Improving Insulin Resistance To Treat Non-Alcoholic Fatty Liver Disease: A Pilot Study

Study Overview
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Brief Summary
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Metformin is being compared to exercise and diet modifications. The researchers are interested in learning if the addition of metformin to lifestyle modifications is more helpful in treating the condition or disorder. Although metformin is FDA approved to treat type 2 diabetes, it is not FDA approved for the treatment of Non-alcoholic fatty liver (NAFLD) and is considered investigational for the purpose of this study.

Detailed Description
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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and a common cause of unexplained mildly elevated serum aminotransferase levels. NAFLD, initially felt to be benign, is now known to potentially progress to cirrhosis and its complications, including the development of liver cancer. NAFLD is strongly correlated with Type 2 Diabetes, insulin resistance, and the metabolic syndrome (1-6). It is hypothesized that the pathogenesis of hepatic injury in NAFLD is due to insulin resistance and the oxidative stress associated with obesity and metabolic syndrome (7). No adequate medical treatment has been shown to be effective for the treatment of NAFLD. Several studies (8-22) have evaluated the effect of metformin in patients with NAFLD in relation to insulin resistance, Homeostatic Model Assessment Insulin Resistance Index (HOMA-IR) values, aminotransferase levels, liver morphology, and histological improvement with treatment. These studies however have shown discrepant results with relation to aminotransferase levels and only a few studies have been able to evaluate histological improvement with follow-up biopsies. There have been no studies focusing specifically on the pre-diabetic population. These patients who are at an increased risk of progressing to diabetes may exhibit a different response to treatment with metformin than non-diabetic or diabetic patients. All the studies support the fact that metformin has a beneficial effect on improving insulin resistance and decreasing the incidence of metabolic syndrome, but there is no consensus thus far on its influence on NAFLD. The majority of published studies were limited by small sample size. Randomized controlled trials with adequate sample size and of longer duration are needed as well as studies assessing endpoints such as liver morphology and histology. The results of this pilot study are significant in that metformin may be a relatively safe and inexpensive way, in addition to lifestyle modifications, to treat NAFLD. The results of this pilot study will pave the way for the larger power, longer duration study required to answer this question.

Official Title
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Improving Insulin Resistance to Treat Non-Alcoholic Fatty Liver Disease: A Pilot Study

Conditions
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Non-alcoholic Fatty Liver Disease (NAFLD)

Intervention / Treatment
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* Drug: Metformin
* Behavioral: Lifestyle modifications
* Device: Fibroscan device (Echosens)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: subjects between ages 18-80 diagnosed with NAFLD by alanine aminotransferase (ALT) levels >1.5x the upper limit of normal with an otherwise nondiagnostic hepatic serology workup, ultrasound evidence, and/or histologically confirmed NAFLD within the past 1 year. The upper limit of normal for ALT will be defined as 35 U/L in males and 19 U/L in females Exclusion Criteria: A prior history of diabetes Failure to meet criteria for HbA1C screening Evidence of hepatic disorders Use of insulin or oral hypoglycemic agents eGFR <30 Blood transfusion within past 3 months Steroid use in the past 6 months Excessive alcohol use (more than 20g per day in women and more than 30g per day in men) Acute or unstable congestive heart failure Age >80 years old Lactic acidosis Inability to consent due to cognitive impairment. Pregnancy

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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Accepts Healthy Volunteers

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Metformin is being compared to exercise and diet modifications. The study will be incorporating the use of a Fibroscan device (Echosens) at the initial visit and upon completion of the study, which works by measuring shear wave velocity. In this technique, a 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe | Drug: Metformin<br>* Although metformin is FDA approved to treat type 2 diabetes, it is not FDA approved for the treatment of NAFLD and is considered investigational for the purpose of this study.<br>* Other names: Glucophage;Behavioral: Lifestyle modifications<br>* Recommendations for lifestyle modification will be based on the Diabetes Prevention Program 2002 (26) and will include recommendations for greater than 150 minutes of physical activity weekly, referrals to group and/or individualized sessions with nutritionists and/or lifestyle coaches as well as educational materials<br>Device: Fibroscan device (Echosens)<br>* This study will be incorporating the use of a Fibroscan device (Echosens) at the initial visit and upon completion of the study, which works by measuring shear wave velocity.<br>|
| Experimental: Lifestyle modification<br>The researchers are interested in learning if the addition of metformin to lifestyle modifications is more helpful in treating participants condition or disorder. The study will be incorporating the use of a Fibroscan device (Echosens) at the initial visit and upon completion of the study, which works by measuring shear wave velocity. In this technique, a 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe | Behavioral: Lifestyle modifications<br>* Recommendations for lifestyle modification will be based on the Diabetes Prevention Program 2002 (26) and will include recommendations for greater than 150 minutes of physical activity weekly, referrals to group and/or individualized sessions with nutritionists and/or lifestyle coaches as well as educational materials<br>Device: Fibroscan device (Echosens)<br>* This study will be incorporating the use of a Fibroscan device (Echosens) at the initial visit and upon completion of the study, which works by measuring shear wave velocity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in NAFLD as measured by ALT levels | The primary endpoint variable is the improvement in NAFLD after 12 months of treatment, as measured by the change in ALT levels from baseline to the end of a one year follow-up. A decrease of at least 25% from baseline will be considered a clinically relevant response. | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of metabolic syndrome (insulin resistance) | The study will be using measurements of BMI, waist circumference, blood pressure, lipids and fasting blood glucose levels to assess insulin resistance. | 12 months | 
| Incidence of NAFLD fibrosis scores after 12 months of treatment as measured by Fibroscan | A NAFLD Fibrosis Score (28), a noninvasive scoring system for liver fibrosis in patients with NAFLD, can be calculated and potentially used to assess for histologic improvement with metformin, which thus far has never been assessed. | 12 months |