Clinical trial NCT00529204: Effects Of Exenatide On Liver Biochemistry, Liver Histology And Lipid Metabolism In Patients With Fatty Liver Disease
Official title: Effects Of Exenatide (Byetta®) On Liver Biochemistry, Liver Histology And Lipid Metabolism In Patients With Non-Alcoholic Fatty Liver Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Diabetes Complications
Fatty Liver
Keywords: Fatty Liver
Nonalcoholic fatty liver disease
NAFDL
Diabetes
ALT
exenatide
Lead sponsor: University of California, Davis
Sponsor class: OTHER
Collaborators: name: Amylin Pharmaceuticals, LLC.
name: Eli Lilly and Company
First posted: 2007-09-14
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Reduction in Serum ALT From Baseline to 24 Weeks of Exenatide Therapy
timeFrame: 24 weeks
Secondary outcomes:
measure: Changes in Components of Liver Histology at Baseline and Week 24 Including Steatosis, Inflammation and Fibrosis
timeFrame: 24 weeks
measure: Safety of Exenatide in Patients With NAFLD and Type 2 Diabetes
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
Study officials:
affiliation: University of California, Davis
name: Christopher L Bowlus, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Lars Berglund, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Maggs DG, Wintle ME. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007 Jan;29(1):139-53. doi: 10.1016/j.clinthera.2007.01.015.