Anacetrapib
The present therapeutic role of CETP inhibitors: REVEAL numbers, HDL-C +104%, LDL-C -18%, major coronary events RR 0.91, against three prior failures (Pharmacol Res 2018)
Original title: Present therapeutic role of cholesteryl ester transfer protein inhibitors
Therapeutic strategies to raise HDL and reduce residual cardiovascular risk had not proven convincing, though transfer of cholesterol from tissues to the liver remains the leading atheroprotective function of HDL. This review covers CETP inhibition, which raises HDL-C and apoA-I while lowering LDL-C and apoB, as a promising route to that goal. Off-target effects and no reduction in cardiovascular events or mortality doomed torcetrapib, dalcetrapib and evacetrapib in phase 3, possibly partly because trial duration was too short to reveal benefit. The secondary-prevention REVEAL trial then showed anacetrapib significantly raised HDL-C by 104%, lowered LDL-C by 18%, and reduced major coronary events (relative risk 0.91, 95% CI, 0.85 to 0.97, P = 0.004), alongside reductions in non-HDL cholesterol (18%) and Lp(a) (25%). Whether LDL-C lowering fully explains this benefit, or HDL-C raising also contributes, remains unresolved. Despite this positive REVEAL result, Merck chose not to pursue regulatory approval for anacetrapib, leaving dalcetrapib (in the Dal-GenE study) and the investigational molecule CKD-519 as the remaining CETP inhibitors still in clinical development.
Original 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, 0.85-0.97; 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.
anacetrapibthe classoutcomes trials
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.