Sodium-Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized, Open-Label Trial Study

Abstract

Background: 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. Methods: We conducted a 48-week, randomized, open-label, parallel-group trial involving patients with biopsy-confirmed NAFLD. A total of 40 patients were randomly assigned to receive once-daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary endpoint was an improvement in histologic scores of NAFLD. The secondary endpoints were the changes of liver enzymes, metabolic markers, and hepatic gene expression profiles. Findings: 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). 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). Gene expression profiling revealed tofogliflozin accelerated the catabolism of fat and protein that could be utilized for gluconeogenesis. Histological changes in the liver were correlated with substantial improvement of inflammation and fibrosis. Interpretation: Tofogliflozin led to liver histologic and metabolic improvement in patients with type 2 diabetes and NAFLD. The improvements were well supported by the hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors. Clinical Trial Registration Details: This trial is registered with ClinicalTrials.gov, number NCT02649465 (January 7, 2016) and Japan Registry of Clinical Trials; jRCTs041180132 from UMIN 000020544 (January 13, 2016). Funding Information: This work was supported, in part, by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science (grant number 19K08975) and by research grants from Kowa Company Ltd. Declaration of Interests: TTakamura received research grants from Kowa Company Ltd., Mitsubishi Tanabe Pharma Corp., Taisyo Pharma Co., Astellas, Novo Nordisk, Ono Pharmaceutical Co. Ltd., Takeda, Sanwa Kagaku Kenkyusho Co., Ltd., and Life scan Japan. SK received research grants from Takeda, Mitsubishi Tanabe Pharma Corp., EA Pharma Co., Ltd., AbbVie Inc., Eizai Co., Ltd., SANOFI, ZEON MEDICAL INC., ZERIA, Boston Scientific Co., Mylan, TSUMURA, Kyowa Kirin Co., Ltd., Mochida Pharma Co., Ltd., Otsuka Pharma Co., Ltd., Sumitomo Dainippon Pharma, TAIHO PHARMA, Chugai Pharma. Co., Ltd., Lilly, Boehringer Ingelheim, NIHON Pharma. Co., Ltd., and Bristol Myers Squibb. TTakamura and YT received consulting fees from Kowa Company Ltd. TTakamura received lecture fees from MSD, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma Corp. SK received lecture fees from MSD, Sumitomo Dainippon Pharma, AbbVie Inc., EA Pharma Co., Ltd., Eizai Co., Ltd., TAIHO PHARMA, Ono Pharma. Co., Ltd., Takeda and BAYER. EM received lecture fees from MSD, AbbVie Inc., Chugai Pharma. Co., Ltd., EA Pharma Co., Ltd., Bristol Myers Squibb, Ono Pharma. Co., Ltd., Daiichi-Sankyo, and Taisyo Pharma Co. TY received lecture fees from MSD, Sumitomo Dainippon Pharma, AbbVie Inc., Chugai Pharma. Co., Ltd., Eizai Co., Ltd., TAIHO PHARMA, Bristol Myers Squibb, Takeda, BAYER, and Lilly. YT received lecture fees from Sumitomo Dainippon Pharma. YN received lecture fees from Kyowa Kirin Co., Ltd. NI received lecture fees from Miyarisan Pharma. Co., Ltd. MH, KH, YK, NT, HT, TTanaka, HG, KA, and HN have nothing to disclose. Ethics Approval Statement: The institutional review board of each participating institution approved the study protocol in compliance with the Declaration of Helsinki and current legal regulations in Japan. All procedures followed the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1964, as revised in 2013. The study was conducted with the approval of the Certified Review Board, Kanazawa University, Ishikawa, Japan, by the guidelines of the Declaration of Helsinki (2018-020, CRB4180005, November 11, 2015). Written informed consent was obtained from all of the subjects before enrollment in the study.