Effect of Empagliflozin on Liver Fat in Non-diabetic Patients

Effect of Empagliflozin on Liver Fat in Non-alcoholic Fatty Liver Disease Patients Without Diabetes Mellitus: a Randomized, Double-blind, Placebo-controlled Trial

Non-alcoholic fatty liver disease (NAFLD) is a global epidemic with a prevalence of 25%. Currently therapies for NAFLD patients without diabetes mellitus (DM) are limited, and are associated with various adverse side effects. Sodium-glucose cotransporter type-2 (SGLT2) inhibitors can reduce hepatic fat content in patients with DM. However, the role of SGLT2 inhibitors in NAFLD patients without DM has not been investigated. Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) and liver stiffness measurement (LSM) are non-invasive methods to diagnose hepatic steatosis and fibrosis/cirrhosis, respectively.

The investigators propose a double-blind, randomized, placebo-controlled trial to compare the effects of empagliflozin (a type of SLGT2 inhibitors) versus placebo (in a 1:1 ratio) in reducing hepatic fat content as measured by MRI-PDFF in NAFLD patients without DM. A total of 98 adult patients will be randomly sampled from the liver clinic in our local hospital. Empagliflozin 10mg daily will be given to the treatment arm. The placebo pill will be manufactured to be identical in appearance to the study drug. Eligible subjects will be followed up until week 52, and will undergo clinical, anthropometric and laboratory assessments (including liver function test and fasting blood) at baseline, week 6, 12, 26, 40 and 52. They will undergo LSM at baseline, week 26 and 52, and MRI-PDFF at baseline and week 52. The primary outcome will be a difference in change of liver fat content (measured by MRI-PDFF) at week 52 from baseline between the two groups.

The study results will determine whether SGLT2 inhibitors can reduce hepatic steatosis in NAFLD patients without DM.

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Empagliflozin 10 MG; Drug: Placebo pills

Detailed Description

Non-alcoholic fatty liver disease (NAFLD) is a global epidemic with a prevalence of 25%. Currently therapies for NAFLD patients without diabetes mellitus (DM) are limited, and are associated with various adverse side effects. Sodium-glucose cotransporter type-2 (SGLT2) inhibitors are antidiabetic drugs that reduce hepatic fat content in patients with DM, which is independent of glycemic control. However, the role of SGLT2 inhibitors in NAFLD patients without DM has not been investigated. Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) is an emerging non-invasive imaging technique, and is more sensitive than liver biopsy/histology in quantifying liver fat change. Liver stiffness measurement (LSM) by transient elastography is a non-invasive method to diagnose fibrosis/cirrhosis with high accuracy.

The novelty of utilizing the concept of "drug repositioning" by changing the role of SGLT2 inhibitors in treating DM to treating NAFLD in patients without DM deserves exploration. The investigators propose a double-blind, randomized, placebo-controlled trial to compare the effects of empagliflozin (a type of SLGT2 inhibitors) versus placebo (in a 1:1 ratio) in reducing hepatic fat content as measured by MRI-PDFF in NAFLD patients without DM. A total of 98 adult patients will be randomly sampled from the liver clinical in our local hospital. Empagliflozin 10mg daily will be given to the treatment arm. The placebo pill will be manufactured to be identical in appearance to the study drug. Eligible subjects will be followed up until week 52, and will undergo clinical, anthropometric and laboratory assessments (including liver function test and fasting blood) at baseline, week 6, 12, 26, 40 and 52. They will undergo LSM at baseline, week 26 and 52, and MRI-PDFF at baseline and week 52. The primary outcome will be a difference in change of liver fat content (measured by MRI-PDFF) at week 52 from baseline between the two groups. The secondary outcomes will be remission of steatosis (MRI-PDFF <5%) at week 52, reduction of liver fibrosis (LSM) at week 26 and 52, improvement of laboratory results (including liver transaminases and ductal enzymes, fasting glucose, HbA1c, lipid profile), improvement of anthropometric measurements, and combined cardiovascular and cerebrovascular events.

The study results will determine whether SGLT2 inhibitors can reduce hepatic steatosis and regress fibrosis in NAFLD patients without DM.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 4

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, China
    • Hong Kong, Hong Kong, China, Hong Kong, 852
      • The University of Hong Kong/Queen Mary Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Potential study subjects will first be screened by transient elastography for the presence of hepatic steatosis (defined as a measurement of controlled attenuation parameter [CAP] >= 248 db/M).
• They will be recruited into study if steatosis is >= 5% as confirmed by MRI-PDFF

Exclusion Criteria:

• DM (defined as hemoglobin A1c [HbA1c] >= 6.5% or fasting glucose >= 7.0 mmol/L)
• alcohol intake > 20g within past 2 years
• concurrent chronic liver diseases (including chronic viral hepatitis infection, autoimmune hepatitis, Wilson's disease, hemochromatosis, congestive hepatopathy, primary biliary cholangitis, primary sclerosing cholangitis, biliary tract obstruction)
• drug-induced liver disease
• usage of drugs that can lead to hepatic steatosis (e.g. steroids, amiodarone, valproate, methotrexate, tamoxifen)
• decompensated cirrhosis (including ascites, hepatic hydrothorax, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome)
• history of malignancy including HCC
• recreational substance abuse
• pregnancy
• contraindications to empagliflozin use (estimated glomerular filtration rate [eGFR] <45mL/min/1.73m2 as measured by the MDRD equation, history of recurrent genitourinary tract infections, gangrene, or allergy)
• contraindications to MRI (e.g., claustrophobia, certain cardiac pacemakers, implanted medical devices with ferromagnetic properties).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin group; Empagliflozin 10mg daily for 52 weeks	Drug: Empagliflozin 10 MG; Empagliflozin 10mg daily; Other Names: empagliflozin
Placebo Comparator: Placebo group; Placebo pills (identical in appearance to empagliflozin 10mg) daily for 52 weeks	Drug: Placebo pills; Identical in appearance to empagliflozin 10mg daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in liver fat content	Difference in the change of liver fat content between the two groups at week 52 from the baseline as measured by MRI-PDFF	week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission of steatosis	Remission of steatosis (defined as MRI-PDFF < 5%) at week 52	week 52
Change of liver fat content	Difference in the change of liver fat content between the two groups at week 26 and 52 from the baseline (CAP measured by transient elastography)	week 26 and 52
Changes of alanine aminotransferase (ALT)	Changes of ALT at week 52	week 52
Changes of aspartate aminotransferase (AST)	Changes of AST at week 52	week 52
Changes of alkaline phosphatase (ALP)	Changes of ALP at week 52	week 52
Changes of gamma glutamyl transferase (GGT)	Changes of GGT at week 52	week 52
Changes of fasting glucose	Changes of fasting glucose at week 52	week 52
Changes of haemoglobin A1c (HbA1c)	Changes of HbA1c at week 52	week 52
Changes of total cholesterol	Changes of total cholesterol at week 52	week 52
Changes of low density lipoprotein (LDL)	Changes of LDL at week 52	week 52
Changes of high density lipoprotein (HDL)	Changes of HDL at week 52	week 52
Changes of body weight	Changes of body weight at week 52	week 52
Changes of height	Changes of height at week 52	week 52
Changes of body mass index (BMI)	Changes of BMI at week 52	week 52
Changes of waist circumference	Changes of waist circumference at week 52	week 52
Changes of systolic blood pressure	Changes of systolic blood pressure at week 52	week 52
Changes of diastolic blood pressure	Changes of diastolic blood pressure at week 52	week 52

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: Food and Health Bureau, Hong Kong
• Investigators: Principal Investigator: Ka Shing Cheung, MD, MPH, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Actual): May 31, 2023
• Study Completion (Actual): June 30, 2023

Study Registration Dates

• First Submitted: November 6, 2020
• First Submitted That Met QC Criteria: November 21, 2020
• First Posted (Actual): November 24, 2020

Study Record Updates

• Last Update Posted (Estimated): December 7, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: NAFLD; NASH; fatty liver; SGLT2 inhibitors; empagliflozin
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: UW 20-065

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will be made available in the form of excel files upon request by other researchers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No