Therapeutic approaches to raising plasma HDL-cholesterol levels.
Epidemiologic data from the Framingham and Prospective Cardiovascular Munster studies, demonstrating an inverse correlation between the plasma concentration of HDLs and the incidence of cardiovascular disease, have driven research to explore precisely how HDLs confer this cardioprotective effect. HDLs are anti-inflammatory, antithrombogenic and have vasoactive effects, as well as being efficient cholesterol acceptors enabling the removal of cholesterol from peripheral tissues, all functions that are likely to protect the vasculature. The first part of this article will review the clinical evidence in support of the pleiotropic effects of HDLs, along with laboratory-based investigations of the molecular mechanisms of action. As the evidence of clinical benefits of raising plasma HDL concentration has increased, so has the number of strategies currently being considered to achieve this goal. The second part of this article will review three current strategies: infusion of HDL-like products, comparing physicopharmacologic characteristics of the two commercial products currently under trial; the use of fibrates to raise plasma HDLs (although fibrates primarily reduce triglyceride levels, certain derivatives are able to induce significant increases in plasma HDLs); and the use of drugs that inhibit cholesterol ester transfer protein (these drugs increase plasma HDL concentration either alone or as an adjunct therapy with statins). The clinical efficacy and mechanism of action of fibrates and inhibitors of cholesterol ester transfer protein will be reviewed.