American Diabetes Association
220421-Takeshita-Diabetes_care-Additional_Appendix.pdf (291.46 kB)

Comparison of Tofogliflozin and Glimepiride Effects on Nonalcoholic Fatty Liver Disease in Participants with Type 2 Diabetes: A randomized, 48 -Weeks, Open-Label, Active-controlled Trial

Download (291.46 kB)
posted on 2022-07-27, 14:40 authored by Yumie Takeshita, Masao Honda, Kenichi Harada, Yuki Kita, Noboru Takata, Hiromasa Tsujiguchi, Takeo Tanaka, Hisanori Goto, Yujiro Nakano, Noriho Iida, Kuniaki Arai, Tatsuya Yamashita, Eishiro Mizukoshi, Hiroyuki Nakamura, Shuichi Kaneko, Toshinari Takamura



Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. 


We conducted a 48-week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once-daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least one point. The secondary endpoints were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles.


Fibrosis scores improved in the tofogliflozin group (60%, P=0.001), whereas the change from baseline did not differ significantly between the groups (P=0.172). All histologic variables: steatosis (65%, P=0.001), hepatocellular ballooning (55%, P=0.002), and lobular inflammation (50%, P=0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P=0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin.


Tofogliflozin and, to a lesser degree, glimepiride led to liver histologic and metabolic improvement in participants with type 2 diabetes and NAFLD with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.


This work was supported, in part, by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science (grant number 19K08975), by research grants from Kowa Company Ltd, and by Japan Agency for Medical Research and Development (AMED) under Grant Number JP20fk0210073.


Usage metrics

    Diabetes Care


    Ref. manager