Comparing the effect of Empagliflozin, Pioglitazone and their combination, on sonographic and biochemical features of non-alcoholic fatty liver disease in diabetic patients

Comparing the effects of Empagliflozin, Pioglitazone and their dual-therapy on the severity of non-alcoholic fatty liver disease, based on sonographic and biochemical findings.

Randomized, phase 2-3 trial with three parallel groups on 120 patients. Permutation randomization block technique was used.

This study will be done in Amiralmomenin clinic, Arak, Iran. Sonographies and laboratory tests will be done with the same instrument/kit and by the same sonographist/technician. Initially, laboratory tests will be requested to rule out secondary causes of liver disease and to check liver enzymes, CBC, lipid profile and HbA1c. Treatment duration will be 6 months, physician visits every 3 months and phone calls to assess compliance, every month. After 6 months, sonography and lab tests (except those used for exclusion of other causes) will be repeated. In this study the patients will receive a random drug envelope from a non-researcher collaborator.

Inclusion criterion: Type-2 diabetes patients aged 20-65 years with fatty liver by sonography. Exclusion criteria: Other causes of chronic liver disease or secondary fatty liver End-stage disease of other organs(Heart, Kidney) Cirrhosis Current use of ٍEmpagliflozin or Pioglitazone BMI>40, HbA1c>9 or <7 Glococorticoid use for at least 2 weeks during the last 2 months Pregnancy and lactation Hypothyroidism

1- Empagliflozin tablet 10 mg once daily 2- Pioglitazone tablet 15 mg once daily 3- Empagliflozin tablet 10 mg+ Pioglitazone tablet 15 mg once daily

Percentage of patients in each group who achieve meaningful decrease in fibrosis and steatosis after treatment (sonographic). Mean change in fatty liver grade in each group after treatment (sonographic). Mean change in APRI, FIB-4 index scores after treatment.

The patients will not be aware of the pattern of drug allocation for other patients. The patients will be visited by the physician, then go to one of the collaborators of the study to recieve their drugs. The collaborator will have no role in the treatment of the patients or analysis of the data. Each patient is placed in one of the groups based on the "permutation randomization block" method and recieve the corresponding drug box. In this study, the "permutation randomization block" method will be used for randomization with 6-ply blocks. In each block, each of the the following letters will be written on three cards: letter "E" (Empagloflozin), letter "P" (Pioglitazone) and letter "D" (Dual). The randomized 6-letter blocks will be PDPEED،DPDPEE ، EDPDPE، EEDPDP، PEEDPD، PPDPDEE،EDPPED ،PDPEPDE ،PDPEDE ، DPEEPD، PDEEPD،DPPEED ، PDEPDE، PPDDEE،DPEDEP ، DEPEPD ، DPPEDE، EPPDPDE، EPDPEPD، DEPDPEP. For example, the random allocation in the PDPEED block will be: The first patient allocated to D, the second to E, the third to E, the fourth to P, the fifth to D, and the sixth patient allocated to P.