Torcetrapib
Hypothesis paper proposes that the ILLUMINATE deaths from torcetrapib trace to eNOS inhibition via HDL-SR-BI signaling loss (Med Hypotheses 2007)
Original title: The strange case of Dr HDL and Mr HDL: does a NO's story illuminate the mystery of HDL's dark side uncovered by Dr HDL's drug targeting CETP?
After the ILLUMINATE trial, the first large morbidity-and-mortality trial of a CETP inhibitor (torcetrapib), was prematurely stopped for significantly increased mortality in the treated group, the authors propose a mechanistic hypothesis for why. Because HDL interacts with endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) secretion, which partly controls blood pressure, the authors hypothesize that CETP inhibition enlarges HDL particles enough to impair their interaction with scavenger receptor class B type I (SR-BI), a key link between HDL and eNOS activation, thereby inhibiting eNOS. They suggest the resulting NO deficit could destabilize atherosclerotic plaques in all patients, but only raise blood pressure pathogenically in patients with naturally weak eNOS activity from genetic polymorphisms. The authors further hypothesize that CETP-inhibition-driven HDL elevation, combined with the capacity of HDL to induce endothelin-1 secretion, aggravated cardiovascular risk under torcetrapib treatment.
Original abstract
Recently, the first large-scale morbidity and mortality trial (ILLUMINATE) to evaluate the cardiovascular end points of a CETP inhibitor (torcetrapib) has been prematurely stopped because the mortality was significantly increased in the treated group. Why torcetrapib caused excess death is not known. Based on the fact that HDL interacts with endothelial nitric oxyde synthase (eNOS) and nitric oxide (NO) secretion, which partly controlled blood pressure and than torcetrapib could increase blood pressure among some patients, we hypothesize that CETP inhibition could have significantly inhibit eNOS. CETP inhibition would have enlarged HDL size resulting in a deficit in the interaction between HDL and the Scavenger Receptor class B type I (SR-BI), which is an important link between HDL and eNOS activation. We suggest than the deficit in NO secretion would have been sufficient among all patients to induce a destabilization of the plaques of atheroma, but could have induced a pathogenic increase in blood pressure only in patients whose eNOS activity was naturally weak due to genetic polymorphisms of this enzyme. We also hypothesize that the increase in HDL levels, induced by CETP inhibition, coupled with the capacity of HDL to induce endothelin-1 secretion would have aggravated the cardiovascular risks under this CETP inhibitor treatment.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.