MOST of us know that "bad" cholesterol (LDL cholesterol or LDL-C) is the cholesterol that is deposited in the arteries resulting in degeneration and narrowing of the arteries, and "good" cholesterol (HDL cholesterol or HDL-C ) is the "garbage collector" that removes the cholesterol from the wall of the arteries to the liver. Multiple studies have shown that high levels of LDL-C and low levels of HDL-C are associated with an increased risk of heart disease, and that low levels of LDL-C and high levels of HDL-C are associated with a decreased risk of heart disease. However, more recent data suggests that the cholesterol story does not appear to be as simple as this.

The HDL cholesterol surprise

It has long been noted that having a high level of HDL-C is associated with a lower likelihood of blocked heart arteries. Cells carrying cholesterol (called foam cells) that enter into the walls of arteries are responsible for the formation of plaques. HDL-C exerts its protective effect by a process that involves the transfer of cholesterol from the foam cells to the liver for removal through the bile into the small intestine; the process is termed reverse cholesterol transport or RCT.

In the ILLUMINATE study published in November 2007 in the New England Journal of Medicine, more than 15,000 patients were divided into two groups and were given atorvastatin (a statin type of cholesterol-lowering drug) with or without a new drug called Torcetrapib. Torcetrapib belongs to a class of drugs called cholesterylester transfer protein (CETP) inhibitors which work by blocking CETP. CETP is a protein that transfers cholesterol from HDL-C to LDL-C; the net effect of CETP inhibition will be an increase in HDL-C. In the study, those on Torcetrapib, as expected, showed a 72 per cent increase in HDL-C and 25 per cent decrease in LDL-C levels. However, instead of lowering the risks of heart events, there was an increased risk of heart events and death for those on Torcetrapib.

These results caught almost everyone by surprise as the significant increase in HDL-C and lowering of LDL-C did not translate into a beneficial effect. Although subsequent data attributed this to the elevation of blood pressure by Torcetrapib, what it also meant was that the effect of lowering LDL-C and increasing HDL-C alone may not necessarily ensure there will be beneficial effects for the heart. It also meant that the potential benefits of HDL-C elevation required further understanding.

The "bad" HDL cholesterol

What we are beginning to understand is that there are different subtypes of HDL-C and while some may be protective, other subtypes may actually promote plaque formation and blockage in the arteries. Hence, when using different approaches to increase HDL-C, it is the quality and not just the quantity that has an important bearing on prevention of heart disease.

In two independent studies of healthy men (Health Professionals Follow-Up Study) and women (The Nurses' Health Study) published in 2012 in the Journal of the American Heart Association, researchers from Harvard University found that HDL-C can be divided into two major fractions having opposite effects on the heart. The smaller cohort (about 13 per cent), which had a fraction of HDL-C that was associated with a higher risk of heart disease, had an additional protein called apoC-III present on the surface of the HDL-C. The larger cohort, which had a fraction of HDL-C which was associated with a protective effect on the heart, did not have apoC-III on the surface of HDL-C.

Several studies have shown that apoC-III is a predictor of outcomes of heart disease. Studies including CLAS (Cholesterol-Lowering Atherosclerosis Study) and MARS (Monitored Atherosclerosis Regression Study) showed that the presence of plasma apoC-III predicted progression of heart artery disease.

Managing cholesterol

While the effects of other CETP inhibitors await the results of further trials, other cholesterol-lowering drugs, such as the statins and fibrates, have established roles in reducing heart disease. Statins, a class of cholesterol-lowering medication that block the production of cholesterol in the liver resulting in significant reduction of LDL cholesterol but only a mild elevation of HDL cholesterol, lower the blood levels of apoC-III by about 27 per cent. Fibrates also lower apoC-III by 36 per cent.

What is the key cholesterol parameter that should be monitored to reduce the risk of heart attacks? While there are those who suggest that measuring subfractions of LDL-C and HDL-C may be helpful, the consensus among experts is that the single most useful parameter is LDL-C. There is little evidence to show that measuring subfractions of HDL-C and LDL-C will provide any additional beneficial information towards decision-making in the management of cholesterol levels.

How low should the LDL-C be in order to prevent heart disease? Generally, for those with risk factors for heart disease but do not have proven existing heart artery disease, keeping the LDL-C at 100 mg/dl or less is desirable. For those with significant heart artery disease, keeping the LDL-C at 70 mg/dl or less is desirable.

How low can the LDL-C be lowered to? There is no data to show that lowering the LDL-C to levels way below 70 mg/dl is harmful. There is data to show that lowering the LDL-C to below 60mg/dl may result in incremental benefit for those with heart artery disease. For those with low LDL-C, it may be good to know that there is no scientific evidence as yet to show that a very low LDL-C by itself is dangerous or detrimental to health. We are learning more about the cholesterol story but as the studies with Torcetrapib have shown, we do not have all the answers yet.

• Dr Lim is medical director at the Singapore Heart, Stroke & Cancer Centre. He is also editor-in-chief, Heart Asia (a journal of the British Medical Journal Publishing Group), chairman of the scientific advisory board of the Asia-Pacific Heart Association, and honorary professor and senior medical adviser to the Peking University Heart Centre

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