Human and rabbit plasma contain a
cholesteryl ester transfer protein (CETP) that promotes net mass transfers of
cholesteryl esters from
high density lipoproteins (HDL) to other plasma
lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of
cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced
atherosclerosis. However, use of the CETP inhibitor
torcetrapib in humans did not reduce
atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by
torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor
dalcetrapib, which raises HDL levels less effectively than
torcetrapib and does not lower non-HDL
lipoprotein levels, was terminated early for reasons of futility. There was no evidence that
dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with
anacetrapib and
evacetrapib, two CETP inhibitors that are much more potent than
dalcetrapib and that do not share the off-target adverse effects of
torcetrapib.