Ipragliflozin Additively Ameliorates Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Controlled with Metformin and Pioglitazone: A 24-Week Randomized Controlled Trial

Abstract

Despite the benefits of pioglitazone in the treatment of non-alcoholic fatty liver disease (NAFLD), many treated patients continue to experience disease progression. We aimed to investigate the additive effect of ipragliflozin on NAFLD in patients with type 2 diabetes treated with metformin and pioglitazone. In this 24-week randomized controlled trial, 44 patients with type 2 diabetes and comorbid NAFLD were either randomized to receive 50 mg/day of ipragliflozin as an add-on treatment (n = 29) or maintained on metformin and pioglitazone (n = 15). The fatty burden was assessed using the fatty liver index, NAFLD liver fat score, and controlled attenuation parameter (CAP). Changes in fat and muscle depots were measured by dual-energy x-ray absorptiometry and abdominal computed tomography scans. The enrolled patients were relatively controlled (mean baseline glycated hemoglobin of 6.6% +/- 0.6%) and centrally obese (mean waist circumference of 101.6 +/- 10.9 cm). At week 24, patients in the ipragliflozin add-on group exhibited reduced hepatic fat content (fatty liver index: -9.8 +/- 1.9, p = 0.002; NAFLD liver fat score: -0.5 +/- 0.2, p = 0.049; CAP: -8.2 +/- 7.8 dB/m(2), p = 0.133). Ipragliflozin add-on therapy also reduced whole-body visceral fat and the ratio of visceral to subcutaneous fat (change in whole-body visceral fat: -69.6 +/- 21.5 g; change in abdominal visceral fat: -26.2 +/- 3.7 cm(2); abdominal visceral to subcutaneous fat ratio: -0.15 +/- 0.04; all p < 0.05). In conclusion, ipragliflozin treatment significantly ameliorates liver steatosis and reduces excessive fat in euglycemic patients with type 2 diabetes and NAFLD taking metformin and pioglitazone.