Dyslipidemias
Conditions
Keywords
Niacin, HDL, Reverse cholesterol transport
Brief summary
This study looks at whether niacin improves reverse cholesterol transport (RCT) in healthy volunteers. 3H-Cholesterol will be used to measure RCT by analyzing changes in the tracer activity in total plasma, lipoproteins, red blood cells (RBCs) and stool. The hypothesis is that niacin augments reverse cholesterol transport.
Detailed description
The study will use 3H-cholesterol bound to albumin (particulate cholesterol) to assess the ability of high density lipoprotein (HDL) to transport cholesterol to the liver to be eliminated. This process is called Reverse Cholesterol transport and is one of the main mechanisms by which HDL protect against atherosclerotic cardiovascular disease. The availability of a method to assess RCT is important for the development of new drugs which affect RCT and may result in useful treatments for atherosclerosis. This study will evaluate the use of radiolabeled particulate cholesterol administered intravenously in association with albumin, as a method to study reverse cholesterol transport (RCT) in humans before and after treatment by niacin by analyzing changes in the tracer activity in total plasma and lipoproteins. The study population is healthy volunteers.
Interventions
DRUGNiacin
Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.
OTHERPlacebo
Placebo
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Men and women between the ages of 18 and 75 inclusive * HDL cholesterol \>= 25 mg/dL in all subjects, and \<= 60 mg/dL in men and \<= 70 mg/dL in women * Women must be of non-childbearing potential. They must have been surgically sterilized at least 6 months prior to screening or be postmenopausal. Postmenopausal women must have no regular menstrual bleeding for at least 2 years prior to inclusion. * Subjects must be in good overall health. * Subjects must be able to comprehend and willing to provide a signed Institutional Regulatory Board (IRB) approved Informed Consent Form. * Subjects must be willing to comply with all study-related procedures. * Subjects must weigh at least 140 pounds to participate in the HDL kinetics Substudy.
Exclusion criteria
* Clinically-manifest cardiovascular disease, including coronary disease, cerebrovascular disease, or peripheral vascular disease * History of diabetes mellitus or fasting glucose \> 126 mg/dL at the screening visit * Presence of New York Heart Association (NYHA) Class III or IV chronic heart failure or unstable angina pectoris * History of any other endocrine disease * History of a non-skin malignancy within the previous 5 years * Anemia defined as hemoglobin less than 12 g/dL * Renal insufficiency as defined by creatinine ³ 1.3 mg/dl * Any major active rheumatologic, pulmonary, or dermatologic disease or inflammatory condition * Uncontrolled hypertension (Systolic \>160 mm Hg and/or Diastolic \>100 mmHg on two consecutive measurements * Use of warfarin, or any known coagulopathy and /or elevated Prothrombin time/Partial Thromboplastin Time (PT/PTT) \>1.5 x upper limit of normal (ULN) * Self-reported history of Human immunodeficiency virus (HIV) positive * Previous organ transplantation * Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2x ULN, or self-reported history of positive for Hepatitis B or Hepatitis C * Any major surgical procedure that occurred within the previous 3 months of the screening visit * History of illicit drug abuse (\< 1 year) * Regular use of alcoholic beverages (\> 2 drinks/day) * Body mass index (BMI) \> 35 kg/m2 or \< 18.5 kg/m2 * Administration of an investigational drug within 6 weeks prior to the screening visit * Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful participation in the study will be excluded. * Use of daily lipid-altering therapy prior to the initiation of study medication is exclusionary under the following circumstances (washout of non-statins is permitted): * Statins within 4 weeks * Niacin \> 250 mg/ day within 6 weeks: Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, or supplemental niacin * Fibrates within 12 weeks: fenofibrate (Antara, Lofibra, Tricor, Triglide), gemfibrozil (Lopid), or clofibrate * Enterically active lipid-altering drugs within 4 weeks: colestipol (Colestid), cholestyramine (Questran), colesevelam (Welchol), ezetimibe (Zetia, Vytorin), orlistat (Xenical, Alli) * Red yeast rice * Fish oil \> 2 g/day within 4 weeks: Lovaza (née Omacor), numerous supplements * Altered dose of a selective estrogen receptor modulator (SERM) within 4 weeks * History of severe intolerance of niacin * Men who plan to conceive a child within 3 months of the conclusion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Appearance of 3H Cholesterol in the Total HDL Fraction Before and After 12 Weeks of Treatment With Niacin | Baseline and 12 weeks | Subjects were injected with a bolus of 3-H cholesterol mixed with human serum albumin as an intravenous bolus. This injected labelled cholesterol is taken up by macrophages. The rate of appearance of labelled cholesterol in plasma HDL- cholesterol is a measure of reverse cholesterol transport. We assessed HDL cholesterol enrichment as percent of injected tritiated tracer appearing in plasma total HDL cholesterol between 60 and 240 minutes post-injection expressed as percent 3-H cholesterol/mol HDL cholesterol/hour. The tracer study was performed at baseline and after 12 weeks of niacin or placebo. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Niacin Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.
Niacin: Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated. | 11 |
| Placebo Placebo tablet with 50 mg niacin for the first 4 weeks to maintain blinding of the study team and subjects, changed to pure placebo after that.
Placebo: Placebo | 11 |
| Total | 22 |
Baseline characteristics
| Characteristic | Niacin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 11 Participants | 22 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 11 Participants | 11 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 11 | 0 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
Rate of Appearance of 3H Cholesterol in the Total HDL Fraction Before and After 12 Weeks of Treatment With Niacin
Subjects were injected with a bolus of 3-H cholesterol mixed with human serum albumin as an intravenous bolus. This injected labelled cholesterol is taken up by macrophages. The rate of appearance of labelled cholesterol in plasma HDL- cholesterol is a measure of reverse cholesterol transport. We assessed HDL cholesterol enrichment as percent of injected tritiated tracer appearing in plasma total HDL cholesterol between 60 and 240 minutes post-injection expressed as percent 3-H cholesterol/mol HDL cholesterol/hour. The tracer study was performed at baseline and after 12 weeks of niacin or placebo.
Time frame: Baseline and 12 weeks
Population: Of the 22 subjects enrolled, only subjects who completed the baseline and 12 week reverse cholesterol transport studies were included in the final outcome analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Niacin | Rate of Appearance of 3H Cholesterol in the Total HDL Fraction Before and After 12 Weeks of Treatment With Niacin | Pre-treatment | 3.24 %/mol/h |
| Niacin | Rate of Appearance of 3H Cholesterol in the Total HDL Fraction Before and After 12 Weeks of Treatment With Niacin | Post-treatment | 2.61 %/mol/h |
| Placebo | Rate of Appearance of 3H Cholesterol in the Total HDL Fraction Before and After 12 Weeks of Treatment With Niacin | Pre-treatment | 4.16 %/mol/h |
| Placebo | Rate of Appearance of 3H Cholesterol in the Total HDL Fraction Before and After 12 Weeks of Treatment With Niacin | Post-treatment | 3.72 %/mol/h |
Comparison: This is a pilot study to assess the effects of niacin on reverse cholesterol transport. The null hypothesis is that niacin has no effect on reverse cholesterol transport.p-value: 0.8t-test, 2 sided