Tofogliflozin and Pemafibrate Combination Therapy Prevents Nonalcoholic Steatohepatitis (NASH) Development of Novel Metabolic Syndrome–Related NASH Model Mice

Nonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and widely defined by the presence of steatosis with inflammation and progressive fibrosis that causes to the liver transplantation and hepatocellular carcinoma (HCC). Here, we developed a novel NASH/HCC model represented metabolic syndrome like phenotypes (obesity, hyperglycemia, and glucose intolerance), and evaluated the therapeutic potential of Tofogliflozin and Pemafibrate combination therapy on NASH development. Male C57BL/6J mice were injected multiple low dose STZ (40 mg/kg) for 5 days and fed high-fat diet (HFD). These mice revealed hyperglycemia and higher body weight gain, and glucose intolerance compared with wild type mice. In addition, novel NASH/HCC model shows sequential histological changes from fatty liver to NASH (20 weeks), and all mice developed hepatocellular carcinoma after 52-week HFD feeding. Using our NASH/HCC model, we conducted the prevention study of Tofogliflozin and Pemafibrate (mono-therapy or combination therapy) against NASH development. The combination therapy has significantly prevented body weight gain from 3 weeks after treatment and this effect was persisted throughout study. While Tofogliflozin or Pemafibrate treatment markedly decreased blood glucose and triglyceride levels, the combination therapy showed the synergistic effect compared to mono-therapy groups. Histological analysis revealed Tofogliflozin or combination therapy group markedly suppressed ER-TR7 (fibroblast) and ballooning degeneration. Furthermore, these treatment groups significantly improved NAS score (NAFLD activity score). These results suggested that Tofogliflozin/Pemafibrate combination therapy would be a beneficial for NASH/NAFLD treatment. Disclosure Y. Sasaki: Employee; Self; Kowa Company, Ltd. M. Asahiyama: Employee; Self; Kowa Company, Ltd.. Employee; Spouse/Partner; Kowa Company, Ltd.. W. Kamiya: None. J. Sakai: None. T. Kodama: Consultant; Self; Kowa Company, Ltd. T. Tanaka: Research Support; Self; Kowa Company, Ltd..