Fatty Liver, Type 2 Diabetes
Conditions
Brief summary
This exploratory study will assess the efficacy of combined pioglitazone and empagliflozin therapy in improving hepatic and metabolic outcomes in patients with type 2 diabetes mellitus and metabolic dysfunction-associated fatty liver disease (MAFLD). Although each agent has shown beneficial effects individually, evidence on their combined impact on liver health is scarce. This study seeks to determine whether the combination therapy yields additive improvements in hepatic steatosis, inflammation, and fibrosis, potentially offering a new therapeutic strategy for diabetic patients with fatty liver disease.
Interventions
DRUGPioglitazone 15 MG [Actos]
Participants will receive pioglitazone 15 mg, administered orally once daily. The tablet may be taken with or without food.
Participants will receive empagliflozin 10 mg, administered orally once daily. The tablet may be taken with or without food.
DRUGEmpagliflozin 10 MG [Jardiance] + Pioglitazone 15 MG [Actos]
Participants will receive one tablet of pioglitazone 15 mg and one tablet of empagliflozin 10 mg, administered orally once daily. Both tablets may be taken with or without food.
Sponsors
Celltrion
Seoul National University Bundang Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Masking description
A randomization sequence will be generated prior to patient enrollment. Patients will be enrolled before the treatment allocation is disclosed. The allocation sequence will be revealed at the time of group assignment, after which the prescribed intervention will be administered. Until group assignment, both the enrolling investigators and the patients who have provided informed consent will remain unaware of the assigned treatment group.
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults aged 20 years or older. 2. 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. 3. 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). 4. 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. 5. 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.
Exclusion criteria
1. Patients receiving insulin therapy or diagnosed with type 1 diabetes mellitus. 2. Use of the following medications within the past 3 months: GLP-1 receptor agonists, SGLT2 inhibitors, rosiglitazone (TZD), vitamin E, or ursodeoxycholic acid (UDCA). 3. Presence of secondary causes of hepatic steatosis unrelated to metabolic dysfunction, such as hepatitis B, hepatitis C, or alcoholic fatty liver disease. 4. Use of medications known to induce hepatic steatosis, including valproic acid, estrogen, tamoxifen, amiodarone, or chloroquine. 5. 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. 6. Presence of hepatocellular carcinoma, active malignancy, or metastatic cancer. 7. History of or active bladder cancer. 8. History of heart failure or current diagnosis of heart failure. 9. Presence of terminal illnesses. 10. History of gallstone disease, chronic pancreatitis, or acute pancreatitis. 11. Underweight patients (body mass index \[BMI\] \< 18.5 kg/m²). 12. Pregnant women or women planning to become pregnant. 13. Known hypersensitivity to the active ingredients or excipients of the study medications. 14. History of diabetic ketoacidosis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Achieving HbA1c Treatment Targets | 24 weeks | Percentage of participants who achieve the predefined HbA1c treatment goal at 24 weeks. |
| Change in Fibroscan Controlled Attenuation Parameter (CAP) Score | 24 weeks | Assessment of changes in hepatic steatosis as measured by the controlled attenuation parameter (CAP) score using Fibroscan technology over a 24-week period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Liver Stiffness Measurement | 24 weeks | Change in liver stiffness measurement (LSM) assessed using Fibroscan |
| Change in Non-Invasive Blood-Based Fibrosis Markers | 12 weeks, 24 weeks | Change in NAFLD score, Fibrosis-4 (FIB-4) index, and AST to Platelet Ratio Index (APRI) over 12 and 24 weeks. |
| Change in Anthropometric Measures | 12 weeks, 24 weeks | Changes in metabolic parameters including body weight, body mass index (BMI), waist circumference |
| Change in Liver Function Tests | 12 weeks, 24 weeks | Change in liver function markers including AST, ALT, gamma-glutamyl transferase (gamma-GT), albumin, bilirubin, and prothrombin time |
| Change in Fibrosis Biomarker | 12 weeks, 24 weeks | Change in serum type IV collagen levels |
| Change in Inflammatory Biomarker | 12 weeks, 24 weeks | Change in high-sensitivity C-reactive protein (hs-CRP) levels |
| Change in Lipid Parameters | 12 weeks, 24 weeks | Changes in blood lipid profile (total cholesterol, LDL-c, HDL-c, triglycerides) |
| Change in HbA1c Levels | 24 weeks | Change in glycated hemoglobin (HbA1c) from baseline after 24 weeks of treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Other Blood Biomarkers | 24 weeks | Change in ketone body levels |
| Change in Proteinuria | 24 weeks | Change in urinary albumin-to-creatinine ratio, protein-to-creatinine ratio |
Countries
South Korea
Contacts
Primary ContactSoo Lim Dr, MD PhD
Backup ContactMinji Sohn Dr, PhD
Outcome results
None listed