Torcetrapib
A review weighs four possible explanations for why torcetrapib raised cardiovascular risk despite raising HDL cholesterol (Ann Med 2009)
Original title: Is high HDL cholesterol always good?
Because of the inverse relationship between HDL cholesterol and cardiovascular disease, and the substantial residual risk that persists even with high-dose statin therapy, there has been urgent interest in whether raising HDL cholesterol offers therapeutic benefit. While the marked HDL-raising effect of nicotinic acid has been encouraging, no evidence yet shows that specifically raising HDL cholesterol reduces cardiovascular disease, and treatment with the CETP inhibitor torcetrapib actually increased cardiovascular disease risk. This review discusses the lively debate that followed, weighing suggested explanations for the negative torcetrapib result: an off-target, non-CETP-related effect specific to this inhibitor, an inability of very high HDL cholesterol to protect, induction of dysfunctional HDL, or a direct atherogenic effect of CETP inhibition itself, concluding that little is still known about the cardiovascular effect of specifically raising HDL cholesterol through CETP inhibition.
Original abstract
Because of the obvious negative relation between high-density lipoprotein (HDL) cholesterol and cardiovascular disease and the substantial residual risk of this disease even during treatment with high-dose statin there has been an urgent need to investigate the possible therapeutic benefit of increasing HDL. Even if treatment with nicotinic acid with its marked HDL-increasing effect has been encouraging, there is no evidence so far that specific increase of HDL cholesterol results in less cardiovascular disease. Treatment with the cholesterol ester transfer protein (CETP) inhibitor and HDL-increasing drug torcetrapib resulted in increased risk of cardiovascular disease. These negative results were followed by a lively discussion regarding the possible benefit of HDL-increasing treatment in general and CETP inhibition in particular. Suggested possible causes for the negative outcome by torcetrapib treatment are off-target non-CETP-related effect of this particular inhibitor, inability of very high blood HDL cholesterol levels to protect, induction of dysfunctional HDL, and direct atherogenic effect of CETP inhibition. It is concluded that still today little is known about the effect of specific therapeutic elevation of HDL cholesterol, particularly so through CETP inhibition on cardiovascular risk. New interventional studies on this therapeutic principle are welcomed and under way.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.