Torcetrapib
Torcetrapib impairs blood vessel dilation through a mechanism unrelated to CETP inhibition or HDL elevation, unlike a structurally different CETP inhibitor (J Cardiovasc Pharmacol 2010)
Original title: Torcetrapib produces endothelial dysfunction independent of cholesteryl ester transfer protein inhibition
Because the hypertensive and aldosterone-elevating effects of torcetrapib identified in earlier work may not fully explain its increased cardiovascular events in clinical trials, researchers assessed endothelial-mediated vasodilation in vivo using ultrasound imaging of acetylcholine-induced changes in rabbit central ear artery diameter. Torcetrapib produced hypertension and baseline vasoconstriction and markedly inhibited acetylcholine-induced vasodilation, while a structurally distinct CETP inhibitor, JNJ-28545595, did not impair endothelial function despite producing similar degrees of CETP inhibition and HDL elevation. Nitroprusside normalized the baseline vasoconstriction caused by torcetrapib and produced dose-dependent vasodilation in norepinephrine-preconstricted arteries from torcetrapib-treated animals, showing torcetrapib did not impair smooth muscle function itself. The findings indicate torcetrapib significantly impairs endothelial function independent of CETP inhibition and HDL elevation, an activity that may have contributed to its increased cardiovascular risk in clinical trials.
Original abstract
Objective: Torcetrapib, a prototype cholesteryl ester transfer protein (CETP) inhibitor with potential for decreasing atherosclerotic disease, increased cardiovascular events in clinical trials. The identified hypertensive and aldosterone-elevating actions of torcetrapib may not fully account for this elevated cardiovascular risk. Therefore, we evaluated the effects of torcetrapib on endothelial mediated vasodilation in vivo.
Methods And Results: In vivo endothelial mediated vasodilation was assessed using ultrasound imaging of acetylcholine-induced changes in rabbit central ear artery diameter. Torcetrapib, in addition to producing hypertension and baseline vasoconstriction, markedly inhibited acetylcholine-induced vasodilation. A structurally distinct CETP inhibitor, JNJ-28545595, did not affect endothelial function despite producing similar degrees of CETP inhibition and high-density lipoprotein elevation. Nitroprusside normalized torcetrapib's basal vasoconstriction and elicited dose-dependent vasodilation of norepinephrine preconstricted arteries in torcetrapib-treated animals, indicating torcetrapib did not impair smooth muscle function.
Conclusions: Torcetrapib significantly impairs endothelial function in vivo, independent of CETP inhibition and high-density lipoprotein elevation. Given the well-documented association of endothelial dysfunction with cardiovascular disease and risk, this activity of torcetrapib may have contributed to increased cardiovascular risk in clinical trials.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.