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Effect of Empagliflozin on Liver Fat in Non-diabetic Patients

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ClinicalTrials.gov Identifier: NCT04642261
Recruitment Status : Not yet recruiting
First Posted : November 24, 2020
Last Update Posted : November 24, 2020
Sponsor:
Collaborator:
Food and Health Bureau, Hong Kong
Information provided by (Responsible Party):
Cheung Ka Shing, The University of Hong Kong

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Non-alcoholic Fatty Liver Disease Drug: Empagliflozin 10 MG Drug: Placebo pills Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 98 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Eligible subjects will be randomly allocated to either the empagliflozin group or placebo group (i.e. control group)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The placebo pills will be manufactured in identical appearance to the study drug (empagliflozin)
Primary Purpose: Treatment
Official Title: Effect of Empagliflozin on Liver Fat in Non-alcoholic Fatty Liver Disease Patients Without Diabetes Mellitus: a Randomized, Double-blind, Placebo-controlled Trial
Estimated Study Start Date : January 1, 2021
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022


Arm Intervention/treatment
Experimental: Empagliflozin group
Empagliflozin 10mg daily for 52 weeks
Drug: Empagliflozin 10 MG
Empagliflozin 10mg daily
Other Name: 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




Primary Outcome Measures :
  1. Change in liver fat content [ Time Frame: week 52 ]
    Difference in the change of liver fat content between the two groups at week 52 from the baseline as measured by MRI-PDFF


Secondary Outcome Measures :
  1. Remission of steatosis [ Time Frame: week 52 ]
    Remission of steatosis (defined as MRI-PDFF < 5%) at week 52

  2. Change of liver fat content [ Time Frame: week 26 and 52 ]
    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)

  3. Changes of alanine aminotransferase (ALT) [ Time Frame: week 52 ]
    Changes of ALT at week 52

  4. Changes of aspartate aminotransferase (AST) [ Time Frame: week 52 ]
    Changes of AST at week 52

  5. Changes of alkaline phosphatase (ALP) [ Time Frame: week 52 ]
    Changes of ALP at week 52

  6. Changes of gamma glutamyl transferase (GGT) [ Time Frame: week 52 ]
    Changes of GGT at week 52

  7. Changes of fasting glucose [ Time Frame: week 52 ]
    Changes of fasting glucose at week 52

  8. Changes of haemoglobin A1c (HbA1c) [ Time Frame: week 52 ]
    Changes of HbA1c at week 52

  9. Changes of total cholesterol [ Time Frame: week 52 ]
    Changes of total cholesterol at week 52

  10. Changes of low density lipoprotein (LDL) [ Time Frame: week 52 ]
    Changes of LDL at week 52

  11. Changes of high density lipoprotein (HDL) [ Time Frame: week 52 ]
    Changes of HDL at week 52

  12. Changes of body weight [ Time Frame: week 52 ]
    Changes of body weight at week 52

  13. Changes of height [ Time Frame: week 52 ]
    Changes of height at week 52

  14. Changes of body mass index (BMI) [ Time Frame: week 52 ]
    Changes of BMI at week 52

  15. Changes of waist circumference [ Time Frame: week 52 ]
    Changes of waist circumference at week 52

  16. Changes of systolic blood pressure [ Time Frame: week 52 ]
    Changes of systolic blood pressure at week 52

  17. Changes of diastolic blood pressure [ Time Frame: week 52 ]
    Changes of diastolic blood pressure at week 52



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04642261


Contacts
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Contact: Ka Shing Cheung, MD, MPH 22553632 ext 852 cks634@hku.hk

Locations
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Hong Kong
The University of Hong Kong/Queen Mary Hospital
Hong Kong, Hong Kong, China, Hong Kong, 852
Contact: Ka Shing Cheung, MD, MPH    22553632 ext 852    cks634@hku.hk   
Sponsors and Collaborators
The University of Hong Kong
Food and Health Bureau, Hong Kong
Investigators
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Principal Investigator: Ka Shing Cheung, MD, MPH The University of Hong Kong
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Responsible Party: Cheung Ka Shing, Clinical Assistant Professor, The University of Hong Kong
ClinicalTrials.gov Identifier: NCT04642261    
Other Study ID Numbers: UW 20-065
First Posted: November 24, 2020    Key Record Dates
Last Update Posted: November 24, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: IPD will be made available in the form of excel files upon request by other researchers

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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
Keywords provided by Cheung Ka Shing, The University of Hong Kong:
NAFLD
NASH
fatty liver
empagliflozin
SGLT2 inhibitors
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases
Empagliflozin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs