Anti-inflammatory Effects of Simvastatin

Study Overview
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Brief Summary
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The purpose of this research study is to determine which of the two ingredients of Vytorin (Simvastatin or Ezetimibe) is responsible for the anti-inflammatory effects of Vytorin

Detailed Description
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Cardiovascular disease is currently the leading cause of death in the developed countries. Atherosclerosis is the most important cause of cardiovascular disease. Statins are known to exert a powerful anti-atherogenic action which is reflected in a marked beneficial effect on the prevention of cardiovascular effects and cardiovascular mortality. They induce a reduction in the progression and an increase in the regression of atherosclerotic lesions. Statins exert powerful effect on lowering LDLc and are also anti-inflammatory due to their ability to lower CRP concentrations. But little is known about their anti-inflammatory effects at a cellular and molecular levels in humans, in vivo. Vytorin, a preparation containing simvastatin and ezetimibe, has a powerful effect on lowering LDLc concentration through a combination of effects on the absorption of cholesterol from the gut and hepatic cholesterol biosynthesis. In our previous study we have shown that Vytorin exerts a potent anti-inflammatory effect in the obese in the fasting state and following acute inflammatory changes induced by the intake of cream. The IMPROVE-IT trial, which examined the benefits of adding ezetimibe to simvastatin, showed a small additional benefit of ezetimibe (a 6% reduction in cardiovascular events) compared to simvastatin alone. This is marginal when compared to the established cardiovascular benefits of statins. We, therefore, explore further into the anti-inflammatory actions of the two components of Vytorin by comparing the effects of simvastatin versus ezetimibe on intracellular lipid and inflammation in obese patients to determine which of the two ingredients of Vytorin is responsible for the specific combination of these effects.

Official Title
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Comparison of Effects of Simvastatin Versus Ezetimibe on Intracellular Lipid and Inflammation in Obese Subjects

Conditions
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Inflammation, Atherosclerosis, Hypercholesterolemia

Intervention / Treatment
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* Drug: Simvastatin 40mg
* Drug: Ezetimibe 10mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18 to 75 years of age. Obese (BMI ≥30 kg/m2) LDL cholesterol of ≥100 mg/dl Not taking any vitamins or antioxidants Exclusion Criteria: Currently using anti-hyperlipidemic therapies Triglycerides >500 mg/dl. Myocardial infarction, angioplasty/stent placement or coronary artery bypass surgery in the past 6 months. Patient on chronic use of non-steroidal anti-inflammatory drugs or steroids Hepatic disease Renal impairment. History of drug or alcohol abuse Participation in any other concurrent clinical trial Use of an investigational agent or therapeutic regimen within 30 days of study. Smoker Pregnancy Premenopausal women who are not on birth control pills and have not had a hysterectomy or tubal ligation Anemia with hemoglobin <12 g/dl

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Simvastatin<br>Obese subjects with elevated cholesterol | Drug: Simvastatin 40mg<br>* Simvastatin administered daily for 6 weeks<br>* Other names: Simvastatin;|
| Active Comparator: Ezetimibe<br>Obese subjects with elevated cholesterol | Drug: Ezetimibe 10mg<br>* Ezetimibe administered daily for 6 weeks<br>* Other names: Zetia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in markers of monocyte activation | Percentage change in mRNA expression of CD68 on MNC following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks | 
| Change in markers of monocyte activation | Percentage change in mRNA expression of PECAM on MNC following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in markers of inflammation and oxidative stress | Percentage change in mRNA expression of IL-1β on MNC following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks | 
| Change in markers of inflammation and oxidative stress | Percentage change in mRNA expression of TNFα on MNC following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks | 
| Change in markers of inflammation and oxidative stress | Percentage change in mRNA expression of MMP-9 on MNC following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks | 
| Change in the expression of toll like receptor | Percentage change in mRNA expression of TLR-2 on MNC following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks | 
| Change in the expression of toll like receptor | Percentage change in mRNA expression of TLR-4 on MNC following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks | 
| Change in plasma concentrations of pro inflammatory end points | Percentage change in plasma levels of IL-1β following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks | 
| Change in plasma concentrations of pro inflammatory end points | Percentage change in plasma levels of IL-18 following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks | 
| Change in plasma concentrations of pro inflammatory end points | Percentage change in plasma levels of MMP-9 following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe | 6 weeks |