Studies fail to show a convincing beneficial reduction in heart attacks and strokes with elevation of HDL-C. By Michael Lim

WHEN you pay a visit to your physician and he reviews your blood cholesterol results, he will invariably talk about “bad” cholesterol (low- density lipoprotein cholesterol or LDL-C) and “good” cholesterol (high-density lipoprotein cholesterol or HDL-C). If your HDL-C happens to be low, your physician will discuss with you the fact that a low HDL-C is associated with increased risk of heart disease and measures should be taken to increase your HDL-C.

After all, physicians have been told that data from early population studies suggest that a 1 mg/dL increase in HDL is associated with a 2 per cent to 3 per cent decrease in the risk of heart complications.

Does raised HDL cholesterol reduce heart disease?

However, when researchers tried to prove this beneficial association between elevation in HDL-C with reduction in heart complications in subsequent studies, this beneficial relationship was not consistently seen despite elevation of HDL-C with drugs in these studies. These large studies which involved treatment which raised HDL-C levels have failed to show significant beneficial effects on the heart.

Two studies which used large doses of niacin (Vitamin B3) to raise HDL-C in patients with heart disease, namely the AIM-HIGH study and the HPS-2 THRIVE study, were unable to demonstrate a beneficial effect in patients with heart disease. Another two studies which used a new class of drugs called cholesteryl ester transfer protein (CETP) inhibitors which can increase HDL-C significantly, namely the ILLUMINATE study and the Dal-OUTCOMES study, were unable to demonstrate benefits.

All these studies failed to demonstrate a convincing beneficial reduction in heart attacks, stroke or death with HDL-C elevation. More alarming, in the ILLUMINATE trial, there was an increased risk of heart events and death despite significant HDL-C elevation in those who received treatment with CETP inhibitors. Nevertheless, firm believers of the potential benefits of HDL-C elevation on heart disease have tried to attribute this lack of benefits in these major trials to confounding factors.

These findings were further reinforced by a 2012 publication in the Lancet journal of a multicentre trial by Voight which demonstrated that HDL-C elevation due to genetic conditions did not lower heart attack risk.

Even the most ardent advocate of HDL-C elevation will find it hard to fault the data of this genetic study.

Is low HDL bad for the heart?

Genetic mutations resulting in low HDL-C provide interesting insights into the effect of low HDL-C. A genetic variant HDL which contains a protein named ApoA-1 Milanois is associated with a reduction in HDL levels.

However, instead of being associated with an increase in heart disease, the presence of ApoA-1 Milano is associated with a significant reduction in heart disease despite the low HDL-C.

Another genetic variant where there is deficiency of an enzyme called lecithin cholesterol acyltransferase is also associated with low HDL-C but is not associated with an increased risk of premature heart disease.

In the most severe form of genetic HDL deficiency, Tangier disease, where there is an extremely low level of HDL-C, premature heart disease was only seen in a minority (about 30 per cent) of patients. Hence, using these genetic examples, there is no consistent trend that low HDL equals premature heart disease.

Raising the good cholesterol

Despite the mixed data, most physicians will still attempt to increase the HDL level especially if the baseline HDL level is low. Regular exercise of 30 minutes duration can raise the HDL by 5-10 per cent.

However, overzealous physical exertion will not translate into further incremental elevation in HDL-C; running a marathon is not going to raise your HDL any higher than mild regular exercise.

For obese individuals, weight loss whether through diet, drugs or surgery will result in HDL elevation. Smoking lowers HDL by 5-10 per cent and hence smoking cessation will increase HDL.

While drinking modest amounts of alcohol has been associated with up to 12 per cent elevation of HDL, encouraging alcohol intake for the purpose of HDL elevation is unwarranted and generally not advised as the HDL elevation is modest.

While doses of up to 2gm of niacin or Vitamin B3 have been shown to elevate HDL-C by up to 30 per cent, the data from recent trials (where benefit for the heart is not seen despite HDL-C elevation with niacin) have made the use of niacin less compelling.

Among the drugs used for cholesterol reduction , statins and fibrates increase HDL by up to 10 and 20 per cent respectively.

The new HDL paradox

For a long time, data from animal studies have led physicians to believe that HDL-C promotes cholesterol efflux (flow out of the cell) from the cholesterol laden cells in the vessel wall to the liver for removal through the bile. Hence, if there is increased “removal” or efflux of cholesterol from the cholesterol laden cells in the vessel wall, it would have been expected that the risks of heart attack will be reduced.

New findings published in the Circulation journal in March 2013 by researchers from Cleveland Clinic showed that paradoxically, increased cholesterol efflux was associated with increased heart attack, stroke and death.

The findings of this study has thrown into disarray the traditional concepts on cholesterol efflux and has sent physicians scurrying back to the research bench to further understand the complex relationship between HDL, HDL-C and plaque formation.

Being practical about HDL-C

Given the absence of benefit of HDL-C elevation in recent large HDL-C raising clinical trials and genetic studies, and the surprising paradoxical finding of increased risk of heart attack with increased cholesterol removal from cholesterol laden cells in vessel wall, physicians will have to review the traditional relationship between HDL elevation and heart disease.

These data challenge the very foundations of our belief that HDL-C elevation will reduce the risk of heart attack.

Given these findings, one must not go to extreme means to raise the HDL-C level. Hence, statins such as simvastatin, atorvastatin and rosuvastatin should be given primarily to reduce LDL-C and not for HDL-C elevation, although they do elevate HDL-C.

Similarly, fibrates such as fenofibrate should be given primarily to reduce triglycerides and not for HDL-C elevation. If you do not drink alcohol, do not start doing so for the purpose of raising your HDL-C as there is no definitive data to indicate that this will translate into beneficial effects for the heart.

Given that most patients are troubled by the side effect of flushing when taking high dose niacin, there is even less reason to commence on niacin in the light of current evidence.

It is invariable that the contrarian findings of these more recent studies will force physicians to re-examine the role of HDL-C-raising therapies, reduce their enthusiasm to place emphasis on HDL elevation and redirect their energies to LDL-C reduction.