Abstract
Subnormal levels of HDL cholesterol constitute a major cardiovascular risk factor. Inhibitors of cholesteryl ester transfer protein (CETP) are presently the most potent HDL-raising agents. Torcetrapib was the first CETP inhibitor to enter a large-scale, prospective, placebo-controlled interventional trial, which was prematurely terminated in December 2006 because of excess cardiovascular and noncardiovascular mortality in the active treatment group. Therapy with torcetrapib was associated with considerable increases in aldosterone level and blood pressure and changes in serum electrolytes indicative of mineralocorticoid excess. These findings indicate that torcetrapib has off-target toxic effects unrelated to HDL raising that involve the activation of mineralocorticoid receptors by aldosterone and result in the induction of hypertension. In contrast with torcetrapib, other CETP inhibitors such as JTT-705 and MK-825 do not increase blood pressure in humans, an observation which discounts a class effect. The available data do not, however, exclude potential adverse effects of CETP inhibition such as the generation of HDL particles that have deficient biological activities and a deleterious impact on reverse cholesterol transport and steroid metabolism. Normalization of both defective HDL function and diminished HDL levels should, therefore, be the focus of pharmacological HDL raising in future studies.
Key Points
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Inhibitors of cholesteryl ester transfer protein (CETP) are presently the most potent agents for raising HDL cholesterol
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Torcetrapib, the first CETP inhibitor to enter a large-scale, prospective, placebo-controlled interventional trial (ILLUMINATE), was associated with excess cardiovascular and noncardiovascular mortality in the active-treatment group
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Torcetrapib treatment resulted in significantly increased aldosterone levels, altered serum electrolytes indicative of mineralocorticoid excess, and elevated blood pressure, indicating an off-target mechanism of torcetrapib-related toxic effects involving activation of mineralocorticoid receptors by aldosterone with subsequent induction of hypertension
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Other CETP inhibitors such as JTT-705 and MK-825 do not increase blood pressure in humans, an observation that tends to discount a class effect
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Potential adverse effects of CETP inhibition cannot, however, be excluded; CETP inhibition could result in the generation of HDL particles that have deficient antiatherogenic activities and a deleterious impact on reverse cholesterol transport and steroid metabolism
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Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.
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Anatol Kontush has been a consultant for, and has received speaker honoraria and grant/research support from Pfizer.
Maryse Guérin has received grant/research support from Pfizer.
M John Chapman has been a consultant for, and has received speaker honoraria and grant/research support from Pfizer.
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Kontush, A., Guérin, M. & Chapman, M. Spotlight on HDL-raising therapies: insights from the torcetrapib trials. Nat Rev Cardiol 5, 329–336 (2008). https://doi.org/10.1038/ncpcardio1191
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DOI: https://doi.org/10.1038/ncpcardio1191