HDL-Replacement Therapy

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HDL-Replacement Therapy

Abstract and Introduction

Abstract


HDL-replacement therapy is a promising new treatment strategy involving the acute administration of HDL to rapidly stabilize patients at imminent risk for developing a myocardial infarction, such as those with acute coronary syndrome. This review will first focus on the anti-atherogenic mechanisms for HDL, such as the stimulation of the reverse cholesterol transport pathway, and then discuss the other potential beneficial biological effects of HDL on atherosclerosis. The various types of HDL-replacement therapies that are being investigated and developed will be reviewed and ongoing clinical trials and other possible clinical indications for HDL-replacement therapy besides the prevention of myocardial infarction will also be described. Finally, HDL-replacement therapy will be put into perspective by summarizing the current gaps in our knowledge of HDL metabolism and identifying challenges for future research in this area.

Introduction


It has been over 50 years since the respective pro- and anti-atherogenic effects of LDL and HDL were first described, but the main focus has been on developing agents for decreasing LDL-cholesterol (LDL-C). There is now great interest in identifying new agents for raising HDL or for improving its function, with the expectation that a combined approach of simultaneously lowering LDL and raising HDL will be more effective in reducing cardiovascular events than only lowering LDL, which in most trials reduces clinical events by only approximately 30%. Currently, the most effective drug for increasing HDL is niacin but its use has been limited because of side effects, although newer slower release formulations of niacin coupled with selective prostaglandin D2 receptor antagonists may ameloriate this problem. Cholesteryl ester transfer protein inhibitors are also an effective way to elevate HDL but the recent setbacks of the late-stage clinical trials of torcetrapib, perhaps due to unanticipated off-target effects, has delayed the development of this class of drug.

Besides creating small-molecule-type drugs, a new treatment strategy has been described for acutely raising HDL that involves the infusion of synthetic or reconstituted HDL or HDL mimetics. This treatment approach can be viewed as a replacement-type therapy because, as opposed to the chronic use of a drug to increase endogenous levels of HDL, HDL or HDL mimetics from an exogenous source are administered to a patient. The rationale behind this therapy is that it has been observed that HDL infusion can have a surprisingly rapid effect in reducing plaque volume in both animal models and humans, and thus it could quickly stabilize patients with acute coronary syndrome, who are at great risk of myocardial infarction. In this review, we will first discuss the anti-atherogenic mechanisms of HDL. Next, we will review the different types of HDL-replacement agents that are currently being investigated, as well as their possible clinical indications besides the prevention of myocardial infarction.

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