Abstract

‘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.

The changing nature of dyslipidaemia and associated elevations of cardiovascular risk

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.14 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.1013 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.1518 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

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

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.

HDL inhibits this process at key steps (Figure 1). First, HDL inhibits the expression of adhesion molecules and MCP-1.2531 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

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.

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 (Figure4). 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).

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 (PPARα). 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.5356

Discussion

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

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.

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

  Botnia Study20 Sleep Heart Health Study21 
  
 

 
  Diabetes (n=133) No diabetes (n=144) P Diabetes (n=470) No diabetes (n=4402) P 
LDL-cholesterol        
 mmol/L 4.49 (0.09) 4.17 (1.10) NS — — — 
 mg/dL 174 (3) 161 (43)     
Total cholesterol        
 mmol/L 6.43 (0.12) 6.70 (1.10) 0.013 5.09 (1.14) 5.35 (0.98) <0.001 
 mg/dL 249 (5) 259 (4)  197 (44) 207 (38)  
HDL-cholesterol        
 mmol/L 1.07 (0.03) 1.34 (0.03) <0.05 1.11 (0.34) 1.34 (0.41) <0.001 
 mg/dL 41 (1) 52 (1)  43 (13) 52 (16)  
Triglycerides        
 mmol/L 2.41 (0.14) 1.60 (0.10) <0.05 2.12 (1.65) 1.61 (1.08) <0.001 
 mg/dL 213 (12) 142 (9)  188 (146) 143 (96)  
  Botnia Study20 Sleep Heart Health Study21 
  
 

 
  Diabetes (n=133) No diabetes (n=144) P Diabetes (n=470) No diabetes (n=4402) P 
LDL-cholesterol        
 mmol/L 4.49 (0.09) 4.17 (1.10) NS — — — 
 mg/dL 174 (3) 161 (43)     
Total cholesterol        
 mmol/L 6.43 (0.12) 6.70 (1.10) 0.013 5.09 (1.14) 5.35 (0.98) <0.001 
 mg/dL 249 (5) 259 (4)  197 (44) 207 (38)  
HDL-cholesterol        
 mmol/L 1.07 (0.03) 1.34 (0.03) <0.05 1.11 (0.34) 1.34 (0.41) <0.001 
 mg/dL 41 (1) 52 (1)  43 (13) 52 (16)  
Triglycerides        
 mmol/L 2.41 (0.14) 1.60 (0.10) <0.05 2.12 (1.65) 1.61 (1.08) <0.001 
 mg/dL 213 (12) 142 (9)  188 (146) 143 (96)  

LDL-cholesterol was not measured in the Sleep Heart Health Study. NS, not statistically significant (P>0.05).

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.

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.

Figure 2

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

Figure 2

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

Table 2

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

Drug class Specific drug Dose (mg) Mean % change in HDL-C 
Nicotinic acid (Goldberg et al.)42 Niaspan® 500 10  
  1000 15  
  1500 22  
  2000 26  
Fibrate (VA-HIT)46 Gemfibrozil 1200  
Statin (CURVES)39 and STELLAR40   CURVES STELLAR 
 Atorvastatin 10 
  20 
  40 
  80 
 Pravastatin 10 10 
  20 
  40 
 Simvastatin 10 
  20 
  40 10 
  80 — 
 Lovastatin 20 — 
  40 — 
  80 — 
 Rosuvastatin 10 — 
  20 — 10 
  40 — 10 
Drug class Specific drug Dose (mg) Mean % change in HDL-C 
Nicotinic acid (Goldberg et al.)42 Niaspan® 500 10  
  1000 15  
  1500 22  
  2000 26  
Fibrate (VA-HIT)46 Gemfibrozil 1200  
Statin (CURVES)39 and STELLAR40   CURVES STELLAR 
 Atorvastatin 10 
  20 
  40 
  80 
 Pravastatin 10 10 
  20 
  40 
 Simvastatin 10 
  20 
  40 10 
  80 — 
 Lovastatin 20 — 
  40 — 
  80 — 
 Rosuvastatin 10 — 
  20 — 10 
  40 — 10 

VA-HIT, Veterans Administration HDL Intervention; CURVES, Comparative study of HMG-CoA Reductase inhibitor, atorvastatin, vs. equivalent dose strengths of statins; STELLAR, Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin.

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 PPARα activation.

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 PPARα activation.

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

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

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.

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.

References

1
Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T, Zheng ZJ, Flegal K, O'Donnell C, Kittner S, Lloyd-Jones D, Goff DC Jr., Hong Y. (
2006
) Heart Disease and Stroke Statistics–2006 Update. A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
Circulation
 
113
:
e85
–e151 [Advance publication online: http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.105.171600v1 (February 2006)].
2
Carroll MD, Lacher DA, Sorlie PD, Cleeman JI, Gordon DJ, Wolz M, Grundy SM, Johnson CL. (
2005
) Trends in serum lipids and lipoproteins of adults, 1960–2002.
JAMA
 
294
:
1773
–1781.
3
Jemal A, Ward E, Hao Y, Thun M. (
2005
) Trends in the leading causes of death in the United States, 1970–2002.
JAMA
 
294
:
1255
–1259.
4
Unal B, Critchley JA, Capewell S. (
2005
) Modelling the decline in coronary heart disease deaths in England and Wales, 1981–2000: comparing contributions from primary prevention and secondary prevention.
BMJ
 
331
:
614
.
5
Expert Panel on Detection Evaluation Treatment of High Blood Cholesterol in Adults. (
2001
) Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) (Adult Treatment Panel III).
JAMA
 
285
:
2486
–2497.
6
Third Joint Task Force of European:other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of eight societies:by invited experts). (
2003
) European guidelines on cardiovascular disease prevention in clinical practice.
Eur J Cardiovasc Prev Rehabil
 
10
:
S1
–S10.
7
Clinical Guidelines Task Force International Diabetes Federation. 2005 Global Guideline for Type 2 Diabetes. www.idf.org (February 2006).
8
American Diabetes Association. (
2005
) Standards of medical care in diabetes.
Diab Care
 
28
:Suppl. 1,
S4
–S36.
9
Ogilvie D and Hamlet N. (
2005
) Obesity: the elephant in the corner.
BMJ
 
331
:
1545
–1548.
10
Vasan RS, Pencina MJ, Cobain M, Freiberg MS, D'Agostino RB. (
2005
) Estimated risks for developing obesity in the Framingham Heart Study.
Ann Intern Med
 
143
:
473
–480.
11
Bélanger-Ducharme F and Tremblay A. (
2005
) Prevalence of obesity in Canada.
Obes Rev
 
6
:
183
–186.
12
Centers for Disease Control:Prevention (CDC). (
2006
) Overweight among students in grades K-12–Arkansas, 2003–04 and 2004–05 school years.
Morb Mortal Wkly Rep
 
55
:
5
–8.
13
Thorburn AW. (
2005
) Prevalence of obesity in Australia.
Obes Rev
 
6
:
187
–190.
14
Golay A and Ybarra J. (
2005
) Link between obesity and type 2 diabetes.
Best Pract Res Clin Endocrinol Metab
 
19
:
649
–663.
15
Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, Lang CC, Rumboldt Z, Onen CL, Lisheng L, Tanomsup S, Wangai P Jr., Razak F, Sharma AM, Anand SS. INTERHEART Study Investigators. (
2005
) Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case–control study.
Lancet
 
366
:
1640
–1649.
16
Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH. (
2006
) Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. An update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease From the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism.
Circulation
 
113
:
898
–918.
17
Murphy NF, MacIntyre K, Stewart S, Hart CL, Hole D, McMurray JJ. (
2006
) Long-term cardiovascular consequences of obesity: 20-year follow-up of more than 15,000 middle-aged men and women (the Renfrew-Paisley study).
Eur Heart J
 
27
:
96
–106.
18
Thomas F, Bean K, Pannier B, Oppert JM, Guize L, Benetos A. (
2005
) Cardiovascular mortality in overweight subjects. The key role of associated risk factors.
Hypertension
 
46
:
654
–659.
19
Whincup PH, Gilg JA, Donald AE, Katterhorn M, Oliver C, Cook DG, Deanfield JE. (
2005
) Arterial distensibility in adolescents: the influence of adiposity, the metabolic syndrome, and classic risk factors.
Circulation
 
112
:
1789
–1797.
20
Niskanen L, Turpeinen A, Penttila I, Uusitupa MI. (
1998
) Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis.
Diab Care
 
21
:
1861
–1869.
21
Resnick HE, Redline S, Shahar E, Gilpin A, Newman A, Walter R, Ewy GA, Howard BV, Punjabi NM. (
2003
) Diabetes and sleep disturbances: findings from the Sleep Heart Health Study.
Diab Care
 
26
:
702
–709.
22
Selby JV, Austin MA, Newman B, Zhang D, Quesenberry CP Jr., Mayer EJ, Krauss RM. (
1993
) LDL subclass phenotypes and the insulin resistance syndrome in women.
Circulation
 
88
:
381
–387.
23
Rizzo M and Berneis K. (
2005
) Lipid triad or atherogenic lipoprotein phenotype: a role in cardiovascular prevention?
J Atheroscler Thromb
 
12
:
237
–239.
24
Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. (
2004
) Antiinflammatory properties of HDL.
Circ Res
 
95
:
764
–772.
25
Cockerill GW, Huehns TY, Weerasinghe A, Stocker C, Lerch PG, Miller NE, Haskard DO. (
2001
) Elevation of plasma high-density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation.
Circulation
 
103
:
108
–112.
26
Cockerill GW, Saklatvala J, Ridley SH, Yarwood H, Miller NE, Oral B, Nithyanathan S, Taylor G, Haskard DO. (
1999
) High-density lipoproteins differentially modulate cytokine-induced expression of E-selectin and cyclooxygenase-2.
Arterioscler Thromb Vasc Biol
 
19
:
910
–917.
27
Cockerill GW, Rye KA, Gamble JR, Vadas MA, Barter PJ. (
1995
) High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules.
Arterioscler Thromb Vasc Biol
 
15
:
1987
–1994.
28
Clay MA, Pyle DH, Rye KA, Vadas MA, Gamble JR, Barter PJ. (
2001
) Time sequence of the inhibition of endothelial adhesion molecule expression by reconstituted high density lipoproteins.
Atherosclerosis
 
157
:
23
–29.
29
Navab M, Imes SS, Hama SY, Hough GP, Ross LA, Bork RW, Valente AJ, Berliner JA, Drinkwater DC, Laks H. (
1991
) Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein.
J Clin Invest
 
88
:
2039
–2046.
30
Moudry R, Spycher MO, Doran JE. (
1997
) Reconstituted high density lipoprotein modulates adherence of polymorphonuclear leukocytes to human endothelial cells.
Shock
 
7
:
175
–181.
31
Nofer JR, Geigenmuller S, Gopfert C, Assmann G, Buddecke E, Schmidt A. (
2003
) High density lipoprotein-associated lysosphingolipids reduce E-selectin expression in human endothelial cells.
Biochem Biophys Res Commun
 
310
:
98
–103.
32
Mackness B, Hine D, Liu Y, Mastorikou M, Mackness M. (
2004
) Paraoxonase-1 inhibits oxidised LDL-induced MCP-1 production by endothelial cells.
Biochem Biophys Res Commun
 
318
:
680
–683.
33
Barter P. (
2004
) Metabolic abnormalities: high-density lipoproteins.
Endocrinol Metab Clin North Am
 
33
:
393
–403.
34
Oram JF. (
2003
) HDL apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol.
Arterioscler Thromb Vasc Biol
 
23
:
720
–727.
35
Schmitz G, Langmann T, Heimerl S. (
2001
) Role of ABCG1 and other ABCG family members in lipid metabolism.
J Lipid Res
 
42
:
1513
–1520.
36
Barter PJ, Brewer HB Jr., Chapman MJ, Hennekens CH, Rader DJ, Tall AR. (
2003
) Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis.
Arterioscler Thromb Vasc Biol
 
23
:
160
–167.
37
Nicholls SJ, Rye KA, Barter PJ. (
2005
) High-density lipoproteins as therapeutic targets.
Curr Opin Lipidol
 
16
:
345
–349.
38
Moreno PR and Fuster V. (
2004
) New aspects in the pathogenesis of diabetic atherothrombosis.
J Am Coll Cardiol
 
44
:
2293
–2300.
39
Jones P, Kafonek S, Laurora I, Hunninghake D. (
1998
) Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study).
Am J Cardiol
 
81
:
582
–587.
40
Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW. (
2003
) Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial).
Am J Cardiol
 
92
:
152
–160.
41
McGovern ME. (
2005
) Niaspan®: creating a new concept for raising HDL-cholesterol.
Eur Heart J
 
7
:Suppl. F,
F41
–F47.
42
Goldberg A, Alagona P Jr., Capuzzi DM, Guyton J, Morgan JM, Rodgers J, Sachson R, Samuel P. (
2000
) Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.
Am J Cardiol
 
85
:
1100
–1105.
43
Kashyap ML, McGovern ME, Berra K, Guyton JR, Kwiterovich PO, Harper WL, Toth PD, Favrot LK, Kerzner B, Nash SD, Bays HE, Simmons PD. (
2002
) Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia.
Am J Cardiol
 
89
:
672
–678.
44
Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. (
2004
) Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.
Circulation
 
110
:
3512
–3517.
45
Wolfe ML, Vartanian SF, Ross JL, Bansavich LL, Mohler ER III, Meagher E, Friedrich CA, Rader DJ. (
2001
) Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia.
Am J Cardiol
 
87
:
476
–479.
46
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. (
1999
) Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
N Engl J Med
 
341
:
410
–418.
47
Rinninger F, Kaiser T, Windler E, Greten H, Fruchart J-C, Castro G. (
1998
) Selective uptake of cholesteryl esters from high-density lipoprotein-derived LPA-I and LPA-I:A-II particles by hepatic cells in culture.
Biochim Biophys Acta
 
1393
:
277
–291.
48
Nicholls SJ, Rye KA, Barter PJ. (
2005
) High-density lipoproteins as therapeutic targets.
Curr Opin Lipidol
 
16
:
345
–349.
49
McGovern ME. (
2005
) Symposium on dyslipidaemia. Taking aim at HDL-C: Raising levels to reduce cardiovascular risk.
Postgrad Med
 
117
:
29
–39.
50
Sakai T, Kamanna VS, Kashyap ML. (
2001
) Niacin but not gemfibrozil selectively increases LP-AI a cardioprotective subfraction of HDL in patients with low HDL cholesterol.
Arterioscler Thromb Vasc Biol
 
21
:
1783
–1789.
51
Morgan JM, Capuzzi DM, Baksh RI, Intenzo C, Carey CM, Reese D, Walker K. (
2003
) Effects of extended-release niacin on lipoprotein subclass distribution.
Am J Cardiol
 
91
:
1432
–1436.
52
Bays HE and McGovern ME. (
2003
) Once-daily niacin extended release/lovastatin combination tablet has more favorable effects on lipoprotein particle size and subclass distribution than atorvastatin and simvastatin.
Prev Cardiol
 
6
:
179
–188.
53
Ikewaki K, Noma K, Tohyama J, Kido T, Mochizuki S. (
2005
) Effects of bezafibrate on lipoprotein subclasses and inflammatory markers in patients with hypertriglyceridemia–a nuclear magnetic resonance study.
Int J Cardiol
 
101
:
441
–447.
54
Sasaki J, Yamamoto K, Ageta M. (
2002
) Effects of fenofibrate on high-density lipoprotein particle size in patients with hyperlipidemia: a randomized, double-blind, placebo-controlled, multicenter, crossover study.
Clin Ther
 
24
:
1614
–1626.
55
Durrington PN, Mackness MI, Bhatnagar D, Julier K, Prais H, Arrol S, Morgan J, Wood GN. (
1998
) Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia.
Atherosclerosis
 
138
:
217
–225.
56
Kahri J, Sane T, van Tol A, Taskinen MR. (
1995
) Effect of gemfibrozil on the regulation of HDL subfractions in hypertriglyceridaemic patients.
J Intern Med
 
238
:
429
–436.
57
Chapman MJ, Assmann G, Fruchart JC, Shepherd J, Sirtori C. (
2004
) Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid—a position paper developed by the European Consensus Panel on HDL-C.
Curr Med Res Opin
 
20
:
1253
–1268.
58
Nam BH, Kannel WB, D'Agostino RB. (
2006
) Search for an optimal atherogenic lipid risk profile: from the Framingham study.
Am J Cardiol
 
97
:
372
–375.
59
Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. (
1977
) High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study.
Am J Med
 
62
:
707
–714.