The plasma levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk.
Traditional HDL-raising therapies, like fibrates, PPAR-γ agonists, and nicacin, among others, are associated with undesirable
side effects, limited efficacy, or have not yet been shown to improve morbidity and mortality on top of statins in
clinical outcome trials. A novel pharmacological target for raising circulating HDL-C levels is the cholesterol ester transfer
protein (CETP), an enzyme that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins.
Four pharmacological small-molecule inhibitors of CETP, i.e. torcetrapib (Pfizer), dalcetrapib (JTT-705; Roche), anacetrapib
(Merck), and evacetrapib (Eli Lilly) have been developed. Notwithstanding a marked increase in HDL, torcetrapib
was associated with an increase in all-cause mortality in the ILLUMINATE trial and raised safety concerns related to the
off-target effects of CETP inhibition. Most recently, development of dalcetrapib was abruptly stopped due to a lack of
clinically meaningful efficacy. Thus, it will be of utmost importance to demonstrate that the remaining CETP inhibitors in
development not only increase HDL-C levels in plasma, but also improve HDL-function in patients with coronary disease
or an acute coronary syndrome.