Abstract
Negative relationship between plasma high-density lipoprotein (HDL) levels and risk of cardiovascular disease (CVD) is a firmly established medical fact, but attempts to reproduce protective properties of HDL by pharmacologically elevating HDL levels were mostly unsuccessful. This conundrum presents a fundamental question: were the approaches used to raise HDL flawed or the protective effects of HDL are an epiphenomenon? Recent attempts to elevate plasma HDL were universally based on reducing HDL catabolism by blocking reverse cholesterol transport (RCT). Here, we argue that this mode of HDL elevation may be mechanistically different to natural mechanisms and thus be counterproductive. We further argue that independently of whether HDL is a driving force or a surrogate measure of the rate of RCT, approaches aimed at increasing HDL supply, rather than reducing its catabolism, would be most beneficial for speeding up RCT and improving protection against CVD.
Highlights
Reviewed by: Angelo Baldassare Cefalù, University of Palermo, Italy Jeonga Kim, University of Alabama at Birmingham, USA
Negative relationship between plasma high-density lipoprotein (HDL) levels and risk of cardiovascular disease (CVD) is a firmly established medical fact, but attempts to reproduce protective properties of HDL by pharmacologically elevating HDL levels were mostly unsuccessful. This conundrum presents a fundamental question: were the approaches used to raise HDL flawed or the protective effects of HDL are an epiphenomenon? Recent attempts to elevate plasma HDL were universally based on reducing HDL catabolism by blocking reverse cholesterol transport (RCT)
We further argue that independently of whether HDL is a driving force or a surrogate measure of the rate of RCT, approaches aimed at increasing HDL supply, rather than reducing its catabolism, would be most beneficial for speeding up RCT and improving protection against CVD
Summary
Reviewed by: Angelo Baldassare Cefalù, University of Palermo, Italy Jeonga Kim, University of Alabama at Birmingham, USA. Recent attempts to elevate plasma HDL were universally based on reducing HDL catabolism by blocking reverse cholesterol transport (RCT). The outcome of the trial of first CETP inhibitor, Trocetrapib, was negative: torcetrapib significantly elevated HDL-C levels and reduced LDL-C levels, but total and cardiovascular mortality and morbidity increased [5].
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