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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Non-alcoholic Fatty Liver Disease (NAFLD)
• Intervention / Treatment: Drug: Metformin; Behavioral: Lifestyle modifications; Device: Fibroscan device (Echosens)

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; 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; 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.; Other Names: Glucophage; Behavioral: Lifestyle modifications; 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; Device: Fibroscan device (Echosens); 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.
Experimental: Lifestyle modification; 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; 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; Device: Fibroscan device (Echosens); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Northwell Health
• Investigators: Principal Investigator: David Bernstein, MD, Northwell Health

Publications and helpful links

General Publications

• Ortiz-Lopez C, Lomonaco R, Orsak B, Finch J, Chang Z, Kochunov VG, Hardies J, Cusi K. Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). Diabetes Care. 2012 Apr;35(4):873-8. doi: 10.2337/dc11-1849. Epub 2012 Feb 28.
• Arase Y, Suzuki F, Ikeda K, Kumada H, Tsuji H, Kobayashi T. Multivariate analysis of risk factors for the development of type 2 diabetes in nonalcoholic fatty liver disease. J Gastroenterol. 2009;44(10):1064-70. doi: 10.1007/s00535-009-0091-1. Epub 2009 Jun 17.
• Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005 Jul;42(1):44-52. doi: 10.1002/hep.20734.
• Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol. 2009 Apr;104(4):861-7. doi: 10.1038/ajg.2009.67. Epub 2009 Mar 17.
• Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol. 2009 Jun;46(2):113-8. doi: 10.1007/s00592-008-0067-2. Epub 2008 Oct 7.
• Lidofsky SD. Nonalcoholic fatty liver disease: diagnosis and relation to metabolic syndrome and approach to treatment. Curr Diab Rep. 2008 Feb;8(1):25-30. doi: 10.1007/s11892-008-0006-1.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: May 14, 2015
• First Submitted That Met QC Criteria: May 26, 2015
• First Posted (Estimate): May 29, 2015

Study Record Updates

• Last Update Posted (Actual): July 28, 2017
• Last Update Submitted That Met QC Criteria: July 26, 2017
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Liver Diseases; Fatty Liver; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: IRB# 13-204