Increase HDL-cholesterol, a new approach in cardiovascular risk reduction

Historically, atherosclerosis has been considered a chronic, slowly progressive disease for which the treatments are largely preventive in nature and exert their effects over long periods. Over the last decade, investigators have found that coronary atherosclerosis may be much more dynamic in nature; many acute coronary events are caused by the rupture of an inflammatory unstable plaque. (1) Indeed, aggressive cholesterol-lowering therapy with statins appears to have clinical benefit within 4 to 6 months of initiation of therapy, suggesting rather rapid effects on the stability of preexisting coronary lesions. Large-scale clinical trials in which inhibitors of statins have been used to reduce low-density lipoprotein (LDL) cholesterol levels have shown marked improvements in clinical outcomes. (2,3) Despite the favorable effects of statins on the risk of coronary heart disease, many cardiovascular events are not prevented by statin therapy.

Hence, there is a great deal of interest in identifying therapies capable of further reducing the risk of coronary heart disease. One such potential therapeutic target is a low level of high-density lipoprotein (HDL) cholesterol. Plasma levels of high-density lipoprotein cholesterol (HDL-C) and its major protein apolipoprotein A-I are consistently inversely associated with coronary heart disease (CHD) risk in observational studies. 

In addition, HDL and apoA-I have been proposed to have other properties that could contribute to their antiatherogenic effect, including antioxidant, antiinflammatory, nitric oxide–promoting, prostacyclin-stabilising, and platelet-inhibiting properties. (4) This issue is important because if these properties contribute substantially to protection from atherosclerosis by HDL, in theory a treatment that increases HDL-C and apoA-I levels could be beneficial even if it does not increase the rate of reverse cholesterol transport.

In the guidelines set forth by the third Adult Treatment Panel of the National Cholesterol Education Program, a low HDL cholesterol level is defined categorically as a level below 40 mg per deciliter. (5) The results of clinical trials indicate that even small increases in the HDL cholesterol level can significantly reduce the risk of coronary heart disease. Primarily on the basis of epidemiologic data, an increase in HDL cholesterol by 1 mg per deciliter is associated with a 2 to 4 percent reduction in the risk of cardiovascular events. Statins have only moderate effects on HDL cholesterol levels, raising them by 5 to 10 percent. Although fibrates and niacin can raise HDL cholesterol levels, the increases are rarely greater than 25 percent. (6)

There are two different approaches to increasing the HDL cholesterol level that are currently under development.
An HDL cholesterol–raising strategy actively being explored is the inhibition of cholesteryl ester transfer protein (CETP). CETP is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from HDL cholesterol to apolipoprotein B–containing lipoproteins. (7) Humans with CETP deficiency due to molecular defects in the CETP gene have markedly elevated plasma levels of HDL cholesterol and apolipoprotein A-I, leading to the concept that CETP inhibition might increase HDL cholesterol levels. Torcetrapib is a well-tolerated and effective CETP inhibitor that has pronounced effects on plasma lipoproteins in patients with low HDL cholesterol levels. Torcetrapib not only increased the levels of HDL cholesterol and apolipoprotein A-I, it also reduced the levels of LDL cholesterol and apolipoprotein B, both when given as monotherapy and when given in combination with atorvastatin.(8) Ultimately, the question of whether CETP inhibition is effective in reducing atherosclerotic cardiovascular disease in humans will be resolved only by trials based on hard clinical end points. Nissen and co-workers used a unique form of synthetic HDL, an ApoA-I Milano/phospholipid complex, because the naturally occurring carriers of ApoA-I Milano are protected from vascular disease. (9) In this initial study, this new strategy had a favorable effect on atherosclerotic disease burden despite a short duration of treatment.

The potential for significant reduction in atherosclerosis within a period of weeks rather than months led to a new concept: short-term HDL-infusion therapy, whereby patients with cardiovascular disease would receive infusions of HDL for six to eight weeks in conjunction with lipid therapy in order to reduce atherosclerosis and the risk of cardiac events in the short term. Additional approaches to short-term HDL therapy that are under development include the infusion of synthetic peptides based on the amphipathic structure of apolipoprotein A-I and the reinfusion of autologous delipidated HDL. Detailed data from clinical trials will now be required in order to establish definitively whether short-term therapy consisting of HDL infusions will provide protection against cardiovascular events, cardiovascular disease.

Further translational research by clinical trials will guide us to evidence-based medicine data regarding the potential clinical benefits of increasing HDL-cholesterol within the broad spectrum of atherosclerotic cardiovascular Disease.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.