Raising HDL cholesterol for cardiovascular disease prevention: Is this still feasible?
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Corresponding author Guido Franceschini, PhD Center E. Grossi Paoletti, Department of Pharmacological Sciences, via Balzaretti 9, 20133 Milano, Italy. E-mail: [email protected] Current Cardiovascular Risk Reports 2008, 2:35–40 Current Medicine Group LLC ISSN 1932-9520 Copyright © 2008 by Current Medicine Group LLC
Plasma high-density lipoprotein cholesterol (HDLC) has received considerable attention as a potential therapeutic target to further reduce cardiovascular risk in the statin era. However, doubts about the clinical benefit achievable with treatments enhancing plasma HDLC levels have been raised by the premature termination of a large phase 3 trial with torcetrapib—the most potent and furthest developed HDLC-raising compound— resulting from excess mortality in patients receiving the drug. The causes of torcetrapib failure are unknown and may be related to the drug’s mode of action, off-target toxic effects, or a mixture of both. The failure of torcetrapib does not mean that the concept of targeting HDL in cardiovascular prevention is dead. Other HDLC–raising therapies, which act through disparate molecular mechanisms, are in various stages of preclinical and clinical development. The alternative is the direct administration of synthetic HDL, which has proven activity on atherosclerosis regression in coronary patients.
Introduction Current guidelines for cardiovascular prevention focus on lowering low-density lipoprotein cholesterol (LDLC) to defined levels and using statins as first-line drug therapy in high-risk patients because of their well-established efficacy in lowering LDLC and preventing cardiovascular disease. However, most large-scale statin trials report no more than a 25% to 35% reduction in major cardiovascular events [1], and there are many statin-treated patients in whom cardiovascular events are not prevented. This highlights the need for novel therapeutic strategies targeting other components of the dyslipidemic state to complement statins in achieving further reductions of
cardiovascular morbidity and mortality. In this regard, plasma high-density lipoprotein cholesterol (HDLC) has received considerable attention, given strong epidemiologic evidence of its protective effects, rational scientific mechanisms for HDL-mediated atheroprotection, and encouraging data on clinical benefit with even modest increases in HDL [2,3]. This evidence provides the background for the development of novel therapeutic interventions targeting HDL for the treatment of atherosclerotic cardiovascular disease. However, doubts about the clinical benefit achievable with such interventions have been raised by the recent failure of torcetrapib [4], the most potent and furthest developed HDLC–raising compound to date.
HDL Heterogeneity and Atheroprotective Activity Plasma HDLs are a highly heterogeneous lipoprotein family consisting of several subspecies with varying density, size, shape, and composition. When separated according to particle density, two major subfractions can be identified: HDL 2 particles
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