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The European Society of Cardiology

Non-high-density lipoprotein cholesterol as a risk factor: addressing risk associated with apolipoprotein B-containing lipoproteins

M.J Chapmana,* and M Caslakeb

a Hôpital de la Pitiè, Paris, France
b Institute of Pathological Biochemistry, Glasgow, UK

* M. John Chapman, PhD, DSc, Pavillon Benjamin Delassert, INSERM Unite 321, Hôpital de la Pitiè, 83 Boulevard de l’hôpital, Paris Cedex 13 75651, France. Tel: +33-142177878; fax: +33-145828198
chapman{at}infobiogen.fr

Abstract

There is increasing interest in the use of non-high-density lipoprotein (non-HDL-C) cholesterol as a marker of coronary heart disease risk. Non-HDL-C provides a measure of all apolipoprotein B-containing lipoproteins, including very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL (including small, dense LDL) and lipoprotein(a), all of which have the potential to deliver cholesterol into the arterial wall. This measure thus reflects atherogenic risk not captured by low-density lipoprotein cholesterol (LDL-C) measurement alone, particularly in the context of elevated triglycerides – a setting in which there are increased concentrations of VLDL and atherogenic VLDL remnants. In patients requiring lipid-lowering therapy, non-HDL-C is currently recommended for use as a secondary outcome measure, after LDL-C, in patients with elevated triglycerides. Statins are the most effective agents for reducing levels of atherogenic lipoproteins. Consistent with its distinct pharmacologic properties compared with earlier members of the statin class, rosuvastatin reduces LDL-C significantly more than other statins and produces marked attenuation in atherogenic lipid profiles at a low dose across a wide range of dyslipidaemic phenotypes and patient subpopulations. A recent randomised, double-blind, crossover trial assessed the effects of rosuvastatin 40 mg in hypercholesterolaemic patients with normal triglyceride levels (type IIa dyslipidaemia) or elevated triglyceride levels (type IIb dyslipidaemia). In hypertriglyceridaemic patients, rosuvastatin reduced VLDL1 by 46%, VLDL2 by 42%, IDL by 54%, LDL by 58% and small, dense LDL by 69%. In normotriglyceridaemic patients, who have lower VLDL and remnant concentrations, rosuvastatin reduced VLDL1 by 18%, VLDL2 by 26%, IDL by 57%, LDL by 52% and small, dense LDL by 44%. Rosuvastatin thus has the ability to correct substantially the atherogenic lipoprotein profile across a wide range of phenotypes even when elevated concentrations of atherogenic lipoproteins are present as VLDL.

Key Words: Non-high-density lipoprotein cholesterol • Coronary heart disease • Low-density lipoprotein • Hypercholesterolaemia • Atherogenic risk • Statins

Introduction

Cholesterol may be the most extensively studied biomolecule; indeed, the study of the structure and biological functions of cholesterol has resulted in the largest number of Nobel prizes associated with any biomolecule. Cholesterol has intriguing properties: although it is for the most part highly hydrophobic, it possesses a hydroxyl group that allows it to orient to lipid–water interfaces. It is a critical structural component of cell membranes, but it is also a precursor of steroid hormone synthesis in several organs, a precursor of vitamin D and a precursor of bile acid synthesis in the liver. Clearly, however, cholesterol is not a completely beneficial molecule. Many years ago, examination of coronary atherosclerotic plaques revealed the presence of pure cholesterol crystals as a central component of these lesions, and study of the process of atherogenesis demonstrated that expansion of this lipid core was associated with weakening of the fibrous cap of the lesion, lesion rupture and occlusive thrombotic events.

Most of the cholesterol in atherosclerotic plaques is derived from circulating lipoproteins, primarily low-density lipoprotein (LDL). Like all lipoproteins, LDL has a pseudo-micellar structure. It possesses a hydrophobic core primarily enriched in cholesteryl esters and a small amount of triglyceride covered by a uni-lamellar layer of phospholipids and free cholesterol; the structure is stabilised by the presence on its surface of a large apolipoprotein, apoB-100, the exclusive origin of which is the liver. LDL transports cholesterol, liposoluble vitamins and antioxidants to peripheral tissues, where it is taken up via the non-atherogenic LDL receptor pathway. LDL, however, is not the only cholesterol-rich lipoprotein in plasma that can contribute cholesterol to atherosclerotic plaques. The entire spectrum of apoB-100-containing lipoproteins has the biologic capacity to penetrate the arterial intima, where they may be retained, thereby contributing to plaque progression; these include the larger (VLDL1) and smaller (VLDL2) very-low-density lipoproteins, intermediate-density lipoproteins (IDL), LDL and small, dense LDL (Fig. 1). Although VLDL particles are relatively triglyceride-enriched, they also carry cholesterol in amounts (more than 2000 molecules per particle) similar to the cholesterol content of LDL. Among lipoproteins, high-density lipoprotein (HDL) is unique in its capacity to remove cholesterol from peripheral tissues, including the arterial wall, and delivering it to the liver for elimination in the form of bile acids (the process of reverse cholesterol transport). Atherogenic dyslipidaemias (e.g., hypercholesterolaemia, mixed hyperlipidaemia, hypertriglyceridaemia and dyslipidaemias characteristic of type 2 diabetes, the metabolic syndrome and renal disease) are characterised by a disequilibrium between atherogenic apoB-containing lipoproteins and anti-atherogenic HDL, resulting in enhanced arterial cholesterol deposition, attenuated reverse cholesterol transport (e.g., due to reduced HDL concentration or dysfunction of HDL) and accelerated atherogenesis.



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  		Fig. 1 All apolipoprotein (apo)B-containing lipoproteins possess the potential to penetrate the arterial wall and to contribute cholesterol to atherosclerotic lesions.

 
Given this array of lipoproteins with atherogenic potential, how is risk for atherosclerotic disease best measured? LDL cholesterol (LDL-C) has proven to be an accurate measure of risk and has been particularly informative in the framework of prospective intervention studies. Trials of statins, including both primary and secondary coronary heart disease (CHD) prevention studies, have shown a linear relationship between LDL-C levels achieved on treatment in statin and placebo groups and risk of CHD.1,2 HDL cholesterol (HDL-C) has also proven to be a useful measure of risk. It has been shown, for example, that decreasing HDL-C levels are associated with increased CHD risk at every level of LDL-C.3 Recently, increased attention has been given to non-HDL-C as a risk marker. The non-HDL-C concentration equals the plasma total cholesterol concentration minus the HDL-C concentration. This measure thus includes cholesterol in all atherogenic apoB-containing lipoproteins and may therefore be expected to capture atherogenic risk not represented by LDL-C alone.

Non-high-density lipoprotein cholesterol as an atherogenic risk marker

The relationship among non-HDL-C, LDL-C and atherogenic risk was addressed by the National Cholesterol Education Program Adult Treatment Panel III (ATP III).4,5 In brief, when triglycerides are elevated (e.g., >=1.7 mmol/l [150 mg/dl]), LDL-C alone is not sufficient to define the risk associated with atherogenic lipoproteins. Triglycerides are primarily carried by VLDL, with high levels indicating increased quantities of triglyceride-enriched VLDL and remnant particles. To improve measurement of atherogenic particles in the setting of elevated triglycerides, it is recommended that levels of VLDL-C be added to those of LDL-C (a combination that yields the non-HDL-C concentration). In the ATP III guidelines, non-HDL-C concentration is identified as a secondary target of lipid-lowering therapy, after target LDL-C levels have been achieved, with target levels set at 0.8 mmol/l (30 mg/dl) higher than the risk-based LDL-C targets. The guidelines note that total serum apoB has strong predictive power for severity of coronary atherosclerosis and CHD events, and that non-HDL-C is highly correlated with apoB levels;6 it is thus proposed that non-HDL-C represents an acceptable surrogate marker of total apoB for use in routine clinical practice.

A number of studies have indeed shown that non-HDL-C is a strong and independent predictor of cardiovascular morbidity and mortality. Among recent studies, the Lipid Research Clinics Program Follow-up Study in subjects without initial cardiovascular disease showed that risk of cardiovascular mortality was increased by more than 2-fold in both men and women with the highest non-HDL-C levels (>=5.7 mmol/l [220 mg/dl]);7 both non-HDL-C and HDL-C were independent predictors of cardiovascular mortality in a model including lipid levels and age at baseline, with both remaining significant predictors after adjustment for additional cardiovascular disease risk factors. An analysis in the Bypass Angioplasty Revascularization Investigation (BARI) population of CHD patients8 showed that non-HDL-C was the strongest lipid predictor of non-fatal myocardial infarction based on a multivariate analysis including a large number of covariates, and that it was also the only significant predictor of angina, with a 4.9% increase in risk reported for each 0.3 mmol/l (10 mg/dl) increase in non-HDL-C. In the Strong Heart Study in diabetic patients without cardiovascular disease,9 the highest tertile of non-HDL-C was associated with a hazard ratio for CHD of 2.75, exceeded only by the 3.06 hazard ratio in the highest tertile of total cholesterol:HDL-C ratio; for myocardial infarction alone, the highest tertile of non-HDL-C was associated with a hazard ratio of 3.17, highest among all lipid measures.

How do apolipoprotein B-containing lipoproteins promote atherogenesis at the arterial wall?

There is considerable evidence for the direct atherogenic effects of apoB-containing lipoproteins other than LDL. VLDL and triglyceride-rich VLDL remnant particles have been shown to induce endothelial dysfunction.10 Triglyceride-rich lipoproteins have been shown to enter human atherosclerotic plaques and bind to the connective tissue matrix.11 Native triglyceride-rich lipoproteins isolated from fasting and postprandial plasma induce foam cell formation in human monocyte/macrophages,12 and elevated levels of these lipoproteins contribute significantly to progression of coronary disease.13 Ultrasound studies show that echolucent carotid artery plaques are associated with elevated fasting and postprandial levels of these lipoproteins.14 Further, triglyceride-rich lipoproteins enhance the prothrombotic state.15

The triglyceride-rich VLDL remnant particles are cholesteryl ester-rich, apoB-48- or -100-rich, relatively triglyceride-poor (compared with native VLDL) particles resulting from intravascular remodeling (i.e., by lipoprotein lipase, cholesteryl ester transfer protein, hepatic lipase and phospholipid transfer protein) of apoB-100-containing VLDL from the liver or apoB-48-containing VLDL or chylomicrons from the intestine in the postprandial phase. These remnants can potentially be taken up by the liver, peripheral tissues or the arterial wall. Fig. 2 is a photomicrograph showing VLDL-sized particles and remnants in the extracellular matrix of an arterial intimal atherosclerotic lesion.16



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  		Fig. 2 Photomicrograph showing very-low-density-sized particles and remnants in the extracellular matrix of an arterial intimal atherosclerotic lesion in a cholesterol-fed rabbit. (Adapted with permission from Frank and Fogelman.16)

 
Similarly, small, dense LDL is known to have considerable atherogenic potential.17 There is extensive evidence that small, dense LDL has considerably prolonged plasma residence time (up to 5 days in dyslipidaemic individuals). These particles have low affinity for the cellular LDL receptor, and are primarily taken up and undergo catabolism by alternative proatherogenic pathways. The small size of these particles (<=26 nm) facilitates transendothelial transport, and they exhibit enhanced binding affinity with extracellular matrix components, with electrostatic interaction of apoB-100 with proteoglycans resulting in intimal retention. The particles are highly susceptible to oxidative and proteolytic modification, in part due to depletion of lipophilic antioxidant content (e.g., vitamin E, ubiquinol-10). This modification facilitates macrophage uptake of these particles, resulting in cholesteryl ester accumulation and foam cell formation.17

Therapeutic reduction of atherogenic lipoprotein levels: action of rosuvastatin

Among the five major families of lipid-modulating drugs currently available – i.e., statins, fibrates, niacin, cholesterol absorption inhibitors and sequestrant resins and gels – the statins have the greatest ability to reduce levels of atherogenic apoB-containing lipoproteins. These agents reduce VLDL production in the liver and inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme involved in cholesterol biosynthesis; the upregulation of LDL receptor expression resulting from enzyme inhibition enhances the clearance of the entire spectrum of apoB-containing lipoproteins, reducing the potential impact of these lipoproteins in initiation and progression of atherosclerotic lesions. Fig. 3 shows reduction in both lipid content and oxidised LDL content in carotid plaques after statin treatment.18



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  		Fig. 3 Top: Representative sections showing oil red O stain for lipid content in subjects with carotid artery stenosis receiving no lipid-lowering therapy (a) or pravastatin 40 mg (b) for 3 months. Bottom: Sections showing immunostaining for oxidised low-density lipoprotein (oxLDL) in control subject (c) and subject receiving pravastatin (d). (Reproduced with permission from Crisby et al.18)

 
It is now evident that significant differences exist among the pharmacologic properties of the statins.19–21 Binding studies have indicated that rosuvastatin exhibits a greater number of bonding interactions with HMG-CoA reductase compared with other statins, including a unique polar interaction between the electronegative sulfone group of the drug molecule and an enzyme side chain. Consistent with these binding characteristics, rosuvastatin exhibits the greatest potency in human HMG-CoA reductase inhibition, having a 50% inhibitory concentration of 5.4 nM, compared with values of 8.2 nM for atorvastatin, 11.2 nM for simvastatin and 44.1 nM for pravastatin.22 Owing to a polar methane sulfonamide group, rosuvastatin is also relatively hydrophilic compared with other statins; statin octanol–water coefficients at pH 7.4 are for pravastatin, the other relatively hydrophilic agent, and for rosuvastatin, compared with relatively lipophilic values of 1.0 to 2.0 for atorvastatin, fluvastatin and simvastatin. The relative hydrophilicity of rosuvastatin contributes to its greater selectivity for hepatic vs non-hepatic tissues by reducing passive diffusion into cells; cell selectivity log ratios for activity in hepatocytes vs fibroblasts were found to be 2.7 for rosuvastatin, 2.4 for pravastatin, 0.5 for atorvastatin and –0.3 for simvastatin. Rosuvastatin’s relative hydrophilicity also contributes to the absence of significant metabolism via the cytochrome P450 3A4 isoenzyme,23 a characteristic shared by pravastatin; metabolism via this route, which may occur with hydrophobic statins, may give rise to potential problems in terms of adverse interactions with the large number of other drugs and substances that share this metabolic pathway.

The distinct pharmacologic properties of rosuvastatin result in elevated efficacy in reducing LDL-C. As shown in Fig. 4, the recent Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial, conducted in 2431 patients with hypercholesterolaemia (LDL-C >=4.1 and 6.5 mmol/l [>=160 and 250 mg/dl] and triglycerides 4.5 mmol/l [400 mg/dl]), showed that 6 weeks of treatment with rosuvastatin significantly reduced LDL-C compared with atorvastatin, simvastatin and pravastatin at milligram-equivalent doses.24 Data from other rosuvastatin trials indicate substantial beneficial effects with the starting 10-mg dose in reducing non-HDL-C across a wide range of hypercholesterolaemic patient populations (Fig. 5).25 The safety profile of this agent is also consistent with its pharmacologic profile; thorough review of safety involving 14,000 patient-years indicates tolerability comparable to that of other statins, a low rate of withdrawal due to adverse events (comparable to rates for placebo) and a low incidence of skeletal muscle and hepatic adverse effects.26



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  		Fig. 4 Low-density lipoprotein cholesterol reductions in hypercholesterolaemic patients after 6 weeks of treatment with rosuvastatin 10–40 mg, atorvastatin 10–80 mg, simvastatin 10–80 mg or pravastatin 10–40 mg in the STELLAR trial. for rosuvastatin vs all comparator statins for all milligram-equivalent comparisons. (Adapted with permission from Jones et al.24)

 


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  		Fig. 5 Reductions in non-high-density lipoprotein (HDL) cholesterol and total cholesterol after 12 weeks of treatment with rosuvastatin 10 mg in various patient populations. Hypertension>=140/90 mmHg or taking antihypertensive medication; Obesity=body mass index 30 kg/m2. (Adapted from Blasetto et al.25)

 
To specifically evaluate the impact of rosuvastatin treatment on the profile of atherogenic apoB-containing subfractions, we performed a randomised, double-blind, placebo-controlled, crossover trial in which 14 normotriglyceridaemic patients (type IIa dyslipidaemia, triglycerides 2.0 mmol/l [177 mg/dl], LDL-C of 3.40–5.70 mmol/l [130–220 mg/dl]) and 18 hypertriglyceridaemic patients (type IIb dyslipidaemia, triglycerides >=2.0 mmol/l [177 mg/dl], LDL-C of 2.75–5.55 mmol/l [106–215 mg/dl]) received rosuvastatin 40 mg or placebo over two treatment periods (Fig. 6).27 The findings indicate that treatment was associated with particularly large reductions in VLDL subfractions (46% in VLDL1, 42% in VLDL2) and small, dense LDL (69%) in the setting of hypertriglyceridaemia, in which levels of these atherogenic lipoproteins are elevated (Fig. 6). Substantial reductions in all lipoprotein fractions were also observed in normotriglyceridaemic patients, including reductions of 57% in IDL, 52% in LDL and 44% in small, dense LDL. Total apoB was reduced by 49% in normotriglyceridaemic patients and by 48% in hypertriglyceridaemic patients. Thus, there is substantial attenuation of the atherogenic profile by rosuvastatin when elevated concentrations of atherogenic lipoproteins are present in the form of VLDL, VLDL remnants, IDL and small, dense LDL (as in mixed hyperlipidaemia), as well as when LDL-C levels are elevated in the context of normal triglyceride levels (as in hypercholesterolaemia).



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  		Fig. 6 Top: Design of crossover trial of rosuvastatin 40 mg in normotriglyceridaemic (NTG) and hypertriglyceridaemic (HTG) patients. Bottom: Results for atherogenic lipoproteins. Total apoB, NTG=–49%, HTG=–48%. *, ** vs placebo. (Adapted from Caslake et al.27)

 
Conclusion

All apoB-containing lipoproteins are potentially atherogenic. Since non-HDL-C reflects the total plasma levels of these atherogenic lipoproteins, it is especially promising as a biomarker of atherogenic risk and can be integrated into clinical practice as a secondary target of lipid-lowering therapy. Statins are the most powerful agents for reducing levels of atherogenic lipoproteins. Consistent with its distinct pharmacologic properties, rosuvastatin is the most effective statin in reducing LDL-C and has been shown to correct substantially the atherogenic lipoprotein profile across dyslipidaemia phenotypes. Equally, this agent is highly effective at low doses in a wide range of patient populations and is associated with a low incidence of adverse effects. These characteristics also suggest the utility of combining rosuvastatin with other agents (e.g., niacin or fenofibrate) in dyslipidaemias, including those characterised by reduced HDL-C levels. Indeed, such combinations are currently attracting wide clinical interest – especially as they take advantage of complementary mechanisms of action that frequently result in additive therapeutic effects, not only in reducing circulating levels of atherogenic particles but equally in raising those of antiatherogenic HDL.

Acknowledgement

The authors are indebted to the following colleagues for their research contributions to these studies: Prof. C.J. Packard and Dr. F. McTaggart.

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