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Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults.

ABSTRACT: We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib.Healthy volunteers received multiple daily doses of evacetrapib (10-600?mg) administered for up to 15 days in a placebo-controlled study.Mean peak plasma concentrations of evacetrapib occurred at 4-6?h and terminal half-life ranged 24-44?h. Steady state was achieved at approximately 10 days; all subjects had undetectable levels of evacetrapib 3 weeks after their last dose. The trough inhibition of cholesteryl ester transfer protein (CETP) activity was 65 and 84% at 100 and 300?mg, respectively. At the highest dose (600?mg), evacetrapib significantly inhibited CETP activity (91%), increased HDL-C (87%) and apo AI (42%), and decreased LDL-C (29%) and apo B (26%) relative to placebo. For the highest dose tested, levels of evacetrapib, CETP activity, CETP mass, HDL-C and LDL-C returned to levels at or near baseline after a 2-week washout period. Evacetrapib at the highest dose tested did not produce any significant effect on 24-h ambulatory systolic or diastolic blood pressure.Multiple doses of evacetrapib potently inhibited CETP activity, leading to substantial elevations in HDL-C and lowering of LDL-C. Evacetrapib was devoid of clinically relevant effects on blood pressure and mineralocorticoid levels.

SUBMITTER: Suico JG

PROVIDER: S-EPMC4284021 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults.

Suico Jeffrey G JG Wang Ming-Dauh MD Friedrich Stuart S Cannady Ellen A EA Konkoy Christopher S CS Ruotolo Giacomo G Krueger Kathryn A KA

The Journal of pharmacy and pharmacology 20140624 11

<h4>Objectives</h4>We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib.<h4>Methods</h4>Healthy volunteers received multiple daily doses of evacetrapib (10-600 mg) administered for up to 15 days in a placebo-controlled study.<h4>Key findings</h4>Mean peak plasma concentrations of evacetrapib occurred at 4-6 h and terminal half-life ranged 24-44 h. Steady state was achieved at approximately 10 days; all subjects had undetectable levels of evacetrapib 3 we ...[more]

PMID: 24961753

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Project description:This narrative review focuses on the role of cholesteryl ester transfer protein (CETP) and peripheral lipoproteins in the vascular contributions to cognitive impairment and dementia (VCID). Humans have a peripheral lipoprotein profile where low-density lipoproteins (LDL) represent the dominant lipoprotein fraction and high-density lipoproteins (HDL) represent a minor lipoprotein fraction. Elevated LDL-cholesterol (LDL-C) levels are well-established to cause cardiovascular disease and several LDL-C-lowering therapies are clinically available to manage this vascular risk factor. The efficacy of LDL-C-lowering therapies to reduce risk of all-cause dementia and AD is now important to address as recent studies demonstrate a role for LDL in Alzheimer's Disease (AD) as well as in all-cause dementia. The LDL:HDL ratio in humans is set mainly by CETP activity, which exchanges cholesteryl esters for triglycerides across lipoprotein fractions to raise LDL and lower HDL as CETP activity increases. Genetic and pharmacological studies support the hypothesis that CETP inhibition reduces cardiovascular risk by lowering LDL, which, by extension, may also lower VCID. Unlike humans, wild-type mice do not express catalytically active CETP and have HDL as their major lipoprotein fraction. As HDL has potent beneficial effects on endothelial cells, the naturally high HDL levels in mice protect them from vascular disorders, likely including VCID. Genetic restoration of CETP expression in mice to generate a more human-like lipid profile may increase the relevance of murine models for VCID studies. The therapeutic potential of existing and emerging LDL-lowering therapies for VCID will be discussed. Figure Legend. Cholesteryl Ester Transfer Protein in Alzheimer's Disease. CETP is mainly produced by the liver, and exchanges cholesteryl esters for triglycerides across lipoprotein fractions to raise circulating LDL and lower HDL as CETP activity increases. Low CETP activity is associated with better cardiovascular health, due to decreased LDL and increased HDL, which may also improve brain health. Although most peripheral lipoproteins cannot enter the brain parenchyma due to the BBB, it is increasingly appreciated that direct access to the vascular endothelium may enable peripheral lipoproteins to have indirect effects on brain health. Thus, lipoproteins may affect the cerebrovasculature from both sides of the BBB. Recent studies show an association between elevated plasma LDL, a well-known cardiovascular risk factor, and a higher risk of AD, and considerable evidence suggests that high HDL levels are associated with reduced CAA and lower neuroinflammation. Considering the potential detrimental role of LDL in AD and the importance of HDL's beneficial effects on endothelial cells, high CETP activity may lead to compromised BBB integrity, increased CAA deposits and greater neuroinflammation. Abbreviations: CETP - cholesteryl transfer ester protein; LDL - low-density lipoproteins; HDL - high-density lipoproteins; BBB - blood-brain barrier; CAA - cerebral amyloid angiopathy, SMC - smooth muscle cells, PVM - perivascular macrophages, RBC - red blood cells.

Dataset Information

Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults.

Publications

Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults.

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