What are high-density lipoproteins?

There are two main cholesterol-carrying fractions in plasma.

Low density lipoproteins (LDL): these cause atherosclerosis by depositing cholesterol in the wall of arteries
High-density lipoproteins (HDL): these protect against the development of atherosclerosis by removing cholesterol from the artery wall.

HDL exist in the plasma as a number of subpopulations of particles of varying shape, size, density and composition. These particles carry cholesterol from the body's tissues to the liver for reprocessing or excretion. HDL are the smallest and densest of the plasma lipoproteins.

Most HDL in the plasma are spherical particles. They consist of a fatty core that contains cholesteryl esters with a small amount of triglyceride, surrounded by a surface layer of phospholipids, unesterified cholesterol and apolipoproteins.

The main apolipoproteins in HDL are apolipopotein A-I (apoA-I) and apolipoprotein A-II (apoA-II). These comprise about 70% and 20% of the total HDL protein, respectively. Most HDL particles also contain other minor apolipoproteins.

Figure 1 The structure of spherical HDL

Fig. The structure of spherical HDL

Modified from Rye K-A et al. Atherosclerosis 1999;145:227-38.

HDL also transport proteins that are involved in HDL formation and remodelling. These include cholesteryl ester transfer protein (CETP), which remodels HDL into particles of varying size.

Why is it important to have high levels of HDL cholesterol?

Large prospective studies, such as the Framingham Heart Study in the USA and the Prospective Cardiovascular M�nster (PROCAM) study in Germany, have clearly shown that high-density lipoprotein (HDL) cholesterol is a powerful inverse predictor of cardiovascular disease. For every 1 mg/dL (0.025 mmol/L) increase in HDL cholesterol, the risk of having a cardiovascular event reduces by 2-3%.

Figure 2 Relationship between HDL cholesterol and coronary heart disease in the Framingham Study

Fig. Relationship between HDL cholesterol and coronary heart disease in the Framingham Study.

Adapted from Gordon T et al. Am J Med 1977;62:707-14.

Importantly, a low HDL cholesterol level (generally regarded by current treatment guidelines as <40 mg/dL or <1.0 mmol/L in men and <50 mg/dL or <1.3 mmol/L in women) increases cardiovascular risk, irrespective of whether levels of low-density lipoprotein (LDL) cholesterol are low, average or high.

Atherosclerosis is an inflammatory disorder that is caused by accumulation of atherogenic lipoproteins in the artery wall. Research has shown that HDL protect against atherosclerosis by a number of mechanisms. First of all, HDL inhibit the progression of atherosclerosis by promoting the efflux of cholesterol from foam cells. Foam cells are macrophages containing excess lipid, which originate from monocytes or smooth muscle cells. . HDL also have other activities that protect against the development of atherosclerosis. These include inhibiting the oxidation of atherogenic lipoproteins, inhibiting vascular inflammation and inhibiting thrombosis.

Findings from INTERHEART, a global case control study of heart attack involving 52 countries, imply that even in patients with low levels of LDL cholesterol, if the level of HDL cholesterol is not sufficiently high, there remains an increased risk of further cardiovascular events. This scenario can be explained on the basis of an imbalance between the deposition and removal of cholesterol in the arterial wall. Maintaining high levels of HDL cholesterol in the plasma ensures that the HDL can counter the effects of atherogenic lipoproteins and prevent or even reduce progression of atherosclerosis.

What are the targets for HDL cholesterol?

International guidelines currently recommend that levels of high-density lipoprotein (HDL) cholesterol should be at least 40 mg/dL or 1.0 mmol/L (50 mg/dL or 1.3 mmol/L in women) in people at high risk of cardiovascular events.

However, evidence suggests that the beneficial inverse relationship between HDL cholesterol and cardiovascular risk extends further, even up to levels of 80 mg/dL (2.1 mmol/L). If this is the case, targets for HDL cholesterol should be substantially higher. In fact, recent evidence from the Honolulu Heart Program indicates that we should be aiming to raise HDL cholesterol levels to at least 60 mg/dL (1.5 mmol/L) to significantly impact on cardiovascular risk in primary and secondary prevention settings.

A note on HDL cholesterol units

HDL cholesterol levels are measured in mg/dL or mmol/L.

To convert from mg/dL to mmol/L multiply by 0.0259
To convert from mmol/L to mg/dL multiply by 38.7

What causes low HDL cholesterol?

A low level of high-density lipoprotein (HDL) cholesterol is generally regarded by current treatment guidelines as <40 mg/dL or <1.0 mmol/L in men (<50 mg/dL or <1.3 mmol/L in women).

Low HDL cholesterol may be caused by various genetic conditions. However, the two main causes of low HDL cholesterol in the 21st century are type 2 diabetes and the metabolic syndrome. The prevalence of both of these conditions is increasing exponentially, both in developed and developing countries.

Causes of low HDL cholesterol in man

Inherited genetic conditions
Familial combined hyperlipidaemia
Elevated plasma triglycerides
Type 2 diabetes mellitus
Metabolic syndrome

Low HDL cholesterol appears to be especially important in older women (50 years or more). The onset of the menopause is associated with potentially adverse metabolic changes, including an increase in low-density lipoprotein (LDL) cholesterol and a decrease in HDL cholesterol in the plasma, which together increase the risk of cardiovascular events.

The metabolic syndrome is a cluster of abnormalities that markedly increase cardiovascular risk. These abnormalities include:

Central obesity
Insulin resistance
Lipid abnormalities, including low HDL cholesterol and elevated triglycerides
Mild hypertension
Pro-inflammatory state

Low levels of HDL cholesterol in people with type 2 diabetes or metabolic syndrome are mainly caused by an increase in the rate of catabolism of HDL, possibly as a result of triglyceride enrichment of the HDL particles.

Although the relation between metabolic syndrome and type 2 diabetes is not known, the co-existence of the two conditions suggests that there is a link.

What lifestyle interventions are effective in raising HDL cholesterol?

Losing weight, increasing physical activity and stopping smoking all have beneficial effects on raising high-density lipoprotein (HDL) cholesterol.

Many (although not all) overweight people have low HDL cholesterol levels (generally regarded as <40 mg/dL or <1.0 mmol/L). Low HDL cholesterol is also a feature of the metabolic syndrome (see What causes low HDL cholesterol?. Meta-analysis of a large number of studies has shown that for every kilogram decrease in body weight, there is up to 1% increase in plasma HDL cholesterol levels (increase in actual values of 0.35 mg/dL or 0.009 mmol/L) in people who maintain a stable, reduced weight. To be properly effective, the weight loss needs to be sustained.

Increasing the level of physical activity can increase HDL cholesterol levels by 3-9% in healthy sedentary people. In overweight or obese people, aerobic exercise has been shown to raise HDL cholesterol by about 3%. It is worth noting that the increase in HDL cholesterol achieved is dependent on the frequency and intensity of exercise, with little evidence that walking has any significant effect on HDL cholesterol levels.

Smoking is known to decrease HDL cholesterol levels. However, this effect is reversible, as stopping smoking can raise HDL cholesterol levels by up to 10%.

Moderate alcohol consumption has also been shown to raise plasma levels of HDL cholesterol. In a recent meta-analysis, drinking 30 g (1 fluid oz) of alcohol per day was associated with an increase in HDL cholesterol of up to 10% (about 4 mg/dL or 0.01 mmol/L). However, it should be borne in mind that alcohol also increases levels of potentially atherogenic lipoproteins and triglycerides, which would counteract any benefit associated with raising HDL cholesterol levels.

In general, the mechanisms underlying these effects have not yet been confirmed.

Dietary fat increases HDL cholesterol levels, although the effects of saturated fat are greater than those of unsaturated fats. Monosaturated fats, found in olive oil or canola (rape seed) oil, nuts, salmon, mackerel and shellfish, do not significantly influence HDL cholesterol. However, as these fats do contribute a lower glycaemic load, which is negatively correlated with HDL cholesterol, they could be recommended. In the case of saturated fat in the diet, the benefits of raising HDL cholesterol, 'good cholesterol', are probably more than outweighed by detrimental effects associated with the accompanying increase in 'bad cholesterol'.

What treatments are available for raising HDL cholesterol?

Currently available treatments for raising levels of high-density lipoprotein (HDL) cholesterol are statins, fibrates and nicotinic acid (niacin). Of these, nicotinic acid is the most potent.

Statins
Statins are well established as the primary lipid-modifying intervention based on their efficacy in reducing plasma levels of low-density lipoprotein (LDL) cholesterol. However, statins also have modest effects on reducing triglycerides (by 15-35%) and raising HDL cholesterol (typically by less than 10%). There are exceptions to this, as in ASTEROID (A study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden), in which treatment with rosuvastatin increased HDL cholesterol by 14%, in addition to lowering LDL cholesterol.

The mechanism by which statins increase HDL cholesterol is uncertain.

However, many patients taking a statin still have a low level of HDL cholesterol. In a recent pan-European survey, more than one third of patients using a statin had low HDL cholesterol (defined in the survey as <40 mg/dL [1.0 mmol/L] in men and <50 mg/dL [1.3 mmol/L] in women).

Fibrates
Fibrates are effective in lowering serum triglycerides (by 20-50%) and to a lesser extent, LDL cholesterol (by 5-20%). Their efficacy in raising HDL cholesterol is more modest (by 5-15%). A recent meta-analysis including data from 53 trials using fibrates reported that treatment raised HDL cholesterol by 10%.

Fibrates increase HDL cholesterol by several mechanisms, all of which involve activation of the PPAR Alpha receptor. The effect of treatment on HDL cholesterol levels depends on the net effect of several factors that contribute to raising HDL cholesterol (such as increased synthesis of apolipoproteins A-I and A-II ), as well as those that tend to reduce plasma levels of HDL cholesterol.

Nicotinic acid
Nicotinic acid (niacin) is the most potent agent currently available for raising HDL cholesterol, by up to 30%. Nicotinic acid also reduces triglycerides by 40-50% and LDL cholesterol by up to 20%.

The action of nicotinic acid in raising HDL cholesterol involves a number of mechanisms. These are discussed in the commentary Functionally defective HDL in diabetic dyslipidaemia: new therapeutic horizons

The profile of activity of nicotinic acid suggests that it would be useful in treating patients with type 2 diabetes and metabolic syndrome, who typically exhibit low levels of HDL cholesterol and elevated triglycerides. Initial reports indicated that nicotinic acid might reduce insulin sensitivity; however, subsequent prospective studies have shown that this is not a problem if a recently developed prolonged-release formulation of nicotinic acid is administered.

Future treatments
A number of potential treatments for raising HDL cholesterol are under development. Of these, the cholesteryl ester transfer protein (CETP) inhibitors are most advanced.

CETP is a key player in cholesterol homeostasis. This protein facilitates transfer of cholesteryl ester from HDL to atherogenic lipoproteins (very low-density lipoproteins and LDL). Blocking CETP increases HDL cholesterol by 50-60% with the doses likely to be used in clinical practice.

However, the potential role of CETP inhibitors has been called into question following termination of the ILLUMINATE trial.

For further information on these and other potential agents, see Why we need new therapeutic strategies for raising HDL-C.

What are high-density lipoproteins?

Further reading

Why is it important to have high levels of HDL cholesterol?

Fig. Relationship between HDL cholesterol and coronary heart disease in the Framingham Study.

Further reading

What are the targets for HDL cholesterol?

A note on HDL cholesterol units

Further reading

What causes low HDL cholesterol?

Causes of low HDL cholesterol in man

Further reading

What lifestyle interventions are effective in raising HDL cholesterol?

Further reading

What treatments are available for raising HDL cholesterol?

Further reading

What are high-density lipoproteins?

Further reading

Why is it important to have high levels of HDL cholesterol?

Fig. Relationship between HDL cholesterol and coronary heart disease in the Framingham Study.

Further reading

What are the targets for HDL cholesterol?

A note on HDL cholesterol units

Further reading

What causes low HDL cholesterol?

Causes of low HDL cholesterol in man

Further reading

What lifestyle interventions are effective in raising HDL cholesterol?

Further reading

What treatments are available for raising HDL cholesterol?

Further reading

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