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
Life
MHR - Metabolic Health Research
ELSS - Earth, Life and Social Sciences
Biomedical Innovation
Biology
Healthy Living
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
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