Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1–3 fibrosis

Yuya Seko,1 Taichiro Nishikawa,1 Atsushi Umemura,1 Kanji Yamaguchi,1 Michihisa Moriguchi,1 Kohichiroh Yasui,1 Mayumi Kimura,2 Hiroaki Iijima,3 Toshio Hashimoto,3 Yoshio Sumida,4 Takeshi Okanoue,5 Yoshito Itoh1 1Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan; 3Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan; 4Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan; 5Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan Aim: Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is known to be associated with type 2 diabetes mellitus (T2DM) in high rate. The improvement in hepatic function due to sodium-glucose co-transporter 2 (SGLT2) inhibitors has been reported in T2DM patients with and without NAFLD. However, only a few studies have attempted to evaluate the role of SGLT2 inhibitors in T2DM patients with biopsy-proven NASH, and no detailed prospective studies including the individual hepatic fibrosis stage have been reported. Therefore, we investigated the effect of canagliflozin on hepatic function in T2DM patients with biopsy-confirmed NASH. Methods: T2DM patients with NASH (hepatic fibrosis stage 1–3 confirmed via liver biopsy, n=10) were enrolled and received canagliflozin (100 mg) once a day for 12 weeks. The primary end point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. Secondary end points were liver function/fibrosis markers, metabolic parameters, and safety. Results: The change in ALT from baseline to week 12 was -23.9 U/L (95% CI –48.1 to 0.3, P=0.0526). Significant improvements in several hepatic function/fibrosis markers, such as aspartate aminotransferase, fibrosis-4 index, and FM-fibro index, and metabolic parameters including hemoglobin A1c and body weight were found. No serious or liver-related adverse events were reported. Regarding individual patients, different trends in ALT-lowering effects between stage 1 and stage 2/3 subjects were observed; the degree of ALT-lowering effect tended to be greater in the stage 1 group than in the stage 2/3 group. Conclusion: Our results suggest that canagliflozin is effective and well-tolerated in patients with T2DM and NASH. Canagliflozin may be useful for the treatment of T2DM patients with NASH, especially those in early stages of NASH. Keywords: canagliflozin, Japanese, NASH, fibrosis stages, SGLT2 inhibitor, type 2 diabetes mellitus