Polyunsaturated Fatty Acids (PUFA) in Diabetic Fatty Liver

Randomized Controlled Trial of Omega-3 Fatty Acids in the Treatment of Non-Alcoholic Steatohepatitis in Patients With Type 2 Diabetes Mellitus

Non-alcoholic steatohepatitis (NASH), the most severe form of liver injury in the spectrum of non-alcoholic fatty liver disease (NAFLD), has emerged as the major cause of chronic liver disease in developed countries. Among adults in the United States, the prevalence is between 5.7% and 17%. These rates are expected to increase concurrent with the epidemics of obesity and type 2 diabetes mellitus, which are the major risk factors for NAFLD and NASH. In addition to its high prevalence, NASH is also a progressive fibrotic disease that advances to cirrhosis and liver related death in 20% and 12% of patients, respectively. Among NASH patients with cirrhosis, 40% have liver related death. Diabetics are particularly prone to experience these poor outcomes. No therapy has been proven effective for patients with NASH.

The purpose of this study is to find out whether treatment with polyunsaturated fatty acids (eicosapentaenoic acid [EPA] combined with docosahexaenoic acid [DHA] called Opti-EPA) improves NASH compared to treatment with placebo pills. The placebo pills will contain corn oil and will be contained in a capsule, but have no medical effect on the body. The investigators will determine improvement in NASH from microscopic changes in the subject's liver tissue during 48 weeks of treatment. This means that the subject will need to have a liver biopsy before and after the treatment.

Omega-3 fatty acids are a form of polyunsaturated fats, one of the four basic types of fat that the body gets from food. (Cholesterol, saturated fat, and monounsaturated fat are the others.) One's body does not make this type of fat; it comes from food sources. These fats are found in foods like cold water fish (tuna, salmon, and mackerel), and vegetable products like flaxseed oil and walnuts.

Research shows that polyunsaturated fats are good for people. Studies have shown that it is good for heart health by playing a role in keeping blood cholesterol levels low, keeping irregular heart rhythms stable, and reducing blood pressure.

The drug being studied, Opti-EPA, is a nutritional supplement. They do not have to be reviewed by the Food and Drug Administration (FDA) like medicines do. Opti-EPA is considered experimental in this study. This means that the United States Food and Drug Administration (FDA) has not approved it for use in people with nonalcoholic fatty liver disease.

Study Overview

• Status: Completed
• Conditions: Fatty Liver
• Intervention / Treatment: Drug: Polyunsaturated fatty acid (Opti-EPA); Drug: Placebo

Detailed Description

Although there is no proven effective treatment of NASH, dietary supplementation with long chain omega-3 polyunsaturated fatty acids (PUFA's) may be beneficial. This suggestion is based on three previously reported observations: first, patients with NASH consume less PUFAs and more saturated fats than subjects without NASH. Second, PUFAs are beneficial in patients with hypertension and hypertriglyceridemia. Third, PUFAs decrease lipid peroxidation and ameliorate hepatic steatosis in animal models of NAFLD.

We therefore hypothesize that the administration of these PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) will reduce hepatic fat content, inflammation and hepatic injury in patients with type 2 diabetes mellitus who have NASH.

Aims

To determine in patients with type 2 diabetes mellitus who have NASH if dietary supplementation with purified omega-3 fatty acids (EPA and DHA) will:

1. Decrease the histologic severity of NASH.
2. Alter the expression of genes important in the pathways of hepatic lipid synthesis and oxidation.

Study design:

Patients who meet the inclusion criteria will be randomized to receive omega-3 fatty acids or placebo. Stratified randomization will be done based on the NASH Clinical Research Network pathology score of 5.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients (age >18 years)
• Have type 2 diabetes mellitus with good control of blood sugar (hemoglobin A1c [HbA1c] <7.5%) and will have been on a stable regimen of anti-diabetic agents for more than 4 months.
• NASH established on liver biopsy done within 6 months prior to inclusion in the study as determined by established histologic criteria

Exclusion Criteria:

• Cirrhosis of the liver
• End stage target organ damage in diabetes mellitus: advanced renal failure (serum creatinine > 2.0 mg/dl) with or without dialysis, severe neuropathy, or advanced peripheral vascular disease.
• Any organ dysfunction with anticipated life expectancy of less than 2 years
• Co-existent etiologies for liver disease
• Significant alcohol consumption, defined as more than 30 g per day in men and more than 20 g per day in women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Polyunsaturated fatty acid (Opti-EPA); Polyunsaturated fatty acid will consist of purified EPA:DHA (360 mg EPA and 240 mg DHA) 6 gelcaps-3 capsules by mouth 2x per day x 48 weeks	Drug: Polyunsaturated fatty acid (Opti-EPA); Active experimental arm to patients with diabetes mellitus and non alcoholic steatohepatitis: Eicosapentaenoic acid (EPA):Docosahexaenoic acid (DHA)[360 mg EPA and 240 DHA in each capsule] 6 capsules-3 capsules by mouth 2 x per day x 48 weeks; Other Names: Fish oil
Placebo Comparator: Placebo; Gelcaps containing corn oil as placebo 6 capsules 3 capsules by mouth 2 x per day for 48 weeks	Drug: Placebo; Placebo gelcaps containing corn oil identical to the PUFA gelcaps 6 capsules-3 capsules by mouth 2x per day x 48 weeks; Other Names: Corn oil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Improvement of >= 2 Points in NAFLD Activity Score (NAS)	The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) is a score based on the liver biopsy. It represents the sum of scores for steatosis, lobular inflammation, and ballooning, and ranges from 0-8, with high scores indicating more activity.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) Values	Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) measures insulin resistance, calculated by fasting insulin (μU/mL) multiplied by fasting glucose (mg/dL), and divided by a constant (405). A higher score indicates higher insulin resistance.	48 weeks
Aspartate Amino Transferase (AST) Levels	Aspartate amino transferase (IU/dL) at 48 weeks	48 weeks
Alanine Amino Transferase (ALT) Levels	Alanine amino transferase (IU/dL) ay 48 weeks	48 weeks
Blood Glucose Levels	Fasting blood glucose	48 weeks
HbA1C Levels	Hemoglobin A1c	48 weeks

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Arthur J. McCullough, M.D., MetroHealth Medical Center; Principal Investigator: Srinivasan Dasarathy, M.D., The Cleveland Clinic

Publications and helpful links

General Publications

• Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2004 Mar;2(3):262-5. doi: 10.1016/s1542-3565(04)00014-x. Erratum In: Clin Gastroenterol Hepatol. 2004 Jun;2(6):522.
• Dasarathy S, Dasarathy J, Khiyami A, Yerian L, Hawkins C, Sargent R, McCullough AJ. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol. 2015 Feb;49(2):137-44. doi: 10.1097/MCG.0000000000000099.

Helpful Links

• Nonalcoholic Steatohepatitis Clinical Research Network

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: May 5, 2006
• First Submitted That Met QC Criteria: May 5, 2006
• First Posted (Estimate): May 9, 2006

Study Record Updates

• Last Update Posted (Actual): February 23, 2018
• Last Update Submitted That Met QC Criteria: February 22, 2018
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Metabolic syndrome; Insulin resistance; NASH; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Type 2 Diabetes Mellitus; Fatty Liver; PUFA
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver
• Other Study ID Numbers: DK61732; U01DK061732 (U.S. NIH Grant/Contract)