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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.
Kühnast, Susan; van der Tuin, Sam J L; van der Hoorn, José W A; van Klinken, Jan B; Simic, Branko; Pieterman, Elsbet; Havekes, Louis M; Landmesser, Ulf; Lüscher, Thomas F; Willems van Dijk, Ko; Rensen, Patrick C N; Jukema, J Wouter; Princen, Hans M G.
Afiliación
  • Kühnast S; 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.
  • van der Tuin SJ; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands Department of Endocrinology and Metabolic Diseases, LUMC, Leiden, The Netherlands.
  • van der Hoorn JW; 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.
  • van Klinken JB; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands Department of Human Genetics, LUMC, Leiden, The Netherlands.
  • Simic B; Center for Molecular Cardiology, Campus Schlieren, University of Zurich, Zurich, Switzerland.
  • Pieterman E; Gaubius Laboratory, TNO, Metabolic Health Research, Zernikedreef 9, 2333 CK, PO Box 2215, 2301 CE, Leiden, The Netherlands.
  • Havekes LM; 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.
  • Landmesser U; University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
  • Lüscher TF; University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
  • Willems van Dijk K; 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.
  • Rensen PC; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands Department of Endocrinology and Metabolic Diseases, LUMC, Leiden, The Netherlands.
  • Jukema JW; Department of Cardiology, LUMC, Leiden, The Netherlands.
  • Princen HM; Gaubius Laboratory, TNO, Metabolic Health Research, Zernikedreef 9, 2333 CK, PO Box 2215, 2301 CE, Leiden, The Netherlands hans.princen@tno.nl.
Eur Heart J ; 36(1): 39-48, 2015 Jan 01.
Article en En | MEDLINE | ID: mdl-25142968
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirroles / Oxazolidinonas / Aterosclerosis / Ácidos Heptanoicos / Anticolesterolemiantes Límite: Animals Idioma: En Revista: Eur Heart J Año: 2015 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirroles / Oxazolidinonas / Aterosclerosis / Ácidos Heptanoicos / Anticolesterolemiantes Límite: Animals Idioma: En Revista: Eur Heart J Año: 2015 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido