Study Protocol for Pleiotropic Effects and Safety of Sodium–Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

INTRODUCTION: Clinicopathological analyses revealed that reduction in HbA1c and use of insulin independently contribute to reduction in liver fibrosis scores during the course of nonalcoholic fatty liver disease (NAFLD) development. We will test our hypothesis that lowering glucose and increasing insulin reduce liver fibrosis in NAFLD. Sodium–glucose cotransporter 2 (SGLT2) inhibitors lower insulin levels and sulfonylureas increase insulin levels, while both lower glucose levels. METHODS: This study is a 48-week, one-center (only Kanazawa University Hospital), open-label, randomized, parallel trial. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily 20 mg tofogliflozin or 0.5 mg glimepiride. The sample size was calculated to be 14 in each group with a significance level of 0.05 and power of 0.90. The design required 40 evaluable patients in this study. The primary endpoint of this study will be the improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. The secondary efficacy endpoints in the present study include organ-specific insulin sensitivity, insulin/glucagon secretion, ectopic fat accumulation, bioelectrical impedance analysis, sympathetic nerve activity, comprehensive gene expression analyses in the liver and blood cells, and gut microbiota profiling. PLANNED OUTCOMES: Recruitment into this study started in November 2015 and will end in September 2020, with 40 patients randomized into the two groups. The treatment follow-up of the participants is currently ongoing and is due to finish by the end of 2022. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. TRIAL REGISTRATION: This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000020544) and ClinicalTrials.gov (NCT02649465).