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

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

Study Overview

• Status: Completed
• Conditions: Inflammation
• Intervention / Treatment: Drug: Placebo; Drug: Vytorin

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14209
      • Diabetes Endocrinology Center of WNY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. On any antilipid agents.
2. Triglyceride >500mg/dl
3. Myocardial infarction, angioplasty/stent placement or coronary artery bypass surgery in the past 6 months
4. Patient on chronic use of non-steroidal anti-inflammatory drugs or steroids
5. Hepatic disease
6. Renal impairment
7. History of drug or alcohol abuse
8. Participation in any other concurrent clinical trial
9. Use of an investigational agent or therapeutic regimen within 30 days of study.
10. Smoker
11. Pregnancy
12. 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Arm; Obese subjects treated with placebo for 6 weeks	Drug: Placebo; Placebo treatment for 6 weeks; Other Names: Placebo for Vytorin
Active Comparator: Vytorin Arm; Obese subjects treated with Vytorin for 6 weeks	Drug: Vytorin; Simvastatin 40 mg and Ezetimibe 10 mg daily combination pill (Vytorin) for 6 weeks; Other Names: Ezetimibi/Simvastatin 10/40

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CD68 mRNA Expression in MNC	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	0 weeks and 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cream-induced Expression of CD16	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	6 weeks
Change IL-1b mRNA Expression	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	6 weeks
Change in Plasma Endotoxin (LPS) Concentrations	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)	6 weeks

Collaborators and Investigators

• Sponsor: University at Buffalo
• Collaborators: Kaleida Health
• Investigators: Principal Investigator: Paresh Dandona, MD, University at Buffalo, NY

Publications and helpful links

General Publications

• Ghanim H, Green K, Abuaysheh S, Patel R, Batra M, Chaudhuri A, Makdissi A, Kuhadiya ND, Dandona P. Ezetimibe and simvastatin combination inhibits and reverses the pro-inflammatory and pro-atherogenic effects of cream in obese patients. Atherosclerosis. 2017 Aug;263:278-286. doi: 10.1016/j.atherosclerosis.2017.06.010. Epub 2017 Jun 7.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2011
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: May 26, 2011
• First Submitted That Met QC Criteria: August 18, 2011
• First Posted (Estimated): August 19, 2011

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin; Ezetimibe, Simvastatin Drug Combination
• Other Study ID Numbers: MED7120311A