The Effect of Empagliflozin on NAFLD in Asian Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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Non-Alcoholic Fatty Liver Disease( NAFLD) is common in patients with type 2 diabetes. Empagliflozin, an FDA-approved oral medication used to treat type 2 diabetes, has been shown to reduce production and deposition of fat in the liver in animal experiments. There is little published evidence that this is so in Asian patients with type 2 diabetes. The investigators designed this pilot study to determine if use of empagliflozin for 6 months in patients with type 2 diabetes can improve scan, blood marker and biopsy features of NAFLD.

Detailed Description
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Empagliflozin, an FDA-approved SGLT2 (Sodium glucose transporter 2) inhibitor used to treat type 2 diabetes, has been shown to reduce hepatic de novo lipogenesis and hepatic steatosis in animal models. There is little published evidence that this is so in Asian patients with type 2 diabetes. The investigators designed this open label proof of concept trial to determine if use of empagliflozin for 6 months in patients with type 2 diabetes can improve biomarkers and histological features of biopsy proven NAFLD. Hypotheses 1. 6 months of empagliflozin will result in improved histology on liver biopsy in type 2 dm patients with NAFLD 2.6 months of empagliflozin will result in changes in liver enzymes, adipocytokines and FGF levels in type 2 dm patients with NAFLD 3.6 months of empagliflozin will result in improved liver stiffness measurement in type 2 dm patients with NAFLD Study protocol This is a prospective open-label proof-of-concept study. The investigators plan to recruit 25 Asian patients with biopsy-proven NASH and type 2 diabetes and commence them on empagliflozin 25 mg daily for 6 months. Upon recruitment clinical information will be obtained via an interview and use of a structured questionnaire. Anthropometric measurements will be obtained at baseline and 6 months. A repeat liver biopsy will be performed after 6 months of empagliflozin therapy. MRI and fibroscan of the liver will be conducted at baseline and 6 months. Fasting blood samples will be drawn for glucose, insulin, c-peptide, triglyceride, HDL, LDL, total cholesterol, NEFA(non-esterified fatty acid), HbA1c , liver function test(including albumin, AST, ALT, gamma GT, uric acid, inflammatory markers, FGF(fibroblast growth factor) and other biomarkers at baseline and 6 months. Patients will be reviewed by a physician at 1 month and 6 months for development of any potential adverse events while on empagliflozin therapy. Patients will be instructed not to make any significant changes to diet and lifestyle in these 6 months in order to assess to full effect of the intervention with no possible confounding factors.

Official Title
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The Effect of Empagliflozin on NAFLD in Asian Patients With Type 2 Diabetes

Conditions
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Type2 Diabetes, NAFLD

Intervention / Treatment
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* Drug: Empagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: biopsy proven NASH Type 2 DM HbA1c :>6.5% BMI < 45kg/m2 Any anti-diabetic agent except SGLT2 inhibitors, TZDs(thiazolidinediones), DPP4(Dipeptidyl peptidase4) inhibitors and GLP1 RAs(Glucagon-like Peptide 1-Receptor Agonists) Exclusion Criteria: eGFR <45 ml/min structural and functional urogenital abnormalities, that predispose for urogenital infections Investigational product use in the last 6 months SGLT2 inhibitor, TZD, DPP4 inhibitor and GLP1 RA use within the past 6 months DKA(Diabetic Ketoacidosis) or HHS(Hyperosmoloar Hyperglycaemic Syndrome) within the last 6 months Pregnancy Presence of major contraindications to magnetic resonance imaging (cardiac pacemakers, claustrophobia, foreign bodies and implanted medical devices with ferromagnetic properties). Liver cirrhosis Type 1 diabetes Severe uncorrected insulin insufficiency Significant alcohol intake HIV infection Use of Traditional Chinese Medication or alternative therapies Coexisting causes of chronic liver disease - chronic viral hepatitis(B & C), autoimmune liver disease, hemochromatosis, Wilson's etc. Use of medications associated with steatosis eg. Methotrexate, anticonvulsants, antiretroviral therapy etc. h/o stroke Steroid therapy Endogenous Cushing's Familial hypertriglyceridemia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interventional arm<br>Patients with NAFLD and Type 2 Diabetes prescribed 25mg empagliflozin(JARDIANCE) daily for 6 months | Drug: Empagliflozin<br>* 25 mg daily for 6 months<br>* Other names: Jardiance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in histological Grade as evaluated with Non-alcoholic Steatohepatitis Clinical Research Network Scoring System | liver biopsy | baseline, 6 months | 
| Change in serum FGF 21 | blood test | baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in fibroscan and elastography measure of liver stiffness | imaging | baseline and 6 months | 
| Change in Liver enzymes | blood test - AST,ALT, gamma GT | baseline and 6 months | 
| Change in steatosis | histological | baseline and 6 months | 
| Change in lobular inflammation | histological | baseline and 6 months | 
| Change in ballooning | histological | baseline and 6 months | 
| Change in fibrosis | histological | baseline and 6 months | 
| Change in metabolic outcome -HbA1c | serum concentration | baseline and 6 months | 
| Change in metabolic outcome - fasting NEFA | serum concentration | baseline and 6 months | 
| Change in metabolic outcome - fasting Tg | serum concentration | baseline and 6 months | 
| Change in serum FGF 19 | serum concentration | baseline and 6 months | 
| Change in serum adiponectin | serum concentration | baseline and 6 months | 
| Change in serum IL-6 | serum concentration | baseline and 6 months | 
| Change in serum TNF alpha | serum concentration | baseline and 6 months | 
| Change in serum uric acid | serum concentration | baseline and 6 months | 
| Change in MRI features of NASH | serum concentration | baseline and 6 months |