Effects Of Exenatide On Liver Biochemistry, Liver Histology And Lipid Metabolism In Patients With Fatty Liver Disease

University of California (UC) Davis

Status and phase

Terminated

Phase 2

Conditions

Fatty Liver

Diabetes Complications

Treatments

Drug: exenatide

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00529204

200715325

H80-MC-X006 (Other Identifier)

Details and patient eligibility

About

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common complications of type 2 diabetes and leading causes of liver disease in the US and Europe. The prevalence of NAFLD and NASH are expected to become a major cause of liver disease related deaths and liver transplantation. Currently, there are no specific therapies that alter the natural history of NAFLD.Preliminary evidence suggests that exenatide (Byetta®) may have several beneficial direct and indirect effects on NAFLD and liver lipid metabolism.

Full description

Preliminary evidence suggests that exenatide (Byetta®) may have several beneficial direct and indirect effects on NAFLD and liver lipid metabolism. Ad hoc analysis of phase III studies has shown that exenatide treatment is associated with improvement and normalization of alanine aminotransferase (ALT), a marker of liver injury, and that this effect is most pronounced in those with the greatest weight loss. In addition, treatment of leptin deficient ob/ob mice with exenatide reduced weight, liver lipid content, serum ALT and liver lipid peroxidation. Additional evidence suggests that the effects of exenatide on the liver are not simply a result of weight loss, but rather due to direct effects on the liver. Hepatocytes express GLP-1 receptors that are responsive to both GLP-1 and exenatide. Furthermore, exenatide treatment of ob/ob mice or isolated hepatocytes reduces mRNA for stearoyl-CoA desaturase-1 (SCD-1) and SREBP-1c, which would be expected to reduce DNL.

Based upon this data, we hypothesize that exenatide treatment of diabetic patients with NAFLD and NASH will reduce liver injury through multiple mechanisms including weight reduction associated with exenatide, improved lipid metabolism by decreased expression of hepatic genes involved in DNL and reduction of adipokines and cytokines associated with severe NASH. This study is aimed to address the potential safety and efficacy of exenatide in the treatment of NAFLD and test these hypotheses.

This will be an open label, single-arm, non-comparative trial of 20 patients with type 2 diabetes and NAFLD treated with exenatide for 6 months with the following specific aims to be assessed:

Determine the safety and efficacy of 24 weeks of exenatide treatment in diabetic patients with Non-Alcoholic Fatty Liver Disease (NAFLD) Efficacy will be measured by changes in serum ALT (primary endpoint) and liver histology.

Characterize the effects of exenatide on serum levels of adipokines and inflammatory cytokines including adiponectin, leptin and TNF- in NAFLD patients.

Compare the hepatic expression of SCD1, SREBP-1c and PPAR- mRNA in NAFLD patients pre- and post-treatment with exenatide.

Establish the effects of exenatide on post-prandial lipid metabolism.

Determine the effects of exenatide on liver fibrosis in NAFLD.

Enrollment

1 patient

Sex

All

Ages

18 to 70 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Age >18 years, < 70 years, inclusive
Type 2 diabetes on stable doses of sulfonylurea and/or metformin
Body mass index > 35 kg/m2
Presumed diagnosis of NAFLD based upon
an ALT > 1.5 times the upper limit of reference range,
no evidence of other causes of liver disease and
ultrasound findings compatible with fatty liver

Exclusion criteria

Clinical signs of cirrhosis as evidenced by any of the following
spider angiomata,
splenomegaly,
ascites
jaundice
encephalopathy
INR > 1.2
Platelet count < 100,000/ml
Serum albumin < 3.0 g/dL
Other liver disease including chronic viral hepatitis (B or C), alcohol abuse, hemochromatosis, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, primary sclerosing cholangitis or primary biliary cirrhosis.
Current use of > 20 g of alcohol per day or unwillingness to avoid alcohol during the course of the study
Treatment with a thiazolidinedione or exenatide within 6 months of enrolling in the study
AST or ALT > 10 times the upper limit of normal
Treatment with any investigational drug within 4 weeks of enrollment
Pre-menopausal, fertile women unwilling to use contraceptives during the study period.
Pregnancy or lactation
Initiation or change in dose of hypolipidemic drugs (statins, niacin, cholestyramine are allowed) within 6 months of enrollment
Use of anticoagulation, bleeding disorders or other contraindications to liver biopsy