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.

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.

• Authors: Susan Kühnast, Sam J L van der Tuin, José W A van der Hoorn, Jan B van Klinken, Branko Simic, Elsbet Pieterman, Louis M Havekes, Ulf Landmesser, Thomas F Lüscher, Ko Willems van Dijk, Patrick C N Rensen, J Wouter Jukema, Hans M G Princen
• Journal: European heart journal (Eur Heart J) Vol. 36 Issue 1 Pg. 39-48 (Jan 01 2015) ISSN: 1522-9645 [Electronic] England
• PMID: 25142968 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

Chemical References

• Anticholesteremic Agents
• Cholesterol Ester Transfer Proteins
• Cholesterol, HDL
• Drug Combinations
• Heptanoic Acids
• Oxazolidinones
• Pyrroles
• Serum Amyloid A Protein
• Atorvastatin
• anacetrapib

Topics

• Animals
• Anticholesteremic Agents (pharmacology)
• Atherosclerosis (prevention & control)
• Atorvastatin
• Cholesterol Ester Transfer Proteins (metabolism)
• Cholesterol, HDL (drug effects, physiology)
• Disease Progression
• Drug Combinations
• Female
• Heptanoic Acids (administration & dosage, pharmacology)
• Mice, Transgenic
• Oxazolidinones (administration & dosage, pharmacology)
• Pyrroles (administration & dosage, pharmacology)
• Serum Amyloid A Protein (metabolism)