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

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.

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