Sitagliptin for the Treatment of Non-alcoholic Steatohepatitis in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled trial evaluating the impact of sitagliptin therapy in patients with concomitant type 2 diabetes and non-alcoholic steatohepatitis (NASH) on improving liver disease based on biopsy results. The effect of sitagliptin on other measures such as hormones modifying insulin release and sensitivity (termed adipocytokines), fat distribution, and biomarkers of cardiovascular risk will also be evaluated.

Official Title
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Sitagliptin for the Treatment of Non-alcoholic Steatohepatitis in Patients With Type 2 Diabetes.

Conditions
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Type 2 Diabetes, Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: sitagliptin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Known DM2 (receiving lifestyle management and/or metformin and/or sulfonylurea Stable therapy for DM2 for the past 3 months All other medications and doses stable for past 3 months HbA1c 8.9% or lower (can be done in past 30 days) Known NASH based on the accepted American Gastroenterological Association Criteria: Alcohol consumption (< 10g/day in women and <20g/day in men) Cause of liver disease other than NAFLD (negative investigations for: viral hepatitis, iron overload, a-1 antitrypsin, ceruloplasmin, autoimmune disease) Liver histology demonstrating macrovesicular fatty change of hepatocytes, with evidence of steatohepatitis, manifested by the presence of Mallory Bodies, ballooning degeneration, lobular neutrophilic inflammation and perisinusoidal fibrosis. (If liver biopsy done within 2 years prior to screening for this trial, that biopsy will be reviewed to ensure it meets criteria for diagnosis). Exclusion Criteria: Any contraindication for undergoing MRI Child class B or C cirrhosis Participation in another clinical trial Use of thiazoledinedione (rosiglitazone or pioglitazone) in past 6 months Current use of plavix Previous exposure to sitagliptin Prior history of pancreatitis History of anaphylaxis to another Canadian-marketed DPP-IV inhibitor (saxagliptin) Creatine clearance <30 ml/min Anaemia (haemoglobin < 110 mg/dL) Platelet count < 50 000 cells/mm3 Known heart or kidney failure Comorbid condition that decreases natural life span (e.g. known cancer) Pregnant or breastfeeding or wishing to become pregnant in the next 6 months Current or past treatment with medications that can induce steatohepatitis (e.g. glucocorticoids, methotrexate, amiodarone etc.)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sitagliptin<br>sitagliptin 100mg/daily for 6 months | Drug: sitagliptin<br>* pill, 100mg/daily for 6 months<br>|
| Placebo Comparator: placebo<br>placebo match for 6 months | Drug: placebo<br>* placebo match for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate improvement in liver disease (based on liver biopsy)with sitagliptin. |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In individuals with NASH and DM2: To document the impact of sitagliptin therapy on adipocytokines, inflammatory markers, non-traditional cardiovascular risk factors, adipose distribution, and dyslipidemia. |  | 3 years | 
| In individuals with NASH and DM2: To delineate the effect of sitagliptin therapy on platelet aggregation and oxidative stress. |  | 3 years | 
| In individuals with NASH and DM2: To determine the correlation between changes in histology with changes in hepatic fat demonstrated by MRI and changes in fibrosis by Fibroscan. |  | 3 years |