Cholesteryl ester transfer-protein modulator and inhibitors and their potential for the treatment of cardiovascular diseases Full Text
Vascular Health and Risk Management, 05/30/2012
Clinical Article
Shinkai H – The dal–OUTCOMES study is testing whether dalcetrapib can reduce cardiovascular events and the REVEAL study is testing whether anacetrapib can reduce cardiovascular events.
- Elevated low–density lipoprotein (LDL) cholesterol and lowered high–density lipoprotein (HDL) cholesterol are important risk factors for cardiovascular disease.
- Accordingly, raising HDL cholesterol induced by cholesteryl ester transfer protein (CETP) inhibition is an attractive approach for reducing the residual risk of cardiovascular events that persist in many patients receiving low–density LDL cholesterol–lowering therapy with statins.
- The development of torcetrapib, a CETP inhibitor, was terminated due to its adverse cardiovascular effects.
- These adverse effects did not influence the mechanism of CETP inhibition, but affected the molecule itself.
- Therefore a CETP modulator, dalcetrapib, and a CETP inhibitor, anacetrapib, are in Phase III of clinical trials to evaluate their effects on cardiovascular outcomes.
- In the dal–VESSEL (dalcetrapib Phase IIb endothelial function study) and the dal–PLAQUE (safety and efficacy of dalcetrapib on atherosclerotic disease using novel non–invasive multimodality imaging) clinical studies, dalcetrapib reduced CETP activity by 50% and increased HDL cholesterol levels by 31% without changing LDL cholesterol levels.
- Moreover, dalcetrapib was associated with a reduction in carotid vessel–wall inflammation at 6 months, as well as a reduced vessel–wall area at 24 months compared with the placebo.
- In the DEFINE (determining the efficacy and tolerability of CETP inhibition with anacetrapib) clinical study, anacetrapib increased HDL cholesterol levels by 138% and decreased LDL cholesterol levels by 36%.
- In contrast with torcetrapib, anacetrapib had no adverse cardiovascular effects.
