefGoogle Scholar
  5. 5.
    Kimura T, Kobayashi A, Tanaka N, et al. Clinicopathological characteristics of non-B non-C hepatocellular carcinoma without past hepatitis B virus infection. Hepatol Res. 2017;47:405–18.CrossRefGoogle Scholar
  6. 6.
    Seko Y, Sumida Y, Tanaka S, et al. Insulin resistance increases the risk of incident type 2 diabetes mellitus in patients with non-alcoholic fatty liver disease. Hepatol Res. 2018;48:42–51.CrossRefGoogle Scholar
  7. 7.
    Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–31.CrossRefGoogle Scholar
  8. 8.
    Ghadieh HE, Russo L, Muturi HT, et al. Hyperinsulinemia drives hepatic insulin resistance in male mice with liver-specific Ceacam1 deletion independently of lipolysis. Metabolism. 2019;93:33–43.CrossRefGoogle Scholar
  9. 9.
    ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.CrossRefGoogle Scholar
  10. 10.
    Bengtsson B, Stål P, Wahlin S, et al. Characteristics and outcome of hepatocellular carcinoma in patients with NAFLD without cirrhosis. Liver Int. 2019.  https://doi.org/10.1111/liv.14087.Google Scholar
  11. 11.
    Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.CrossRefGoogle Scholar
  12. 12.
    Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefGoogle Scholar
  13. 13.
    Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–57.CrossRefGoogle Scholar
  14. 14.
    Komiya C, Tsuchiya K, Shiba K, et al. Ipragliflozin improves hepatic steatosis in obese mice and liver dysfunction in type 2 diabetic patients irrespective of body weight reduction. PLoS One. 2016;11:e0151511.CrossRefGoogle Scholar
  15. 15.
    Akuta N, Watanabe C, Kawamura Y, et al. Effects of a sodium-glucose cotransporter 2 inhibitor in nonalcoholic fatty liver disease complicated by diabetes mellitus: preliminary prospective study based on serial liver biopsies. Hepatol Commun. 2017;1(1):46–52.CrossRefGoogle Scholar
  16. 16.
    Shibuya T, Fushimi N, Kawai M, et al. 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(2):438–42.CrossRefGoogle Scholar
  17. 17.
    Sumida Y, Murotani K, Saito M, et al. 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.CrossRefGoogle Scholar
  18. 18.
    Fujimori N, Tanaka N, Shibata S, et al. Controlled attenuation parameter is correlated with actual hepatic fat content in patients with non-alcoholic fatty liver disease with none-to-mild obesity and liver fibrosis. Hepatol Res. 2016;46:1019–27.CrossRefGoogle Scholar
  19. 19.
    Eddowes PJ, Sasso M, Allison M, et al. Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156:1717–30.CrossRefGoogle Scholar
  20. 20.
    Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.CrossRefGoogle Scholar
  21. 21.
    Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165(5):305–15.CrossRefGoogle Scholar
  22. 22.
    Tanaka N, Aoyama T, Kimura S, et al. Targeting nuclear receptors for the treatment of fatty liver disease. Pharmacol Ther. 2017;179:142–57.CrossRefGoogle Scholar
  23. 23.
    Boettcher E, Csako G, Pucino F, et al. Metaanalysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35:66–75.CrossRefGoogle Scholar
  24. 24.
    Mahady SE, Webster AC, Walker S, et al. The role of thiazolidinediones in non-alcoholic steatohepatitis—a systematic review and meta analysis. J Hepatol. 2011;55:1383–90.CrossRefGoogle Scholar
  25. 25.
    Said A, Akhter A. Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis. Ann Hepatol. 2017;16:538–47.CrossRefGoogle Scholar
  26. 26.
    Komatsu M, Tanaka N, Kimura T, et al. Miglitol attenuates non-alcoholic steatohepatitis in diabetic patients. Hepatol Res. 2018;48:1092–8.CrossRefGoogle Scholar
  27. 27.
    Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–97.CrossRefGoogle Scholar
  28. 28.
    Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65:1557–65.CrossRefGoogle Scholar
  29. 29.
    Pelusi S, Cespiati A, Rametta R, et al. Prevalence and risk factors of significant fibrosis in patients with nonalcoholic fatty liver without steatohepatitis. Clin Gastroenterol Hepatol. 2019.  https://doi.org/10.1016/j.cgh.2019.01.027.Google Scholar
  30. 30.
    Nishimura N, Kitade M, Noguchi R, et al. Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, ameliorates the development of liver fibrosis in diabetic Otsuka Long-Evans Tokushima fatty rats. J Gastroenterol. 2016;51:1141–9.CrossRefGoogle Scholar
  31. 31.
    Wang H, Wang YH, Yang F, et al. Effect of acid-sensing ion channel 1a on the process of liver fibrosis under hyperglycemia. Biochem Biophys Res Commun. 2015;468(4):758–65.CrossRefGoogle Scholar
  32. 32.
    Lai LL, Vethakkan SR, Nik Mustapha NR, et al. Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus. Dig Dis Sci. 2019.  https://doi.org/10.1007/s10620-019-5477-1.Google Scholar
  33. 33.
    Tang L, Wu Y, Tian M, et al. Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes. Am J Physiol Endocrinol Metab. 2017;313:E563–76.CrossRefGoogle Scholar
  34. 34.
    Sola D, Rossi L, Schianca GP, et al. Sulfonylureas and their use in clinical practice. Arch Med Sci. 2015;11:840–8.CrossRefGoogle Scholar
  35. 35.
    Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut. 2013;62(4):606–15.CrossRefGoogle Scholar
  36. 36.
    Kawaguchi T, Kohjima M, Ichikawa T, et al. The morbidity and associated risk factors of cancer in chronic liver disease patients with diabetes mellitus: a multicenter field survey. J Gastroenterol. 2015;50:333–41.CrossRefGoogle Scholar
  37. 37.
    Kimura T, Tanaka N, Fujimori N, et al. Mild drinking habit is a risk factor for hepatocarcinogenesis in non-alcoholic fatty liver disease with advanced fibrosis. World J Gastroenterol. 2018;24:1440–50.CrossRefGoogle Scholar
  38. 38.
    Shiba K, Tsuchiya K, Komiya C, et al. Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH. Sci Rep. 2018;8:2362.CrossRefGoogle Scholar
  39. 39.
    Sasaki T, Sugawara M, Fukuda M. Sodium-glucose cotransporter 2 inhibitor-induced changes in body composition and simultaneous changes in metabolic profile: 52-week prospective LIGHT (Luseogliflozin: the Components of Weight Loss in Japanese Patients with Type 2 Diabetes Mellitus) Study. J Diabetes Investig. 2019;10:108–17.CrossRefGoogle Scholar
  40. 40.
    Sugiyama S, Jinnouchi H, Kurinami N, et al. Dapagliflozin reduces fat mass without affecting muscle mass in type 2 diabetes. J Atheroscler Thromb. 2018;25:467–76.CrossRefGoogle Scholar
  41. 41.
    Sano M, Meguro S, Kawai T, et al. Increased grip strength with sodium-glucose cotransporter 2. J Diabetes. 2016;8:736–7.CrossRefGoogle Scholar
  42. 42.
    Messeri S, Messerini L, Vizzutti F, et al. Glycogenic hepatopathy associated with type 1 diabetes mellitus as a cause of recurrent liver damage. Ann Hepatol. 2012;11:554–8.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2019

Authors and Affiliations

  • Naoyuki Fujimori
    • 1
  • Naoki Tanaka
    • 2
    • 3
    Email author
  • Takefumi Kimura
    • 1
  • Kenji Sano
    • 4
  • Akira Horiuchi
    • 5
  • Naoyuki Kato
    • 6
  • Yoshiyuki Takahashi
    • 1
  • Naoya Kuribayashi
    • 1
  • Ayumi Sugiura
    • 1
  • Tomoo Yamazaki
    • 1
  • Satoru Joshita
    • 1
  • Takeji Umemura
    • 1
  • Akihiro Matsumoto
    • 1
  • Eiji Tanaka
    • 1
  1. 1.Department of Internal Medicine, Division of GastroenterologyShinshu University School of MedicineMatsumotoJapan
  2. 2.Department of Metabolic RegulationShinshu University School of MedicineMatsumotoJapan
  3. 3.Research Center for Social SystemsShinshu UniversityMatsumotoJapan
  4. 4.Department of PathologyIida Municipal HospitalIidaJapan
  5. 5.Digestive Disease CenterShowa Inan General HospitalKomaganeJapan
  6. 6.Minakata ClinicNakagawaJapan

Personalised recommendations