Article ; Online: Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin.
2014 Volume 36, Issue 1, Page(s) 39–48
Abstract: ... 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. ... independently determined lesion size.: Conclusion: Anacetrapib dose-dependently reduces atherosclerosis, and ...
| 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. |
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| MeSH term(s) | Animals ; Anticholesteremic Agents/pharmacology ; Atherosclerosis/prevention & control ; Atorvastatin ; Cholesterol Ester Transfer Proteins/metabolism ; Cholesterol, HDL/drug effects ; Cholesterol, HDL/physiology ; Disease Progression ; Drug Combinations ; Female ; Heptanoic Acids/administration & dosage ; Heptanoic Acids/pharmacology ; Mice, Transgenic ; Oxazolidinones/administration & dosage ; Oxazolidinones/pharmacology ; Pyrroles/administration & dosage ; Pyrroles/pharmacology ; Serum Amyloid A Protein/metabolism | ||||||||||
| Chemical Substances | Anticholesteremic Agents ; Cholesterol Ester Transfer Proteins ; Cholesterol, HDL ; Drug Combinations ; Heptanoic Acids ; Oxazolidinones ; Pyrroles ; Serum Amyloid A Protein ; Atorvastatin (A0JWA85V8F) ; anacetrapib (P7T269PR6S) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2014-08-20 | ||||||||||
| Publishing country | England | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 603098-1 | ||||||||||
| ISSN | 1522-9645 ; 0195-668X | ||||||||||
| ISSN (online) | 1522-9645 | ||||||||||
| ISSN | 0195-668X | ||||||||||
| DOI | 10.1093/eurheartj/ehu319 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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