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.
Highlights
The cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, was prematurely terminated from phase 3 clinical trials due to an increase in cardiovascular and noncardiovascular mortality
Effects of CETP inhibitor (CETPI) on LPS binding by lipopolysaccharide binding protein (LBP) and bactericidal/permeability increasing protein (BPI)
For analysis of the potential effects of CETPIs, the inhibitors were preincubated at three concentrations with a fixed concentration, 50 nM, of the test proteins
Summary
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. The most potent means for raising plasma HDL has been through the use of cholesteryl ester transfer protein (CETP) inhibitors Both torcetrapib [1, 2] and anacetrapib [3] have demonstrated 2-fold elevations in human trials. That nearly half of the noncardiovascular excess in mortality for the ILLUMINATE trial was associated with infection raises the question as to whether torcetrapib, apart from its intended effect on CETP, might have interfered with the function of two other proteins in the same family of lipid binding proteins, both of which play important roles in antibacterial defense [6].
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