Journal of Lipid Research
Volume 55, Issue 10, October 2014, Pages 2103-2112
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Research Articles
Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin[S]

https://doi.org/10.1194/jlr.M051326Get rights and content
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potential novel strategy for treatment of CVD. Alirocumab is a fully human PCSK9 monoclonal antibody in phase 3 clinical development. We evaluated the antiatherogenic potential of alirocumab in APOE*3Leiden.CETP mice. Mice received a Western-type diet and were treated with alirocumab (3 or 10 mg/kg, weekly subcutaneous dosing) alone and in combination with atorvastatin (3.6 mg/kg/d) for 18 weeks. Alirocumab alone dose-dependently decreased total cholesterol (−37%; −46%, P < 0.001) and TGs (−36%; −39%, P < 0.001) and further decreased cholesterol in combination with atorvastatin (−48%; −58%, P < 0.001). Alirocumab increased hepatic LDL receptor protein levels but did not affect hepatic cholesterol and TG content. Fecal output of bile acids and neutral sterols was not changed. Alirocumab dose-dependently decreased atherosclerotic lesion size (−71%; −88%, P < 0.001) and severity and enhanced these effects when added to atorvastatin (−89%; −98%, P < 0.001). Alirocumab reduced monocyte recruitment and improved the lesion composition by increasing the smooth muscle cell and collagen content and decreasing the macrophage and necrotic core content. Alirocumab dose-dependently decreases plasma lipids and, as a result, atherosclerosis development, and it enhances the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. In addition, alirocumab improves plaque morphology.

APOE*3Leiden.CETP mice
proprotein convertase subtilisin/kexin type 9
atorvastatin

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This work was supported by Sanofi-Aventis and Regeneron. J. W. Jukema received research grants from and was speaker on (CME-accredited) meetings sponsored by Amgen, Astellas, Astra-Zeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Genzyme, Medtronic, Merck-Schering-Plough, Pfizer, Orbus Neich, Novartis, Roche, Servier, Sanofi-Aventis, the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Community Framework KP7 Programme. W. J. Sasiela and V. Gusarova are employees of Regeneron. A. Peyman, H-L. Schäfer, and U. Schwahn are employees of Sanofi-Aventis.

    Abbreviations:

    FH

    familial hypercholesterolemia

    HPS

    hematoxylin-phloxine-saffron

    ICAM-1

    intercellular adhesion molecule 1

    LDL-C

    LDL cholesterol

    LDLR

    LDL receptor

    PCSK9

    proprotein convertase subtilisin/kexin type 9

    SMC

    smooth muscle cell

    TC

    total cholesterol

[S]

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of four tables, one figure, Methods, and Results.

1

S. Kühnast and J. W. A. van der Hoorn contributed equally to this article.