Sitagliptin Versus Placebo in the Treatment of Non-alcoholic Fatty Liver Disease
Condition: Non-alcoholic Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Sitagliptin; Placebo
Intervention MeSH terms: Sitagliptin Phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No

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.
    

Eligibility 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.