Is good cholesterol always good?

Cholesterol has an essential physiological role in humans, but an excess is pathogenic. Its metabolism is regulated by various enzymes, receptors, and transfer proteins present in the small intestine, liver, peripheral cells, and plasma. Cholesterol is secreted from the liver into plasma as very low density lipoprotein (VLDL), which gets converted to low density lipoprotein (LDL). LDL cholesterol is a risk factor for coronary heart disease, hence its synonym—bad cholesterol. High density lipoprotein (HDL) helps to carry cholesterol mobilised from peripheral cells and destined for disposal by the liver, a process termed reverse cholesterol transport. This role and epidemiological evidence that the concentration of HDL cholesterol in plasma correlates inversely with risk of coronary heart disease have earned it the reputation of being “good” cholesterol.¹ The recent report of a drug that markedly raises HDL cholesterol by interfering with reverse cholesterol transport poses the question whether this method of increasing HDL will prevent or promote coronary heart disease.²

The new drug, torcetrapib, raises HDL cholesterol by inhibiting cholesterol ester transfer protein (CETP), which mediates reverse cholesterol transport (figure). A recent study shows that almost 40% of the variation in HDL cholesterol between individuals is genetically determined, one quarter of which is attributable to polymorphisms of the CETP gene.³ Lower concentrations of CETP mean increased concentrations of HDL cholesterol. Lifestyle factors that raise HDL cholesterol include alcohol consumption, which decreases CETP activity and accounts for half the environmental variation in men.⁴,⁵

Figure 1.

Schematic diagram of cholesterol metabolism showing the physiological compartments involved. Also shown are the key enzymes, receptors, transfer proteins, and lipoproteins participating in cholesterol synthesis, transport, and degradation. Abbreviations: ACAT, acyl-coA: cholesterol acyltransferase; CE, cholesterol ester; TG, triglyceride; apoB, apolipoprotein B; MTP, microsomal triglyceride transfer protein; SR-B1, scavenger receptor class B type 1; ABC A1, ATP binding cassette transporter A1; FC, free cholesterol; LCAT, lecithin cholesterol acyltransferase; CETP, cholesterol ester transfer protein. Reverse cholesterol transport involves transport of free (unesterified) cholesterol from peripheral cells to HDL. This is initiated by the ATP binding cassette transporter A1 (ABC A1). It is subsequently esterified by lecithin:cholesterol acyltransferase (LCAT). CETP mediates the transfer of cholesterol ester from HDL to VLDL and LDL, for disposal via the LDL receptor pathway, and of triglyceride in the opposite direction (plasma panel). Lack of CETP causes accumulation of cholesterol ester in HDL and thus increases the HDL cholesterol concentration in plasma

Evidence that an increase in HDL cholesterol is associated with longevity and inversely correlated with incidence of coronary heart disease implies that genetically determined increases in HDL cholesterol should be protective. Several CETP gene mutations decrease CETP activity and raise HDL but the evidence as to whether they are beneficial is conflicting. For example, a case-control study of Ashkenazi Jews with exceptional longevity showed a highly significant increase in the frequency of a mutation associated with reduced CETP activity compared with two groups of controls.⁶ In contrast, an earlier observational study showed that the frequency of a CETP mutation associated with markedly raised concentrations of HDL cholesterol, common in the north of Japan, was reduced in subjects over the age of 80, but at only a borderline level of significance.⁷ An increased prevalence of coronary heart disease was seen in men of Japanese ancestry with a different CETP mutation and moderately (but not markedly) raised HDL cholesterol in the Honolulu heart programme's cohort,⁸ and a large case-control study showed a graded increase in coronary heart disease in Danish women (but not men) according to whether they were heterozygous or homozygous for another CETP mutation that reduced its function.⁹

The adverse effects of CETP deficiency have been attributed to impairment of reverse cholesterol transport and loss of the anti-atherogenic properties of HDL resulting from its increased cholesterol content and particle size.⁸,⁹ This explanation is challenged by three studies. One showed that increased HDL size was associated with longevity in Ashkenazi Jews.⁶ The population based Framingham offspring study found that another common CETP polymorphism conferred a reduced risk of coronary heart disease in a sample of men (but not women).¹⁰ CETP polymorphism also reduced the risk in men participating in the Veterans' Affairs HDL cholesterol intervention trial (VA-HIT), a randomised controlled trial of gemfibrozil.¹¹

Clearly, the answer is still not known and judgment must await the results of further intervention trials. The efficacy of the novel CETP inhibitor, torcetrapib, which alone and in combination with atorvastatin raised HDL cholesterol concentrations by 46% and 61%, respectively, indicates that this question could soon be answered.²

In the meantime, how should clinicians react? Firstly, they should continue to measure HDL cholesterol, since a low value (< 1 mmol/l in men, < 1.2 mmol/l in women) remains a strong and independent risk factor for coronary heart disease. If the concentration is low, efforts should be made to increase HDL by encouraging exercise and discouraging smoking. Fibrates raise HDL cholesterol moderately and may decrease the risk of coronary heart disease. Alternatively, statins lower LDL cholesterol and the ratio of total cholesterol to HDL cholesterol.

Less clear is how we should manage raised HDL cholesterol values. If the trait is asymptomatic and no other risk factors exist, reassurance is appropriate. Often, however, LDL cholesterol is concomitantly raised but with a normal ratio of total cholesterol to HDL cholesterol. Although the latter is usually regarded as a useful index of risk of coronary heart disease, the Danish women with CETP deficiency were at increased risk despite normal ratios.⁹ When in doubt, evidence of preclinical vascular disease should be sought by non-invasive means, such as multislice computed tomography scanning for coronary calcification.¹² A calcification score above the 75th percentile for age and sex is an indication for preventive measures, including lowering of LDL. Alternatively, thickness of the carotid intima and media may be measured by using ultrasound. The efficacy of statins in reducing coronary heart disease events is well established and was independent of the baseline HDL cholesterol concentration in the heart protection study. Notably, combined administration of torcetrapib and atorvastatin has additive effects not only in raising HDL but also on lowering LDL.²