Torcetrapib
Torcetrapib inhibits every common CETP genetic variant equally, even the two that are naturally more stable in the body (J Biol Chem 2005)
Original title: Cholesteryl ester transfer protein variants have differential stability but uniform inhibition by torcetrapib
Because the CETP gene is highly variable, with multiple single nucleotide polymorphisms altering both its transcription and sequence, researchers examined nine missense variants of CETP for their effects on CETP mass and HDL cholesterol levels. Some variants showed significant associations with CETP mass and HDL cholesterol, and two variants, Pro-373 and Gln-451, appeared more stable in vivo, an observation mirrored by in vitro partial proteolysis studies. Since these naturally occurring variant proteins could be present in clinical populations treated with CETP inhibitors, all commonly occurring haplotypes were tested for inhibition by torcetrapib, then in clinical trials combined with atorvastatin. Torcetrapib behaved similarly across all variants, with no significant differences in inhibition, showing that natural CETP genetic variation does not affect the ability of torcetrapib to inhibit the protein.
Original abstract
Cholesteryl ester transfer protein (CETP) is an important modulator of high density lipoprotein cholesterol in humans and thus considered to be a therapeutic target for preventing cardiovascular disease. The gene encoding CETP has been shown to be highly variable, with multiple single nucleotide polymorphisms responsible for altering both its transcription and sequence. Examining nine missense variants of CETP, we found some had significant associations with CETP mass and high density lipoprotein cholesterol levels. Two variants, Pro-373 and Gln-451, appear to be more stable in vivo, an observation mirrored by partial proteolysis studies performed in vitro. Because these naturally occurring variant proteins are potentially present in clinical populations that will be treated with CETP inhibitors, all commonly occurring haplotypes were tested to determine whether the proteins they encode could be inhibited by torcetrapib, a compound currently in clinical trials in combination with atorvastatin. Torcetrapib behaved similarly with all variants, with no significant differences in inhibition.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.