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Anacetrapib Reduces Progression of Atherosclerosis, Mainly by Reducing Non-HDL- Cholesterol, Improves Lesion Stability and Adds

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Anacetrapib Reduces Progression of Atherosclerosis, Mainly by Reducing Non-HDL- Cholesterol, Improves Lesion Stability and Adds European Heart Journal (2015) 36,39–48 BASIC SCIENCE doi:10.1093/eurheartj/ehu319 Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL- cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin Susan Ku¨hnast1,2,3†, Sam J.L. van der Tuin3,4†, Jose´ W.A. van der Hoorn1,2,3, Jan B. van Klinken3,5, Branko Simic6, Elsbet Pieterman1, Louis M. Havekes1,3,4, Ulf Landmesser7, Thomas F. Lu¨scher7, Ko Willems van Dijk3,4,5, Patrick C.N. Rensen3,4, J. Wouter Jukema2, and Hans M.G. Princen1* 1Gaubius Laboratory, TNO, Metabolic Health Research, Zernikedreef 9, 2333 CK, PO Box 2215, 2301 CE, Leiden, The Netherlands; 2Department of Cardiology, LUMC, Leiden, The Netherlands; 3Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands; 4Department of Endocrinology and Metabolic Diseases, LUMC, Leiden, The Netherlands; 5Department of Human Genetics, LUMC, Leiden, The Netherlands; 6Centerfor Molecular Cardiology, Campus Schlieren, University of Zurich, Zurich, Switzerland; and 7University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland Received 14 February 2014; revised 24 June 2014; accepted 23 July 2014; online publish-ahead-of-print 20 August 2014 Background The residual risk that remains after statin treatment supports the addition of other LDL-C-lowering agents and has sti- mulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. The CETP inhibitor anacetrapib decreases (V)LDL-C by 15–40% and increases HDL-C by 40–140% in clinical trials. We evaluated the effects of a broad dose range of anacetrapib on atherosclerosis and HDL function, and examined possible additive/synergistic effects of anacetrapib on top of atorvastatin in APOE*3Leiden.CETP mice. ..................................................................................................................................................................................... Methods Mice were fed a diet without or with ascending dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/day), atorvastatin (2.4 mg/ and results kg/day) alone or in combination with anacetrapib (0.3 mg/kg/day) for 21 weeks. Anacetrapib dose-dependently reduced CETP activity (259 to 2100%, P , 0.001), thereby decreasing non-HDL-C (224 to 245%, P , 0.001) and increasing HDL-C (+30 to +86%, P , 0.001). Anacetrapib dose-dependently reduced the atherosclerotic lesion area (241 to 292%, P , 0.01) and severity, increased plaque stability index and added to the effects of atorvastatin by further decreas- ing lesion size (295%, P , 0.001) and severity. Analysis of covariance showed that both anacetrapib (P , 0.05) and non- HDL-C (P , 0.001), but not HDL-C (P ¼ 0.76), independently determined lesion size. ..................................................................................................................................................................................... Conclusion Anacetrapib dose-dependently reduces atherosclerosis, and adds to the anti-atherogenic effects of atorvastatin, which is mainly ascribed to a reduction in non-HDL-C. In addition, anacetrapib improves lesion stability. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords Cholesteryl ester transfer protein † Non-HDL-cholesterol † HDL-cholesterol † HDL function † Atherosclerosis † Anacetrapib † Atorvastatin † S.K. and S.J.L.v.d.T. contributed equally. * Corresponding author. Tel: +31 888666124, Fax: +31 888660603, Email: [email protected] & The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 40 S. Ku¨hnast et al. Translational Perspective The present study is the first intervention study in a well-established, translational mouse model for hyperlipidaemia and atherosclerosis showing that anacetrapib dose-dependently reduces atherosclerosis development and adds to the anti-atherogenic effects of atorvastatin. This effect is mainly ascribed to the reduction in non-HDL-C despite a remarkable increase in HDL-C and without affecting HDL functionality. In addition, anacetrapib improves lesion stability. Introduction information on the background of the APOE*3Leiden.CETP mice and their response to hypolipidaemic drugs. Interventiontrialsprovideampleevidencethatloweringoflow-density lipoprotein-cholesterol (LDL-C) contributes to a reduction in cardio- Methods vascular (CV) risk.1–3 However, the residual risk that remains after statin treatment, as well as failure for some patients to reach recom- Animals and diet 13 mended LDL-C targets despite statin treatment, support the addition Female APOE*3Leiden.CETP transgenic mice were fed a semi- synthetic cholesterol-rich diet for a run-in period of 5 weeks (see Supple- of other LDL-C-lowering agents and also stimulate the search for sec- 3,4 mentary material online). Animals were matched based on body weight, ondary treatment targets. Prospective epidemiological studies ¼ 5 total cholesterol (TC), TG, HDL-C and age (n 15 per group) and propose high-density lipoprotein (HDL)-C as a potential target. Cho- received a control Western-type diet without or with incremental lesteryl ester transfer protein (CETP) plays an important role in lipid dosages of anacetrapib (0.03; 0.3; 3; and 30 mg/kg/day; Dalton Chemical metabolism by facilitating the transfer of cholesteryl esters from ather- Laboratories, Inc., Canada), atorvastatin (2.4 mg/kg/day) or a combin- oprotective HDL to atherogenic (V)LDL in exchange for triglycerides ation of atorvastatin (2.4 mg/kg/day) and anacetrapib (0.3 mg/kg/day) (TG),andinhibitionofCETPactivityhasbeenproposedasatherapeut- for a treatment period of 21 weeks. All animals were sacrificed by CO2 ic way to increase HDL-C levels.6–11 inhalation and hearts were isolated to assess atherosclerosis develop- In mouse models for atherosclerosis, CETP expression aggravated ment. Animal experiments were approved by the Institutional Animal atherosclerosis development.12,13 Most but not all studies in rabbits Care and Use Committee of The Netherlands Organization for and mice showed that CETP inhibition reduced atherosclerosis devel- Applied Research (TNO). opment.14–19 However, torcetrapib failed to enhance the anti- atherogenic effects of atorvastatin and induced a pro-inflammatory, Plasma lipids, lipoprotein profile, endogenous vulnerable plaque phenotype in APOE*3Leiden.CETP mice.19 In the cholesteryl ester transfer protein activity, large clinical outcome trial (ILLUMINATE), torcetrapib increased the cholesteryl ester transfer protein risk of major CV events and mortality despite a 72% increase in concentration, serum amyloid A and HDL HDL-C and a 25% reduction in LDL-C.20 The unexpected detrimental functionality effects were ascribed to either an off-target blood pressure effect or Plasma TC, TG, and HDL-C were determined every 2–4 weeks and the possible generation of dysfunctional HDL particles.20 The much average TC, TG, and HDL-C levels were calculated by total exposure less potent CETP inhibitor dalcetrapib increased HDL-C by 31–40% over number of weeks. To measure HDL-C, apoB-containing particles with a minimal reduction in LDL-C, but did not translate into clinical were precipitated from plasma with 20% polyethylene glycol in benefit and resulted in premature termination of the dal-OUTCOMES 200 mM glycine buffer (pH 10) and cholesterol was measured in the supernatant. The distribution of cholesterol over plasma lipoproteins trial.21 Nonetheless, other CETP inhibitors are currently in clinical was determined by fast-performance liquid chromatography (FPLC) as development. Among these, anacetrapib and evacetrapib have previously described.13 remarkable lipid-modulating abilities without the unwanted blood Plasma endogenous CETP activity and CETP concentration were 22 pressure effect as observed with torcetrapib. In phase II trials, anace- determined as previously described.28 Serum amyloid A (SAA; Tridelta trapib (10–300 mg) decreased LDL-C by 15–40% and increased development, Co. Kildare, Ireland) was measured by using ELISA accord- HDL-C by 40–140% and evacetrapib (30–500 mg) decreased ing to manufacturer’s instructions. LDL-C by 15–35% and increased HDL-C by 50–130%.23,24 Cultured arterial endothelial cells were incubated with HDL isolated To elucidate whether pharmacological CETP inhibition is anti- from control- and anacetrapib-treated mice and pro-inflammatory atherogenic and to what extent this is due to its LDL-C-lowering cytokine-induced vascular cell adhesion molecule 1 (VCAM-1) expres- and HDL-C-raising abilities, we evaluated the effects of partial to sion and apoptotic cell death were assessed. full inhibition of CETP activity with a broad dose range of anacetrapib monotreatment on lipid modulation, atherosclerosis development, Atherosclerosis quantification and HDL functionality in APOE*3Leiden.CETP mice. Secondly, to Cross-sections throughout the entire
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