Torcetrapib
Torcetrapib does not block CETP or LPS-binding-protein interactions, ruling out a direct sepsis-mortality mechanism (J Lipid Res 2010)
Original title: Assessment of cholesteryl ester transfer protein inhibitors for interaction with proteins involved in the immune response to infection
Because nearly half of the noncardiovascular deaths in the ILLUMINATE trial involved infection, researchers tested whether torcetrapib and other CETP inhibitors interfere with lipopolysaccharide (LPS) binding protein (LBP) or bactericidal/permeability-increasing protein (BPI), immune proteins that neutralize or transfer bacterial LPS. None of the potent CETP inhibitors tested affected LPS binding to LBP or BPI. Purified CETP itself bound LPS only weakly (Kd >= 25 uM) compared with LBP and BPI (0.8 and 0.5 nM, respectively), and torcetrapib did not block this weak CETP-LPS binding; in whole blood, torcetrapib did not alter LPS-induced TNF-alpha, and LPS did not affect CETP activity. The authors conclude the sepsis-related mortality in ILLUMINATE was unlikely due to torcetrapib directly disrupting LBP, BPI, or CETP-LPS interactions, and speculate instead that lipoprotein composition changes or the known off-target aldosterone elevation caused by torcetrapib may have aggravated sepsis outcomes.
Original abstract
The CETP inhibitor, torcetrapib, was prematurely terminated from phase 3 clinical trials due to an increase in cardiovascular and noncardiovascular mortality. Because nearly half of the latter deaths involved patients with infection, we have tested torcetrapib and other CETPIs to see if they interfere with lipopolysaccharide binding protein (LBP) or bactericidal/permeability increasing protein (BPI). No effect of these potent CETPIs on LPS binding to either protein was detected. Purified CETP itself bound weakly to LPS with a Kd >or= 25 microM compared with 0.8 and 0.5 nM for LBP and BPI, respectively, and this binding was not blocked by torcetrapib. In whole blood, LPS induced tumor necrosis factor-alpha normally in the presence of torcetrapib. Furthermore, LPS had no effect on CETP activity. We conclude that the sepsis-related mortality of the ILLUMINATE trial was unlikely due to a direct effect of torcetrapib on LBP or BPI function, nor to inhibition of an interaction of CETP with LPS. Instead, we speculate that the negative outcome seen for patients with infections might be related to the changes in plasma lipoprotein composition and metabolism, or alternatively to the known off-target effects of torcetrapib, such as aldosterone elevation, which may have aggravated the effects of sepsis.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.