Is HDL cholesterol an independent cardiovascular disease risk factor?

Multiple studies have demonstrated that cardiovascular risk increases with increasing total and low-density lipoprotein (LDL) cholesterol, and that this risk can be reduced with decreased levels of LDL cholesterol. Many studies have also linked increases in cardiovascular risk with decreasing high-density lipoprotein (HDL) cholesterol levels, but until recently there was controversy regarding whether HDL cholesterol was an independent indicator of risk. A low HDL cholesterol level is the most common lipid abnormality observed in men with coronary artery disease (CAD).

The Veterans Affairs HDL Intervention Trial and the Helsinki Heart Study demonstrated that most of the reduction in cardiovascular risk was due to the increase in HDL cholesterol levels as a consequence of the use of fibrate drugs in patients with normal levels of LDL and reduced levels of HDL cholesterol.1, 2 Epidemiologic studies have suggested that there is a 2% to 3% reduction in CAD events for each mg/dL increase in HDL cholesterol.

Lipid-lowering therapies are now capable of lowering LDL cholesterol levels by more than 50% in 90% of patients, with an associated 20% to 35% reduction in cardiovascular events. One question, however, is whether further reductions in LDL cholesterol will result in greater reductions in cardiovascular risk, or whether a threshold is reached unless there is also an effect on raising HDL cholesterol levels. Although HMG-CoA reductase inhibitors (statins), fibrates, and nicotinic acid do have effects on HDL cholesterol levels, their effect is modest (about a 5% to 10% increase, on average).

Recent research has identified a number of promising therapeutic targets to increase HDL cholesterol levels, and several of these are now in phase 1-3 trials. For example, some studies have suggested that inhibition of cholesteryl ester transfer protein (CETP) can raise HDL cholesterol levels by 50%.3 This target was revealed with the discovery of human genetic CETP-deficiency states, which are characterized by elevated HDL levels. The first mutation in the CETP gene was discovered in Japan, and because atherosclerosis is low in the Japanese, epidemiologic studies were undertaken in order to determine the mutation’s prevalence. This mutation was found to occur in about 11% of the population, and these 11% were particularly resistant to developing atherosclerosis. Briefly, CETP is a plasma glycoprotein manufactured in the liver that circulates in the blood. The primary action of CETP is to mediate transfer of cholesteryl esters from HDL to LDL and very low-density lipoprotein in exchange for triglyceride. CETP inhibitors thereby delay the catabolism of apo A-I and A-II and thus increase HDL.

The first phase 2 clinical trial of a CETP inhibitor was published in 2002. The study consisted of 198 patients with mild hyperlipidemia, treated with three different doses

of the CETP inhibitor JTT-705. A 37% increase in HDL was noted

in the high-dose group after 4 weeks of therapy. More recently, in a small study, the CETP inhibitor torcetrapib was administered either alone or in combination with atorvastatin (Lipitor). Increases in plasma HDL of 106% were observed in six patients administered this CETP inhibitor for 8 weeks.4

The role of HDL in the development of atherosclerosis will undoubtedly undergo more investigation now that we have the ability to substantially alter HDL levels. My impression is it is a likely additional factor that will need to be managed in the atherogenic complex.