Inflammation, Atherosclerosis, Hypercholesterolemia
Conditions
Brief summary
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
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.
Interventions
DRUGSimvastatin 40mg
Simvastatin administered daily for 6 weeks
DRUGEzetimibe 10mg
Ezetimibe administered daily for 6 weeks
Sponsors
paresh Dandona
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age: 18 to 75 years of age. 2. Obese (BMI ≥30 kg/m2) 3. LDL cholesterol of ≥100 mg/dl 4. Not taking any vitamins or antioxidants
Exclusion criteria
1. Currently using anti-hyperlipidemic therapies 2. Triglycerides \>500 mg/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 mRNA Expression of CD68 in MNC | 6 weeks | Percentage change in mRNA expression of CD68 in MNC following cream challenge at weeks 0 and 6 of treatment with simvastatin or ezetimibe. Percent change (using the formula: (x-y)/y\*100) is calculated using data collected before (0hr) and after the cream challenge (peak effect) at weeks 0 and 6 of treatment with simvastatin or ezetimibe. |
| Change in mRNA Expression of PECAM on MNC | 6 weeks | Percentage change in mRNA expression of PECAM on MNC following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe. Percent change (using the formula: (x-y)/y\*100) was calculated using data collected before (0hr) and after the cream challenge (peak effect) at weeks 0 and 6 of treatment with simvastatin or ezetimibe. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in mRNA Expression of IL-1β in MNC | 6 weeks | Percentage change in mRNA expression of IL-1β in MNC following cream challenge calculated from data collected before (at 0 week) and after (at 6 weeks) treatment with simvastatin or ezetimibe |
| Change in TNF-a mRNA Expression in MNC | 6 weeks | Percentage change in mRNA expression of TNFα in MNC following cream challenge calculated using data collected before and after the cream challenge at weeks 0 and 6 of treatment with simvastatin or ezetimibe |
| Change in mRNA Expression of MMP-9 in MNC | 6 weeks | Percentage change in mRNA expression of MMP-9 in MNC calculated from data collected following cream challenge before (0 week) and after (6 weeks) of treatment with simvastatin or ezetimibe |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin Obese subjects with elevated cholesterol
Simvastatin 40mg: Simvastatin administered daily for 6 weeks | 5 |
| Ezetimibe Obese subjects with elevated cholesterol
Ezetimibe 10mg: Ezetimibe administered daily for 6 weeks | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Simvastatin | Ezetimibe | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Continuous | 53.2 years STANDARD_DEVIATION 4.2 | 53.2 years STANDARD_DEVIATION 4.2 | 53.2 years STANDARD_DEVIATION 4.2 |
| Change in CD68 mRNA expression | 48 Percent of Change STANDARD_DEVIATION 11 | 44.5 Percent of Change STANDARD_DEVIATION 7 | 46 Percent of Change STANDARD_DEVIATION 9 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Change in mRNA Expression of CD68 in MNC
Percentage change in mRNA expression of CD68 in MNC following cream challenge at weeks 0 and 6 of treatment with simvastatin or ezetimibe. Percent change (using the formula: (x-y)/y\*100) is calculated using data collected before (0hr) and after the cream challenge (peak effect) at weeks 0 and 6 of treatment with simvastatin or ezetimibe.
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin | Change in mRNA Expression of CD68 in MNC | week 0 | 48 percentage change | Standard Error 11 |
| Simvastatin | Change in mRNA Expression of CD68 in MNC | week 6 | 38 percentage change | Standard Error 9 |
| Ezetimibe | Change in mRNA Expression of CD68 in MNC | week 0 | 44.5 percentage change | Standard Error 7 |
| Ezetimibe | Change in mRNA Expression of CD68 in MNC | week 6 | 35 percentage change | Standard Error 5 |
Primary
Change in mRNA Expression of PECAM on MNC
Percentage change in mRNA expression of PECAM on MNC following cream challenge before and after 6 weeks of treatment with simvastatin or ezetimibe. Percent change (using the formula: (x-y)/y\*100) was calculated using data collected before (0hr) and after the cream challenge (peak effect) at weeks 0 and 6 of treatment with simvastatin or ezetimibe.
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin | Change in mRNA Expression of PECAM on MNC | week 0 | 38 percentage change | Standard Error 8 |
| Simvastatin | Change in mRNA Expression of PECAM on MNC | week 6 | 36 percentage change | Standard Error 10 |
| Ezetimibe | Change in mRNA Expression of PECAM on MNC | week 0 | 42 percentage change | Standard Error 6 |
| Ezetimibe | Change in mRNA Expression of PECAM on MNC | week 6 | 38 percentage change | Standard Error 8 |
Secondary
Change in mRNA Expression of IL-1β in MNC
Percentage change in mRNA expression of IL-1β in MNC following cream challenge calculated from data collected before (at 0 week) and after (at 6 weeks) treatment with simvastatin or ezetimibe
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin | Change in mRNA Expression of IL-1β in MNC | week 0 | 41 percentage of change | Standard Error 15 |
| Simvastatin | Change in mRNA Expression of IL-1β in MNC | week6 | 36 percentage of change | Standard Error 7 |
| Ezetimibe | Change in mRNA Expression of IL-1β in MNC | week 0 | 38 percentage of change | Standard Error 11 |
| Ezetimibe | Change in mRNA Expression of IL-1β in MNC | week6 | 40 percentage of change | Standard Error 12 |
Secondary
Change in mRNA Expression of MMP-9 in MNC
Percentage change in mRNA expression of MMP-9 in MNC calculated from data collected following cream challenge before (0 week) and after (6 weeks) of treatment with simvastatin or ezetimibe
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin | Change in mRNA Expression of MMP-9 in MNC | week 0 | 34 percentage of change | Standard Error 8 |
| Simvastatin | Change in mRNA Expression of MMP-9 in MNC | week 6 | 28 percentage of change | Standard Error 12 |
| Ezetimibe | Change in mRNA Expression of MMP-9 in MNC | week 0 | 35 percentage of change | Standard Error 6 |
| Ezetimibe | Change in mRNA Expression of MMP-9 in MNC | week 6 | 36 percentage of change | Standard Error 8 |
Secondary
Change in TNF-a mRNA Expression in MNC
Percentage change in mRNA expression of TNFα in MNC following cream challenge calculated using data collected before and after the cream challenge at weeks 0 and 6 of treatment with simvastatin or ezetimibe
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin | Change in TNF-a mRNA Expression in MNC | week 0 | 48 percentage of change | Standard Error 17 |
| Simvastatin | Change in TNF-a mRNA Expression in MNC | week 6 | 41 percentage of change | Standard Error 13 |
| Ezetimibe | Change in TNF-a mRNA Expression in MNC | week 0 | 43 percentage of change | Standard Error 9 |
| Ezetimibe | Change in TNF-a mRNA Expression in MNC | week 6 | 38 percentage of change | Standard Error 6 |