Combination of SGLT2 Inhibitor and Novel Selective PPARα Modulator, Tofogliflozin (Tofo) and Pemafibrate (Pema), Improves Survival Rate in STAM Mice as a Diabetic NASH Model

Patients with type 2 diabetes have a high prevalence of nonalcoholic fatty liver disease (NAFLD) which is emerging as a major public health concern in the world. Nonalcoholic steatohepatits (NASH), a severe form of NAFLD, can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). To establish the effective therapeutic method for NASH, we evaluate the therapeutic potential of the combination of SGLT2 inhibitor, tofogliflozin (Tofo), and a novel selective PPARα modulator (SPPARMα), pemafibrate (Pema), in STAM mice as a diabetic animal model of NASH to HCC. STAM mice were administered Tofo and Pema from 6 weeks of age. After 3 weeks of treatment, plasma triglyceride (TG) level was tended to reduce with 0.1 mg/kg Pema monotherapy, and decreased significantly to normal level in combination with 10 mg/kg Tofo. Blood glucose (BG) level was not altered in Pema-treated group, but lowered significantly with the combination therapy. Histological analysis of the liver revealed a tendency to reduce lipid droplet size and ballooning degeneration in Pema group. The combination of Pema and Tofo exhibited the synergistic effects on lipid droplet size and ballooning significantly. Liver TG content was also decreased in mice with the combination therapy. The survival rate of control group was decreased to 10% at 22 weeks of age. STAM mice with Pema in diet showed a tendency to increase the survival rate (30%) and the combination of Pema and Tofo significantly improved the survival rates (50%) compared to control group. Also, both of treated groups markedly reduced the number of tumors in the liver. These results suggested that, in addition of lipid metabolism, glycemic control might play an important role in the treatment of NASH. Combination therapy of SGLT2 inhibitor and SPPARMα would be a potent therapeutic strategy for the treatment of NAFLD, NASH and HCC.