| From Center For Clinical Age Management, Inc. Cardiac Risk Factor Summary Epidemiological studies have established that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk of coronary heart disease (CHD). Recent studies have demonstrated that low HDL-C levels, and high triglycerides and total cholesterol levels are independent predictors of CHD, and that the combination of these lipid abnormalities increases the risk of coronary events. In lipid-modifying intervention studies, agents that raise HDL-C levels have been shown to reduce the incidence of major coronary events. The VA-HIT study consisted of patients with low-density lipoprotein cholesterol (LDL-C) levels similar to those recommended by several guidelines but with low levels of HDL-C. This trial demonstrated that raising HDL-C levels with gemfibrozil reduced the risk of CHD-related events. While the mechanisms by which HDL-C exerts its anti-atherogenic effects have yet to be fully elucidated, its role in the reverse transport of cholesterol and the beneficial effects on endothelial function are plausible explanations for these actions. Although LDL-C reduction is the primary goal in the treatment of dyslipidaemia, current guidelines recognise low HDL-C levels as a major risk factor for CHD. Indeed, the NCEP ATP III guidelines suggest that the treatment of isolated low HDL-C levels in CHD patients or individuals with CHD risk equivalents should be considered. The differing abilities of statins to raise HDL-C levels may be an important factor when making treatment decisions. New lipid-modifying drugs with beneficial effects on both HDL-C and LDL-C levels would be desirable additions to the currently available therapeutic options. Introduction The importance of reducing low-density lipoprotein cholesterol (LDL-C) levels for the prevention of coronary heart disease (CHD) has been well established in clinical trials; the risk of nonfatal myocardial infarction (MI) and coronary death was reduced by 20%-40% following treatment with LDL-C-lowering drugs[1-5]. Indeed, current guidelines for the treatment of dyslipidaemia identify the reduction of LDL-C levels as the primary target of therapy[6-8]. However, it is recognised that modifying other components of the lipid profile may result in additional clinical benefits[9]. The level of high-density lipoprotein cholesterol (HDL-C) is being suggested increasingly as a key variable involved in vascular risk assessment, and raising HDL-C is a concomitant goal of therapy[4,6-8,10]. The importance of low levels (< 1.0 mmol/l [40 mg/dl]) of HDL-C as a risk factor for the development of CHD is recognised by current British, European and US guidelines[6-8], although a target for raising HDL-C is not specified. Indeed, the recently published NCEP ATP III guidelines[8] place greater emphasis on low HDL-C levels than the previous version[11] and have revised the level below which HDL-C is considered to be a CHD risk factor from 0.9 mmol/l (35 mg/dl) to 1.0 mmol/l (40 mg/dl). Furthermore, the guidelines recommend the use of drugs for raising HDL-C levels in individuals with isolated low HDL-C levels and CHD or CHD risk equivalents[8]. A low level of HDL-C is a common dyslipidaemia and often occurs in the absence of raised LDL-C levels; 40% of patients with CHD without a definite indication for lipid-lowering therapy have low levels of HDL-C[12], and up to 29% of patients with CHD are reported to have low levels of HDL-C but LDL-C levels below that recommended for the initiation of treatment (within the Lipid Research Clinic 10th and 90th percentile values for HDL-C and LDL-C, respectively)[13]. Although low HDL-C levels may occur as an isolated abnormality, they are frequently associated with raised levels of plasma triglycerides (TG)[13-15]. This combination is a common finding in familial combined hyperlipidaemia[16] and is the predominant lipid abnormality in type 2 diabetes[17,18]. Indeed, low HDL-C levels are often accompanied by a cluster of other abnormalities referred to as the metabolic syndrome, or syndrome X, and include features such as insulin resistance, obesity and hypertension that predispose the patient to the development of atherosclerotic disease[18,19]. The association between low levels of HDL-C and an increased risk of cardiovascular disease is supported by epidemiological studies[20,21]. However, only a few primary and secondary prevention trials have been conducted in patients with low HDL-C levels. We will review the evidence supporting the benefits of increasing HDL-C levels and examine the efficacy and safety of existing dyslipidaemia treatments used to achieve this aim. In addition, the improvements in raising HDL-C offered by new therapies for dyslipidaemia are discussed. The Relationship Between HDL-C, Atherosclerosis and Coronary Heart Disease Cholesterol uptake from the blood by the peripheral tissues is via a process of LDL receptor-mediated endocytosis[22]. LDL-C can also pass from the blood into the arterial wall where it may be oxidised and engulfed by macrophages producing foam cells, which accumulate to form fatty streaks[23]. A complex interplay of cell necrosis, smooth muscle recruitment and collagen deposition leads to the development of atherosclerotic plaques. Mature plaques may protrude into the lumen of arteries and restrict blood flow, resulting in symptoms such as angina. Other plaques can remain 'silent'; however, unstable plaques are prone to rupture, potentially leading to major clinical events such as MI as a result of arterial thrombosis[24]. HDL is involved in the reverse transport of cholesterol from the peripheral tissues to the liver, thereby reducing the uptake of cholesterol by macrophages and providing a protective effect against atherosclerosis. It also has beneficial effects upon endothelial function[25,26] either by inhibiting LDL-C oxidation or by directly protecting the arterial wall from oxidative stress[27,28]. The relationship between low levels of HDL-C and the development of CHD can be inferred from epidemiological studies, where even small differences in the level of HDL-C are associated with substantial variations in the risk of major coronary events. Data from the Framingham population indicated that, at any given level of total cholesterol, the relative risk of CHD increases with decreasing levels of HDL-C[20]. The incidence of MI was increased almost twofold in men with HDL-C levels £ 1.3 mmol/l (52 mg/dl) compared with men who had higher HDL-C levels (p < 0.05)[21]. This relationship was even more apparent in women, in whom HDL-C levels £ 1.3 mmol/l (52 mg/dl) were associated with a fourfold to sixfold increased risk of MI (p < 0.01). In addition, prospective clinical studies have demonstrated a link between low HDL-C and an increased risk of atherosclerosis. For example, the Prospective Cardiovascular Münster (PROCAM) study assessed the incidence of death owing to atherosclerotic CHD and nonfatal MI in asymptomatic men[29]. Low levels of HDL-C and elevated TG levels were associated with a high incidence of atherosclerotic CHD. The relationship between HDL-C and CHD remained after adjustment for age and TG levels; the incidence of events was four times greater among men whose HDL-C levels were < 0.9 mmol/l (< 35 mg/dl). In contrast, the association between TG levels and CHD disappeared after adjusting for other risk factors. Similarly, in a 21-year follow-up study of asymptomatic men assessed for vascular risk factors, low HDL-C levels were reported to be associated with an increased risk of CHD at all levels of total cholesterol and were particularly apparent in subjects with diabetes[30]. The relationship between HDL-C and the incidence of CHD in the Framingham Study, Lipid Research Clinics Prevalence Mortality Follow-up Study, Coronary Primary Prevention Trial control group and the Multiple Risk Factor Intervention Trial control group was examined by Gordon et al.[31]. Analysis of these studies demonstrated that for every 0.025 mmol/l (1 mg/dl) rise in HDL-C, the risk of CHD decreased by 2% in men and 3% in women, and this effect was independent of LDL-C levels. Collectively, these studies demonstrate that the risk of CHD is higher in individuals with low levels of HDL-C and that this relationship is independent of the total cholesterol level. These data support the inclusion of HDL-C within the current treatment guidelines as a risk factor for the development of CHD[6-8]. The LDL-C/HDL-C and total cholesterol/HDL-C ratio has also been used to estimate cardiovascular risk[6-8,20]. However, these ratios do not focus on individual LDL-C and HDL-C values and therefore are not part of the core statements for target values set in several guidelines[6-8]. This is especially true for the most recently published guidelines (NCEP ATP III), where treating an isolated low HDL-C level is considered[8]. However, these guidelines[8] do consider another manner of estimating risk-the non-HDL cholesterol. This latter index may eventually gain wide acceptance. Clinical Evidence for the Benefits of Raising HDL-C Levels Although the association between low HDL-C levels and risk of CHD is well established, studies conducted to date have been unable to demonstrate clearly a causal link between low levels of HDL-C and atherosclerosis. While evidence from animal studies suggests that HDL-C is directly anti-atherogenic[32-35], the mechanism by which it exerts its protective effect is not fully understood[36]. The benefits of raising HDL-C remain controversial owing to the lack of evidence for the role of low HDL-C levels in promoting atherogenesis, and further clinical studies are required to confirm whether increasing HDL-C levels reduces CHD risk[36]. Landmark statin trials have mainly focused on lowering LDL-C levels as the primary target of therapy and none has specifically examined the effects of raising HDL-C alone on the incidence of CHD[1-5]. Only the Veterans Affairs cooperative studies program High-density Intervention Trial (VA-HIT) assessed the effect of raising HDL-C levels on CHD risk in patients with 'low' levels of both LDL-C and HDL-C[37]. However, TG levels were reduced by gemfibrozil therapy in this study, and this may have contributed to the clinical benefits observed. Indeed, owing to the complexity of lipid metabolism, it is difficult to isolate the effect of HDL-C on CHD in trials of lipid-modifying therapies. Lipid-modifying therapies that raise HDL-C levels include bile acid binding resins, fibrates, nicotinic acid (niacin) and statins (Table 1; for a full review see Chong and Bachenheimer[39]). Niacin and fibrates are the most potent HDL-C raising agents. Niacin raises HDL-C levels by up to 30%, and increases of 10%-15% have been reported with fibrates (Table 1). In addition to raising HDL-C levels, niacin produces modest reductions in levels of total cholesterol (around-9%) and has been demonstrated to reduce the incidence of coronary events in secondary prevention studies[38]. Immediate-release niacin is often poorly tolerated and is associated with cutaneous flushing in the majority of patients; a newer extended-release formulation has been demonstrated to be as effective in raising HDL-C but is better tolerated[40-43]. Several clinical studies demonstrated that lipid-modifying therapy with fibrates is associated with a decreased risk of CHD (Table 2). In the Helsinki Heart Study (HHS) of asymptomatic middle-aged men with primary dyslipidaemia, gemfibrozil therapy was associated with an 11% increase in HDL-C levels and the incidence of CHD was reduced[44] (Table 2). However, LDL-C levels were also reduced from high baseline values and this is likely to have contributed to the decreased risk of CHD observed with gemfibrozil treatment. VA-HIT conducted in men with CHD and low levels of HDL-C, but with mean LDL-C and TG levels below those recommended for the initiation of lipid-modifying therapy, showed that raising HDL-C levels significantly reduced the rate of coronary events[37] (Table 2). After one year, gemfibrozil treatment in comparison with placebo had significant beneficial effects upon the levels of HDL-C and total cholesterol (p < 0.001) but not LDL-C, and was associated with a reduction of 22% (p = 0.006) in nonfatal MI or death due to CHD. For every 0.13 mmol/l (5 mg/dl) increase in HDL-C, CHD death or MI decreased by 11% (p = 0.02)[46]. Although baseline mean TG levels were within the reference range (1.82 mmol/l [161 mg/dl]), the observed decrease of 31% in TG may have contributed to the reduction in CHD events by improving the distribution of LDL-C subfractions[37]. The Bezafibrate Infarction Prevention (BIP) study in CHD patients with low HDL-C and moderately elevated LDL-C and TG levels, failed to demonstrate a significant reduction in coronary death or nonfatal MI with bezafibrate treatment[45] (Table 2). The risk of CHD was lower for patients in the BIP study compared with VA-HIT (15% vs. 22% events in the placebo groups). This may have contributed to the difference in effects of fibrate therapy in these two trials[37,45]. In addition, mean baseline LDL-C level was higher in the BIP study compared with VA-HIT (Table 2), suggesting that statin therapy was indicated in the BIP patients and treatment with a fibrate was less appropriate[47]. A detailed comparison of BIP and VA-HIT has been published elsewhere[48]. Statins (hydroxy-methylglutaryl coenzyme A reductase inhibitors) are well tolerated, effective LDL-C-lowering drugs with beneficial effects upon HDL-C[49]. In the Scandinavian Simvastatin Survival Study (4S), simvastatin treatment was associated with a 22% reduction in CHD risk[1] (Table 2). A subgroup analysis of 4S examined the combined influence of HDL-C and TG levels on CHD events[50]. In the placebo group, patients with high levels of LDL-C and TG, and low HDL-C had a significantly greater risk of major coronary events compared with patients with high LDL-C levels alone (p = 0.03). Furthermore, despite similar reductions in LDL-C in both groups, patients with high TG and low HDL-C levels derived greater benefit from treatment than patients with high LDL-C levels as an isolated abnormality. These results suggest that raising HDL-C levels may have contributed to the reduction in CHD risk. Further support for the increased risk of events in patients with a combination of lipid abnormalities is provided by the Caerphilly and Speedwell cohort study which demonstrated that high TG, high total cholesterol and low HDL-C levels are independent predictors of CHD and that the combination of these lipid abnormalities increases the overall risk of coronary events[51]. In the West of Scotland Coronary Prevention Study (WOSCOPS)[5], Cholesterol and Recurrent Events (CARE)[2] and the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID)[3], pravastatin treatment was associated with beneficial effects upon levels of HDL-C in addition to LDL-C (Table 2). The observed increases in HDL-C levels are comparable to those achieved in VA-HIT[37] and may have contributed to the clinical benefits reported (Table 2). However, when data from these trials were combined in the Prospective Pravastatin Pooling project, the relative risk reduction with pravastatin therapy did not vary with baseline HDL-C levels[52]. The Air Force/Texas Coronary Atherosclerosis Prevention (AFCAPS/TexCAPS) Study in asymptomatic subjects with below average HDL-C levels and mild to moderate elevations in LDL-C and total cholesterol, supports the association between increasing HDL-C levels and the clinical benefits of statins[4] (Table 2). A subanalysis of the placebo group by baseline lipid level revealed that patients in the highest tertile for LDL-C and the lowest for HDL-C had the greatest incidence of major coronary events, and baseline HDL-C level was a significant predictor of CHD risk[53]. As a result, the authors suggested that these results support the inclusion of HDL-C levels as an essential component of risk factor assessment in patients with average LDL-C levels. In conclusion, clinical trials with lipid-modifying therapies suggest that raising HDL-C levels reduces CHD risk. However, more studies are required to elucidate fully the clinical benefits of raising HDL-C levels. Use of Statins to Raise HDL-C Levels In addition to the dose-dependent reduction of LDL-C levels, statins exert beneficial effects across the lipid profile; however, they differ in their ability to raise HDL-C and this may be an important consideration when choosing an appropriate drug for the treatment of dyslipidaemia[54]. A direct comparison of the lipid-modifying effects of atorvastatin, pravastatin, lovastatin, fluvastatin and simvastatin was performed in the CURVES study[55]. Atorvastatin produced greater reductions (p £ 0.01) in LDL-C and total cholesterol levels than the other statins at milligram-equivalent doses but had a low potential for increasing HDL-C (Figure 1). Indeed, increasing doses of atorvastatin were associated with progressively smaller increases in HDL-C levels and a dose of 80 mg was associated with a mean decrease of 0.1% from baseline HDL-C level, suggesting a negative dose response, although this observation was limited by the small number of patients (n = 10) involved[55]. Similarly, fluvastatin 40 mg lowered HDL-C levels by 3%, indicating that its effects were dose-dependent. Figure 1. Comparative efficacy of atorvastatin, simvastatin, pravastatin, lovastatin and fluvastatin in the CURVES study[55]. Key: LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol. A dose-titration study in patients with documented atherosclerosis also suggested a negative dose response with respect to HDL-C levels across the dose range studied following treatment with atorvastatin but not fluvastatin, lovastatin or simvastatin[56]. Atorvastatin raised HDL-C levels by 9% at a start dose of 10 mg; however, smaller elevations in HDL-C levels were observed as the dose of atorvastatin was increased. The effect of higher doses of atorvastatin on HDL-C was the subject of other large studies reviewed elsewhere[54]. Additional studies comparing simvastatin and atorvastatin at doses resulting in similar reductions in LDL-C, showed that simvastatin produced greater increases in HDL-C[57,58]. This variability in HDL-C effects is but one example of the documented differences between statins and on a wider scale between all lipid-lowering drugs[59,60]. The effective LDL-C-lowering properties of statins and their good tolerability have established them as the first-line drug therapy for the treatment of dyslipidaemia. However, as the benefits of optimising the lipid profile as a whole are increasingly being recognised, the additional benefits of different statins should be considered. Raising HDL-C Levels: A New Target of Therapy Drugs with beneficial effects in raising levels of HDL-C in addition to lowering LDL-C would be welcome additions to the current therapeutic options for the management of dyslipidaemia. One approach for maximising the effects of treatment on both LDL-C and HDL-C levels is to co-administer appropriate lipid-modifying drugs, but the statin-fibrate combination has only been studied in small-scale trials[61]. Such combination therapy has been demonstrated to improve the entire lipid profile in patients with low HDL-C and elevated LDL-C levels[62]. In addition, statins and fibrates have beneficial effects on clotting factors and proteins[63,64], insulin resistance[65,66] and blood pressure[67,68]. However, high incidences of myalgia and rhabdomyolysis have consistently been reported with combination therapies involving gemfibrozil[69,70] and an excess of these adverse events precipitated the withdrawal of cerivastatin in 2001[71]. Therefore, owing to the increased risk of adverse events, including liver and muscle toxicity, it is recommended that statin-fibrate therapy should be used with caution[69]. An updated guideline for the use of such therapies is in the process of being developed, based upon a United Kingdom consensus group meeting (Mikhailidis et al., personal communication). A combination of lovastatin plus extended-release niacin, currently in clinical development, has been demonstrated to produce greater effects on LDL-C, HDL-C and TG levels than either of the two drugs alone; HDL-C levels were increased by 30% and LDL-C levels were decreased by 47% from baseline after 16 weeks of treatment[72]. However, cutaneous flushing, commonly associated with niacin therapy, resulted in the withdrawal of 7% of patients from the study. Ezetimibe is a new selective cholesterol absorption inhibitor that blocks the uptake of dietary and biliary cholesterol by preventing its transport through the intestinal wall without affecting the passage of other fat-soluble nutrients[73,74]. Ezetimibe can reduce LDL-C levels by up to 19% and moderately increase HDL-C by up to 3.5% in hyperlipidaemic patients[75,76]. It is well tolerated when administered in combination with a statin[77,78] or a fibrate[79], with additive effects upon LDL-C-lowering, although further research is required to determine the effects on HDL-C[76]. Rosuvastatin (Crestor‰) is a new statin shown to have superior efficacy in lowering levels of LDL-C in comparison with atorvastatin, pravastatin and simvastatin, with beneficial effects upon HDL-C[80-82]. Increases in HDL-C levels of up to 18% have been reported in hypertriglyceridaemic patients[83]. These positive effects on HDL-C have been shown to be consistent across the dose range in patients with familial hypercholesterolaemia, and to be greater than those produced by atorvastatin[84] (Table 3). The introduction of therapies with greater HDL-C raising effects, which are well tolerated as monotherapy and in combination with other lipid-modifying drugs, will potentially result in patients achieving greater increases in HDL-C levels than with currently available therapies. However, the benefits of raising HDL-C are still to be definitively established and further trials designed to evaluate specifically the effect of increasing HDL-C levels on clinical outcomes are required. Manipulating the HDL receptor and the metabolic pathway involved with this lipoprotein fraction may prove to be a target for the development of future treatments[39]. Conclusion While reducing LDL-C levels is the priority for the treatment of dyslipidaemia, not all coronary events are prevented despite aggressive LDL-C lowering, and risk reduction may be improved by the treatment of additional lipid abnormalities. Clinical trials have demonstrated that therapies with beneficial effects across the lipid profile reduce the incidence of CHD, and there is little to contradict that, achieving LDL-C goals while also raising HDL-C levels, is of greater value than just targeting LDL-C alone. Current guidelines for the treatment of dyslipidaemia identify low levels of HDL-C as a major risk factor for CHD[6-8] although further research is required to establish the mechanisms by which HDL-C exerts its effects. Of the lipid-modifying drugs available, niacin and fibrates are the most effective at increasing HDL-C levels but they produce only modest LDL-C lowering. Statins are generally accepted as the therapy of choice for the treatment of dyslipidaemia owing to their efficacy in lowering LDL-C, although they vary in their potential to raise HDL-C. New treatments with beneficial effects upon HDL-C in addition to LDL-C, administered in combination or as monotherapy, may provide additional benefits for the reduction of CHD risk. ©
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