ezetimibe reverse cholesterol transport (rct) pilot study

Conditions: Hypercholesterolemia

Summary: this is a prospective, placebo-controlled, cross-over trial comparing the the effects of approximately 7 weeks of placebo treatment to 7 weeks of ezetimibe (10mg/day) treatment on several parameters of reverse cholesterol transport (rct) in men and post-menopausal women diagnosed with hypercholesterolemia. the primary hypothesis is that the ezetimibe treatment will increase the excretion of endogenous (plasma-derived) cholesterol as fecal sterols, with secondary hypotheses that there will be a significant increase in de novo cholesterol synthesis, treatment will increase cholesterol efflux from tissues into the bloodstream, and increase global rct.

the study will compare the effects of approximately 7 weeks of placebo treatment to 7 weeks of ezetimibe (10mg/day) on: 1) the efficiency of endogenous (plasma-derived) cholesterol excretion (%/day) 2) de novo cholesterol (dnc) synthesis ((%/day) 3) cholesterol efflux from tissues into blood (ra), and 4) global rct (efflux from tissues that is excreted as fecal sterols). subjects will receive 7 weeks of either treatment or placebo, undergo rct and dnc measurements, taking 10 days, then cross-over to the alternate placebo or treatment for an additional 7 weeks, followed by a second set of rct and dnc measurements.

Eligibility criteria:
inclusion criteria: * male, non-smoker, 21-75 years of age * female, non-smoker, 40-75 years of age * post-menopausal women, as defined by lack of menses for at least 2 years and age \>55, or history of documented bilateral oophorectomy, confirmed with an elevated fsh at screening * low-density lipoprotein (ldl) concentration between 130-200 mg/dl. * triglyceride (tg) concentration \<350 mg/dl, inclusive * high-density lipoprotein (hdl) between 30-60 mg/dl for men and 40 -70 mg/dl for women * ability to give informed consent exclusion criteria: * subject has history of diabetes mellitus, active hepatitis, gall bladder disease, gastric or ileal bypass surgery, irritable bowel syndrome, and gastrointestinal disorder/condition associated with malabsorption, or clinically significant abnormalities on screening (prestudy) physical examination of laboratory tests. * screening laboratory tests with hematocrit \ 2\*upper limit of normal, abnormal thyroid-stimulating hormone (tsh), fasting glucose \>=126mg/dl * renal impairment with creatinine clearance (crcl)\<80ml/min * treatment within the last 2 months with drugs known to alter lipid metabolism including beta blockers, thiazide diuretics, bile acid resins, statins, ezetimibe, niacin, fibrates, plant stanol esters (eg benecol,phyto sterols) and fishoils * history of known coronary heart disease (chd), stroke or prior revascularization procedure or peripheral vascular disease * history of allergy to egg or soy products * current or recent (past 12 months) of drug abuse or alcohol abuse. alcohol use must be limited to no more than 2 drinks/day (1 drink=12 oz beer, 5 oz wine, or 1.5 oz hard liquor). subject must be willing to avoid large day-to-day fluctuations in alcohol intake. * participation in another clinical trial or exposure to any investigational agent within 30 days prior to visit 1 * individual has a condition the principal investigator believes would interfere with his/her ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results, or put the subject at undue risk

Keywords: metabolic diseases metabolic disorder dyslipidemias lipid metabolism disorders