Skip to main content
Top
Published in: Clinical Journal of Gastroenterology 1/2020

01-02-2020 | Sulfonylurea | Case Report

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

Authors: Naoyuki Fujimori, Naoki Tanaka, Takefumi Kimura, Kenji Sano, Akira Horiuchi, Naoyuki Kato, Yoshiyuki Takahashi, Naoya Kuribayashi, Ayumi Sugiura, Tomoo Yamazaki, Satoru Joshita, Takeji Umemura, Akihiro Matsumoto, Eiji Tanaka

Published in: Clinical Journal of Gastroenterology | Issue 1/2020

Login to get access

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.
Literature
1.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
2.
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.CrossRef 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.CrossRef
7.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
8.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
9.
go back to reference 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.CrossRef 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.CrossRef
11.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
12.
go back to reference 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.PubMed 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.PubMed
13.
go back to reference Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–57.CrossRefPubMed Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–57.CrossRefPubMed
14.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
15.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
18.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
21.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
22.
23.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference Said A, Akhter A. Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis. Ann Hepatol. 2017;16:538–47.CrossRefPubMed Said A, Akhter A. Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis. Ann Hepatol. 2017;16:538–47.CrossRefPubMed
26.
go back to reference Komatsu M, Tanaka N, Kimura T, et al. Miglitol attenuates non-alcoholic steatohepatitis in diabetic patients. Hepatol Res. 2018;48:1092–8.CrossRefPubMed Komatsu M, Tanaka N, Kimura T, et al. Miglitol attenuates non-alcoholic steatohepatitis in diabetic patients. Hepatol Res. 2018;48:1092–8.CrossRefPubMed
27.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
28.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
30.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
31.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
33.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
35.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
36.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
37.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
38.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
39.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
40.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
41.
go back to reference Sano M, Meguro S, Kawai T, et al. Increased grip strength with sodium-glucose cotransporter 2. J Diabetes. 2016;8:736–7.CrossRefPubMed Sano M, Meguro S, Kawai T, et al. Increased grip strength with sodium-glucose cotransporter 2. J Diabetes. 2016;8:736–7.CrossRefPubMed
42.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
Metadata
Title
Long-term luseogliflozin therapy improves histological activity of non-alcoholic steatohepatitis accompanied by type 2 diabetes mellitus
Authors
Naoyuki Fujimori
Naoki Tanaka
Takefumi Kimura
Kenji Sano
Akira Horiuchi
Naoyuki Kato
Yoshiyuki Takahashi
Naoya Kuribayashi
Ayumi Sugiura
Tomoo Yamazaki
Satoru Joshita
Takeji Umemura
Akihiro Matsumoto
Eiji Tanaka
Publication date
01-02-2020
Publisher
Springer Japan
Published in
Clinical Journal of Gastroenterology / Issue 1/2020
Print ISSN: 1865-7257
Electronic ISSN: 1865-7265
DOI
https://doi.org/10.1007/s12328-019-01018-1

Other articles of this Issue 1/2020

Clinical Journal of Gastroenterology 1/2020 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.