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

This study has been terminated.
(Lack of recruitment)
Sponsor:
Collaborators:
Amylin Pharmaceuticals, LLC.
Eli Lilly and Company
Information provided by (Responsible Party):
Christopher Bowlus, MD, University of California, Davis
ClinicalTrials.gov Identifier:
NCT00529204
First received: September 12, 2007
Last updated: October 31, 2012
Last verified: October 2012
History of Changes

September 12, 2007
October 31, 2012
October 2007
July 2009   (final data collection date for primary outcome measure)
Reduction in serum ALT from baseline to 24 weeks of exenatide therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
Reduction in serum ALT from baseline to 24 weeks of exenatide therapy [ Time Frame: 24 weeks ]
Complete list of historical versions of study NCT00529204 on ClinicalTrials.gov Archive Site
  • changes in components of liver histology at baseline and week 24 including steatosis, inflammation and fibrosis [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • safety of exenatide in patients with NAFLD and type 2 diabetes [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  • changes in components of liver histology at baseline and week 24 including steatosis, inflammation and fibrosis [ Time Frame: 24 weeks ]
  • safety of exenatide in patients with NAFLD and type 2 diabetes [ Time Frame: 24 weeks ]
Not Provided
Not Provided
 
Effects Of Exenatide On Liver Biochemistry, Liver Histology And Lipid Metabolism In Patients With Fatty Liver Disease
Effects Of Exenatide (Byetta®) On Liver Biochemistry, Liver Histology And Lipid Metabolism In Patients With Non-Alcoholic Fatty Liver Disease

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.

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.
Interventional
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Diabetes Complications
  • Fatty Liver
  • Lipid Metabolism
  • Drug: exenatide
    Subjects meeting the inclusion criteria will be treated with exenatide 5 µg BID s.c. for 3-7 days, followed by 10 µg BID s.c. daily to week 24
    Other Name: BYETTA
  • Drug: Exenatide
Experimental: Exenatide
Interventions:
  • Drug: exenatide
  • Drug: Exenatide
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
1
February 2010
July 2009   (final data collection date for primary outcome measure)

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
Both
18 Years to 70 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00529204
H80-MC-X006
Yes
Christopher Bowlus, MD, University of California, Davis
University of California, Davis
  • Amylin Pharmaceuticals, LLC.
  • Eli Lilly and Company
Principal Investigator: Christopher L Bowlus, MD University of California, Davis
Principal Investigator: Lars Berglund, MD, PhD University of California, Davis
University of California, Davis
October 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP