HDL-Replacement Therapy: Mechanism of Action, Types of Agents and Potential Clinical Indications

Expert Commentary & Five-year View

Great progress has been made in understanding HDL metabolism, which has made possible the development of various HDL-replacement agents that are currently being explored. However, there are still many unresolved issues concerning how to use HDL as a therapeutic agent. First, despite a renewed interest in HDL research we still do not completely understand how HDL protects against atherosclerosis. The prevailing hypothesis is that it potentiates the reverse cholesterol transport pathway but the other beneficial effects of HDL may also contribute to its atheroprotective function. A better understanding of how HDL prevents atherosclerosis is critical in the design and optimization of HDL-replacement agents and also in monitoring the clinical efficacy of such drugs or treatments. This is a particularly important issue for short apoA-I mimetic peptides, which may not share all of the features or biological properties of the full length apoA-I molecule. The majority of HDL-replacement agents have employed a combination of an apolipoprotein or peptide mimic with a phospholipid, which makes the production and preparation of these agents more difficult and expensive. It is still not clear from most studies to what degree the added phospholipid contributes to the observed protection against atherosclerosis. The effect of different types of phospholipids and/or the optimum ratio of lipid-protein has also not been systematically investigated. In both animal and human studies, the route of administration of these agents has been primarily intravenous, which would limit the use of this type of treatment to the acute stabilization of patients. Other approaches, such as oral administration or subcutaneous injection, may be possible, particularly for lipid-free apoA-1 mimetic peptides (e.g., D-4F).

The most important issue is that only early-stage clinical trials have been completed for the various HDL-replacement agents. Although data from preclinical animal studies are encouraging and the various treatments examined to date appear to be safe, the efficacy of this approach has not been fully investigated and no studies based on clinical end points have been reported. Therefore, much work remains to be carried out before HDL-replacement therapy can be added to our standard treatment approach for cardiovascular disease, but it shows great promise and research in this area has already greatly added to our basic understanding of HDL metabolism.

Expert Rev Cardiovasc Ther. 2008;6(9):1203-1215. © 2008  Expert Reviews Ltd.

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Cite this: HDL-Replacement Therapy: Mechanism of Action, Types of Agents and Potential Clinical Indications - Medscape - Oct 01, 2008.