1. Potential Mechanisms of Adverse Outcomes Associated with Torcetrapib
Figure 1. Potential Mechanisms of Adverse Outcomes Associated with Torcetrapib. Treatment with torcetrapib has both mechanism-based and off-target effects that may have contributed to an increased rate of adverse cardiovascular and noncardiovascular outcomes. The drug inhibits cholesteryl ester transfer protein (CETP), blocking the transfer of cholesteryl esters to lipoproteins containing apolipoprotein B (ApoB), such as low-density lipoprotein (LDL), resulting in increased levels of high-density lipoprotein (HDL) cholesterol and enlarged HDL particles. Although HDL cholesterol can be taken up directly by the liver through the HDL scavenger receptor, class B, type I (SR-BI), inhibition of CETP may reduce the rate of return of HDL cholesterol to the liver, thus impairing reverse cholesterol transport and increasing cardiovascular risk. In addition, the change in HDL composition could conceivably impair immune function associated with HDL, thus increasing noncardiovascular risks such as infection and cancer. On the other hand, the molecule torcetrapib clearly has the off-target effects of elevating levels of aldosterone and blood pressure, changes that probably contributed to the increased cardiovascular risk. The potential that torcetrapib has off-target effects that contributed to an increased risk of noncardiovascular events is possible but speculative. Finally, CETP inhibition has the potentially beneficial effects of increasing cholesterol efflux from macrophages mediated by ATP-binding cassette transporter G1 (ABCG1) (which could increase the rate of physiologically relevant reverse cholesterol transport from macrophages) and of increasing the uptake of LDL cholesterol by the liver (which reduces LDL cholesterol levels), effects that could be important for CETP inhibitors that do not have the off-target effects of torcetrapib.
Rader D. N Engl J Med 2007; 357:2180-3