Pioglitazone and Empagliflozin for Fatty Liver Disease in Type 2 Diabetes

Prior treatment

• Patients receiving insulin therapy or diagnosed with type 1 diabetes mellitus.
• Use of the following medications within the past 3 months: GLP-1 receptor agonists, SGLT2 inhibitors, rosiglitazone (TZD), vitamin E, or ursodeoxycholic acid (UDCA).
• Use of medications known to induce hepatic steatosis, including valproic acid, estrogen, tamoxifen, amiodarone, or chloroquine.

Other illness

• Presence of secondary causes of hepatic steatosis unrelated to metabolic dysfunction, such as hepatitis B, hepatitis C, or alcoholic fatty liver disease.
• Presence of hepatocellular carcinoma, active malignancy, or metastatic cancer.
• History of or active bladder cancer.
• History of heart failure or current diagnosis of heart failure.
• Presence of terminal illnesses.
• History of gallstone disease, chronic pancreatitis, or acute pancreatitis.
• Known hypersensitivity to the active ingredients or excipients of the study medications.
• History of diabetic ketoacidosis.

Lab values

• Severe organ failure, defined as:
  • Liver failure: AST or ALT \> 5 times the upper normal limit (UNL), serum albumin \< 3.2 g/dL, platelet count \< 60,000/µL, or Child-Pugh-Turcotte stage B or C.
  • Renal failure: Serum creatinine ≥ 2.0 mg/dL, estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m² (CKD-EPI formula), or patients with end-stage renal disease or on dialysis.

Other

• Underweight patients (body mass index \[BMI\] \< 18.5 kg/m²).
• Pregnant women or women planning to become pregnant.

• Adults aged 20 years or older.
• Patients with inadequately controlled type 2 diabetes mellitus, defined as HbA1c between 7% and 10%, who are currently treated with either:
  • Combination therapy of metformin and a sulfonylurea, or
  • Combination therapy of metformin and a DPP-4 inhibitor, or
  • Metformin monotherapy, or
  • Triple therapy (including metformin) provided that sulfonylurea will be discontinued upon study enrollment.
• Evidence of hepatic steatosis within the past 3 months, confirmed by Fibroscan with a controlled attenuation parameter (CAP) ≥ 268 dB/m (consistent with S2 or greater \[≥10% hepatocyte steatosis\] according to the 2024 EASL-EASD-EASO guidelines).
• Presence of at least one of the following metabolic abnormalities:
  • Waist circumference ≥90 cm for men or ≥85 cm for women.
  • Blood pressure ≥130 mmHg systolic or ≥85 mmHg diastolic, or use of antihypertensive medication.
  • Serum triglycerides ≥150 mg/dL or current use of lipid-lowering agents.
  • HDL-cholesterol ≤45 mg/dL for men or ≤50 mg/dL for women.
  • HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) ≥2.5.
  • Serum C-reactive protein (CRP) ≥2 mg/L.
• No changes in anti-diabetic or metabolic medications within the past 3 months, unless the changes are deemed by the investigator not to affect study outcomes.