Print Email Facebook Twitter Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin Title Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin Author Kühnast, S. van der Tuin, S.J.L. van der Hoorn, J.W.A. van Klinken, J.B. Simic, B. Pieterman, E. Havekes, L.M. Landmesser, U. Lüscher, T.F. van Dijk, K.W. Rensen, P.C.N. Jukema, J.W. Princen, H.M.G. Publication year 2015 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 Subject LifeMHR - Metabolic Health ResearchELSS - Earth, Life and Social SciencesBiomedical InnovationBiologyHealthy LivingAnacetrapibAtherosclerosisAtorvastatinCholesteryl ester transfer proteinHDL functionHDL-cholesterolNon-HDL-cholesterolApolipoprotein E3AtorvastatinHigh density lipoprotein cholesterolAnalysis of covarianceAnimal cellAnimal modelAorta atherosclerosisAorta rootAtherosclerotic plaqueCholesterol blood levelControlled studyDietDisease severityDrug efficacyDrug potentiationEnzyme activityFemaleIn vivo studyMouseNonhumanRisk reductionTreatment duration To reference this document use: http://resolver.tudelft.nl/uuid:2bde9459-96be-4750-9ebd-c28731973421 DOI https://doi.org/10.1093/eurheartj/ehu319 TNO identifier 524713 ISSN 0195-668X Source European Heart Journal, 36 (1), 39-48 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.