Clinical trial NCT02457286: Improving Insulin Resistance To Treat Non-Alcoholic Fatty Liver Disease: A Pilot Study
Official title: Improving Insulin Resistance to Treat Non-Alcoholic Fatty Liver Disease: A Pilot Study
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Non-alcoholic Fatty Liver Disease (NAFLD)
Lead sponsor: Northwell Health
Sponsor class: OTHER
First posted: 2015-05-29
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Improvement in NAFLD as measured by ALT levels
timeFrame: 12 Months
Secondary outcomes:
measure: Incidence of metabolic syndrome (insulin resistance)
timeFrame: 12 months
measure: Incidence of NAFLD fibrosis scores after 12 months of treatment as measured by Fibroscan
timeFrame: 12 months
Other outcomes:
Locations:
city: Manhasset
country: United States
facility: North Shore Hospital
state: New York
Study officials:
affiliation: Northwell Health
name: David Bernstein, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.