Coronary Heart Disease, Hypercholesterolemia
Conditions
Keywords
Phytosterols, Ezetimibe, Cholesterol Excretion, Cholesterol Absorption, Diet, Mass Spectrometry, Deuterium
Brief summary
Phytosterols and ezetimibe each reduce intestinal cholesterol absorption by 30-55% but appear to have different mechanisms of action. The investigators' hypothesis is that phytosterols and ezetimibe given together will block cholesterol absorption in an additive fashion. In a randomized, placebo-controlled crossover trial the effects of placebo, ezetimibe treatment and ezetimibe plus phytosterol treatment will be measured.
Detailed description
The investigators will perform a randomized, placebo-controlled crossover feeding study in 25 subjects with greater than ideal levels of LDL cholesterol who do not require anti-cholesterol drug treatment. Subjects will consume a baseline diet provided by a feeding center that is deficient in phytosterols for three periods of 21 days separated by 7-day washout periods. Treatments will be given in random order During period B placebo phytosterols and placebo ezetimibe will be given; during period C placebo phytosterols and active ezetimibe will be given; during period A active phytosterols and active ezetimibe will be given. Study endpoints are fecal cholesterol excretion and percent cholesterol absorption determined by gas chromatography/mass spectrometry and circulating LDL cholesterol.
Interventions
DRUGEzetimibe
Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.
OTHERPhytosterols + ezetimibe
Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.
OTHERPlacebo
Sponsors
Utah State University
National Heart, Lung, and Blood Institute (NHLBI)
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Phytosterols solutions were provided as food oil only (placebo) or food oil containing 2000 mg/day phytosterols (Phytosterols). Active and placebo ezetimibe tablets were provided by Merck.
Intervention model description
This is a randomized, crossover design. There are three periods of 21 days separated by two 7 day washouts. All subjects eat a controlled low-phytosterol diet for each of the three periods. During period B placebo phytosterols and placebo ezetimibe are given. During period C phytosterol placebo and active ezetimibe are given. During period A active phytosterols and active ezetimibe are given. Periods are assigned in random order as described in Arms below.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female of any race or ethnicity between 18 to 80 years of age; * Body mass index between 20 - 35 kg/m2; * LDL-cholesterol between 130 - 189 mg/dL based on the average of duplicate screening measures. If the two LDL-C levels differ by more than 30 mg/dL, a third test will be scheduled with all three results averaged; * Free of chronic disease; * Willing to eat only the foods that are provided by the Center during the diet periods; * Willing to abstain from the consumption of alcohol for 48-hours prior to blood draw days; * Willing to drink no more than 5 cups of caffeine-containing beverages a day.
Exclusion criteria
* Age \< 18 or \> 80 years; * Based on duplicate screening laboratory values: 1)LDL-C \>=190 mg/dL; 2)TG \>=250 mg/dL;3)blood pressure \>= 160 mm Hg systolic or 95 mm Hg diastolic; * Documented presence of atherosclerotic disease; * Diabetes mellitus; * Renal, hepatic, endocrine, gastrointestinal, hematological or other systemic disease; * Body mass index \> 35; * For women, pregnancy, breast feeding or postpartum \< 6 months; * For women, peri-menopausal; * For women, sexually active but not practicing effective birth control methods; * History of drug or alcohol abuse; * History of depression or mental illness requiring treatment or medication within the last 6 months; * multiple food allergies or significant food preferences or restrictions that would interfere with diet adherence; * Chronic use of over-the-counter medication which would interfere with study endpoints including laxatives and antacids; * Lifestyle or schedule incompatible with the study protocol; * Planned continued use of dietary supplements through the study trial; * Taking any lipid-lowering, or other medications known to affect blood cholesterol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cholesterol Excretion | At the end of week 3 on each diet | Milligrams of fecal cholesterol and cholesterol metabolites excreted per day |
| Percent Cholesterol Absorption | Determined on the final 5 days of each dietary period | Percent of intestinal cholesterol absorbed. Intestinal cholesterol is comprised of dietary cholesterol intake and endogenous cholesterol secreted into the intestinal lumen. Cholesterol absorption is the percent of intestinal cholesterol that is taken back up into the body and excluded from fecal excretion. It is also referred to as the efficiency of intestinal cholesterol absorption. |
| LDL Cholesterol | At the end of week 3 on each diet | — |
Countries
United States
Participant flow
Pre-assignment details
175 subjects were screened and 153 were excluded prior to randomization. 75 did not meet screening criteria, 39 declined to participate and 39 were not able to perform functions needed for the study. 22 Subjects were randomized and 21 completed the study.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All study participants. | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 15 |
| Race/Ethnicity, Customized race asian | 1 Participants |
| Race/Ethnicity, Customized race hispanic | 1 Participants |
| Race/Ethnicity, Customized race white | 20 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 0 / 22 | 0 / 22 | 0 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 22 |
Outcome results
Primary
Cholesterol Excretion
Milligrams of fecal cholesterol and cholesterol metabolites excreted per day
Time frame: At the end of week 3 on each diet
Population: Healthy subjects
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phytosterol-Deficient Diet | Cholesterol Excretion | 505 mg per day |
| Diet Plus Ezetimibe | Cholesterol Excretion | 794 mg per day |
| Diet Plus Ezetimibe Plus Phytosterols | Cholesterol Excretion | 962 mg per day |
Comparison: Phytosterol Diet compared to Ezetimibep-value: 0.01ANOVA
Comparison: Placebo vs. Ezetimibe Plus Phytosterolsp-value: <0.01ANOVA
Comparison: Ezetimibe vs. Ezetimibe Plus Phytosterolsp-value: <0.01ANOVA
Primary
LDL Cholesterol
Time frame: At the end of week 3 on each diet
Population: Healthy subjects
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phytosterol-Deficient Diet | LDL Cholesterol | 129 mg/deciliter |
| Diet Plus Ezetimibe | LDL Cholesterol | 108 mg/deciliter |
| Diet Plus Ezetimibe Plus Phytosterols | LDL Cholesterol | 101 mg/deciliter |
Comparison: The hypothesis is that groups are equal.p-value: <0.01ANOVA
Comparison: The hypothesis is that all groups are equalp-value: <0.01ANOVA
Comparison: The hypothesis is that groups are equal.p-value: <0.05ANOVA
Primary
Percent Cholesterol Absorption
Percent of intestinal cholesterol absorbed. Intestinal cholesterol is comprised of dietary cholesterol intake and endogenous cholesterol secreted into the intestinal lumen. Cholesterol absorption is the percent of intestinal cholesterol that is taken back up into the body and excluded from fecal excretion. It is also referred to as the efficiency of intestinal cholesterol absorption.
Time frame: Determined on the final 5 days of each dietary period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phytosterol-Deficient Diet | Percent Cholesterol Absorption | 69.0 Percent |
| Diet Plus Ezetimibe | Percent Cholesterol Absorption | 46.2 Percent |
| Diet Plus Ezetimibe Plus Phytosterols | Percent Cholesterol Absorption | 32.6 Percent |
Comparison: The hypothesis is that groups are equalp-value: <0.01ANOVA
Comparison: Placebo vs. Ezetimibe Plus Phytosterolsp-value: <0.01ANOVA
Comparison: The hypothesis is that groups are equal.p-value: <0.01ANOVA