Pioglitazone and Empagliflozin for Fatty Liver Disease in Type 2 Diabetes

Evaluation of Pioglitazone and Empagliflozin Combination Therapy in Type 2 Diabetes Patients With Metabolic Dysfunction-Associated Fatty Liver Disease

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.

Study Overview

• Status: Recruiting
• Conditions: Fatty Liver; Type 2 Diabetes
• Intervention / Treatment: Drug: Empagliflozin 10 MG [Jardiance]; Drug: Pioglitazone 15 MG [Actos]; Drug: Empagliflozin 10 MG [Jardiance] + Pioglitazone 15 MG [Actos]

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Soo Lim Dr, MD PhD; Phone Number: +82-31-787-7035; Email: limsoo@snu.ac.kr
• Study Contact Backup: Name: Minji Sohn Dr, PhD; Email: rainbowmjs@naver.com

Study Locations

• Korea, Republic of
  • Seongnam-si, Korea, Republic of
    • Recruiting
    • Seoul National University Bundang Hospital
    • Contact: Soo Lim Dr; Phone Number: +82-31-787-7035; Email: limsoo@snu.ac.kr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pioglitazone; Pioglitazone 15mg	Drug: Empagliflozin 10 MG [Jardiance]; Participants will receive empagliflozin 10 mg, administered orally once daily. The tablet may be taken with or without food.
Experimental: Empagliflozin; Empagliflozin 10mg	Drug: Pioglitazone 15 MG [Actos]; Participants will receive pioglitazone 15 mg, administered orally once daily. The tablet may be taken with or without food.
Experimental: Pioglitazone & Empagliflozin; Pioglitazone 15mg + Empagliflozin 10mg	Drug: Empagliflozin 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Achieving HbA1c Treatment Targets	Percentage of participants who achieve the predefined HbA1c treatment goal at 24 weeks.	24 weeks
Change in Fibroscan Controlled Attenuation Parameter (CAP) Score	Assessment of changes in hepatic steatosis as measured by the controlled attenuation parameter (CAP) score using Fibroscan technology over a 24-week period.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c Levels	Change in glycated hemoglobin (HbA1c) from baseline after 24 weeks of treatment.	24 weeks
Change in Liver Stiffness Measurement	Change in liver stiffness measurement (LSM) assessed using Fibroscan	24 weeks
Change in Non-Invasive Blood-Based Fibrosis Markers	Change in NAFLD score, Fibrosis-4 (FIB-4) index, and AST to Platelet Ratio Index (APRI) over 12 and 24 weeks.	12 weeks, 24 weeks
Change in Anthropometric Measures	Changes in metabolic parameters including body weight, body mass index (BMI), waist circumference	12 weeks, 24 weeks
Change in Lipid Parameters	Changes in blood lipid profile (total cholesterol, LDL-c, HDL-c, triglycerides)	12 weeks, 24 weeks
Change in Liver Function Tests	Change in liver function markers including AST, ALT, gamma-glutamyl transferase (gamma-GT), albumin, bilirubin, and prothrombin time	12 weeks, 24 weeks
Change in Fibrosis Biomarker	Change in serum type IV collagen levels	12 weeks, 24 weeks
Change in Inflammatory Biomarker	Change in high-sensitivity C-reactive protein (hs-CRP) levels	12 weeks, 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Other Blood Biomarkers	Change in ketone body levels	24 weeks
Change in Proteinuria	Change in urinary albumin-to-creatinine ratio, protein-to-creatinine ratio	24 weeks

Collaborators and Investigators

• Sponsor: Seoul National University Bundang Hospital
• Collaborators: Celltrion

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: April 29, 2025
• First Submitted That Met QC Criteria: May 22, 2025
• First Posted (Actual): May 25, 2025

Study Record Updates

• Last Update Posted (Actual): May 25, 2025
• Last Update Submitted That Met QC Criteria: May 22, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Digestive System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Diabetes Mellitus; Liver Diseases; Fatty Liver; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Pioglitazone; Empagliflozin
• Other Study ID Numbers: B-2407-911-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No