Antidiabetic Drugs for Steatotic Liver Disease

Comparison of The Effects of Thiazolidinediones(TZD), Sodium- Glucose Cotransporter 2 Inhibitors(SGLT2i) Alone and TZD / SGLT2i Combination Therapy on Metabolic Dysfunction-Associated Steatotic Liver Disease in Patients With Type 2 Diabetes

To investigate the synergic therapeutic effect of thiazolidinediones and SGLT2 inhibitor on metabolic dysfunction-associated steatotic liver disease, the effect of empagliflozin 10mg, pioglitazone 15mg monotherapy and combination therapy in patients with type 2 diabetes and steatotic liver disease will be compared and analyzed.

This study was designed to include a total of 60 patients (20 per subgroup) for randomized controlled trials with prospective, open label, randomized, single-institution clinical trials.

The drug will be maintained for a total of 24 weeks. The primary endpoint is the difference of liver fat change measured by MRI-PDFF in the largest possible polygonal region of interest encompassing both lobes of the liver between three groups.

Study Overview

• Status: Completed
• Conditions: Liver Diseases; Fatty Liver; Type 2 Diabetes; Molecular Mechanisms of Pharmacological Action; Digestive System Disease; Non-Alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Hypoglycemic Agents; Empagliflozin; Pioglitazone; Metabolic Dysfunction-Associated Steatotic Liver Disease; MASLD - Metabolic Dysfunction-Associated Steatotic Liver Disease; Sodium-Glucose Cotransporter 2 Inhibitors; Thiazolidinediones
• Intervention / Treatment: Drug: Pioglitazone; Drug: Empagliflozin; Drug: Combination of pioglitazone and empagliflozin

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Men and women aged 19 to 75 years
2. Individuals who are diagnosed with type 2 diabetes (HbA1c ≥ 7.5% and < 11.0%) and treated with antidiabetic drugs excluding TZD and SGLT2i over the previous 12 weeks
3. Individuals diagnosed with steatotic liver disease as documented by abdominal ultrasonography within the previous year
4. Individuals who have voluntarily agreed in written form to participate in the clinical trial after hearing the explanation of this clinical trial
5. Individuals who understand the content of the clinical trial and are able to participate in the trial until the end of the clinical trial

Exclusion Criteria:

1. Type 1 diabetes and gestational diabetes
2. Highly uncontrolled diabetes (HbA1c ≥ 11.0%)
3. Excessive alcohol intake (210 g and 140 g/week for men and women, respectively) within the previous 2 years
4. A history of taking thiazolidinedione or sodium-glucose cotransporter 2 inhibitor class medications within the last 12 weeks, or a history of discontinuing these medications due to severe side effects
5. Treatment with four or more classes of antidiabetic medications
6. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, within 24 weeks
7. Intake of drugs that can cause steatotic liver disease (amiodarone, methotrexate, tamoxifen, valproate, etc.)
8. Allergy or hypersensitivity to the study drugs or their constituents
9. Oral or parenteral chronic corticosteroid therapy (more than 14 consecutive days) that requires continual adjustments in corticosteroid dose for therapeutic purposes within 8 weeks
10. Galactosemia
11. Genetic disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
12. Malignant tumors currently undergoing treatment or progression
13. A history of substance abuse or alcohol intoxication within 12 weeks
14. Infection of human immunodeficiency virus
15. Severe infection
16. Pre- and post-operative status, or severe trauma
17. Cardiac failure within 24 weeks (class III to IV in the NYHA classification)
18. Acute cardiovascular event within 12 weeks (unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular disease, coronary artery bypass grafting, or coronary intervention)
19. AAcute and chronic renal disease (estimated glomerular filtration rate < 45 mL/min/1.73 m²) or dialysis
20. Pregnant or lactating women
21. Individuals whom the investigator determines to be unsuitable for participation in the clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pioglitazone monotherapy; Pioglitazone 15mg 1T daily for 24 weeks	Drug: Pioglitazone; The investigators will compare the degree of liver fat before and after pioglitazone monotherapy.
Experimental: Pioglitazone + Empagliflozin combination therapy; Pioglitazone 15mg 1T + Empagliflozin 10mg 1T combination daily for 24 weeks	Drug: Combination of pioglitazone and empagliflozin; The investigators will compare the degree of liver fat before and after pioglitazone and empagliflozin combination therapy.
Experimental: Empagliflozin monotherapy; Empagliflozin 10mg 1T daily for 24 weeks	Drug: Empagliflozin; The investigators will compare the degree of liver fat before and after empagliflozin monotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in liver fat fraction (%) measured by MRI-PDFF in the largest possible polygonal region of interest encompassing both lobes of the liver	To measure the fat fraction, we drew the largest possible polygonal region of interest encompassing both lobes of the liver on a cross-sectional image, while avoiding blood vessels, bile ducts, and distinct hepatic lesions.	After 24 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver fibrosis measured by magnetic resonance elastography	The secondary endpoint is to analyze the changes before and after drug administration for the following items: liver stiffness (kPa) measured by magnetic resonance elastography.	After 24 weeks of treatment
The changes in glucose metabolism	The secondary endpoint is to analyze the changes before and after drug administration for the following items: The changes in glucose metabolism including fasting glucose (mg/dL), HbA1c (%), fasting insulin (μIU/mL), homeostatic model assessment for insulin resistance (mg/dL*μIU/mL), and homeostasis model assessment of β-cell function (%)	After 24 weeks of treatment
The changes in lipid profile	The secondary endpoint is to analyze the changes before and after drug administration for the following items: The changes in lipid profile including total cholesterol (mg/dL), triglyceride (mg/dL), high-density lipoprotein-cholesterol (mg/dL), low-density lipoprotein-cholesterol (mg/dL), and free fatty acid (μEq/L).	After 24 weeks of treatment
The changes in liver enzyme	he secondary endpoint is to analyze the changes before and after drug administration for the following items: The changes in liver enzyme including aspartate aminotransferase (IU/L), alanine aminotransferase (IU/L), alkaline phosphatase (IU/L), and gamma-glutamyl transferase (IU/L).	After 24 weeks of treatment
The changes in cytokines	The secondary endpoint is to analyze the changes before and after drug administration for the following items: The changes in cytokines including high sensitivity C-reactive protein (mg/L), adiponectin (μg/mL), and leptin (ng/mL).	After 24 weeks of treatment
The changes in other biochemical parameters	The secondary endpoint is to analyze the changes before and after drug administration for the following items: The changes in other biochemical parameters including complete blood count, platelet count (10³/μL), total protein (g/dL), albumin (g/dL), total bilirubin (mg/dL), blood urea nitrogen (mg/dL), creatinine (mg/dL), and uric acid (mg/dL).	After 24 weeks of treatment
The changes in blood pressure and anthropometric parameters	The secondary endpoint is to analyze the changes before and after drug administration for the following items: The changes in blood pressure and anthropometric parameters including systolic and diastolic blood pressure (mmHg), body weight (kg), body mass index (kg/m², defined as weight [kg] divided by the square of the body height [m]), and waist circumference (cm).	After 24 weeks of treatment
The changes in body composition	The secondary endpoint is to analyze the changes before and after drug administration for the following items: The changes in body composition including abdominal subcutaneous fat area (cm²) and abdominal visceral fat area (cm²). To measure the body composition, abdominal fat content was assessed using a 3-mm thick cross-sectional abdominal fat CT scan at the midpoint of the L3 vertebra, with the participants in a supine position.	After 24 weeks of treatment

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2018
• Primary Completion (Actual): June 16, 2022
• Study Completion (Actual): June 16, 2022

Study Registration Dates

• First Submitted: August 10, 2018
• First Submitted That Met QC Criteria: August 22, 2018
• First Posted (Actual): August 24, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 3, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Type 2 Diabetes; Empagliflozin; Liver Diseases; Physiological Effects of Drugs; Fatty Liver; Hypoglycemic Agents; Thiazolidinediones; Molecular Mechanisms of Pharmacological Action; Pioglitazone; Digestive System Disease; Non-alcoholic Fatty Liver Disease; Sodium-Glucose Cotransporter 2 Inhibitors; Metabolic Dysfunction-Associated Steatotic Liver Disease
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Gastrointestinal Diseases; Digestive System Diseases; Diabetes Mellitus, Type 2; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Pioglitazone; Empagliflozin
• Other Study ID Numbers: 4-2018-0655

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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