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Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin

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Author: Kühnast, S. · Tuin, S.J.L. van der · Hoorn, J.W.A. van der · Klinken, J.B. van · Simic, B. · Pieterman, E. · Havekes, L.M. · Landmesser, U. · Lüscher, T.F. · Dijk, K.W. van · Rensen, P.C.N. · Jukema, J.W. · Princen, H.M.G.
Type:article
Date:2015
Source:European Heart Journal, 1, 36, 39-48
Identifier: 524713
doi: DOI:10.1093/eurheartj/ehu319
Keywords: Biology · Anacetrapib · Atherosclerosis · Atorvastatin · Cholesteryl ester transfer protein · HDL function · HDL-cholesterol · Non-HDL-cholesterol · Apolipoprotein E3 · Atorvastatin · High density lipoprotein cholesterol · Analysis of covariance · Animal cell · Animal model · Aorta atherosclerosis · Aorta root · Atherosclerotic plaque · Cholesterol blood level · Controlled study · Diet · Disease severity · Drug efficacy · Drug potentiation · Enzyme activity · Female · In vivo study · Mouse · Nonhuman · Risk reduction · Treatment duration · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences

Abstract

Background The residual risk that remains after statin treatment supports the addition of other LDL-C-lowering agents and has stimulated 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 and results 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/kg/day) alone or in combination with anacetrapib (0.3 mg/kg/day) for 21 weeks. Anacetrapib dose-dependently reduced CETP activity (-59 to -100%, P < 0.001), thereby decreasing non-HDL-C (-24 to -45%, P < 0.001) and increasing HDL-C (+30 to +86%, P < 0.001). Anacetrapib dose-dependently reduced the atherosclerotic lesion area (-41 to -92%, P < 0.01) and severity, increased plaque stability index and added to the effects of atorvastatin by further decreasing lesion size (-95%, 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 = 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. © The Author 2014. Chemicals/CAS: anacetrapib, 875446-37-0; atorvastatin, 134523-00-5, 134523-03-8