Inflammation
Conditions
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.
Interventions
DRUGVytorin
Simvastatin 40 mg and Ezetimibe 10 mg daily combination pill (Vytorin) for 6 weeks
DRUGPlacebo
Placebo treatment for 6 weeks
Sponsors
Kaleida Health
University at Buffalo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| 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) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Arm/Description 10 subjects with obesity but not diabetes and LDL \>100 mg/dl on placebo treatment for 6 weeks | 10 |
| Vytorin Arm/Description 10 subjects with obesity but not diabetes and LDL \>100 mg/dl on Vytorin for 6 weeks
Vytorin: Simvastatin 40 mg and Ezetimibe 10 mg daily combination pill ( | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Placebo Arm/Description | Vytorin Arm/Description | Total |
|---|---|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 4 | 51 years STANDARD_DEVIATION 3 | 50 years STANDARD_DEVIATION 3.5 |
| BMI | 38.1 Kg/m^2 STANDARD_DEVIATION 1.6 | 38.2 Kg/m^2 STANDARD_DEVIATION 1.7 | 38.2 Kg/m^2 STANDARD_DEVIATION 1.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 10 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
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
Time frame: 0 weeks and 6 weeks
Population: All patients entered into study were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Arm | Change in CD68 mRNA Expression in MNC | 10 percentage of change | Standard Error 9 |
| Vytorin Arm | Change in CD68 mRNA Expression in MNC | -68 percentage of change | Standard Error 13 |
Secondary
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
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Arm | Change IL-1b mRNA Expression | -13 percentage of change | Standard Error 8 |
| Vytorin Arm | Change IL-1b mRNA Expression | -74 percentage of change | Standard Error 15 |
Secondary
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
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Arm | Change in Cream-induced Expression of CD16 | -10 percentage of change | Standard Error 12 |
| Vytorin Arm | Change in Cream-induced Expression of CD16 | -57 percentage of change | Standard Error 13 |
Secondary
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)
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Arm | Change in Plasma Endotoxin (LPS) Concentrations | 0.11 EU/ml | Standard Error 0.09 |
| Vytorin Arm | Change in Plasma Endotoxin (LPS) Concentrations | -0.23 EU/ml | Standard Error 0.08 |