Spotlight on HDL-raising Therapies: Insights From the Torcetrapib Trials

Box 1.

Heterogeneity of Circulating HDL Particles

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Author(s)

Anatol Kontush, BSc, PhD

Research Director, Dyslipidemia and Atherosclerosis Research Unit (UMR S.551), National Institute of Health and Medical Research (INSERM), Hôpital de la Pitié, Université Pierre et Marie Curie, Paris, France

Disclosures

Disclosure: Anatol Kontush, BSc, PhD, has disclosed that he has served as a consultant to, is on the speakers' bureau for, and has received grant or research support from Pfizer.

Maryse Guérin, PhD

Senior Investigator, Dyslipidemia and Atherosclerosis Research Unit (UMR S.551), National Institute of Health and Medical Research (INSERM), Hôpital de la Pitié, Université Pierre et Marie Curie, Paris, France

Disclosures

Disclosure: Maryse Guérin, PhD, has disclosed that she has received grant or research support from Pfizer.

M John Chapman, BSc (Hons), PhD, DSc

Director, Dyslipidemia and Atherosclerosis Research Unit (UMR S.551), National Institute of Health and Medical Research (INSERM), Hôpital de la Pitié, Université Pierre et Marie Curie, Paris, France

Disclosures

Disclosure: M. John Chapman, BSc (Hons), PhD, DSc, has disclosed that he has served as a consultant to, is on the speakers' bureau for, and has received grant or research support from Pfizer.

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Summary and Introduction

Summary

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.

Introduction

Evidence from many sources has established that elevated levels of LDL cholesterol represent a major risk factor for premature atherosclerosis and cardiovascular disease. Although 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors—statins—mediate an efficacious reduction in LDL cholesterol and concomitantly decrease cardiovascular morbidity and mortality by up to 40%, substantial residual cardiovascular risk remains.^[1]

In a similar way to raised LDL cholesterol, subnormal levels of HDL cholesterol constitute a major, independent cardiovascular risk factor as documented in several epidemiological studies.^[2] Indeed, in patients at high cardiovascular risk being treated with statins, circulating HDL-cholesterol concentrations predict cardiovascular events even at low LDL-cholesterol levels (<1.8 mmol/l [<70 mg/dl]).^[3] Attention has, therefore, shifted towards novel strategies for raising HDL cholesterol as a preventive therapy for cardiovascular disease. Here we briefly review the latest developments in HDL raising therapy with a focus on recent torcetrapib trials.