Therapeutic interventions aimed at increasing high-density lipoprotein (HDL) levels, in order to reduce the residual cardiovascular (CV) risk of optimally drug treated patients have not provided convincing results, so far. Transfer of cholesterol from extrahepatic tissues to the liver appears to be the major atheroprotective function of HDL, and an elevation of HDL levels could represent an effective strategy. Inhibition of the cholesteryl ester transfer protein (CETP), raising HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, reduces low-density lipoprotein-cholesterol (LDL-C) and apoB levels, thus offering a promising approach. Despite the beneficial influence on cholesterol metabolism, off-target effects and lack of reduction in CV events and mortality (with torcetrapib, dalcetrapib and evacetrapib) highlighted the complex mechanism of CETP inhibition. After the failure of the above mentioned inhibitors in phase III clinical development, possibly due to the short duration of the trials masking benefit, the secondary prevention REVEAL trial has recently shown that the inhibitor anacetrapib significantly raised HDL-C (+104%), reduced LDL-C (-18%), with a protective effect on major coronary events (RR, 0.91; 95%CI, 0.85 to 0.97; p = 0.004). Whether LDL-C lowering fully accounts for the CV benefit, or if HDL-C-rise is a crucial factor, still needs to be determined, although the reduction of non-HDL (-18%) and Lp(a) (-25%), should be also taken into account. In spite of the positive results of the REVEAL Study, Merck decided not to proceed in asking regulatory approval for anacetrapib. Dalcetrapib (Dal-GenE study) and CKD-519 remain the two molecules within this area still in clinical development.

Present therapeutic role of cholesteryl ester transfer protein inhibitors / N. Ferri, A. Corsini, C.R. Sirtori, M. Ruscica. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1043-6618. - 128(2018), pp. 29-41. [10.1016/j.phrs.2017.12.028]

Present therapeutic role of cholesteryl ester transfer protein inhibitors

N. Ferri
Primo
Writing – Review & Editing
;
A. Corsini
Secondo
Writing – Review & Editing
;
M. Ruscica
Ultimo
Writing – Review & Editing
2018

Abstract

Therapeutic interventions aimed at increasing high-density lipoprotein (HDL) levels, in order to reduce the residual cardiovascular (CV) risk of optimally drug treated patients have not provided convincing results, so far. Transfer of cholesterol from extrahepatic tissues to the liver appears to be the major atheroprotective function of HDL, and an elevation of HDL levels could represent an effective strategy. Inhibition of the cholesteryl ester transfer protein (CETP), raising HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, reduces low-density lipoprotein-cholesterol (LDL-C) and apoB levels, thus offering a promising approach. Despite the beneficial influence on cholesterol metabolism, off-target effects and lack of reduction in CV events and mortality (with torcetrapib, dalcetrapib and evacetrapib) highlighted the complex mechanism of CETP inhibition. After the failure of the above mentioned inhibitors in phase III clinical development, possibly due to the short duration of the trials masking benefit, the secondary prevention REVEAL trial has recently shown that the inhibitor anacetrapib significantly raised HDL-C (+104%), reduced LDL-C (-18%), with a protective effect on major coronary events (RR, 0.91; 95%CI, 0.85 to 0.97; p = 0.004). Whether LDL-C lowering fully accounts for the CV benefit, or if HDL-C-rise is a crucial factor, still needs to be determined, although the reduction of non-HDL (-18%) and Lp(a) (-25%), should be also taken into account. In spite of the positive results of the REVEAL Study, Merck decided not to proceed in asking regulatory approval for anacetrapib. Dalcetrapib (Dal-GenE study) and CKD-519 remain the two molecules within this area still in clinical development.
Anacetrapib; CETP inhibitors; Dalcetrapib; Evacetrapib; REVEAL trial; Torcetrapib
Settore BIO/14 - Farmacologia
Settore MED/04 - Patologia Generale
2018
26-dic-2017
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/543096
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