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Low concentrations of high-density lipoprotein (HDL) cholesterol constitute a risk factor for coronary heart disease (CHD). There is increasing evidence that increasing HDL-cholesterol levels reduces cardiovascular risk. The phenotype of low HDL cholesterol with or without elevated triglycerides is common and it is characteristic of patients with central obesity, insulin resistance, hypertension and type 2 diabetes mellitus; conditions associated with increased cardiovascular risk and are part of the rubric of the metabolic syndrome. Epidemiological, experimental and clinical trial evidence suggests that there is a good rationale for raising HDL-cholesterol in these and other high-risk patients. The protective effect of HDL-cholesterol against atherosclerosis and cardiovascular disease is mediated by both enhanced reverse cholesterol transport (RCT) and by direct anti-atherosclerotic mechanisms. Recent studies have elucidated mechanisms whereby HDL acts to reduce cardiovascular risk, supporting the rationale for targeting of HDL with lipid-modifying therapy. Ongoing investigation of mechanisms by which HDL acts to reduce the risk of atherosclerosis will provide opportunities for the development of new therapeutic strategies to decrease the risk of atherosclerosis.
There has been renewed interest in the protective role of HDL against atherosclerosis and CHD. This is chiefly a result of new experimental and clinical trial evidence, which shows that raising HDL may diminish the risk of clinical cardiovascular events.1,2 The burgeoning body of work on HDL is rapidly generating a new clinical paradigm and fresh opportunities for the management of lipid disorders.3 This article reviews HDL metabolism, measurement, and the new evidence for its protective function in atherogenesis, as well as conditions that lower HDL and therapeutic strategies for elevating HDL.
The HDL class of lipoproteins comprises a heterogeneous and polydisperse population of particles that are the most dense and smallest of size.4 HDL is a macromolecular complex of lipids (cholesterol, triglycerides and phospholipids) and proteins [apolipoproteins (apo) and enzymes]. The inside contains a core rich in hydrophobic lipids (cholesterol esters and triglycerides), surrounded by an outer shell in which free cholesterol is interspersed with phospholipids, and the surface contains chiefly the apoproteins A (apoA-I and apoA-II), C (apoC-I, apoC-II and apoC-III) and E. ApoA-IV and apoD are also present in extremely small amounts. The function of some of these apoproteins is to direct HDL from the peripheral tissues to the liver (RCT). By weight, HDL comprises ~50% protein, 15% cholesteryl esters, 5% free cholesterol, 25% phospholipid, and 5% triglyceride. The principal apoproteins are apoA-I and apoA-II, both of which are involved in determining the metabolic fate of HDL. In general, HDL is divided into large lipid-rich HDL2 and smaller more-dense HDL3, with as many as 14 sub-fractions depending on the separation technique. HDL may also be subclassified as LpA-I (contains apoA-I alone) and LpA-I:A-II (contains both apoA-I and apoA-II) particles.
A variety of methods are available for measuring HDL-cholesterol.5 Lipoprotein classes can be readily separated on the basis of their hydrated density by preparative ultracentrifugation. HDL, by definition, includes particles with density 1.063 to 1.210 g/mL. However, ultracentrifugation is tedious, time-consuming, technically demanding and is not practical for routine analysis. Lipoproteins can be separated by electrophoresis and the resulting bands visualised by lipophilic stains (e.g. Oil Red O or Sudan Black). The band corresponding to HDL, as separated by electrophoresis (e.g. agarose, cellulose acetate, or polyacrylamide), is designated α-lipoprotein. Recent modifications of this qualitative technique using enzymatic reagents allow accurate quantitation of HDL-cholesterol content. Other methods include, high-performance liquid chromatography with HDL separated based on size and enzymatic quantitation of cholesterol content, and more recently, nuclear magnetic resonance. However, chemical-precipitation, and more recently homogeneous methods, remain the routine analytical methods of choice. Thus, HDL is defined in terms of the method of isolation and includes a family of similar particles that vary in both size and composition.
The plasma concentration of HDL-cholesterol is determined mainly by the production and catabolism of apoA-I by the liver and intestine.6 In addition, the concentration of cholesterol in HDL is dependent on an exchange process between HDL and the triglyceride-rich lipoproteins [i.e. chylomicrons, chylomicron remnants, and very-low density lipoproteins (VLDL)].1,6 Therefore, when plasma triglyceride concentrations are elevated (e.g. hypertriglyceridaemia of obesity and type 2 diabetes) there is an increased exchange of cholesterol for triglycerides and thus a low plasma HDL-cholesterol concentration.
RCT is a process that shuttles cholesterol from peripheral tissues back to the liver directly via HDL and via other endogenously derived lipoproteins [i.e. VLDL and low-density lipoprotein (LDL)] (Figure 1).1 RCT is a physiological process for maintaining body cholesterol homeostasis in the face of the ~9 mg of cholesterol/kg body weight/day generated by peripheral tissues in humans; the excretion of the excess cholesterol delivered to the liver into bile completes the process required for negative corporeal cholesterol balance. As can be seen in Figure 1, HDL occupies centre-stage in RCT. New evidence has highlighted a series of receptors, transporters and enzymes that are important in the metabolism of HDL and hence in RCT.1,7 In peripheral tissues, the ATP-binding cassette transporter (ABCA1) moves cholesterol out of the cells to lipid-poor apoA-I, or pre-β HDL particles.8 When this protein is deficient or inactive, as in patients with the genetic disorder Tangier Disease or familial high-density lipoprotein deficiency, there is an accumulation of cholesterol in peripheral tissues.9 Other proteins involved in RCT are enzymes (lecithin cholesterol acyl transferase, LCAT, EC 126.96.36.199; lipoprotein lipase, LPL, EC 188.8.131.52; hepatic lipase, HL, EC 184.108.40.206) and transfer proteins (cholesteryl ester transfer protein, CETP; and phospholipid transfer protein, PLTP). LCAT esterifies free cholesterol taken from tissues onto the HDL particle to form mature cholesterol rich HDL, or α-HDL particles. LPL hydrolyses triglyceride-rich lipoproteins, promoting transfer of cholesterol and apoC to HDL. HL hydrolyses HDL-triglyceride and phospholipids to form HDL3 from HDL2 and thereby contributes to the re-generation of the process of RCT. CETP shuttles cholesterol ester from HDL to VLDL, intermediate-density lipoprotein (IDL) and LDL in exchange for triglycerides.10 PLTP transfers phospholipids from other lipoproteins to HDL and potentially contributes to the functionality of HDLs. The precise roles of PLTP and endothelial lipase (EL), another enzyme of the LPL and HL gene family, in RCT in man remains unclear.4
In the liver, receptors such as a scavenger receptor (SRB1) and a HDL receptor facilitate the hepatocellular uptake of the HDL particle and/or its cholesteryl-ester content. Hepatic cholesterol so derived may then be removed from the body in bile as cholesterol per se, or as bile acids; it may also be recycled back into plasma HDL-cholesterol via the hepatic ABCA1 transporter, in a process recently termed ‘RCT’.7
The key proteins involved in HDL metabolism and RCT are summarised in Table 1. The expression and activity of these proteins are partly regulated by several nuclear receptors, including the liver X receptor (LXR), retinoid X receptor (RXR) and peroxisome proliferator-activated receptor-α. (PPAR-α)
The idea that elevated HDL protects against CHD comes chiefly from epidemiological studies.11 Collectively, these have suggested that a 0.026 mmol/L increase in plasma HDL-cholesterol decreases the CHD risk by 2% in men and by 3% in women. These effects of HDL-cholesterol are independent of triglyceride and LDL-cholesterol concentrations. Recent clinical trial evidence from statin and fibrate intervention trials suggests a similar benefit from raising plasma concentrations of HDL-cholesterol. The statin trials, particularly the Scandinavian Simvastatin Survival Study, demonstrate that a 1% increase in HDL translates into a 1% decrease in CHD risk, but the benefits in those trials from lowering LDL-cholesterol are expectedly greater.12 Significantly, although these trials have shown that statins decrease coronary risk in patients with low HDL-cholesterol, risk in those treated patients remains higher than placebo-treated patients with high baseline HDL-cholesterol concentrations.13,14 In the fibrate trials [e.g. Veteran Affairs –HDL Intervention Trial (VA-HIT) and Helsinki Heart Study], where the changes in LDL-cholesterol were minimal, the effects attributable to changes in HDL-cholesterol are more impressive than in statin trials with a 1% increase in HDL translating into a 3% reduction in CHD risk.15,16 The patients who derived most benefit in the fibrate trials were those with obesity, insulin resistance and dyslipidaemia (triglyceride >2.3 mmol/L, HDL-cholesterol <1.08 mmol/L).
Specifically, three clinical trials have recently reported on the benefits of lipid regulating therapy in subjects with normocholesterolaemia and low HDL-cholesterol.16–18 These trials are summarised in Table 2. The VA-HIT results suggest that when LDL-cholesterol concentrations are optimal, increasing HDL-cholesterol with reduction in triglyceride-rich lipoproteins may be a cost-effective approach for decreasing the incidence of coronary events in secondary prevention. This applies especially to patients with the metabolic syndrome,19 as supported by sub-group analyses from the Helsinki Heart Study.20,21 In VA-HIT, a 0.15 mmol/L increase in plasma HDL-cholesterol was associated with an 11% decrease in CHD (Figure 2), which is approximately equivalent to that predicted from epidemiological data. In VA-HIT, it was also the increase in the HDL3–cholesterol subfraction (i.e. smaller particles containing apoA-II) that was specifically associated with fewer coronary events.22 These observations may also apply to cerebrovascular disease, for in VA-HIT gemfibrozil also significantly decrease the incidence of stroke.23 Sub-group analysis from the Bezafibrate Infarction Prevention (BIP) trial shows that in hypertriglyceridaemic individuals with CHD, bezafibrate is a cost-effective treatment for dyslipidaemia when triglyceride concentrations are >2.2 mmol/L.17 The Air Force/Texas Coronary Atherosclerosis Prevention Study(AFCAPS/TexCAPS) results have implications for primary prevention in the general population for individuals with low HDL-cholesterol in whom increased risk of CHD appears to be diminished with statin therapy;18 the cost-effectiveness of this approach, however, remains a significant issue. In these three trials the safety of fibrate and statins therapies in treating patients with low HDL-cholesterol was reaffirmed. The efficacy of fibrates in coronary prevention in patients with low HDL-cholesterol is also well supported by angiographic trials.24,25
The epidemiology and clinical trials of HDL and CHD are complemented well by experimental evidence which corroborates a reciprocal ‘cause and effect’ relationship between this lipoprotein and atherosclerosis.26,27 Thus, intravenous infusion of HDL apoA-I into rabbits inhibits experimental atherosclerosis,28,29 and over-expression of the human apoA-I gene in mice increases the plasma concentration of HDL-cholesterol and results in pronounced regression of established atherosclerosis.30 Local over-expression of apoA-I in the artery wall is also athero-protective, independent of changes in circulating concentrations of HDL apoA-I.31 Over-expression studies of apoA-II have not, however, consistently reported favourable effects on atherosclerosis in various experimental models.32 An exciting report showed recently that the infusion of recombinant HDL apoA-I into human subjects could stimulate the in vivo process of RCT,33 as reflected by an increase in the faecal excretion of sterols. This may potentially be a major mechanism for the protective effect on CHD from therapeutic elevation of plasma HDL concentrations, as suggested recently in a clinical trial of the effect of recombinant apoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes.34Compelling data also indicate that HDL has intrinsic anti-atherosclerotic properties (i.e. anti-inflammatory, anti-oxidant, anti-mitotic, anti-coagulant, anti-aggregatory and pro-fibrinolytic).2 These anti-atherogenic properties are determined by the apoA and enzyme (e.g. paraoxonase) contents, as well as the phospholipid composition, of the HDL particle. Infusion of HDL apoA-I into the brachial artery in human subjects with either hypercholesterolaemia,35 or with low plasma HDL-cholesterol due to heterozygosity for a mutation in the ABCA1 transporter,36 can also improve endothelial dysfunction, an early phase of arterial damage recently shown to predict coronary events. The improvement in endothelial function with HDL partly involves increased release of both nitric oxide and prostacyclin and inhibition of the secretion of endothelin-I from endothelial cells.37 Thus, HDL elevation protects against atherosclerosis, or reverses atherosclerosis, by two basic pathways, RCT and non-lipid pathways (Figure 3). However, the relative contributions of these mechanisms to the athero-protective effect of HDL remains unknown.
Clinicians should always consider that a low plasma HDL-cholesterol concentration may be due to a primary (genetic) or to a secondary disorder of lipid metabolism.3 A genetic cause for low HDL (e.g. familial hypoalphalipoproteinaemia) may be present in 20% of patients with premature coronary artery disease (CAD) and normal or slightly elevated concentrations of LDL-cholesterol.38 A low plasma HDL-cholesterol may also be seen in association with other genetic disorders of lipid metabolism, such as primary chylomicronaemia, familial hypertriglyceridaemia, familial dysbetalipoproteinaemia (type III hyperlipidaemia), and familial combined hyperlipidaemia. In these situations, as explained earlier, it is most certainly a consequence of the co-elevation in plasma triglyceride and the increased exchange of neutral lipids between HDL and triglyceride-rich lipoproteins. Very rare genetic disorders that specifically lower HDL-cholesterol include Tangier disease39–41 and LCAT deficiency.42
In clinical practice, a low plasma HDL-cholesterol is more commonly associated with other disorders that increase plasma triglycerides, for example central obesity, insulin resistance, type 2 diabetes mellitus and renal disease (chronic renal failure or nephrotic proteinuria).43 Unfavourable lifestyle circumstances, such as physical inactivity and cigarette smoking, can also contribute to a low plasma HDL-cholesterol.44 A drug history is important, since β-blockers, thiazide diuretics and androgens and progestins may also depress plasma HDL concentrations. Insulin resistance and hypertriglyceridaemia frequently explains low HDL-cholesterol within populations. Low HDL-cholesterol is, hence, one of the cardinal features of metabolic syndrome.45,46
In routine practice, an accredited clinical laboratory should measure HDL-cholesterol as part of a fasting lipoprotein profile. Requesting a ‘lipid profile’ in Australia does not elicit routine testing of HDL-cholesterol, which needs to be specified on the request form. The new third-generation homogeneous HDL-cholesterol assays are inexpensive, do require pre-treatment and separation, and are readily automated. However, limitations of the technique are apparent in patient groups in whom gross alterations in lipoproteins are found. Interference with HDL-cholesterol measurement may occur with hypertriglyceridaemia (>12 mmol/L),47 as well as in patients with increased lipoprotein remnant concentrations (e.g.familial dysbetalipoproteinaemia and type 2 diabetes),48,49 and liver disease.50 For research purposes, the HDL may be subfractionated into HDL2 and HDL3 and depressed concentrations of both of these subfractions of HDL have been linked to CAD. ApoA-I measurements by immunochemical techniques are of most use in characterising patients with genetic disorders that lead to low HDL-cholesterol concentrations. Any benefit of apoA-I over HDL-cholesterol in determining CHD risk remains unclear.51 In our view, there is no justification at present for measuring apoA-II concentration or HDL size in clinical practice. The value of measuring HDL-cholesterol concentration is underscored by its requirement for calculating the LDL-cholesterol using the Friedewald equation [LDL-cholesterol = total cholesterol - HDL-cholesterol - (triglyceride/2.2), in mmol/L],52 and to estimate the concentration of non-HDL-cholesterol (total cholesterol – HDL-cholesterol), which reflects the apoB-containing atherogenic remnant particles. It should be noted that the Friedewald formula does not apply if the triglyceride concentration exceeds 4.5 mmol/L or if familial dysbetalipoproteinaemia is present. Some diagnostic laboratories report total cholesterol: HDL-cholesterol or LDL-cholesterol:HDL-cholesterol ratios along with an assessment of CAD risk based on the results of the Framingham Heart Study. The validity of HDL-cholesterol ratios can be misleading, especially at extreme ends of total or LDL-cholesterol values. Measuring plasma HDL-cholesterol therefore fulfills important uses beyond its intrinsic merit in assessing and guiding cardiovascular risk management.
Invariably, every national and international set of guidelines for the management of lipid disorders includes low HDL-cholesterol as an important factor for assessing cardiovascular risk and guiding the type and intensity of lipid-regulating therapy.46,53–55 Guidelines agree that a plasma level of HDL-cholesterol <1.05 mmol/L is undesirable and increases the individuals’ 10-year risk of a cardiovascular event, especially in the presence of other risk factors. Clearly, appropriate risk classification mandates the use of accurate methods for HDL-cholesterol measurement. The Australian guidelines propose as a therapeutic target a plasma level of HDL-cholesterol >1.0 mmol/L,55 but any degree of elevation of HDL-cholesterol is likely to be beneficial even if the recommended target is not achieved. Surprisingly, neither the American NCEP III nor European guidelines give an HDL-cholesterol goal for therapy.46,53 A low HDL-cholesterol is, in our view, a critical risk factor for CHD among patients with insulin resistance and type 2 diabetes,56 and by extension all high-risk individuals, that merit use of appropriate therapeutic goals. Accordingly, the American Diabetes Association has recommended that HDL-cholesterol should be raised above 1.2 mmol/L in patients with type 2 diabetes, this may also be appropriate for patients with the metabolic syndrome. In our view, now that LDL-cholesterol treatment targets have been well defined, guidelines should be revised to set a HDL-cholesterol above the 1.2 mmol/L level in all high-risk individuals. Treatment targets for HDL-cholesterol have to be set, however, against the background of the presence and degree of other cardiovascular risk factors.
In general, the approach to the management of low HDL-cholesterol has to be seen in context of other risk factors and in particular to the co-existent level of LDL-cholesterol.57 A preferred recommendation is that in high-risk patients, such as those with diabetes and/or the metabolic syndrome, LDL-cholesterol should be lowered to <2.6 mmol/L with a statin and appropriate lifestyle modification.56 After this has been achieved, then attention should be given to increasing HDL-cholesterol >1.0 mmol/L, with a target of >1.2 mmol/L in type 2 diabetic and metabolic syndrome patients.56
Lifestyle measures are the first therapeutic step and this involves weight reduction, smoking cessation and regular (aerobic) physical exercise (Table 3).3,44Lifestyle modification may benefit other cardiovascular risk factors apart from low HDL-cholesterol, such as hypertension, endothelial dysfunction, hyperglycaemia and coagulopathy. Smoking cessation may increase HDL by up to 10%, and a similar benefit may accrue from a 4 to 5 kg weight loss in obese patients, although the degree of weight loss required in some individuals to significantly elevate their HDL-cholesterol may be quite substantial. A fat-modified diet, high in monounsaturates, may have a more favourable effect on HDL metabolism, compared with a low saturated fat/high carbohydrate diet, because of the decreased tendency of the former to induce hypertriglyceridaemia, which as explained earlier can lower plasma HDL-cholesterol concentrations. All fats, including dietary cholesterol, increase plasma HDL-cholesterol. Total fat intake may be increased up to 35% of energy intake provided saturated fats and trans-unsaturated fatty acids are kept low (<10%). Aerobic physical exercise is the exercise of choice to increase HDL, and this is more effective in those who are initially hypertriglyceridaemic. Regulation of alcohol intake is important, and a modest intake (e.g. maximum of two standard drinks a day for women and four for men; one standard drink = 120 to 150 mL of wine or 8 to 10 g of alcohol) may increase HDL-cholesterol by as much as 10%. This is particularly the case in individuals who metabolise alcohol slowly via the enzyme alcohol dehydrogenase. The synergistic and independent effects of these lifestyle changes remain to be fully established.
As well as adverse lifestyle factors, medications can decrease plasma HDL-cholesterol (e.g. β-blockers, thiazide diuretics, androgens and progestins, anti-retroviral therapy, retinoic acid preparations) (Table 4).3,43These should be identified and where appropriate, replaced with more favourable agents.
Despite appropriate lifestyle modifications, many patients, particularly those with insulin resistance, type 2 diabetes and obesity will require pharmacotherapy. Drugs that increase HDL-cholesterol include statins, fibrates and nicotinic acid (Table 5).3 The efficacy of these agents in increasing HDL-cholesterol is in part related to their triglyceride-lowering effect and is summarised in Table 5.
The mechanisms whereby these drugs increase HDL-cholesterol are complex. In brief, fibrates increase the production and niacin decreases the catabolism of HDL-apoA-I. However, the mechanism for the small effect of statins remains unclear.43,57 Fibrates increase HDL-apoA-I by activating the nuclear hepatic receptors, namely the LXR and PPAR-α.58 Because fibrates do not delay uptake of HDL by the liver, they are probably the most effective drugs for stimulating RCT. The effectiveness of increasing the production of apoA-I in regressing coronary atherosclerosis in humans has recently been well demonstrated in a controlled clinical trial of the intravenous administration of recombinant apoA-I Milano phospholipid complexes.34 Fibrates may also in fact stimulate both the production and catabolism of HDL particles,59 so that an increase in HDL-cholesterol concentration may only partially reflect their ‘real benefit’ on RCT. Although statins may not appreciably raise HDL-cholesterol, they could increase the catabolism of HDL-apoA-I.60 Increase in plasma HDL-cholesterol with statins is more likely with potent agents like rosuvastatin, and in patients with the ‘atherogenic profile’ of the metabolic syndrome;61 the therapeutic mechanism could relate to inhibition of CETP. Although cholestyramine can lead to a slight increase in HDL-cholesterol via stimulation of the hepatic farnesoid X receptor (FXR), its potential triglyceride-elevating effect does not permit its use in treating dyslipidaemia in diabetes or metabolic syndrome.
Because the currently available statins are not generally very effective in elevating plasma HDL-cholesterol, addition of a fibrate or fish oils should always be considered to optimise the overall lipoprotein profile.3 In clinical trials, statin-fibrate combinations have been reported to increase HDL-cholesterol by as much as 30%.62 The use of a statin with gemfibrozil is associated with a small, but significant risk of myositis and rhabdomyolysis and certain precautions should be followed if using this combination (e.g. measure creatine kinase prior to treatment and regularly thereafter; do not use in combination with a macrolide antibiotic).63,64 Some more details of caveats and guidelines for the potential use of statins and fibrates are given in Table 6. In Australia, fenofibrate has recently been registered: this agent is a more specific and potent fibrate than gemfibrozil, has been shown to improve both endothelial dysfunction65 and coronary atherosclerosis25 in diabetes, and has an excellent long-term safety record. Fenofibrate is also currently being studied in a clinical endpoint trial, the Fenofibrate in Event Lowering in Diabetes (FIELD) study.
Newer statins on the horizon, such as rosuvastatin, show promise from preliminary clinical trials in correcting the dyslipoproteinaemia in the metabolic syndrome and type 2 diabetes, including the low concentrations of HDL-cholesterol.61 The drug interaction profile of rosuvastatin compares favourably with other statins, but above a dose of 40 mg/day may cause transient proteinuria. Pitavastatin is another potent statin that may stimulate HDL-apoA-I production, via a PPAR-α mechanism66 but has not yet been trialled in Australia. A statin plus fish oil combination is safer and can effectively correct the dyslipidaemia of insulin resistance, as well as increasing HDL-cholesterol, specifically the HDL2 subfraction. In a recent clinical trial, we reported that atorvastatin (40 mg/d) and fish oils (3 to 4 g/d) have independent and additive mechanisms of action that correct dyslipidaemia in the metabolic syndrome,67,68 the combination increasing HDL-cholesterol concentrations by 13%. Ezetimibe, a specific inhibitor of cholesterol absorption in the brush border of the gut, has recently been registered in Australia, and could potentially be employed in combination therapy with fenofibrate and fish oils to manage the dyslipidaemia of the metabolic syndrome and diabetes.69
Nicotinic acid (niacin) is popular in North America for dyslipidaemia and raising HDL-cholesterol, but the preparations available in Australia are generally unsuitable as a result of side effects (e.g. palpitations and flushing).70 An extended release preparation has recently been approved in North America and may become available in this country. Clinical end-point trials with niacin are lacking, but the recent HDL Atherosclerosis Treatment Study (HATS) reported significant reduction in progression of CAD with the combination of simvastatin and niacin.71 Niacin preparations are subject to drug interactions (e.g. alcohol) and may impair glycaemic control in diabetes.
Oestrogens are effective in increasing HDL-cholesterol, but the use of hormone replacement therapy is not recommended in post-menopausal women owing to the adverse results of recent clinical trials and population studies. Improvement in glycaemic control in diabetic patients with lifestyle changes, oral anti-diabetic agents and possibly insulin will lower hypertriglyceridaemia and reciprocally increase HDL-cholesterol concentrations.56 The weight reducing drug, sibutramine, has been reported to have a specific HDL-cholesterol elevating effect independent of the degree of weight loss,72 but the mechanism for this effect is unknown. Novel agents being developed for regulating HDL metabolism include inhibitors of CETP6 and stimulators of the ABCA1 transporter.3 CETP inhibitors can increase plasma HDL-cholesterol by 60% and lower LDL-cholesterol by 30%.73
In clinical practice, a low plasma HDL-cholesterol is frequently encountered in patients with central obesity, metabolic syndrome and type 2 diabetes mellitus. The epidemiological, experimental and clinical trial evidence suggests that there is a good rationale for raising HDL-cholesterol in these and other high-risk patients. The protective effect of HDL-cholesterol against atherosclerosis and cardiovascular disease is mediated by both enhanced RCT and by direct anti-atherosclerotic mechanisms. The first approach to raising HDL-cholesterol in at risk patients is lifestyle modification aimed at improving body weight and insulin resistance. Smoking cessation can elevate HDL-cholesterol concentrations. Pharmacotherapy is often required to optimise the lipid profile and elevate HDL-cholesterol. Correcting hypertriglyceridaemia usually increases low HDL-cholesterol, but specific elevation in HDL-cholesterol may be required in some patients, particularly those with premature CAD. The currently available statins will often require adjunctive therapy, such as gemfibrozil or fish oil, to raise HDL-cholesterol. Statin-fibrate combinations need to be monitored closely for risk of myositis. Nicotinic acid and its derivatives are not practicable options at present. In insulin resistance associated with type 2 diabetes or the metabolic syndrome plasma HDL-cholesterol should be raised above 1.2 mmol/L. Elevating low plasma HDL-cholesterol concentrations affords a new and exciting paradigm for managing lipid disorders. However, there is still more research to be done, including, for example, elucidating the precise molecular mechanism of the athero-protective effect of HDL and the developing and testing of new clinical therapies for improving HDL metabolism.1 The incremental benefit of adding a fibrate, fish oils or ‘pipeline agents’, such as CETP inhibitors, to a statin in low HDL patients with the metabolic syndrome are clearly burning questions for future clinical endpoint trials.