Diabetes Complications, Fatty Liver
Conditions
Keywords
Fatty Liver, Nonalcoholic fatty liver disease, NAFDL, Diabetes, ALT, exenatide
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.
Interventions
DRUGexenatide
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
Sponsors
Amylin Pharmaceuticals, LLC.
Eli Lilly and Company
University of California, Davis
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Reduction in Serum ALT From Baseline to 24 Weeks of Exenatide Therapy | 24 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
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 | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Exenatide |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Alanine aminotransferase | 84 IU |
| Cholesterol | 317 mg/dL |
| Glucose | 139 mg/dL |
| HbA1c | 8.1 % |
| HDL | 31 mg/dL |
| hsCRP | 8.2 mg/L |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 0 Participants |
| Triglyceride | 482 mg/dL |
| Weight | 72.3 kg |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
Reduction in Serum ALT From Baseline to 24 Weeks of Exenatide Therapy
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Reduction in Serum ALT From Baseline to 24 Weeks of Exenatide Therapy | 61 IU |
Secondary
Changes in Components of Liver Histology at Baseline and Week 24 Including Steatosis, Inflammation and Fibrosis
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exenatide | Changes in Components of Liver Histology at Baseline and Week 24 Including Steatosis, Inflammation and Fibrosis | steatosis | -1 units on a scale |
| Exenatide | Changes in Components of Liver Histology at Baseline and Week 24 Including Steatosis, Inflammation and Fibrosis | inflammation | -1 units on a scale |
| Exenatide | Changes in Components of Liver Histology at Baseline and Week 24 Including Steatosis, Inflammation and Fibrosis | fibrosis | 0 units on a scale |
Secondary
Safety of Exenatide in Patients With NAFLD and Type 2 Diabetes
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Safety of Exenatide in Patients With NAFLD and Type 2 Diabetes | 0 adverse events |