Effect of Empagliflozin on Liver Fat in Non-diabetic Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Non-alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: Empagliflozin 10 MG
* Drug: Placebo pills


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible subjects will be randomly allocated to either the empagliflozin group or placebo group (i.e. control group)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin group<br>Empagliflozin 10mg daily for 52 weeks | Drug: Empagliflozin 10 MG<br>* Empagliflozin 10mg daily<br>* Other names: empagliflozin;|
| Placebo Comparator: Placebo group<br>Placebo pills (identical in appearance to empagliflozin 10mg) daily for 52 weeks | Drug: Placebo pills<br>* Identical in appearance to empagliflozin 10mg daily<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, NASH, fatty liver, empagliflozin, SGLT2 inhibitors