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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Options for therapeutic intervention: how effective are the different agents?

Philip Barter

Heart Research Institute, 145 Missenden Road, Camperdown, Sydney 2050, Australia

Corresponding author. Tel: +61 2 95503560; fax: +61 2 95503302. E-mail address: p.barter{at}hri.org.au


   Abstract
Top
 Abstract
The changing nature of...
 Pathogenetic and therapeutic...
 Discussion
 Conclusions
 References
 
‘Atherogenic dyslipidaemia’ and the ‘lipid triad’ are collective terms for the low HDL-cholesterol, elevated triglycerides, and small, dense LDL that is often found in insulin-resistant patients with abdominal obesity, the metabolic syndrome, or type 2 diabetes. This dyslipidaemia phenotype is believed to underlie a substantial burden of excess cardiovascular risk. Although statins provide effective control of LDL-cholesterol, their effects on the lipid triad are relatively modest and combination therapies will be required to normalize the lipid profiles of these patients. Increasing HDL-cholesterol, in particular, exerts a range of anti-atherogenic effects within the evolving atherosclerotic plaque. Fibrates and nicotinic acid (niacin) each increase HDL-cholesterol, with nicotinic acid being the more effective of the two. Studies with Niaspan®, a prolonged-release formulation of nicotinic acid with equivalent efficacy but superior tolerability compared with immediate-release nicotinic acid, shows that this agent preferentially increases levels of larger, more atheroprotective, ApoAI-containing HDLs. Combinations of nicotinic acid with a statin appears to provide effective control of LDL-cholesterol while maximizing the anti-atherogenic potential of HDL-cholesterol.

Key Words: HDL-cholesterol • Atherosclerosis • Dyslipidaemia • Nicotinic acid • HMG CoA reductase inhibitors • Fibrates


   The changing nature of dyslipidaemia and associated elevations of cardiovascular risk
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 The changing nature of...
Pathogenetic and therapeutic...
 Discussion
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There is no doubt that improved control of cardiometabolic risk factors such as dyslipidaemia, in addition to reduced rates of hypertension and smoking, have contributed to the steady reductions in cardiovascular morbidity and mortality rates observed in developed nations in recent decades.1–4 In recent years, control of dyslipidaemia has effectively been synonymous with control of LDL-cholesterol or total cholesterol, according to guidelines for the management of cardiovascular risk. An improved diet and more exercise remains the primary intervention for dyslipidaemia and other manifestations of increased cardiovascular risk and should be maintained irrespective of other treatments; however, intervention with a statin (HMG-CoA reductase inhibitor) is clearly identified as the principal pharmacological treatment for patients with lipids insufficiently well controlled by diet and exercise, both for the general population under treatment5,6 and more specifically for patients with diabetes.7,8

These recommendations have served us well, but the nature of cardiovascular risk related to dyslipidaemia may be changing. Developed nations have developed an ‘obesogenic environment’, with easy access to high-energy foods and little reason for physical exertion.9 This has resulted in an unprecedented increase in the prevalence of obesity in all age groups in these countries.10–13 It is well known that obesity promotes a markedly increased risk of developing insulin resistance or type 2 diabetes,14 and obesity or obesity-associated risk factors promote increased risk of myocardial infarction and other adverse cardiovascular outcomes.15–18 Clinically significant signs of atherosclerosis are already present by adolescence in obese subjects, with increased brachial artery stiffness significantly related to body mass index (BMI), waist circumference, and body fat mass.19

Obese (especially abdominally obese) subjects, individuals with the metabolic syndrome, or type 2 diabetic subjects with dyslipidaemia often do not present with markedly elevated levels of ApoB-containing lipoprotein. Table 1 shows mean lipid parameters from subjects stratified for the presence or absence of diabetes from the Botnia cohort,20 and from the population of a large clinical trial at baseline (the Sleep Heart Health Study).21 All mean lipid parameters differed significantly between populations. However, mean total cholesterol or LDL-cholesterol in the diabetic groups were within 10% of the corresponding values in non-diabetic subjects, and total cholesterol was actually lower in the diabetic group in both the studies. In contrast, large differences were observed in the diabetic vs. non-diabetic groups in HDL-cholesterol (~20% lower in the diabetic groups) and in triglycerides (~30% and ~50%, respectively, higher in the diabetic group in each study). These lipoprotein abnormalities are typical of insulin-resistant populations, and often accompany a further change in the lipid phenotype characterized by increased numbers of small, dense LDL particles.22


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  		Table 1 Features of atherogenic dyslipidaemia associated with type 2 diabetes: mean (SD) lipid parameters from two populations stratified for the presence or absence of diabetes

 
Together, these three features of dyslipidaemia are termed the ‘lipid triad’. This phenotype is believed to be highly atherogenic. Indeed, it has been suggested that high prevalence of the lipid triad may suggest a higher overall burden of atherosclerotic disease than that associated with hypercholesterolaemia.23 It is reasonable to suggest, therefore, that we should broaden the focus of intervention against dyslipidaemia beyond LDL-cholesterol, in order to encompass features of the lipid triad. This article reviews the effectiveness of current pharmacological lipid-modifying treatments on the individual components of the lipid profile, with reference to the pathophysiology of atherosclerosis.


   Pathogenetic and therapeutic mechanisms
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Discussion
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Pathogenesis of atherosclerosis
Figure 1 outlines key steps in the initiation and progression of atherosclerosis.24 Endothelial dysfunction is an early event in atherogenesis, and the damaged endothelium presents a range of adhesion molecules to the arterial lumen. Monocytes initially bind loosely to E-selectin, and roll along the endothelial surface. Following tighter binding to other adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) or intercellular adhesion molecule-1 (ICAM-1), inflammatory cells then infiltrate the artery wall under the influence of monocyte chemotactic protein-1 (MCP-1). The expression of MCP-1 is enhanced by the accumulation and oxidization of LDL within the artery wall, a further potent stimulus of atherosclerosis. Once inside the arterial intima, the monocytes differentiate into macrophages and secrete cytokines and growth factors that recruit more inflammatory cells and initiate the remodelling of the arterial wall that leads ultimately to an atherosclerotic plaque. During this time, the macrophages avidly take up lipids, especially from oxidized LDL. In due course, a proportion of the macrophages become lipid-packed foam cells, and their degeneration deposits free lipids within the artery wall in the form of fatty streaks. Continued deposition of lipids produces the lipid core of the mature atherosclerotic plaque.


Figure 0411
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  		Figure 1 Principal steps in early atherogenesis. Stages opposed by HDL-cholesterol are shown in white text on a black background. Reproduced from Barter et al.24 with permission from Lippincott Williams & Wilkins.

 
HDL inhibits this process at key steps (Figure 1). First, HDL inhibits the expression of adhesion molecules and MCP-1.25–31 In addition, HDL exerts potent anti-oxidant actions, which inhibit the oxidation of LDL.32 HDL also mediates reverse cholesterol transport.33 ApoAI and ApoAII are secreted by the liver and acquire phospholipids and free cholesterol, initially via the ABCA1 transporter, to form a discoidal HDL (Figure 2).34 HDLs also acquire cholesterol from macrophages via the ABCG1 receptor.35 Esterification of the free cholesterol by lecithin:cholesterol acyltransferase (LCAT) leads to the formation of spherical HDLs of a range of sizes depending on their lipid content and composition (Figure 2). Cholesterol is either returned to the liver via the SR-B1 scavenger receptor for catabolism, or is recycled to ApoB-containing lipoproteins (VLDL or LDL) in exchange for triglycerides, via cholesteryl ester transfer protein (CETP).36


Figure 0412
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  		Figure 2 Anatomy of (A) HDL structure and (B) subpopulations of HDL particles.

 
Thus, HDLs oppose both the initiation of atherosclerosis (inhibition of endothelial activation and binding of inflammatory cells) and its progression (inhibition of LDL oxidation and promotion of cholesterol efflux). HDLs also exert other important vascular protective functions, including stabilization of atherosclerotic plaques and anti-thrombotic effects, which reduce the risk of plaque rupture and subsequent vascular occlusion.33,37,38

Mechanisms of lipid-modifying drugs and their actions on lipoprotein levels
The classes of lipid-modifying drugs considered here are the statins (HMG-CoA reductase inhibitors), nicotinic acid (called niacin in some areas), and fibrates.5 Statins act principally through marked reductions in LDL-cholesterol. Some indirect actions of statins also occur, through modulation of the activity of CETP. As described earlier, this protein mediates the exchange of cholesteryl ester from HDL to VLDL or LDL in exchange for triglyceride in the opposite direction, and a substantial reduction in circulating ApoB-containing lipoproteins would tend to limit the rate of this process. As CETP is involved in the aetiology of the atherogenic dyslipidaemia phenotype, such an effect may also contribute to the modest reductions in triglycerides and the modest elevations of ApoAI and HDL observed after statin treatment. The effects of various statins on HDL-cholesterol in two randomized trials39,40 are shown in Table 2. The increases in HDL-cholesterol of up to about 10% of the baseline value are typical of the effects of statins on this parameter.


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  		Table 2 Effects of Niaspan®, a fibrate, and statins on HDL-cholesterol

 
The main effect of nicotinic acid is a marked increase in HDL-cholesterol (along with increased ApoAI and ApoAII), reduced levels of triglycerides, and a modest reduction in LDL-cholesterol (Figure 3).5 A prolonged-release formulation of nicotinic acid is available (Niaspan®), which has identical effects on lipids to the immediate release version, but is associated with a lower incidence of side-effects, particularly flushing.41 A dose-ranging evaluation of Niaspan® demonstrated increases in HDL-cholesterol of up to 26% at the maximum recommended daily dose of this agent (Table 2). The effects of Niaspan® on HDL-cholesterol are similar with or without concurrent treatment with a statin.42,43 The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER)-2 study randomized men with coronary heart disease, low HDL-cholesterol [<1.16 mmol/L (45 mg/dL)], and LDL-cholesterol well controlled by a statin [mean LDL-cholesterol at baseline was 2.3 mmol/L (89 mg/dL)] to receive additional double-blind Niaspan® (1000 mg) or placebo for 1 year.44 No increase in HDL-cholesterol occurred in the placebo group (Figure 4). In contrast, a progressive increase in HDL-cholesterol occurred in the Niaspan® group during the treatment period, with mean HDL-cholesterol 21% higher at study end compared with baseline (Figure 4).


Figure 0413
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  		Figure 3 Mechanisms of lipid-modifying drug classes. Reductions in circulating LDL-cholesterol or triglycerides decreases the activity of CETP, which transfers cholesterol out of HDLs in exchange for triglyceride (denoted by ‘a’). The effects of fibrates shown are secondary to PPAR{alpha} activation.

 

Figure 0414
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  		Figure 4 Effects on the lipid profile of adding Niaspan® to existing statin therapy in the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study. Drawn from data presented by Taylor et al.44

 
An additional decrease in LDL-cholesterol has been observed following addition of Niaspan® to a statin in patients with mean LDL-cholesterol of 3.4 mmol/L (133 mg/dL) at baseline.45 However, such an effect did not occur in the ARBITER-2 population, where mean LDL-cholesterol was already intensively controlled to below the current guideline target of 2.6 mmol/L (100 mg/dL) for these high-risk patients.5,44

Fibrates activate the alpha isoform of the peroxisome proliferator-activated receptor (PPAR{alpha}). This results in increased APoAI, ApoAII and HDL production, increased synthesis of lipoprotein lipase, which reduces plasma triglycerides. The reduction in plasma triglycerides with a fibrate tends to reduce cholesterol transfer out of HDL by CETP: this effect and increased synthesis of the ABCA1 transporter promote reverse cholesterol transport, as described earlier. The reduction in triglycerides dominates the effects of fibrates on the lipid profile. For example, the administration of gemfibrozil for 5 years in the Veterans Administration HDL Intervention Trial (VA-HIT) reduced triglycerides by 31% from baseline and increased HDL-cholesterol by 6% from baseline (Table 2).46

Effects on lipoprotein sub-profiles
Triglyceride-rich VLDLs and LDLs load HDLs with triglycerides in exchange for cholesteryl ester. Lipolysis of these excess triglycerides leads to the formation of small, dense HDLs which are more rapidly cleared from the circulation than larger HDLs.33,36 Larger HDL particles containing only ApoAI [mostly HDL2 as measured using gel electrophoresis or the H4–H5 fraction as measured by nuclear magnetic resonance (NMR)] may be more efficient at promoting reverse cholesterol transport than particles containing ApoAII or ApoAI and ApoAII (mostly HDL3/H1–H2).47 Consistent with this hypothesis, larger HDLs have been shown to be the preferred acceptor for cholesterol exported from macrophagses via the ABCG1 transporter.48 Accordingly, promotion of the larger, more buoyant HDLs may be more anti-atherogenic than increasing the concentration of smaller HDLs.49

A 19-week, double-blind randomized study in 139 patients showed that treatment with Niaspan® increased production of ApoAI-containing HDL and HDL containing both ApoAI and ApoAII, while a fibrate increased only the latter.50 An analysis of data from 60 patients previously enrolled in a double-blind trial showed that treatment with Niaspan® for 12 weeks resulted in reduced levels of small dense HDL as measured using NMR (H1) and increased levels of larger H4 and H5 HDL (Figure 5).51 An additional study randomized patients to increasing doses of a Niaspan®–lovastatin combination or to simvastatin or atorvastatin monotherapy over a 16-week period.52 Final doses at 16 weeks were Niaspan®–lovastatin 2000/40 mg, atorvastatin 40 mg, and simvastatin 40 mg. Total HDL-cholesterol increased by 33, 6, and 7%, respectively (P<0.001 vs. statins), and the proportion of HDL in the HDL2b subclass increased by 42, 17, and 5%, respectively (P<0.01 vs. statins). Fibrates tend to increase HDL3 cholesterol preferentially: several studies have demonstrated increases in this parameter between about 20% and 70% after treatment with a fibrate.53–56


Figure 0415
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  		Figure 5 Effects of Niaspan® on the HDL subclass distribution as measured by nuclear magnetic resonance spectroscopy. Adapted from Am J Cardiol, Vol 91, Morgan JM, Capuzzi DM, Baksh RI, Intenzo C, Carey CM, Reese D, Walker K. Effects of extended-release niacin on lipoprotein subclass distribution, p. 1432–6. Copyright (2003) with permission from Excerpta Medica.

 

   Discussion
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 Pathogenetic and therapeutic...
 Discussion
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 References
 
The atherogenic lipid triad represents a major source of cardiovascular risk unaddressed by lipid-lowering therapy. The effects on the lipid profile of currently available drugs are complex, and mediated through several direct and indirect mechanisms in each case. However, it is clear that no single agent used alone addresses the lipid triad sufficiently effectively. Statins, supported where necessary with cholesterol absorption inhibitors, will remain the preferred pharmacological agents for controlling LDL-cholesterol, but their effects on HDL-cholesterol and triglycerides are usually insufficient to correct these other facets of atherogenic dyslipidaemia.

Combining nicotinic acid with a statin appears to induce favourable changes to the lipid profile, with increase in total HDL-cholesterol and HDL2, believed to be the most anti-atherogenic HDL subclass. The results of the ARBITER-2 study44 show that the addition of nicotinic acid to a statin provided powerful control of HDL-cholesterol in addition to the excellent control of LDL-cholesterol already achieved with the previous statin treatment. Importantly, this trial also showed that the combination regimen prevented significant progression of atherosclerosis (carotid intima-media thickening), whereas the statin alone did not. Nicotinic acid–statin combinations therefore appear to be the ideal combination of lipid-modifying drugs available today. The availability of CETP inhibitors in the future will add to the options available for correcting atherogenic dyslipidaemia.36

The contribution of low HDL to overall cardiovascular risk is increasingly recognized.57 For example, a recent analysis from 5251 members of the Framingham Offspring cohort set out to define the ‘ideal’ lipid profile.58 Follow-up of 20 years revealed that the risk of coronary heart disease increased more steeply with the ratio of total or LDL-cholesterol to HDL-cholesterol than with total or LDL-cholesterol alone. Moreover, the relationship between high total/LDL-cholesterol:HDL-cholesterol and adverse cardiovascular outcomes held true irrespective of the level of LDL-cholesterol. The authors went so far as to argue that elevated LDL-cholesterol only needs to be managed aggressively when the ratio of total cholesterol to HDL-cholesterol is high. These findings echo the identification of low HDL-cholesterol as an independent cardiovascular risk factor in the Framingham Study more than 30 years ago.59 The strong focus on total cholesterol or LDL-cholesterol in principal cardiovascular management guidelines may also be changing. Recently launched joint guidelines for the management of cardiovascular disease in the UK use total:HDL-cholesterol ratio as a means of stratifying patients for interventions on the basis of their cardiovascular risk, in contrast to the use of total cholesterol only in current European guidelines.6


   Conclusions
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 Pathogenetic and therapeutic...
 Discussion
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References
 
Statins, fibrates, and nicotinic acid increase HDL-cholesterol, although nicotinic acid is clearly more effective than the other drug classes, and these agents decrease triglyceride levels to varying extents. Studies with prolonged-release nicotinic acid (Niaspan®), given alone or with a statin, have demonstrated improvements in HDL subclass distribution, with a preferential increase in the proportion of larger, more atheroprotective HDLs containing ApoAI. A combination of Niaspan® with a statin optimizes control of both LDL-cholesterol and the components of the atherogenic lipid triad often found in subjects with abdominal obesity, the metabolic syndrome, or type 2 diabetes.

Conflict of interest: P.B. has received honorariums from Merck and from Pfizer for presentations given at meetings.


   References
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