Physiological Study of Human Cholesterol Metabolism and Excretion

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01603758
Recruitment Status : Completed
First Posted : May 23, 2012
Last Update Posted : May 6, 2016
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Richard E. Ostlund Jr., MD, Washington University School of Medicine

Brief Summary:
The underlying hypothesis is that whole body cholesterol - including cholesterol present in tissues that cannot be measured by standard blood tests - is related to heart disease risk. Endogenous cholesterol will be labeled with an intravenous infusion of one type of cholesterol tracer and dietary cholesterol will be labeled with another. These tracers will be used to measure how fast cholesterol is synthesized and excreted using mass spectrometry to distinguish the tracers. Data will be related to circulating biomarkers (blood tests) and to the thickness of the lining of the carotid artery. The effect of the drug ezetimibe on these processes will also be determined. Successful completion of this study will give us more knowledge about cholesterol metabolism that may be useful in designing new drugs and treatments for patients with heart disease, especially those that are already receiving maximum amounts of current medications.

Condition or disease Intervention/treatment Phase
Coronary Heart Disease Cardiovascular Disease Dyslipidemia Disorder of Cholesterol Metabolism Drug: Ezetimibe Phase 1

Detailed Description:
The central hypothesis of this proposal is that reverse cholesterol transport is related to coronary heart disease (CHD) risk. It is complementary to the concept that reduction of cholesterol biosynthesis with statin drugs prevents CHD, but it focuses on whole body cholesterol metabolism and kinetic cholesterol transport rather than on static levels of circulating lipoproteins. Although this is an old idea, it has not been adequately tested in humans because of lack of suitable methods. In this proposal we will apply innovative stable isotope and mass spectroscopic technology to study reverse cholesterol transport in human subjects. The first specific aim is to improve the preparation of intravenous deuterated cholesterol tracer, a critical limiting element in the study of whole body cholesterol metabolism. The second aim is to use that intravenous tracer, along with a different oral tracer, to partition fecal cholesterol into excreted endogenous cholesterol, unabsorbed dietary cholesterol and newly-synthesized cholesterol derived from the liver and intestine. Measurements will be made during consumption of a controlled diet provided by the metabolic kitchen. The pool size of the rapidly-mixing body cholesterol pool will be measured along with the fractional rate of cholesterol catabolism. These direct measures of reverse cholesterol transport will be correlated with plasma biomarkers and with metabolic covariates. The relation of reverse cholesterol transport to carotid intima-media thickness will be determined. The third specific aim will use similar methods to study the mechanism of action for the widely-used drug ezetimibe. The fractional rate of endogenous cholesterol excretion and the rate of plasma cholesterol turnover will be determined in two periods, one with drug and one with placebo treatment. This work represents a new direction for cholesterol research with the potential to develop new and complementary methods of reducing CHD risk that can be added to diet and statin drug treatment.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Reverse Cholesterol Transport in Humans
Study Start Date : January 2014
Actual Primary Completion Date : June 2015
Actual Study Completion Date : June 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Ezetimibe

Arm Intervention/treatment
No Intervention: Observational Arm
Cholesterol metabolic parameters will be measured in 100 subjects in an observational study. Results will be related to circulating biomarkers and carotid intima-media thickness.
Placebo Comparator: Ezetimibe Interventional Arm
Cholesterol metabolic parameters will be measured before and after ezetimibe or placebo intervention. Changes due to ezetimibe will be determined
Drug: Ezetimibe
Ezetimibe 10 mg/day or placebo will be given for 6 weeks
Other Name: Zetia

Primary Outcome Measures :
  1. Fractional Excretion of Endogenous Cholesterol [ Time Frame: 4 years ]
    The fractional rate of endogenous cholesterol excretion will be measured and related to circulating biomarkers and carotid intima-media thickness (Aim #2) or the change in fractional endogenous cholesterol excretion after treatment with ezetimibe will be determined (Aim #3)

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Aim II. 100 subjects aged 30-80 with stable medical and/or surgical illnesses.
  • Aim III. 30 subjects age 18-80 with LDL cholesterol <190, fasting triglycerides<250 and stable medical or surgical illnesses.

Exclusion Criteria:

  • Aim II. Subjects taking ezetimibe, bile acid sequestrants or with gastrointestinal or liver disease will be excluded since these may affect whole body cholesterol metabolism.
  • Subjects with coronary heart disease or other medical illnesses will not be excluded if medically stable.
  • Adults under age 30 and children will be excluded because in our current database there is no relation between carotid intima-media thickness and cardiovascular risk factors in this younger group.
  • Aim III. Individuals have risk factors for coronary heart disease that mandate drug treatment according to the National Cholesterol Education Program guidelines will be excluded.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01603758

United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Richard E. Ostlund Jr., MD
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Richard E Ostlund, MD Washington University School of Medicine

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Richard E. Ostlund Jr., MD, Professor of Medicine, Washington University School of Medicine Identifier: NCT01603758     History of Changes
Other Study ID Numbers: 201110042
R01HL108160 ( U.S. NIH Grant/Contract )
First Posted: May 23, 2012    Key Record Dates
Last Update Posted: May 6, 2016
Last Verified: May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Data will be shared subject to IRB and HIPAA restrictions.

Keywords provided by Richard E. Ostlund Jr., MD, Washington University School of Medicine:
Spectrometry, mass
Cholesterol absorption
Coronary Heart Disease

Additional relevant MeSH terms:
Cardiovascular Diseases
Heart Diseases
Coronary Disease
Coronary Artery Disease
Myocardial Ischemia
Lipid Metabolism Disorders
Metabolic Diseases
Vascular Diseases
Arterial Occlusive Diseases
Anticholesteremic Agents
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents