Targeting high-density lipoproteins: increasing de novo production versus decreasing clearance

Although cardiovascular mortality has been decreasing in industrialized countries, there continues to be a substantial residual risk; thus, novel therapeutic agents and new targets of therapy have been sought. One highly plausible therapeutic target is high-density lipoprotein (HDL). HDL is a key player in reverse cholesterol transport and possesses a slew of other cardioprotective properties; however, recent trials with agents known to increase HDL levels have generally not shown any reduction in cardiovascular events. Further analysis of these trials suggest that fibrates have consistently reduced some cardiovascular outcomes, at least in the subgroup of patients with high serum triglycerides and low HDL cholesterol (HDLc) levels. Since fibrates, unlike niacin or cholesterol ester transfer protein inhibitors, increase HDLc level mostly through the stimulation of apolipoprotein A-I production, it is suggested that the quality and functionality of HDL are enhanced when de novo synthesis rather than inhibition of turnover is the mechanism of increasing HDL level. In this communication, the evidence for and against the cardioprotective properties of HDL is reviewed and the contemporary clinical trials are discussed.