Inhibidores de la proteína transferidora de ésteres de colesterol. ¿Cuál es su futuro?

Abstract

Several arguments support the need to increase high-density lipoprotein cholesterol (HDL-c), ranging from scientific evidence that low concentrations are a potent cardiovascular risk factor to findings that indicate that even moderate increases in HDL-c associated with conventional lipid-lowering treatment reduce cardiovascular risk. Therefore, the future of any drug that increases HD L-c safely and effectively is promising. After the failure of torcetrapib due to severe adverse effects unrelated to the mechanism of cholesteryl ester transfer protein (CETP) inhibition, two new CETP inhibitors, dalcetrapib (Roche) and anacetrapib (Merck), are under development. Dalcetrapib, which is in a more advanced phase of clinical trials, increases HDL-c by nearly 35% and lacks significant pharmacological interactions. At therapeutic doses, the drug has shown neither clinically significant increases in blood pressure nor activation of the renin-angiotensin-aldosterone system. Moreover, dalcetrapib was more effective than torcetrapib to enhance reverse cholesterol transport in an animal model, although torcetrapib was more than three times as effective in increasing HDL-c. Finally, there is an ambitious program of phase III studies to evaluate the safety and efficacy of dalcetrapib in the secondary prevention of coronary heart disease, improvement of endothelial function and stabilization of atheroma plaques. Hopefully, in the near future the results of these studies will show the therapeutic potential of the new CETP inhibitors in reducing cardiovascular risk through an increase of HD L fully functional in reverse cholesterol transport.