Effects Of Exenatide On Liver Biochemistry, Liver Histology And Lipid Metabolism In Patients With Fatty Liver Disease
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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 Names:
|
Outcome Measures
Primary Outcome Measures
- Reduction in Serum ALT From Baseline to 24 Weeks of Exenatide Therapy [24 weeks]
Secondary Outcome Measures
- Changes in Components of Liver Histology at Baseline and Week 24 Including Steatosis, Inflammation and Fibrosis [24 weeks]
Steatosis was grades on a scale of 0 (< 5%); 1 (5%- 33%); 2 (> 33% - 66%); and 3 (> 66%). Inflammation was graded on a scale of 0 (No foci); 1 (< 2 foci per 200 X field); 2 (2-4 foci per 200 X field); and 3 (>4 foci per 200 X field) Fibrosis was graded on a scale of 0 (None); 1 (Mild periportal or perisinusoidal); 2 (Moderate periportal or perisinusoidal); 3 (Bridging fibrosis); and 4 (cirrhosis)
- Safety of Exenatide in Patients With NAFLD and Type 2 Diabetes [24 weeks]
Eligibility Criteria
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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | 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
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- 200715325
- H80-MC-X006
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Exenatide |
|---|---|
| Arm/Group Description | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 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 |
| Period Title: Overall Study | |
| STARTED | 1 |
| COMPLETED | 1 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Exenatide |
|---|---|
| Arm/Group Description | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 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 |
| Overall Participants | 1 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
1
100%
|
| >=65 years |
0
0%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
1
100%
|
| Male |
0
0%
|
| Alanine aminotransferase (IU) [Mean (Full Range) ] | |
| Mean (Full Range) [IU] |
84
|
| Glucose (mg/dL) [Mean (Full Range) ] | |
| Mean (Full Range) [mg/dL] |
139
|
| Cholesterol (mg/dL) [Mean (Full Range) ] | |
| Mean (Full Range) [mg/dL] |
317
|
| HDL (mg/dL) [Mean (Full Range) ] | |
| Mean (Full Range) [mg/dL] |
31
|
| Triglyceride (mg/dL) [Mean (Full Range) ] | |
| Mean (Full Range) [mg/dL] |
482
|
| hsCRP (mg/L) [Mean (Full Range) ] | |
| Mean (Full Range) [mg/L] |
8.2
|
| Weight (kg) [Mean (Full Range) ] | |
| Mean (Full Range) [kg] |
72.3
|
| HbA1c (%) [Mean (Full Range) ] | |
| Mean (Full Range) [%] |
8.1
|
Outcome Measures
| Title | Reduction in Serum ALT From Baseline to 24 Weeks of Exenatide Therapy |
|---|---|
| Description | |
| Time Frame | 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Exenatide |
|---|---|
| Arm/Group Description | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 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 |
| Measure Participants | 1 |
| Number [IU] |
61
|
| Title | Changes in Components of Liver Histology at Baseline and Week 24 Including Steatosis, Inflammation and Fibrosis |
|---|---|
| Description | Steatosis was grades on a scale of 0 (< 5%); 1 (5%- 33%); 2 (> 33% - 66%); and 3 (> 66%). Inflammation was graded on a scale of 0 (No foci); 1 (< 2 foci per 200 X field); 2 (2-4 foci per 200 X field); and 3 (>4 foci per 200 X field) Fibrosis was graded on a scale of 0 (None); 1 (Mild periportal or perisinusoidal); 2 (Moderate periportal or perisinusoidal); 3 (Bridging fibrosis); and 4 (cirrhosis) |
| Time Frame | 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Exenatide |
|---|---|
| Arm/Group Description | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 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 |
| Measure Participants | 1 |
| steatosis |
-1
|
| inflammation |
-1
|
| fibrosis |
0
|
| Title | Safety of Exenatide in Patients With NAFLD and Type 2 Diabetes |
|---|---|
| Description | |
| Time Frame | 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Exenatide |
|---|---|
| Arm/Group Description | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 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 |
| Measure Participants | 1 |
| Number [adverse events] |
0
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Exenatide | |
| Arm/Group Description | exenatide 5 µg BID s.c. daily for 28 days, followed by 10 µg BID s.c. daily from day 29 to week 24 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 | |
All Cause Mortality |
||
| Exenatide | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Exenatide | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/1 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| Exenatide | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/1 (0%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Christopher L. Bowlus, MD |
|---|---|
| Organization | University of California Davis Medical Center |
| Phone | 916-734-8986 |
| chris.bowlus@ucdmc.ucdavis.edu |
- 200715325
- H80-MC-X006