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: May 19, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Diabetes Complications
Fatty Liver
Drug: exenatide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Effects Of Exenatide (Byetta®) On Liver Biochemistry, Liver Histology And Lipid Metabolism In Patients With Non-Alcoholic Fatty Liver Disease

Resource links provided by NLM:


Further study details as provided by University of California, Davis:

Primary Outcome Measures:
  • Reduction in serum ALT from baseline to 24 weeks of exenatide therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 1
Study Start Date: October 2007
Study Completion Date: February 2010
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Exenatide
exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24
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

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

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00529204

Locations
United States, California
University of California Davis Medical Center
Sacramento, California, United States, 95817
Sponsors and Collaborators
University of California, Davis
Amylin Pharmaceuticals, LLC.
Eli Lilly and Company
Investigators
Principal Investigator: Christopher L Bowlus, MD University of California, Davis
Principal Investigator: Lars Berglund, MD, PhD University of California, Davis
  More Information

Additional Information:
Publications:
Responsible Party: Christopher Bowlus, MD, Principal Investigator, University of California, Davis
ClinicalTrials.gov Identifier: NCT00529204     History of Changes
Other Study ID Numbers: H80-MC-X006
Study First Received: September 12, 2007
Last Updated: May 19, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of California, Davis:
Fatty Liver
Nonalcoholic fatty liver disease
NAFDL
Diabetes
ALT
exenatide

Additional relevant MeSH terms:
Fatty Liver
Liver Diseases
Diabetes Complications
Digestive System Diseases
Diabetes Mellitus
Endocrine System Diseases
Exenatide
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on September 22, 2014