Non-alcoholic Fatty Liver Disease
Conditions
Brief summary
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the progressive form of liver disease that can lead to cirrhosis and liver-related mortality in persons who drink little or no alcohol. NAFLD is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. NASH is benign in many affected individuals but can cause progressive liver injury and, indeed, may be the major cause of cryptogenic cirrhosis1. Currently, there is no FDA approved treatment for NAFLD. Weight loss and exercise are the recommended but often difficult maintain these lifestyle changes in the long term and therefore therapeutic agents have been investigated. In this study, we propose to treat 50 patients with NAFLD and diabetes with either sitagliptin or placebo for 24 weeks. After an initial evaluation for insulin sensitivity and MRI liver fat distribution, patients will receive either 100 mg/day of sitagliptin or placebo. Patients will be monitored at regular intervals for symptoms of liver disease, side effects of sitagliptin and serum biochemical and metabolic indices. At the end of 24-weeks, patients will have a repeat medical evaluation, liver MRI and an optional liver biopsy. Pre and post treatment MRI-derived liver fat content and insulin sensitivity will be compared. The primary end point of successful therapy will be improvement in hepatic steatosis measured by MRI. Secondary end points will be improvement in insulin sensitivity and liver biochemistry.
Detailed description
Primary objectives: 1\. To examine the efficacy of sitagliptin 100 mg orally daily versus placebo in improving hepatic steatosis assessed by magnetic resonance imaging in patients with NAFLD. Secondary objectives: 1. To examine the efficacy of sitagliptin in improving serum AST in patients with NAFLD. 2. To examine the efficacy of sitagliptin in improving serum ALT in patients with NAFLD. 3. To examine the efficacy of sitagliptin in improving serum LDL in patients with NAFLD. 4. To examine the efficacy of sitagliptin in the improvement of insulin sensitivity in patients with NAFLD.
Interventions
DRUGSitagliptin
DRUGPlacebo
Sponsors
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
44 patients with NAFLD will be randomized to either sitagliptin or placebo for 24-weeks. Enrollment of 50 patients is needed to allow for exclusion of some patients after initial evaluation and a dropout of a small number of patients because of intolerance to sitagliptin. Inclusion criteria: 1. Age at entry at least 18 years. 2. Serum alanine (ALT) or aspartate (AST) aminotransferase activities that are above the upper limits of normal. 19 or more in women and 30 or more in men. 3. Evidence of hepatic steatosis or liver fat (≥5%) by MRI. 4. Prediabetic patients and controlled diabetic patients as defined by the ADA position statement on diabetes mellitus. Prediabetics have a HbA1c of 5.7 to 6.4 and controlled diabetic patients have an HbA1c between 6.4 and 8.0. 5. Written informed consent.
Exclusion criteria
1. Uncontrolled diabetes defined as a Hb A1c ≥ 8.0. 2. Evidence of another form of liver disease. * Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg). * Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum. * Autoimmune hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistent with autoimmune hepatitis or previous response to immunosuppressive therapy. * Autoimmune cholestatic liver disorders as defined by elevation of alkaline phosphatase and anti-mitochondrial antibody of greater than 1:80 or liver histology consistent with primary biliary cirrhosis or elevation of alkaline phosphatase and liver histology consistent with sclerosing cholangitis. * Wilson disease as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilson disease. * Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than normal and liver histology consistent with alpha-1-antitrypsin deficiency. * Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. * Drug-induced liver disease as defined on the basis of typical exposure and history. * Bile duct obstruction as shown by imaging studies. 3. History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol intake averaging greater than 10 gm/day (1 drink per day: 7 drinks per week) in the previous one year. 4. Advanced liver disease: platelet counts \< 75,000/mm3 or prothrombin time \>16 seconds or history of bleeding disorders 5. Decompensated liver disease, Child-Pugh score greater than or equal to 7 points 6. History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months. 7. Recent initiation or change of anti-diabetic drugs, including insulin, sulfonylureas, or thiazolidinediones in the previous 90 days. 8. Use of sitagliptin or other agents in the same class within the 90 days prior to randomization. 9. Significant systemic or major illnesses other than liver disease, including congestive heart failure, coronary artery disease, cerebrovascular disease, pulmonary disease with hypoxia, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator would preclude treatment with Sitagliptin and adequate follow up. 10. History of acute pancreatitis within the last 5 years with the exception of gallstone pancreatitis. 11. Positive test for anti-HIV. 12. Active substance abuse, such as alcohol, inhaled or injection drugs within the previous one year. 13. Pregnancy or inability to practice adequate contraception in women of childbearing potential. 14. Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver mass on imaging study that is suggestive of liver cancer. 15. Any other condition, which, in the opinion of the investigators would impede competence or compliance or possibility hinder completion of the study. 16. Serum creatinine \>1.5 mg/dl. 17. Contraindications to Sitagliptin use : * History of allergic reaction to Sitagliptin * Patients with acute liver injury or unexplained persistent elevations in ALT \> 500 U/L at baseline. * Women who are pregnant or may become pregnant * Nursing mothers 18. Contraindications to MRI: * The subject has any contraindication to MR imaging, such as patients with pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or other conditions that would preclude proximity to a strong magnetic field. * The subject has a history of extreme claustrophobia * The subject cannot fit inside the MR scanner cavity 11\. RECRUITMENT Enrollment of patients may be initiated once IRB approval is acquired and will continue until June 2015. Patients will be recruited from the following populations: * Primary care and internal medicine clinics * Tertiary referral clinics at the Hillcrest Campus and Perlman Clinics: * GI/Liver clinic * Liver transplant clinic * Obesity clinic * Bariatric surgery clinic * Diabetes clinic * Lipid disorders clinic * Physicians taking care of the patients would provide information regarding the study and then either refer the patient to our clinic or ask the patient to directly contact the PI or research assistant. * Patient would be given information regarding possible studies in NAFLD in liver clinic by their providers. We would ask the patient to call or email the PI or research assistant to further discuss the study, if they are interested.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Liver Fat Relative to Baseline Assessed by MRI-PDFF | Baseline and 24 weeks | Participants liver fat was measured at baseline and 24 weeks. This is the percentage change in liver fat assessed by MRI-PDFF and stratified by treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AST, Aspartate Aminotransferase | Baseline and 24 weeks | AST, measured in IU/L at baseline and 24 weeks |
| ALT, Alanine Aminotransferase | Baseline and 24 weeks | ALT, measured in IU/L at baseline and 24 weeks |
| LDL, Low-density Lipoprotein | Baseline and 24 weeks | LDL, measured in mg/dL at baseline and 24 weeks |
| HOMA-IR, Homeostatic Model Assessment of Insulin Resistance | Baseline and 24 weeks | HOMA-IR, calculated as \[(glucose (mg/dL) X insulin (mg/dL)) / 405 \] at baseline and 24 weeks |
Countries
United States
Participant flow
Recruitment details
Jan. 1, 2014 to May 1, 2015
Participants by arm
| Arm | Count |
|---|---|
| Placebo Sitagliptin-matched placebo tablet | 25 |
| Active Drug Sitagliptin 100 mg | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | Placebo | Active Drug | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 4 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 21 Participants | 43 Participants |
| Region of Enrollment United States | 25 participants | 25 participants | 50 participants |
| Sex: Female, Male Female | 17 Participants | 12 Participants | 29 Participants |
| Sex: Female, Male Male | 8 Participants | 13 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 25 | 0 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 |
Outcome results
Primary
Percentage Change in Liver Fat Relative to Baseline Assessed by MRI-PDFF
Participants liver fat was measured at baseline and 24 weeks. This is the percentage change in liver fat assessed by MRI-PDFF and stratified by treatment group.
Time frame: Baseline and 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change in Liver Fat Relative to Baseline Assessed by MRI-PDFF | 13.9 percentage change in liver fat | Standard Deviation 8.5 |
| Active Drug | Percentage Change in Liver Fat Relative to Baseline Assessed by MRI-PDFF | 8.4 percentage change in liver fat | Standard Deviation 11.6 |
p-value: 0.585t-test, 2 sided
Secondary
ALT, Alanine Aminotransferase
ALT, measured in IU/L at baseline and 24 weeks
Time frame: Baseline and 24 weeks
Population: All participants with ALT measurements at baseline and 24 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | ALT, Alanine Aminotransferase | Baseline | 40.0 IU/L |
| Placebo | ALT, Alanine Aminotransferase | 24 weeks | 28.5 IU/L |
| Active Drug | ALT, Alanine Aminotransferase | Baseline | 43.0 IU/L |
| Active Drug | ALT, Alanine Aminotransferase | 24 weeks | 34.0 IU/L |
Comparison: Comparison of change in ALT values from baseline to 24 weeks between the two groups.p-value: 0.8569Wilcoxon (Mann-Whitney)
Secondary
AST, Aspartate Aminotransferase
AST, measured in IU/L at baseline and 24 weeks
Time frame: Baseline and 24 weeks
Population: All participants with AST measurements at baseline and 24 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | AST, Aspartate Aminotransferase | Baseline | 28.5 IU/L |
| Placebo | AST, Aspartate Aminotransferase | 24 weeks | 23.5 IU/L |
| Active Drug | AST, Aspartate Aminotransferase | Baseline | 28.0 IU/L |
| Active Drug | AST, Aspartate Aminotransferase | 24 weeks | 27.0 IU/L |
Comparison: Comparison of change in AST values from baseline to 24 weeks between the two groups.p-value: 0.7583Wilcoxon (Mann-Whitney)
Secondary
HOMA-IR, Homeostatic Model Assessment of Insulin Resistance
HOMA-IR, calculated as \[(glucose (mg/dL) X insulin (mg/dL)) / 405 \] at baseline and 24 weeks
Time frame: Baseline and 24 weeks
Population: All participants with HOMA-IR calculated at baseline and 24 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | HOMA-IR, Homeostatic Model Assessment of Insulin Resistance | Baseline | 5.4 HOMA-IR score |
| Placebo | HOMA-IR, Homeostatic Model Assessment of Insulin Resistance | 24 weeks | 4.9 HOMA-IR score |
| Active Drug | HOMA-IR, Homeostatic Model Assessment of Insulin Resistance | Baseline | 5.9 HOMA-IR score |
| Active Drug | HOMA-IR, Homeostatic Model Assessment of Insulin Resistance | 24 weeks | 6.8 HOMA-IR score |
Comparison: Comparison of change in HOMA-IR values from baseline to 24 weeks between the two groups.p-value: 0.556Wilcoxon (Mann-Whitney)
Secondary
LDL, Low-density Lipoprotein
LDL, measured in mg/dL at baseline and 24 weeks
Time frame: Baseline and 24 weeks
Population: All participants with LDL measurements at baseline and 24 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | LDL, Low-density Lipoprotein | Baseline | 99.0 mg/dL |
| Placebo | LDL, Low-density Lipoprotein | 24 weeks | 101.0 mg/dL |
| Active Drug | LDL, Low-density Lipoprotein | Baseline | 100.0 mg/dL |
| Active Drug | LDL, Low-density Lipoprotein | 24 weeks | 98.0 mg/dL |
Comparison: Comparison of change in LDL values from baseline to 24 weeks between the two groups.p-value: 0.7984Wilcoxon (Mann-Whitney)