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Treatment of Low HDL-C Subjects with the CETP Modulator Dalcetrapib Increases Plasma Campesterol Only in Those Without ABCA1 and/or ApoA1 Mutations

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  • Published:
Lipids

Abstract

We investigated the effect of dalcetrapib treatment on phytosterol levels in patients with familial combined hyperlipidemia (FCH) or familial hypoalphalipoproteinemia (FHA) due to mutations in apolipoprotein A1 (ApoA1) or ATP-binding cassette transporter A1 (ABCA1). Patients (n = 40) with FCH or FHA received dalcetrapib 600 mg or placebo in this 4-week, double-blind, crossover study. Lipids, apolipoproteins, cholesteryl ester transfer protein (CETP) activity and mass, and phytosterols were assessed. Dalcetrapib increased high-density lipoprotein cholesterol (HDL-C) and ApoA1 levels to a similar extent in FHA (+22.8, +13.9 %) and FCH (+18.4, +12.1 %), both p < 0.001 vs. placebo. Changes in CETP activity and mass were comparable for FHA (−31.5, +120.9 %) and FCH (−26.6, +111.9 %), both p < 0.0001 vs. placebo. Campesterol and lathosterol were unchanged in FHA (+3.8, +3.0 %), but only campesterol was markedly increased in FCH (+25.0 %, p < 0.0001 vs. placebo). Campesterol increased with dalcetrapib treatment in FCH but not in FHA, despite comparable HDL-C and ApoA1 increases, suggesting that ApoA1 and/or ABCA1 is essential for HDL lipidation by enterocytes in humans.

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Fig. 1

Abbreviations

ABC:

ATP-binding cassette transporter

Apo:

Apolipoprotein

CETP:

Cholesteryl ester transfer protein

FCH:

Familial combined hyperlipidemia

FHA:

Familial hypoalphalipoproteinemia

HDL:

High-density lipoprotein

HDL-C:

HDL cholesterol

LDL:

Low-density lipoprotein

LDL-C:

LDL cholesterol

MTP:

Microsomal triglyceride transfer

SRB1:

Scavenger receptor class B member 1

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Acknowledgments

This study was funded by F. Hoffmann-La Roche Ltd. Funding for the study and analysis was provided by Japan Tobacco/Akros and F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Prime Healthcare during the preparation of this report and funded by F Hoffmann-La Roche Ltd. We thank the participants of this study.

Conflict of interest

Eric J. Niesor and Darren Bentley are employees of F. Hoffmann-La Roche Ltd. David Kallend was an employee of F. Hoffmann-La Roche Ltd at the time the study was performed. Erik Stroes has received (non-significant) speaker fees from AstraZeneca, Merck, Amgen and Novartis.

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Author notes

  1. David Kallend

    Present address: The Medicines Company, Zurich, Switzerland

Authors and Affiliations

  1. Metabolic and Vascular Diseases, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland

    Eric J. Niesor

  2. Pharma Medicines Development Metabolism, F. Hoffmann-La Roche Ltd, Basel, Switzerland

    David Kallend

  3. Roche Products Ltd, Welwyn Garden City, UK

    Darren Bentley

  4. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

    John J. P. Kastelein, G. Kees Hovingh & Erik S. G. Stroes

Authors
  1. Eric J. Niesor
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  2. David Kallend
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  3. Darren Bentley
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  4. John J. P. Kastelein
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  5. G. Kees Hovingh
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  6. Erik S. G. Stroes
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Correspondence to Eric J. Niesor.

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Niesor, E.J., Kallend, D., Bentley, D. et al. Treatment of Low HDL-C Subjects with the CETP Modulator Dalcetrapib Increases Plasma Campesterol Only in Those Without ABCA1 and/or ApoA1 Mutations. Lipids 49, 1245–1249 (2014). https://doi.org/10.1007/s11745-014-3956-x

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  • DOI: https://doi.org/10.1007/s11745-014-3956-x

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