To Study the Effect of Vytorin on Intracellular Lipid and Inflammation in Obese Subjects

Not Applicable

Completed

Conditions: Inflammation

Interventions: Drug: Placebo
Drug: Vytorin

Registration Number: NCT01420328

Lead Sponsor: University at Buffalo

Brief Summary: This study focuses on the use of Vytorin to study inflammatory markers in subjects with normal cholesterol.

Detailed Description: Following the first demonstration by our group that macronutrient (glucose, cream and a high fat high carbohydrate meal) intake results in increased ROS generation and oxidative stress at the cellular and molecular level, the investigators have now shown in our preliminary data that cream intake induces comprehensive inflammation as reflected in increased intranuclear NFkB binding, decreased IkBα expression, increased expression of IL-1β, IL-12, TNFα and other pro-inflammatory mediators. While carrying out these experiments, the investigators asked whether cream intake was associated with an uptake of lipid by peripheral blood mononuclear cells (MNC). Indeed, there was a significant increase in intracellular lipid which was visualized as intracellular lipid droplets. The increase in intracellular lipid droplets was associated with an increase in intracellular superoxide generation; the expression of CD68, a marker for macrophages; and PECAM, the adhesion molecule which mediates trans- endothelial transfer of leucocytes. The investigators also found that the lipid fractions to increase were cholesterol ester, triglyceride and fatty acids. In view of the tantalizing observation that the lipid droplet laden MNC appeared to be monocytes, looked like foam cells and the fact that CD68 expression had increased, there is a possibility that foam cells may be formed in peripheral circulation by monocytes after a lipid rich meal. This simple model of foam cell formation also lends itself for the study of the effect of various lipid lowering drugs. Our investigation will be the first to study this novel paradigm. The investigators plan to study the effect of a cholesterol lowering agent, Vytorin (simvastatin and ezetimibe), on intracellular lipid in MNC, expression of CD68 and PECAM, ROS generation and inflammation in obese subjects. This investigation may provide an additional mechanism of action by which these drugs may reduce atherosclerosis.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

Inclusion Criteria

Age 18-65years.
Obese BMI >30kg/m2
LDL cholesterol >100 mg/dl
Written and informed consent signed and dated 5. Not on any vitamin/antioxidants

Exclusion Criteria

On any antilipid agents.
Triglyceride >500mg/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 13. Anemia with hemoglobin <12 g/dl

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Arm	Placebo	Obese subjects treated with placebo for 6 weeks
Vytorin Arm	Vytorin	Obese subjects treated with Vytorin for 6 weeks

Primary Outcome Measures

Name	Time	Method
Change in CD68 mRNA Expression in MNC	0 weeks and 6 weeks	Percent change from baseline (0 week) in cream challenge induced change in CD68 mRNA expression in MNC after 6 weeks of treatment with Vytorin or placebo. Outcome calculated as: (change at 6 weeks- change at 0 week)/ change at 0 week\*100

Secondary Outcome Measures

Name	Time	Method
Change in Cream-induced Expression of CD16	6 weeks	Percent change from baseline (0 week) in cream -induced change in CD16 mRNA expression in MNC after 6 weeks of treatment with Vytorin or placebo. Outcome calculated as: (change at 6 weeks- change at 0 week)/ change at 0 week\*100
Change in Plasma Endotoxin (LPS) Concentrations	6 weeks	change from baseline (0 week) in cream -induced change in plasma endotoxin concentration after 6 weeks of treatment with Vytorin or placebo. Outcome calculated as: (change at 6 weeks- change at 0 week)
Change IL-1b mRNA Expression	6 weeks	Percent change from baseline (0 week) in cream -induced change in IL-1b mRNA expression in MNC after 6 weeks of treatment with Vytorin or placebo. Outcome calculated as: (change at 6 weeks- change at 0 week)/ change at 0 week\*100