title: Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Gaubius Laboratory, TNO, Metabolic Health Research, Zernikedreef 9, 2333 CK, PO Box 2215, 2301 CE, Leiden, The Netherlands Department of Cardiology, LUMC, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: Kühnast
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands Department of Endocrinology and Metabolic Diseases, LUMC, Leiden, The Netherlands.
authors.forename: Sam J L
authors.initials: SJ
authors.lastname: van der Tuin
authors.affiliation: Gaubius Laboratory, TNO, Metabolic Health Research, Zernikedreef 9, 2333 CK, PO Box 2215, 2301 CE, Leiden, The Netherlands Department of Cardiology, LUMC, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
authors.forename: José W A
authors.initials: JW
authors.lastname: van der Hoorn
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands Department of Human Genetics, LUMC, Leiden, The Netherlands.
authors.forename: Jan B
authors.initials: JB
authors.lastname: van Klinken
authors.affiliation: Center for Molecular Cardiology, Campus Schlieren, University of Zurich, Zurich, Switzerland.
authors.forename: Branko
authors.initials: B
authors.lastname: Simic
authors.affiliation: Gaubius Laboratory, TNO, Metabolic Health Research, Zernikedreef 9, 2333 CK, PO Box 2215, 2301 CE, Leiden, The Netherlands.
authors.forename: Elsbet
authors.initials: E
authors.lastname: Pieterman
authors.affiliation: Gaubius Laboratory, TNO, Metabolic Health Research, Zernikedreef 9, 2333 CK, PO Box 2215, 2301 CE, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands Department of Endocrinology and Metabolic Diseases, LUMC, Leiden, The Netherlands.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.affiliation: University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.affiliation: University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands Department of Endocrinology and Metabolic Diseases, LUMC, Leiden, The Netherlands Department of Human Genetics, LUMC, Leiden, The Netherlands.
authors.forename: Ko
authors.initials: K
authors.lastname: Willems van Dijk
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands Department of Endocrinology and Metabolic Diseases, LUMC, Leiden, The Netherlands.
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.affiliation: Department of Cardiology, LUMC, Leiden, The Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Gaubius Laboratory, TNO, Metabolic Health Research, Zernikedreef 9, 2333 CK, PO Box 2215, 2301 CE, Leiden, The Netherlands hans.princen@tno.nl.
authors.forename: Hans M G
authors.initials: HM
authors.lastname: Princen
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000517:prevention & control*; D000069059:Atorvastatin; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism; D008076:Cholesterol, HDL / Q000187:drug effects / Q000502:physiology; D018450:Disease Progression; D004338:Drug Combinations; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D008822:Mice, Transgenic; D023303:Oxazolidinones / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D000685:Serum Amyloid A Protein / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004338:Drug Combinations; D006538:Heptanoic Acids; D023303:Oxazolidinones; D011758:Pyrroles; D000685:Serum Amyloid A Protein; D000069059:Atorvastatin; C530884:anacetrapib
keywords: Anacetrapib; Atherosclerosis; Atorvastatin; Cholesteryl ester transfer protein; HDL function; HDL-cholesterol; Non-HDL-cholesterol