Effects of Pitavastatin on Insulin Sensitivity and Liver Fat

Study Overview
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Brief Summary
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HMG co-A reductase inhibitors, commonly called statins, are an effective treatment for dyslipidemia and atherosclerotic heart disease with proven mortality benefit. While the lipid-lowering effects of statins are well-known, other metabolic effects, including effects on glucose tolerance and ectopic fat distribution, are less completely understood. Recent studies have shown that some statins may increase the risk of diabetes. Further, research has suggested that statins may have some benefit in nonalcoholic fatty liver disease (NAFLD), a condition associated with obesity that includes increased fat in the liver (steatosis) and, in some cases, inflammation and hepatocellular damage (steatohepatitis). Pitavastatin, approved by the United States Food and Drug Administration (FDA) in 2009, is the most recent statin to enter the market. Unlike most statins, pitavastatin is not primarily metabolized through cytochrome P450 (CYP450), and thus has reduced potential for interactions with other medications that are metabolized by CYP450. Previous studies have suggested that pitavastatin may be neutral to glucose homeostasis and may improve hepatic lipid. Neither of these effects has been proven definitively, however, and the current proposal aims to characterize in detail the effects of pitavastatin on glucose homeostasis, hepatic steatosis, and steatohepatitis.

Official Title
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Effects of Pitavastatin on Insulin Sensitivity and Liver Fat

Conditions
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Obesity, Fatty Liver, Nonalcoholic

Intervention / Treatment
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* Drug: pitavastatin
* Other: PLACEBO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men age 40-65yo BMI ≥ 27kg/m2 and waist circumference ≥102cm, high probability risk factors for NAFLD At least one of the following indicating insulin resistance: Fasting glucose ≥100mg/dL and <126mg/dL, HOMA-IR >2.0, and/or 2 hour glucose ≥140mg/dL and <200mg/dL following standard glucose tolerance test. 10-year cardiovascular disease risk ≥5% by American Heart Association(AHA)/American College of Cardiology (ACC) Pooled Cohort Equations CV Risk Calculator or LDL ≥ 100mg/dL No use of any statin within 1 year of study entry and not being actively considered for statin therapy by a treating provider. Exclusion Criteria: Diagnosis of diabetes or use of anti-diabetic medications. Use of erythromycin, rifampin, cyclosporin, colchicine, or gemfibrozil. Use of statin therapy within 1 year prior to study entry as above. Use of any other lipid-modifying therapy (including fish oil, fibrates, niacin, gemfibrozil) within 6 months of study entry. Contraindication to statin therapy. Creatinine > upper limit of normal or known renal disease AST or ALT > 3 times the upper limit of normal hemoglobin < 10g/dL Contraindication to undergoing a magnetic resonance scan. Atherosclerotic cardiovascular disease or low-density lipoprotein cholesterol (LDL-C) ≥ 190mg/dL. Triglyceride ≥500mg/dL

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pitavastatin<br>pitavastatin 4mg daily by mouth for 6 months | Drug: pitavastatin<br> <br> * Other names: Livalo;|
| Placebo Comparator: Placebo<br>Identical placebo 4mg by mouth daily for 6 months | Other: PLACEBO<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin-stimulated Glucose Uptake | insulin-stimulated glucose uptake measured by euglycemic hyperinsulinemic clamp | 6 months | 
| Liver Fat | liver fat content as measured by 1H-magnetic resonance spectroscopy | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alanine Aminotransferase (ALT) | alanine aminotransferase at the 6 month timepoint | 6 months | 
| Aspartate Aminotransferase (AST) | aspartate aminotransferase at 6 month timepoint | 6 months | 
| Hepatic Insulin Sensitivity | hepatic insulin sensitivity assessed by glucose infusion rate corrected for fluctuations in serum glucose (M) during low-dose insulin clamp | 6 months | 
| Hemoglobin A1c (HbA1c) |  | 6 months | 
| Quantitative Insulin Sensitivity Check Index (QUICKI) | quantitative insulin sensitivity check index (QUICKI) at 6 months. Measure = 1/((log(glucose in mg/dL) + log(insulin in uU/mL)) | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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obesity, insulin sensitivity, statin (HMG-CoA Reductase Inhibitor), fatty liver