Abstract

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.

Introduction and rationale

Despite considerable improvements in medical care over the past 25 years, cardiovascular disease (CVD) remains a major public health challenge. In Europe, CVD is responsible for nearly 50% of all deaths and is the main cause of all disease burden,1 with management costs estimated at €192 billion annually.2 However, with the increasing incidence of obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM),3 this burden is projected to escalate dramatically. At a time when Europe, like other developed regions, is faced with the need to contain expenditure, urgent action is needed to address this critical problem.

Current best treatment including lifestyle intervention and pharmacotherapy aimed at lowering plasma concentrations of low-density-lipoprotein cholesterol (LDL-C), reducing blood pressure, and preventing thrombotic events fails to ‘normalize' risk in people at high risk of CVD (i.e. SCORE > 5% for CVD death4 or 10-year Framingham risk score >20% for CVD events5). Individuals with acute coronary syndromes (ACS) are at very high risk of recurrent events: ∼10% occur within the first 6–12 months,6,7 and ∼20–30% within 2 years.8,9 As the risk of recurrent events in statin-treated coronary heart disease (CHD) patients increases incrementally with each additional feature of the metabolic syndrome,10 this implies that other CV risk factors beyond LDL-C may deserve attention. These risk factors may be modifiable, e.g. non-LDL-C dyslipidaemia, hypertension, and abdominal obesity, or non-modifiable, e.g. age and gender. Therapeutic interventions targeted to the former group clearly hold potential for reducing this high CV risk that persists even with optimal treatment of LDL-C.

Post hoc analyses of prospective trials in ACS and stable CHD patients reveal that elevated plasma levels of triglycerides and low plasma concentrations of high-density lipoprotein cholesterol (HDL-C) are intimately associated with this high risk, even at or below recommended LDL-C goals.11–14 Furthermore, in T2DM patients, the UKPDS identified HDL-C as the second most important coronary risk factor, after LDL-C.15 Despite these data, guidelines are inconsistent in their recommendations for proposed levels of HDL-C or triglycerides either for initiation of additional therapies or for targets for such treatments in patients at LDL-C goal.4,5,16–19

The aim of this paper is to critically appraise the current evidence relating to triglycerides and HDL-C as CV risk factors or markers and to consider therapeutic strategies for their management. The focus is on individuals with cardiometabolic risk, characterized by the clustering of central obesity, insulin resistance, dyslipidaemia, and hypertension, which together increase the risk of CVD and T2DM.18

The EAS Consensus Panel is well aware of uncertainties and controversies regarding triglycerides and HDL-C levels, both as risk markers or targets of therapy. Triglycerides are predominantly carried in fasting conditions in very low-density lipoproteins (VLDLs) and their remnants, and postprandially in chylomicrons and their remnants. The generic term ‘triglyceride-rich lipoprotein remnants', therefore, relates to chylomicron and VLDL particles which have undergone dynamic remodelling in the plasma after secretion from the intestine (chylomicrons) or liver (VLDL) (Figure 1). This remodelling results in a spectrum of particles which are heterogeneous in size, hydrated density, and lipid and protein composition20 and include intermediate-density lipoprotein (IDL) particles. No single biochemical trait allows the differentiation of remnants from newly secreted chylomicrons, VLDL and IDL.21 Thus, plasma triglyceride levels correspond essentially to the sum of the triglyceride content in nascent VLDL and their remnants in the fasting state, together with that in chylomicrons and their remnants in the postprandial state. Consequently, the Panel has used the generic term ‘triglyceride-rich lipoprotein (TRL) remnants’ as a surrogate for plasma levels of both newly secreted TRLs and their remnants, the latter predominating in the typical person with cardiometabolic risk.21 As discussed below, increasing evidence suggests that remodelled chylomicrons and VLDL are atherogenic, primarily as a result of their progressive enrichment with cholesterol and depletion of triglycerides in the plasma compartment. This process also results in progressive reduction in their size. The term ‘TRL remnants’ has been used to emphasize our focus on atherogenic lipoproteins themselves rather than their major lipids.

Figure 1

Upon entry into the circulation, chylomicrons (containing apo B-48) produced by the small intestine, and VLDL (containing apo B-100) produced by the liver undergo LPL–mediated lipolysis mainly in peripheral tissues, notably adipose tissue and muscle. Intravascular remodelling of TRL equally involves the actions of lipid transfer proteins (CETP, PLTP) and additional lipases (HL and EL) with the formation of remnant particles. TRL remnants are typically enriched in cholesterol and apo E, but depleted in triglyceride; they are principally catabolized in the liver upon uptake through the LRP and LDL receptor pathways. TRL remnants can contribute either directly to plaque formation following penetration of the arterial wall at sites of enhanced endothelial permeability,21 or potentially indirectly following liberation of lipolytic products (such as FFA and lysolecithin) which may activate pro-inflammatory signalling pathways in endothelial cells.20,21 Abbreviations: apo, apolipoprotein; CETP, cholesteryl ester transfer protein; EL, endothelial lipase; FFA, free fatty acids; HL, hepatic lipase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LRP, lipoprotein receptor-related protein; PLTP, phospholipid transfer protein; TRL, triglyceride-rich lipoprotein; VLDL, very-low density lipoprotein.

Figure 1

Upon entry into the circulation, chylomicrons (containing apo B-48) produced by the small intestine, and VLDL (containing apo B-100) produced by the liver undergo LPL–mediated lipolysis mainly in peripheral tissues, notably adipose tissue and muscle. Intravascular remodelling of TRL equally involves the actions of lipid transfer proteins (CETP, PLTP) and additional lipases (HL and EL) with the formation of remnant particles. TRL remnants are typically enriched in cholesterol and apo E, but depleted in triglyceride; they are principally catabolized in the liver upon uptake through the LRP and LDL receptor pathways. TRL remnants can contribute either directly to plaque formation following penetration of the arterial wall at sites of enhanced endothelial permeability,21 or potentially indirectly following liberation of lipolytic products (such as FFA and lysolecithin) which may activate pro-inflammatory signalling pathways in endothelial cells.20,21 Abbreviations: apo, apolipoprotein; CETP, cholesteryl ester transfer protein; EL, endothelial lipase; FFA, free fatty acids; HL, hepatic lipase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LRP, lipoprotein receptor-related protein; PLTP, phospholipid transfer protein; TRL, triglyceride-rich lipoprotein; VLDL, very-low density lipoprotein.

Similarly, the Panel understands that, despite epidemiologic data and evidence from some animal models22 implying a role for HDL as anti-atherogenic and vasculoprotective lipoproteins, the metabolic and functional pathways linking HDL-C levels and protection from CVD are poorly defined. The Panel also recognizes that HDL represent a highly dynamic pool of heterogenous particles.23 As HDL particles vary greatly in terms of lipid and protein composition, it was decided to focus on HDL-C as the marker of CVD risk.

Lipid and lipoprotein metabolism

Cholesterol, in both free and esterified forms, and triglycerides are the two main lipids in plasma. They are transported in lipoproteins, pseudomicellar lipid–protein complexes, in which the main apolipoproteins, apo B-100/48, apo A-I, apo A-II, apo E, and the apo Cs, are integral components. Apo B is a component of all atherogenic lipoproteins (chylomicron remnants, VLDL and their remnants, IDL, lipoprotein(a) [Lp(a)] and LDL), whereas apo A-I and apo A-II are components of HDL. The apo B-containing lipoproteins and the apo A-I/A-II lipoprotein classes are closely interrelated via several metabolic pathways (Figure 2).23–25

Figure 2

Metabolic pathways for HDL and triglyceride-rich lipoprotein remnants highlight their close interrelationship. De novo production of nascent HDL (discs) occurs in the liver and small intestine through the production of apo A-I (the major HDL protein) and lipidation (with cholesterol and phospholipids) of this protein by the ATP-binding cassette transporter (ABCA1) in these organs. Upon secretion, lecithin: cholesterol acyltransferase (LCAT) esterifies cholesterol on these discs which mature into spherical particles (due to the formation of a hydrophobic core resulting from generation of cholesteryl esters by LCAT). HDL undergoes extensive interconversion through triglyceride lipolysis (hepatic lipase, HL), phospholipid hydrolysis (endothelial lipase, EL), fusion (phospholipid transfer protein, PLTP), and lipid exchange among the HDL subpopulations (cholesteryl ester transfer protein, CETP). CETP also mediates major lipid transfer and exchange between HDL and triglyceride-rich lipoproteins (VLDL, chylomicrons) and their remnants [VLDL remnants = intermediate-density lipoproteins (IDLs), chylomicron remnants]. During this process, cholesteryl esters are transfered from HDL to VLDL and triglycrides move from VLDL to HDL.24 Chylomicrons also act as cholestery ester acceptors from LDL and HDL during the post-prandial phase.25 A second route that contributes to the plasma HDL pool involves hydrolysis of triglycerides in VLDL, IDL, and chylomicrons. In this process which is catalysed by lipoprotein lipase (LPL), phospholipids, as well as several apolipoproteins (such as apo CI, CII, CIII, AV) are transferred to HDL. PLTP contributes significantly to this remodelling process.

Figure 2

Metabolic pathways for HDL and triglyceride-rich lipoprotein remnants highlight their close interrelationship. De novo production of nascent HDL (discs) occurs in the liver and small intestine through the production of apo A-I (the major HDL protein) and lipidation (with cholesterol and phospholipids) of this protein by the ATP-binding cassette transporter (ABCA1) in these organs. Upon secretion, lecithin: cholesterol acyltransferase (LCAT) esterifies cholesterol on these discs which mature into spherical particles (due to the formation of a hydrophobic core resulting from generation of cholesteryl esters by LCAT). HDL undergoes extensive interconversion through triglyceride lipolysis (hepatic lipase, HL), phospholipid hydrolysis (endothelial lipase, EL), fusion (phospholipid transfer protein, PLTP), and lipid exchange among the HDL subpopulations (cholesteryl ester transfer protein, CETP). CETP also mediates major lipid transfer and exchange between HDL and triglyceride-rich lipoproteins (VLDL, chylomicrons) and their remnants [VLDL remnants = intermediate-density lipoproteins (IDLs), chylomicron remnants]. During this process, cholesteryl esters are transfered from HDL to VLDL and triglycrides move from VLDL to HDL.24 Chylomicrons also act as cholestery ester acceptors from LDL and HDL during the post-prandial phase.25 A second route that contributes to the plasma HDL pool involves hydrolysis of triglycerides in VLDL, IDL, and chylomicrons. In this process which is catalysed by lipoprotein lipase (LPL), phospholipids, as well as several apolipoproteins (such as apo CI, CII, CIII, AV) are transferred to HDL. PLTP contributes significantly to this remodelling process.

In dyslipidaemic patients with cardiometabolic risk, increased free fatty acid flux may represent a significant abnormality driving increased hepatic assembly and secretion of VLDL, IDL, and/or LDL particles, although other mechanisms are also implicated.26,27 Low plasma levels of HDL-apo A-I are associated with its increased fractional removal.26 This is driven by both cholesteryl ester transfer protein (CETP)-mediated heteroexchange of triglycerides from apo B lipoproteins with cholesteryl ester from apo A-I lipoproteins, and dissociation of apo A-I from triglyceride-enriched HDL with clearance via the kidney.26,28,29 Such metabolic perturbations are frequently associated with insulin resistance, which may in turn influence the activities of lipoprotein lipase (LPL), CETP and potentially, hepatic lipase (HL), phospholipid transfer protein, and endothelial lipase. Within this large dyslipidaemic group, however, many patients do not exhibit insulin resistance but nonetheless display a mixed dyslipidaemia characterized by elevated levels of TRL and LDL. This lipid phenotype typically involves subnormal concentrations of HDL-C and increased cardiovascular risk.30 Finally, although there are close links, both pathophysiologic and genetic, between the dyslipidaemia of insulin resistance and the phenotype of familial combined hyperlipidaemia (FCHL),31 some individuals with elevated levels of TRL remnants do not have insulin resistance or T2DM.30,32,33 Such individuals are at increased risk for premature CVD, although it is not clear if this risk is higher or lower than in those with the dyslipidaemia of insulin resistance and/or T2DM.

Pharmacological correction of hypertriglyceridaemia in T2DM does not usually normalize low apo A-I levels, which probably reflects the complex mechanisms involved.26,29 The complexity of HDL metabolism is clearly relevant when strategies to raise HDL-C are reviewed; indeed, HDL-C concentration is at most an indirect marker of the anti-atherogenic activities that are associated with this lipoprotein.28

What is the experimental evidence that triglyceride-rich lipoprotein remnants and high-density lipoprotein play a role in the pathophysiology of atherothrombosis?

The retention of cholesterol-rich lipoproteins within the subendothelial matrix of the arterial wall is a key initiator of atherosclerosis.34 Sites of endothelial dysfunction constitute preferential arterial locations for lipoprotein penetration, accumulation, and plaque formation.34 Although LDL is considered the main atherogenic cholesterol-rich particle, other apo B-containing lipoproteins (TRL, their remnants, and Lp(a)) also contribute to intimal cholesterol deposition, particularly as they contain a similar number of cholesterol molecules per particle (∼ 2000) as LDL.21,35 In contrast, HDLs were originally thought to readily enter the subendothelial space and then return to the circulation,36 although recent studies highlight the need to reconsider this notion.37

Experimental studies show that particle size is a key determinant. While large chylomicrons and VLDL fail to penetrate the arterial wall, their smaller remnants not only penetrate the arterial intima but may be bound and retained by connective tissue matrix.38,39 Accumulation of both chylomicron and VLDL remnants enriched in apo E has been demonstrated in human and rabbit atherosclerotic plaques.20,39–41 Such particles, also referred to as ‘β-VLDL', can be taken up directly by arterial macrophages with massive cholesterol loading and foam cell formation.42,43 Elevated levels of TRL remnants have also been linked to the progression of coronary artery disease44 and the presence of echolucent carotid artery plaques.45 Clearly, TRL remnant cholesterol can contribute directly to plaque formation and progression.20

Triglyceride-rich lipoprotein remnants may also drive atherogenesis via indirect mechanisms, particularly those involving binding and lipolysis at the artery wall.20 Such mechanisms provide a key link to accelerated atherogenesis in the postprandial phase. Acutely elevated TRL remnants occurring in this phase are associated with impaired vasodilation,46 upregulated pro-inflammatory cytokine production,47 and enhanced inflammatory response and monocyte activation.48–51 All of these mechanisms may underlie endothelial dysfunction. Moreover, TRL remnants are of relevance to plaque disruption and subsequent thrombus formation, key events in the onset of most ACS.52,53 Triglyceride-rich lipoprotein remnants stimulate the secretion of tissue factor from endothelial cells and monocytes,54 and promote thrombin generation at levels similar to those caused by activated platelets.55 Elevated triglycerides are linked with raised concentrations of fibrinogen and coagulation factors VII and XII, and with impaired fibrinolysis as determined by enhanced gene expression and concentrations of plasminogen activator inhibitor-1.56,57

In contrast to TRL remnants, HDLs display a wide spectrum of biological activities (Box 1), of which cellular cholesterol efflux activity, and anti-inflammatory and anti-oxidative actions are key.23,28 HDLs also contribute to pancreatic beta-cell function.58–60 The functionality of HDL is potentially highly vasculoprotective. HDLs maintain endothelial vasoreactivity, attenuate oxidative stress, inhibit endothelial cell apoptosis, contribute to the repair of damaged endothelium,61,62 inhibit monocyte activation,63 and reduce the expression of adhesion molecules and cytokines.28 Apo A–I may also immunoregulate lymphocytes and mononuclear cells.63,64 All of these actions may potentially attenuate component steps of atherosclerotic plaque formation.23,28,65

Box 1
HDL functionality: relevance to athero/vasculo-protection

• Cellular cholesterol efflux and cholesterol homeostasis

• Regulation of glucose metabolism

• Anti-inflammatory activity

• Anti-oxidative activity

• Anti-apoptotic activity

• Endothelial repair

• Vasodilatory activity

• Anti-thrombotic activity

• Anti-protease activity

• Anti-infectious activity

To what degree can HDL counteract the prothrombogenic activity of TRL remnants, particularly since insulin-resistant states associate with thrombotic risk clustering?57 HDL and apo A-I protect erythrocytes against the generation of procoagulant activity66 and augment the anticoagulant activity of protein S. The latter enhances the function of activated protein C, a critical factor in regulating blood coagulation by proteolytic inactivation of factors Va and VIIIa.67 HDL also affect platelet aggregation, inhibiting thrombin-induced binding of fibrinogen to platelets.68 Finally, in T2DM, in which HDL anti–atherogenic function is defective,28 infusion of reconstituted (r)HDL increases the anti-inflammatory and in vitro cholesterol efflux potential of HDL69 and reduces platelet hyperreactivity by lowering the cholesterol content of platelet membranes.70 Considered together, these data suggest a unifying hypothesis for the anti-atherothrombogenic actions of HDL and point to a crucial role in cellular cholesterol homeostasis. Significantly, HDL-mediated cholesterol efflux activity from macrophages was recently shown to be relevant both to carotid-intima thickness and coronary artery disease.71

A critical question is whether HDL impact long-term CV risk via these effects on the atherosclerotic process. The data from animal models have shown that overexpression of the human apo A-I gene increases HDL-C levels, protecting against diet-induced atherosclerosis.72 In addition, infusion of HDL or apo A–IMilano/phospholipid complexes reduced aortic lipid deposition and induced regression of atherosclerosis in rabbits.73,74 In humans, infusion of synthetic rHDL restored endothelial function in hypercholesterolaemic patients.75 Infusion of recombinant apo A–IMilano/phospholipid complexes reduced coronary atherosclerosis in ACS patients, although there was no dose-dependent effect.76 More recently, rHDL infusion reduced atheroma volume in subjects with premature coronary77 or peripheral atherosclerosis.78 Observational data from four intravascular ultrasound trials (two with statins) showed that lowering plasma apo B lipoprotein concentrations together with simultaneous minor elevation of HDL-C levels achieved plaque regression and stabilization.79 All of these findings urgently require confirmation in larger randomized studies.

Thus, in summary, the data indicate that TRL remnants and HDL are relevant throughout all stages of atherothrombosis, especially within the context of the insulin resistance syndrome.57

Prevalence of elevated triglyceride-rich lipoprotein remnants and low high-density lipoprotein cholesterol

First, it is important to ascertain the prevalence of atherogenic dyslipidaemia, i.e. the combination of elevated TRL remnants and/or low HDL-C.80 Among the general population plasma concentrations of total cholesterol, LDL-C and HDL-C are normally distributed. In contrast, the distributions of triglycerides, remnant cholesterol, apo B, and non-HDL-C (i.e. total cholesterol−HDL-C) tend to be skewed with a tail toward the highest levels. In the Copenhagen General Population Study, low HDL-C levels were frequently associated with elevated levels of cholesterol and TRL remnants (Figure 3). Approximately 45% of men and 30% of women in the study had triglycerides ≥1.7 mmol/L (150 mg/dL) with or without HDL-C < 1.0 mmol/L (40 mg/dL) (BG Nordestgaard, unpublished results). HDL-C levels are lower in Turkish populations, largely due to genetic predisposition.81,82 The Turkish Heart Study reported that ∼50% of men and ∼25% of women had HDL-C levels ≤0.9 mmol/L (35 mg/dL).82 As in other countries, atherogenic dyslipidaemia is on the rise, due to the increasing prevalence of the metabolic syndrome. In the Turkish Adults Risk Factor Study, ∼40% of men and 35% of women had triglycerides >1.7 mmol/L with or without low HDL-C (≤0.9 mmol/L or 35 mg/dL).83

Figure 3

Lipoprotein cholesterol as a function of increasing levels of non-fasting triglycerides in the general population. Based on non-fasting samples from 36 160 men and women from the Copenhagen General Population Study collected over the period 2003–2007; 9% of men and 6% of women were on statins, mainly 40 mg/day simvastatin. Remnant cholesterol is calculated from a non-fasting lipid profile as total cholesterol minus HDL cholesterol minus LDL cholesterol; under these conditions, remnant cholesterol represents the total cholesterol transported in IDL, VLDL, and chylomicron remnants. Variable levels of chylomicrons are present in non-fasting samples and usually will only contribute minimally to the calculated remnant cholesterol. Nordestgaard BG 2010, unpublished results.

Figure 3

Lipoprotein cholesterol as a function of increasing levels of non-fasting triglycerides in the general population. Based on non-fasting samples from 36 160 men and women from the Copenhagen General Population Study collected over the period 2003–2007; 9% of men and 6% of women were on statins, mainly 40 mg/day simvastatin. Remnant cholesterol is calculated from a non-fasting lipid profile as total cholesterol minus HDL cholesterol minus LDL cholesterol; under these conditions, remnant cholesterol represents the total cholesterol transported in IDL, VLDL, and chylomicron remnants. Variable levels of chylomicrons are present in non-fasting samples and usually will only contribute minimally to the calculated remnant cholesterol. Nordestgaard BG 2010, unpublished results.

Atherogenic dyslipidaemia is more prevalent in individuals at high risk of CVD. In the Swedish National diabetes register including >75 000 T2DM subjects, 37–38% had untreated hypertriglyceridaemia (>1.7 and ≤4.0 mmol/L, i.e. >150 and ≤354 mg/dL) with or without low HDL-C.84 More than one-third of the CHD patients in EUROASPIRE III had elevated triglycerides (≥1.7 mmol/L or 150 mg/dL) and/or low HDL-C; ∼50% of patients from Turkey had low HDL-C.85 In the PROCAM study, about twice as many myocardial infarction (MI) survivors had elevated triglycerides (≥2.28 mmol/L or 200 mg/dL) and/or low HDL-C (<1.05 mmol/L or 40 mg/dL) vs. matched controls; CV risk associated with this dyslipidaemic profile was higher also at low LDL-C levels.86 Together, these observational data highlight an unmet clinical need for treatment beyond LDL-C lowering in patients at high risk of CVD with atherogenic dyslipidaemia.

What is the evidence that triglyceride-rich lipoprotein remnants and high-density lipoprotein cholesterol contribute to cardiovascular risk?

The data from epidemiological and genetic studies are relevant to this question.

Epidemiology

General populations

Large observational studies clearly show that both elevated triglycerides (either fasting or non-fasting)87–90 and reduced plasma levels of HDL-C91–93 are associated with increased CV risk. Scepticism of the role of elevated levels of TRL remnants in atherosclerosis and CVD has persisted despite the observation that patients with dysbetalipoproteinaemia (remnant hyperlipidaemia) with accumulation of apo E and cholesterol-rich remnants typically display premature atherosclerosis and high CVD risk.94 Some suggested that individuals with lifelong, extremely high triglycerides (25–300 mmol/L or 2200–26550 mg/dL) and familial chylomicronaemia (e.g. due to LPL deficiency) did not present with accelerated atherosclerosis.94 Others observed the opposite,95 consistent with experimental data in animal models.96,97 However, the rarity of this disease prevents firm conclusions to be made.

The Emerging Risk Factors Collaboration (ERFC)93 provides the most robust evidence for the association of HDL-C with CV risk (Figure 4). This analysis of 68 studies in 302 430 participants without prior history of CVD used individual participant data, allowing for harmonization and consistent adjustment of confounding factors, hitherto unfeasible. HDL-C was strongly associated with coronary risk even after adjustment for non-HDL-C and loge triglycerides and non-lipid risk factors. Each unit of standard deviation (SD) increase in HDL-C concentration (0.38 mmol/L or 15 mg/dL) was associated with 22% reduction in CHD risk. Importantly, this protective effect was equal across the range of triglyceride levels. However, it is acknowledged that the data are not clear for HDL-C levels <0.5 or >2.2–2.5 mmol/L (<19 mg/dL or >85–100 mg/dL). Non-HDL-C and apo B each had very similar associations with CHD. Both HDL-C and non-HDL-C were also modestly associated with ischaemic stroke (Figure 4), but not haemorrhagic stroke.

Figure 4

Hazard ratios for coronary heart disease and ischaemic stroke across quantiles of usual concentrations of triglycerides, HDL, and non-HDL cholesterol levels. Reproduced with permission from the Emerging Risk Factors Collaboration.93 Copyright© (2009) American Medical Association. All rights reserved.

Figure 4

Hazard ratios for coronary heart disease and ischaemic stroke across quantiles of usual concentrations of triglycerides, HDL, and non-HDL cholesterol levels. Reproduced with permission from the Emerging Risk Factors Collaboration.93 Copyright© (2009) American Medical Association. All rights reserved.

While coronary risk was increased by 37% (95% CI 31–42%) per SD increase in loge triglycerides, this association was weakened after adjustment for HDL-C and abrogated after correction for non-HDL-C. Additionally, triglycerides were not associated with stroke risk after adjustment for other lipid factors.93 These data are compatible with the view that it is the number of TRL and remnant particles that cause CVD. Thus, the risk associated with elevated triglycerides can be explained by this lipid acting as a marker for increased numbers of TRL, which in turn are closely associated with the combination of higher levels of non-HDL-C and low levels of HDL-C. In the Copenhagen City Heart Study, increased risk for MI, ischaemic stroke, and mortality was evident at markedly elevated triglycerides (>5.0 mmol/L or >450 mg/dL), although these data were not adjusted for non-HDL-C (Figure 5).89,90 Thus, low HDL-C and elevated non-HDL-C and triglycerides appear to be relevant to CV risk beyond LDL-C.

Figure 5

Relationship of non-fasting triglycerides (up to and >5 mmol/L or 440 mg/dL) and risk of myocardial infarction, ischaemic stroke, and total mortality. Results are shown as age-adjusted hazard ratios from the Copenhagen City Heart Study with 26–31 years of follow-up. Reproduced with modification from Nordestgaard et al.89 and Freiberg et al.90 Copyright© (2007, 2008) American Medical Association. All rights reserved.

Figure 5

Relationship of non-fasting triglycerides (up to and >5 mmol/L or 440 mg/dL) and risk of myocardial infarction, ischaemic stroke, and total mortality. Results are shown as age-adjusted hazard ratios from the Copenhagen City Heart Study with 26–31 years of follow-up. Reproduced with modification from Nordestgaard et al.89 and Freiberg et al.90 Copyright© (2007, 2008) American Medical Association. All rights reserved.

Clinical trial populations

Epidemiological evidence for low HDL-C as a major, independent CV risk factor is strengthened when considering clinical trial data in high-risk statin-treated patients (Table 1).12,98–100 In the TNT study, low on-treatment HDL-C concentration was a significant predictor for coronary events at low LDL-C (<1.8 mmol/L or 70 mg/dL), even after adjustment for CV risk factors, including on-treatment LDL-C and triglycerides and baseline HDL-C.12 A meta-regression analysis questioned the relevance of HDL-C to CV risk, although methodological issues may limit its validity101 [the analysis included 299 310 participants at risk of CV events in 108 studies of any lipid-modifying agent (either as monotherapy or in combination) or diet/surgery with a minimum of 6 months follow-up. There were no significant associations between the treatment-induced change in HDL-C and risk ratios for CHD events, CHD death, or total mortality after adjustment for changes in LDL-C. However, there are a number of important methodological issues with this analysis including: (i) the use of aggregated data rather than individual subject data; (ii) the method of analysis which describes an observational association and therefore risks bias by confounding; (iii) the combination of treatments and diets with important differences in pharmacology or mechanism of action; and (iv) failure to take account of the effect of baseline lipid profile which is known to influence the extent of HDL-C-raising]. Recently, a meta-analysis of 170 000 subjects in 26 statin trials (24 332 CVD events) showed that irrespective of the achieved LDL-C level or the intensity of statin therapy, CV risk was always lower at higher levels of achieved HDL-C, with no attenuation of this relationship at low LDL-C levels. The lowest risk was observed in those with both a low LDL-C and a high HDL-C.100 This largely refutes suggestions that HDL-C concentration may be less predictive at very low LDL-C levels as in the JUPITER trial (393 CV events).102

Table 1

Overview of epidemiological evidence in community and clinical intervention populations supporting the association of low high-density lipoprotein cholesterol and/or elevated triglycerides with cardiovascular disease

Data source Population Key findings 
HDL-C 
 ERFC93 General population, no prior CVD HDL-C was independently predictive of coronary events and ischaemic stroke, even after adjustment for lipid and non-lipid risk factors 
 SPARCL98 Patients with previous cerebrovascular disease Greater decrease in recurrent stroke risk with on-treatment HDL-C levels above vs. below the median (1.2 mmol/L), independent of change in LDL-C 
 CTT99,100 Primary and secondary prevention, on statin Irrespective of achieved LDL-C levels or statin intensity, CV risk was lower at higher levels of achieved HDL-C. This was not attenuated at low LDL-C levels 
 TNT12 CHD, on potent statin therapy Predictive power of low on-treatment HDL-C concentrations remained even at low LDL-C (<1.8 mmol/L) 
 MIRACL13 ACS, on statin HDL-C but not LDL-C was an independent predictor of short-term prognosis after ACS 

 
Triglycerides 
 ERFC93 General population, no prior CVD The association of triglycerides and CV outcomes disappeared after adjustment for HDL-C and non-HDL-C 
 PROVE-IT TIMI 2211 ACS, on potent statin therapy On treatment triglycerides <1.7 mmol/L were independently associated with a lower risk of recurrent coronary events in ACS patients at LDL-C goal (<1.8 mmol/L) 
 Pooled analysis of IDEAL and TNT104,105 Secondary prevention (CHD, ACS) on potent statin therapy Decrease in CV events with lowering of triglycerides (P < 0.001 for trend); association attenuated by adjustment for HDL-C and apo B/apo A-I 
Data source Population Key findings 
HDL-C 
 ERFC93 General population, no prior CVD HDL-C was independently predictive of coronary events and ischaemic stroke, even after adjustment for lipid and non-lipid risk factors 
 SPARCL98 Patients with previous cerebrovascular disease Greater decrease in recurrent stroke risk with on-treatment HDL-C levels above vs. below the median (1.2 mmol/L), independent of change in LDL-C 
 CTT99,100 Primary and secondary prevention, on statin Irrespective of achieved LDL-C levels or statin intensity, CV risk was lower at higher levels of achieved HDL-C. This was not attenuated at low LDL-C levels 
 TNT12 CHD, on potent statin therapy Predictive power of low on-treatment HDL-C concentrations remained even at low LDL-C (<1.8 mmol/L) 
 MIRACL13 ACS, on statin HDL-C but not LDL-C was an independent predictor of short-term prognosis after ACS 

 
Triglycerides 
 ERFC93 General population, no prior CVD The association of triglycerides and CV outcomes disappeared after adjustment for HDL-C and non-HDL-C 
 PROVE-IT TIMI 2211 ACS, on potent statin therapy On treatment triglycerides <1.7 mmol/L were independently associated with a lower risk of recurrent coronary events in ACS patients at LDL-C goal (<1.8 mmol/L) 
 Pooled analysis of IDEAL and TNT104,105 Secondary prevention (CHD, ACS) on potent statin therapy Decrease in CV events with lowering of triglycerides (P < 0.001 for trend); association attenuated by adjustment for HDL-C and apo B/apo A-I 

ACS, acute coronary syndromes; apo, apolipoprotein; CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; CTT, Cholesterol Treatment Trialists’ Collaboration; ERFC, Emerging Risk Factors Collaboration; IDEAL, Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering; MIRACL, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering; PROVE-IT TIMI 22, Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22; TNT, Treating to New Targets (study).

While the 4S trial showed no association between on-treatment levels and changes from baseline levels for triglycerides and reduction in CV risk,103 data from more recent trials are indicative of association.11,104,105 In the PROVE IT-TIMI 22 trial, on-treatment triglycerides <1.7 mmol/L (<150 mg/dL) were independently associated with a lower risk of recurrent coronary events in ACS patients at LDL-C goal (<1.8 mmol/L or 70 mg/dL).11 Further, pooled analysis of the TNT and IDEAL trials showed a trend for decreased CV event risk with lowering of triglycerides (P < 0.001), although this was attenuated by adjustment for HDL-C and the ratio of apo B/apo A–I.104

In T2DM patients, the FIELD and ACCORD Lipid studies showed that marked atherogenic dyslipidaemia (triglycerides ≥2.3 mmol/L or 204 mg/dL and low HDL-C levels (≤0.88 mmol/L or 34 mg/dL in ACCORD Lipid) was associated with increased CV event rates (by ∼30–70% vs. those without this profile).106,107 Analyses from FIELD show that the hazard ratios for HDL-C, apo A–I, apo B, and non-HDL-C were comparable for the prediction of CV risk whereas that for serum triglycerides was attenuated by adjustment for HDL-C (P = 0.07),108 concordant with the ERFC analysis.

Taken together, these observational and clinical trial data support the view that (i) a low HDL-C concentration is associated with CVD independent of LDL-C (or non-HDL-C) levels, and (ii) that elevated triglycerides are moderately associated with CVD, potentially largely through the number of TRL remnants. Thus, while LDL-C lowering remains the first priority, therapeutic targeting of low HDL-C and elevated TRL remnants may offer the possibility of incremental reduction in CV risk in high-risk populations.

Genetic studies of triglyceride and high-density lipoprotein metabolism

In contrast, genetic studies do not provide clear insights into CV risk associated with changes in plasma triglycerides and HDL-C levels. This is not unexpected as predictions based on epidemiological studies may be inappropriate tools to assess complex biological pathways, especially for HDL metabolism. Monogenic disorders of triglyceride metabolism (involving functional mutations in the LPL, APOCIII, APOAV, LMF1, and GPIHBP1 genes) and HDL metabolism (involving the APOAI, LCAT, ABCA1, LIPC, LIPG, CETP, and SCARB1 genes) have so far failed to provide answers,109 probably due to the rarity of these disorders. On the other hand, there is unequivocal evidence for markedly accelerated atherosclerosis and CVD in dysbetalipoproteinaemia, a familial dyslipidaemia in which the critical defect is homozygosity for the receptor binding-defective form of apo E, i.e. apo E2/E2,94 resulting in markedly elevated plasma levels of TRL remnants enriched in cholesterol and apo E.

Studies of frequent genetic coding variants and single-nucleotide polymorphisms (SNPs) in non-coding DNA (with no known direct functional significance), such as in the LPL gene, show an association between the combination of elevated triglycerides and low HDL-C and an increase in CV risk.110–114 In the initial genome-wide association studies (GWAS), variation at HDL loci was not associated with CVD risk; however, a recent meta-analysis identified four novel loci associated with CHD that were related to HDL-C or triglycerides (but not LDL-C), suggesting that pathways specifically relating to HDL or triglyceride metabolism may also modulate coronary risk.115 Collaborative analysis of a specific APOA5 variant (−1131T>C) that regulates triglycerides showed an association with coronary risk. The odds ratio for CHD (1.18, 95% CI 1.11–1.26) per C allele was also concordant with the hazard ratio (1.10, 95% CI 1.08–1.12) per 16% higher triglyceride concentrations in prospective studies, suggesting a causal association between triglyceride-mediated pathways (specifically high levels of remnant lipoproteins and low HDL-C) and CHD.116

Data for gene variants associated with isolated changes in plasma HDL-C levels are more conflicting. For example, increased plasma levels of HDL-C were correlated with increased CV risk in individuals with SNPs in the LIPC gene associated with reduced HL activity.117–119 In contrast, genetic variants in ABCA1 associated with substantial reductions in HDL-C levels (with no changes in other lipids) were not associated with increased CV risk.120 On the other hand, three common CETP genotypes (TaqIB, I405V, and −629C>A) associated with lower CETP activity and higher HDL-C levels were inversely associated with coronary risk.114 In GWAS of genes known to impact HDL metabolism, the effects that such variants exert on HDL-C levels account for <5% and frequently <2% of variability.121,122 These data imply that in the general population, HDL-C concentration represents the integral sum of many gene effects on HDL metabolism. The current literature on the human genetics of HDL and TRL and their remnants highlights the need for clarification of the interaction between genes and different metabolic pathways, particularly for HDL.

What is the clinical evidence that modulation of triglyceride-rich lipoprotein, their remnants, and high-density lipoprotein cholesterol impacts atherosclerosis and cardiovascular disease?

Lifestyle approaches

Lifestyle interventions influence the metabolism of HDL and TRL remnants (Table 2).123–140 Smoking increases TRL remnants and decreases HDL-C levels,141 secondary to insulin resistance and hyperinsulinaemia;142 these effects are rapidly reversed on quitting.123 Aerobic exercise causes long-lasting reduction in triglycerides by up to 20% and increases in HDL-C by up to 10%, although the same effects should not be assumed with progressive resistance training (Table 2). In T2DM subjects, intensive lifestyle intervention (weight loss, diet, and increased physical activity) had beneficial effects on glycaemic control and cardiometabolic risk factors, including HDL-C and triglycerides,143–145 and, in the longer term was associated with reduction in CVD risk.146 Other trials showed reduction in risk of progression to diabetes in people with impaired glucose tolerance,147,148 and improvement in other atherogenic processes including inflammation with physical activity.127

Table 2

Effects of lifestyle interventions on plasma concentrations of HDL cholesterol and triglycerides

Intervention ▵ HDL-C Mechanism ▵ triglycerides Mechanism 
Smoking cessation123 ↑ 5–10% ↑ LCAT and cholesterol efflux; ↓CETP No significant change reported – 

 
Weight loss124 ↓ during active weight loss ↑ LCAT, LPL, cholesterol efflux ↓ by 0.015 mmol/L per kg weight loss ↑ VLDL clearance 
↑ after weight stabilization by 0.009 mmol/L per kg weight lost ↓ catabolism of HDL, apo A-I  ↓ hepatic VLDL secretion 

 
Exercise125–131 
 Aerobic ↑ 5–10% (moderate to high intensity) ↑ pre-β HDL, cholesterol efflux, LPL ↓ 10–20% (moderate to high intensity) ↓ hepatic VLDL-TG secretion; 
↑ in HDL size ↓ ∼30% in VLDL-TG Beneficial adaptations in muscle fibre area, capillary density, glycogen synthase, and GLTU4 protein expression in T2DM or impaired glucose tolerance 
 Resistance No significant change reported Improved HDL functionality ↓ ∼ 5% 
 Alcohol132–134 ↑ 5–10% (1–3 drinks/day) ↑ ABCA1, apo A-I Variable response, ↑↑ in obese subjects ↑ synthesis of VLDL–TG with excess intake 
↓ CETP ↑↑ with excess intake 

 
Dietary factors135–140     
 n-3-PUFAs, n-6-PUFAs, MUFAs 0 to ↑ 5% Improves ratio of LDL-C/HDL-C ↓ 10–15% ↑ TG-rich lipoprotein clearance via pathways mediated by apo CIII and apo E 
Improves HDL anti-inflammatory activity ↓ VLDL apo B secretion 
 Omni-Heart ↑ by <5%  ↓ 56% (increased protein)  
  ↓ 33% (increased USFA)  
Intervention ▵ HDL-C Mechanism ▵ triglycerides Mechanism 
Smoking cessation123 ↑ 5–10% ↑ LCAT and cholesterol efflux; ↓CETP No significant change reported – 

 
Weight loss124 ↓ during active weight loss ↑ LCAT, LPL, cholesterol efflux ↓ by 0.015 mmol/L per kg weight loss ↑ VLDL clearance 
↑ after weight stabilization by 0.009 mmol/L per kg weight lost ↓ catabolism of HDL, apo A-I  ↓ hepatic VLDL secretion 

 
Exercise125–131 
 Aerobic ↑ 5–10% (moderate to high intensity) ↑ pre-β HDL, cholesterol efflux, LPL ↓ 10–20% (moderate to high intensity) ↓ hepatic VLDL-TG secretion; 
↑ in HDL size ↓ ∼30% in VLDL-TG Beneficial adaptations in muscle fibre area, capillary density, glycogen synthase, and GLTU4 protein expression in T2DM or impaired glucose tolerance 
 Resistance No significant change reported Improved HDL functionality ↓ ∼ 5% 
 Alcohol132–134 ↑ 5–10% (1–3 drinks/day) ↑ ABCA1, apo A-I Variable response, ↑↑ in obese subjects ↑ synthesis of VLDL–TG with excess intake 
↓ CETP ↑↑ with excess intake 

 
Dietary factors135–140     
 n-3-PUFAs, n-6-PUFAs, MUFAs 0 to ↑ 5% Improves ratio of LDL-C/HDL-C ↓ 10–15% ↑ TG-rich lipoprotein clearance via pathways mediated by apo CIII and apo E 
Improves HDL anti-inflammatory activity ↓ VLDL apo B secretion 
 Omni-Heart ↑ by <5%  ↓ 56% (increased protein)  
  ↓ 33% (increased USFA)  

ABCA1, ATP-binding cassette transporter; apo, apolipoprotein; CETP, cholesteryl ester transfer protein; GLUT4, glucose transporter type 4; HDL, high-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; TG, triglycerides; T2DM, type 2 diabetes mellitus; USFA, unsaturated fatty acids; VLDL, very low-density lipoprotein.

In CHD patients, lifestyle intervention trials have shown reduced progression of atherosclerosis,149–151 as well as reduction in the risk of CV events.152–154 Both the Diet and Reinfarction Trial153 and the Lyon Diet Heart Study154 showed substantial reduction in coronary events (by at least 50%) with lifestyle intervention in MI survivors, but require replication to confirm these benefits. However, while a healthy lifestyle clearly is important in reducing CV risk, poor long-term adherence is a problem, and therefore many of these patients require additional pharmacological intervention.

Clinical intervention studies

Statin therapy alone, in addition to best standards of care, is unable to completely normalize CV risk associated with atherogenic dyslipidaemia. Higher doses may partially correct residual dyslipidaemia, but can also increase the risk of side effects, especially myopathy. Addition of ezetimibe or bile acid resins to statin therapy has little effect on triglycerides and HDL-C levels; resins may even raise triglycerides. Evidence is supportive of therapeutic approaches aimed at concomitantly lowering TRL and raising HDL-C to reduce CV risk.155 Of these options, both niacin and fibrates influence levels of multiple lipids and lipoproteins (Box 235,156,157) and therefore clinically beneficial effects observed cannot be ascribed solely to changes in any single lipoprotein fraction. Pathways implicated in the lipid effects of niacin, fibrates, and omega-3 fatty acids are summarized in Table 3.158–170

Table 3

Mechanisms implicated in the lipid-modifying activity of niacin, fibrates and omega-3 fatty acids

Drug Proposed mechanisms 
Niacin156,158–161,166 Not clear. the following have been implicated: 
↓ TG synthesis and hepatic secretion of VLDL 
Possibly, direct inhibition of DGAT-2 
Partial inhibition of hormone sensitive TG lipase in adipose tissue 
Up-regulation of apo A-I production 
Possibly, delayed catabolism of larger HDL particles 
Potential attenuation of CETP activity 

 
Fibrate156,162–166 Transcriptional regulation mediated via interaction with PPARα. Pathways involved include: 
↑ catabolism of VLDL, IDL, and LDL apo B100 due to ↑ LPL expression and activity 
↓ production rate of apo CIII, thereby potentiating LPL activity (fenofibrate) 
↑ VLDL apo B or VLDL-TG turnover (bezafibrate, gemfibrozil) 
↑ production of apo A-II and lipoprotein AI:AII although no change in lipoprotein A-I with fenofibrate 
↑ HDL2a/HDL3a,linked to reduced CETP activity 

 
Omega-3 fatty acids138,157,167–170 Transcriptional regulation of SREBP-1c and PPARα 
Inhibition of hormone-sensitive TG lipase and stimulation of LPL possibly through regulation of PPARδ 
↓ TG secretion and and lipogenesis 
↑ mitochondrial and peroxisomal fatty acid oxidation 
Inhibition of DGAT-2 
↓ VLDL B secretion, specifically VLDL1 
↑ conversion of VLDL to LDL 
↓ catabolism of HDL apo A-I 
Drug Proposed mechanisms 
Niacin156,158–161,166 Not clear. the following have been implicated: 
↓ TG synthesis and hepatic secretion of VLDL 
Possibly, direct inhibition of DGAT-2 
Partial inhibition of hormone sensitive TG lipase in adipose tissue 
Up-regulation of apo A-I production 
Possibly, delayed catabolism of larger HDL particles 
Potential attenuation of CETP activity 

 
Fibrate156,162–166 Transcriptional regulation mediated via interaction with PPARα. Pathways involved include: 
↑ catabolism of VLDL, IDL, and LDL apo B100 due to ↑ LPL expression and activity 
↓ production rate of apo CIII, thereby potentiating LPL activity (fenofibrate) 
↑ VLDL apo B or VLDL-TG turnover (bezafibrate, gemfibrozil) 
↑ production of apo A-II and lipoprotein AI:AII although no change in lipoprotein A-I with fenofibrate 
↑ HDL2a/HDL3a,linked to reduced CETP activity 

 
Omega-3 fatty acids138,157,167–170 Transcriptional regulation of SREBP-1c and PPARα 
Inhibition of hormone-sensitive TG lipase and stimulation of LPL possibly through regulation of PPARδ 
↓ TG secretion and and lipogenesis 
↑ mitochondrial and peroxisomal fatty acid oxidation 
Inhibition of DGAT-2 
↓ VLDL B secretion, specifically VLDL1 
↑ conversion of VLDL to LDL 
↓ catabolism of HDL apo A-I 

apo, apolipoprotein; CETP, cholesteryl ester transfer protein; DGAT-2, diacylglycerol O-acyltransferase 2; IDL, intermediate-density lipoproteins; LPL, lipoprotein lipase; PPAR, peroxisome proliferator-activated receptor; SREBP, sterol regulatory element binding proteins; TG, triglycerides; VLDL, very low-density lipoproteins.

Box 2
Lipid effects of niacin, fibrates and omega-3 fatty acids
 ▵ LDL-C ▵ HDL-C ▵ TG ▵ Lp(a) 
Niacin (ER, 2 g/day) ↓ 20% ↑ up to 30%a ↓ up to 35% ↓ up to 30–40% 
• Effects are dose-dependent ↑ large LDL ↑ large HDL 
Fibrates Variableb ↑ by 5–20%c ↓ by 25–50% No effect 
• Response dependent on baseline levelsb ↑ large LDL 
Omega-3 fatty acids ↑/no change ↑/no change ↓ by 20–50% No effect 
 ▵ LDL-C ▵ HDL-C ▵ TG ▵ Lp(a) 
Niacin (ER, 2 g/day) ↓ 20% ↑ up to 30%a ↓ up to 35% ↓ up to 30–40% 
• Effects are dose-dependent ↑ large LDL ↑ large HDL 
Fibrates Variableb ↑ by 5–20%c ↓ by 25–50% No effect 
• Response dependent on baseline levelsb ↑ large LDL 
Omega-3 fatty acids ↑/no change ↑/no change ↓ by 20–50% No effect 

aConsistent HDL-C raising by up to 25% has been observed in patients with T2DM.

bEffects depend on the individual fibrate, baseline lipid profile, and metabolic nature of dyslipidaemia.

cAlthough increases in HDL-C with fibrates may be up to 20% in short-term studies, in long-term outcome studies in patients with T2DM the response to fenofibrate was much less (<5% at study close out), suggesting that fibrate treatment may be ineffective for raising HDL-C in this patient group.

Niacin

Niacin at therapeutic doses has a broad spectrum of effects on lipid and lipoprotein metabolism, including raising of HDL-C (Box 2).156 While various pathways are implicated,158–161 its mechanism of action is incompletely elucidated (Table 3). Niacin may also promote beneficial vasoprotective and anti-inflammatory effects independent of its lipid-modifying activity.171–173

Imaging trials clearly document attenuated progression of atherosclerosis and intima-media thickening by niacin (Supplementary material online, Table S1).174–182 The only major outcome study to date, the Coronary Drug Project, showed that niacin (immediate-release 3 g/day) was associated with a 26% reduction in non-fatal MI (P < 0.005) at 6–7 years, and 11% reduction in all-cause mortality (P = 0.0004) at 15 years (∼9 years after the end of treatment).183,184 These clinical benefits were similar in patients with or without hyperglycaemia, diabetes, or metabolic syndrome.185,186 A recent meta-analysis of niacin studies has confirmed these findings.187

Niacin may increase insulin resistance to a minor degree, although this may be potentially counterbalanced by recently documented protective effects of HDL on pancreatic beta cells.58,59 In the ADMIT and ADVENT studies in diabetic patients, potentially deleterious effects on glycaemia were effectively counteracted by adjusting anti-diabetic medication.188,189 However, the risk of new incident diabetes induced by niacin in insulin-resistant or pre-diabetic individuals remains indeterminate.

In patients with atherogenic dyslipidaemia, the combination of niacin plus statin improved the lipid-modifying efficacy of statin alone and was generally well-tolerated.190–192 Combination of niacin with laropiprant, an inhibitor of the prostaglandin D2 receptor,193 significantly reduced but did not abolish flushing, the main tolerability issue. Among patients with T2DM, transient impairment of glucose control was reported (median increase in HbA1C 0.3% over 12 weeks),194,195 consistent with known effects with niacin.188,189 Emerging evidence suggests that statin plus niacin can reduce progression of atherosclerosis in high-risk patients, including those with low LDL-C, as in the Oxford Niaspan trial182 (Supplementary material online, Table S1). There are limited data concerning the risk of myopathy with niacin-statin combination therapy. Definitive evidence regarding the longer-term risks of incident diabetes, myotoxicity, and hepatoxicity are awaited from the HPS2–THRIVE and AIM-HIGH trials (projected enrolment 25 000 and 3300, respectively). Data from AIM-HIGH are expected in early 2013.

In summary (Box 3), evidence for the anti-atherosclerotic action of niacin is robust.156 A meta-analysis also suggests that adding niacin to a statin may provide superior reduction in CV risk beyond that achieved with statin alone.187 The results of HPS2-THRIVE and AIM–HIGH will help discern whether niacin–statin therapy is effective across a wide spectrum of dyslipidaemic patients, or only in those with high triglycerides/low HDL-C dyslipidaemia.

Box 3
Impact of niacin on atherosclerosis and clinical outcomes

• Anti-atherosclerotic effects of niacin in combination with a statin have been extensively documented in plaque imaging studies in coronary and carotid arteries (see )

• Meta-analysis of niacin trials, several of which involved small patient numbers, is indicative of clinical benefit in patients with cardiometabolic disease187

• Ongoing trials (AIM-HIGH, HPS2-THRIVE) will evaluate whether ER niacin on top of statin therapy can reduce the CV risk that typically persists despite statin monotherapy in patients with atherogenic dyslipidemia and cardiometabolic disease

• HPS2-THRIVE, given the broad range of patients, will reveal whether niacin–statin therapy is effective across a wide spectrum of dyslipidaemic patients or only in those with high triglycerides/low HDL-C dyslipidaemia

Fibrates

Fibrates impact multiple pathways of lipid metabolism and may equally exert pleiotropic effects via regulation of genes influencing vascular inflammation and thrombogenesis. Their lipid-modifying effects (Box 2) are mediated primarily via interaction with peroxisome proliferator-activated receptor alpha (PPARα) (Table 3).156,162–166

Angiographic trials showed that fibrate therapy may attenuate atherosclerosis progression,196–198 although the impact on the progression of intima–media thickening has not been consistent199–201 (Supplementary material online, Table S2). Results from individual monotherapy outcomes trials have been variable and primarily indicate a reduction in nonfatal MI and revascularization, with no effect on stroke or CV death,202–207 subsequently confirmed by a meta-analysis.208Post hoc analyses of several of these trials provided consistent evidence suggestive of clinical benefit in the subgroup of patients with elevated triglycerides and low HDL-C (Table 4).106,206,209,210 Indeed, a recent meta-analysis confirmed enhanced benefit with fibrates in patients with atherogenic dyslipidaemia vs. those without.211 On the basis of such evidence, fibrate treatment appears appropriate in this subgroup (Box 4).

Box 4
Statin-fibrate combination therapy: current status

• Recent evidence from a meta-analysis suggests that fibrate therapy on a background of statin treatment provides clinical benefit in subgroups of patients with atherogenic dyslipidemia (Table 4)

• A large prospective trial to determine the long-term cardiovascular effects of a statin–fibrate combination in patients with the high triglyceride and low HDL-C phenotype is urgently needed

Table 4

Subgroup analyses of cardiovascular outcome studies with fibrates

Trial Treatment (mg/day) Patient characteristics All patients
 
Elevated triglycerides and low HDL-C subgroup 
   Primary endpoint Relative risk reduction Primary endpoint Lipid criteria mmol/L Relative risk reduction 
Fibrate monotherapy vs. placebo 
 WHO trial202 (n= 5331) Clofibrate 1600 Upper-third of cholesterol values, without CHD Non-fatal MI + CHD death 20% (P < 0.05) – –  
 CDP203 (n= 3892) Clofibrate 1800 (n= 1103) CHD Nonfatal MI + CHD death 9% (P= 0.12) – –  
 HHS204,209 (n= 4081) Gemfibrozil 1200 Non-HDL-C ≥200 mg/dL without CHD Fatal + non-fatal MI + cardiac death 34% (P< 0.02) As for all patients TG >2.3 + HDL-C <1.08 65% (P= 0.01) 
 VA-HIT205,210 (n= 2531) Gemfibrozil 1200 CHD + low HDL-C (<40 mg/dL) Non-fatal MI + CHD death 22% (P= 0.006) As for all patients TG >2.03 + HDL-C ≤1.03 28% (P < 0.05) 
 BIP206 (n= 3090) Bezafibrate 400 Previous MI or angina Fatal + non-fatal MI + sudden death 9.4% (P= 0.26) As for all patients TG ≥2.26 + HDL-C <0.91 42% (P = 0.02) 
 FIELD106,207 (n= 9795) Fenofibrate 200 Type 2 diabetes (22% with CVD) Non-fatal MI + CHD death 11% (P= 0.16) Total CV events TG ≥2.30 + low HDL-Ca 27% (P = 0.005) 

 
Statin-fibrate vs. statin monotherapy 
 ACCORD Lipid107 (n= 5518) Fenofibrate 160 + simvastatin Type 2 diabetes (37% with CVD) CVD death, nonfatal MI + non-fatal stroke 8% (P= 0.32) As for all patients TG ≥2.30 + HDL-C ≤0.88 31%; P-value not reported 
Trial Treatment (mg/day) Patient characteristics All patients
 
Elevated triglycerides and low HDL-C subgroup 
   Primary endpoint Relative risk reduction Primary endpoint Lipid criteria mmol/L Relative risk reduction 
Fibrate monotherapy vs. placebo 
 WHO trial202 (n= 5331) Clofibrate 1600 Upper-third of cholesterol values, without CHD Non-fatal MI + CHD death 20% (P < 0.05) – –  
 CDP203 (n= 3892) Clofibrate 1800 (n= 1103) CHD Nonfatal MI + CHD death 9% (P= 0.12) – –  
 HHS204,209 (n= 4081) Gemfibrozil 1200 Non-HDL-C ≥200 mg/dL without CHD Fatal + non-fatal MI + cardiac death 34% (P< 0.02) As for all patients TG >2.3 + HDL-C <1.08 65% (P= 0.01) 
 VA-HIT205,210 (n= 2531) Gemfibrozil 1200 CHD + low HDL-C (<40 mg/dL) Non-fatal MI + CHD death 22% (P= 0.006) As for all patients TG >2.03 + HDL-C ≤1.03 28% (P < 0.05) 
 BIP206 (n= 3090) Bezafibrate 400 Previous MI or angina Fatal + non-fatal MI + sudden death 9.4% (P= 0.26) As for all patients TG ≥2.26 + HDL-C <0.91 42% (P = 0.02) 
 FIELD106,207 (n= 9795) Fenofibrate 200 Type 2 diabetes (22% with CVD) Non-fatal MI + CHD death 11% (P= 0.16) Total CV events TG ≥2.30 + low HDL-Ca 27% (P = 0.005) 

 
Statin-fibrate vs. statin monotherapy 
 ACCORD Lipid107 (n= 5518) Fenofibrate 160 + simvastatin Type 2 diabetes (37% with CVD) CVD death, nonfatal MI + non-fatal stroke 8% (P= 0.32) As for all patients TG ≥2.30 + HDL-C ≤0.88 31%; P-value not reported 

aIn FIELD, low HDL-C was defined as <1.03 mmol/L in men and <1.29 mmol/L in women.

CHD, coronary heart disease; CV, cardiovascular; MI, myocardial infarction; WHO, World Health Organization.

ACCORD, Action to Control Cardiovascular Risk in Diabetes; BIP, Bezafibrate Infarction Prevention study; CDP, Coronary Drug Project; FIELD, Fenofibrate Intervention and Event Lowering in Diabetes study; HHS, Helsinki Heart Study; VA-HIT, Veterans Affairs HDL Intervention Trial.

Combination of a statin with a fibrate (primarily fenofibrate) incrementally decreased plasma triglycerides by 15–20% and raised HDL-C by 5–20% vs. statin monotherapy.212–215 Similar effects were seen in FIELD and ACCORD Lipid, although the placebo-corrected increments in HDL-C in the total study cohorts were less than 3%.107,207 In ACCORD Lipid, the only completed outcome study of combination therapy, fenofibrate–simvastatin had no effect on the primary outcome vs. simvastatin alone for all patients. Importantly, however, in the fenofibrate–simvastatin group, there was a 31% reduction in CV risk in the subgroup with baseline triglycerides in the upper tertile (≥2.3 mmol/L or 204 mg/dL) and HDL-C levels in the lower tertile (≤0.88 mmol/L or 34 mg/dL) vs. simvastatin monotherapy (Table 4).107 The available data also suggest that fenofibrate exerts microvascular benefits, notably in preventing progression of retinopathy in T2DM patients.216,217

Concerns about the safety of statin–fibrate combination therapy relate chiefly to the risk of myopathy, although this is substantially lower with fenofibrate than gemfibrozil.218 Current evidence based on ACCORD Lipid suggests that the incidence of myopathy with fenofibrate–statin combination therapy is similar to that with niacin–statin combination therapy.107,219 There were no reports of rhabdomyolysis with fenofibrate–statin combination therapy in either FIELD or ACCORD Lipid,107,207 and in ACCORD Lipid no increase in the incidence of venous thromboembolic disease, pancreatitis, or non-CV mortality.107 Fenofibrate increased serum creatinine and homocysteine (a rapidly reversible effect),107,220 and in the FIELD Helsinki cohort, decreased creatinine clearance and estimated glomerular filtration rate, with no effect on the urinary albumin creatinine ratio.221 Elevated serum homocysteine levels have been suggested as the basis for the neutral effect of fenofibrate on apo A-I.222 The clinical significance of these effects remains unclear. Finally, all fibrates are known to increase the long-term risk of cholelithiasis.218

In summary, statins firmly remain the first line treatment of choice for attainment of LDL-C goal in patients at high risk of CVD.4,5 After LDL-C goal attainment however, and if triglyceride levels remain elevated (≥1.7 mmol/L or 150 mg/dL, as defined by recent European guidelines4) and HDL-C low (<1.0 mmol/L or 40 mg/dL) despite intensive lifestyle intervention, then addition of a fibrate or niacin may be considered (Figure 6).

Figure 6

Proposed algorithm for the management of high-risk individuals with elevated triglycerides and/or low HDL cholesterol at LDL cholesterol goal. aLDL-C at goal as recommended by the most recent European guidelines (2007);4 <2.5 mmol/L in high-risk patients, decreasing to <2.0 mmol/L in very high risk patients. High-dose omega-3 fatty acids, fibrate, or niacin may be considered if the patient has very high TG (>5.0 mmol/L) to prevent pancreatitis. bIf the patient still has elevated TG (≥1.7 mmol/L, as recommended by the most recent European guidelines4) and/or low HDL-C (<1.0 mmol/L) despite intensive lifestyle intervention, and addressing compliance with pharmacotherapy and secondary causes of dyslipidaemia, additional lipid-modifying therapy may be considered. cBased on clinical outcome data and safety considerations for combination statin–fibrate therapy, fenofibrate is the preferred fibrate. This fibrate may have particular value in patients with T2DM and mild-to-moderate retinopathy. dGreater LDL-C lowering may be achieved by the addition of ezetimibe to a statin. Ezetimibe has a dose-sparing advantage in patients intolerant of higher dose statins, although outcome evidence to support its use is awaited. Note: To convert LDL-C or HDL-C from mmol/L to mg/dL multiply by 38.7; to convert TG from mmol/L to mg/dL multiply by 88.5. Abbreviations: TG, triglycerides; HDL-C, high-density-lipoprotein cholesterol; LDL-C, low-density-lipoprotein cholesterol.

Figure 6

Proposed algorithm for the management of high-risk individuals with elevated triglycerides and/or low HDL cholesterol at LDL cholesterol goal. aLDL-C at goal as recommended by the most recent European guidelines (2007);4 <2.5 mmol/L in high-risk patients, decreasing to <2.0 mmol/L in very high risk patients. High-dose omega-3 fatty acids, fibrate, or niacin may be considered if the patient has very high TG (>5.0 mmol/L) to prevent pancreatitis. bIf the patient still has elevated TG (≥1.7 mmol/L, as recommended by the most recent European guidelines4) and/or low HDL-C (<1.0 mmol/L) despite intensive lifestyle intervention, and addressing compliance with pharmacotherapy and secondary causes of dyslipidaemia, additional lipid-modifying therapy may be considered. cBased on clinical outcome data and safety considerations for combination statin–fibrate therapy, fenofibrate is the preferred fibrate. This fibrate may have particular value in patients with T2DM and mild-to-moderate retinopathy. dGreater LDL-C lowering may be achieved by the addition of ezetimibe to a statin. Ezetimibe has a dose-sparing advantage in patients intolerant of higher dose statins, although outcome evidence to support its use is awaited. Note: To convert LDL-C or HDL-C from mmol/L to mg/dL multiply by 38.7; to convert TG from mmol/L to mg/dL multiply by 88.5. Abbreviations: TG, triglycerides; HDL-C, high-density-lipoprotein cholesterol; LDL-C, low-density-lipoprotein cholesterol.

Omega-3 fatty acids

Long chain omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) 2–4 g/day] are approved as an adjunct to diet for lowering plasma triglycerides when >5.5 mmol/L (490 mg/dL) to prevent pancreatitis. The profile of lipid-modifying activity is given in Box 2 and mechanisms involved are summarized in Table 3.138,157,167–170

Outcome benefits for omega-3 fatty acids have been reported but relate to lower doses than required clinically to lower triglycerides (Supplementary material online, Table S3).223–225 These benefits may be explained by anti-arrhythmic effects, independent of triglycerides.226 The AFORRD trial in T2DM patients showed no benefit after 4 months of omega-3 fatty acids (2 g/day) in combination with atorvastatin on estimated CV risk.227 Adverse effects are limited to minor dyspepsia, with no evidence of increased risk of significant bleeding, even with concomitant aspirin or warfarin.

Future options

HDL-C-raising per se may represent a key determinant of the clinical benefits associated with lipid-modifying therapy,228 although this concept still needs proof from randomized intervention trials.

CETP inhibitors increase HDL-C levels substantially, and some also affect LDL-C and triglyceride levels.166 Dalcetrapib (JTT-705) exerts moderate effects on plasma lipids (raising HDL-C by up to 37%),229 whereas torcetrapib was far more potent (increases in HDL-C >70%), and modestly reduced LDL-C (∼20%) and triglycerides (9%).166 Despite this, the first outcome study with torcetrapib, ILLUMINATE, was prematurely terminated due to excess mortality.230 However, recent evidence231,232 suggests that off-target pharmacological effects of torcetrapib were responsible for this adverse outcome rather than a class effect of CETP inhibitors. In all trials, torcetrapib treatment was associated with an increase in systolic blood pressure and electrolyte changes, mediated via hyperaldosteronism. Concerns that large HDL generated through CETP inhibition would be dysfunctional have not been supported by in vitro studies.233,234 Other CETP inhibitors (e.g. dalcetrapib and anacetrapib) do not show the off-target effects associated with torcetrapib, as indicated by recent studies.235,236 Clinical outcome data from ongoing or planned studies (dal-OUTCOMES with dalcetrapib and REVEAL with anacetrapib) are awaited.

What is the evidence for a causal role of elevated triglyceride-rich lipoprotein and their remnants and/or low high-density lipoprotein cholesterol in premature atherosclerosis and cardiovascular disease?

The EAS Consensus Panel considers that for an interpretation of causality, five types of evidence should each favour causality (Table 5) with consistent evidence required from all three types of clinical evidence (epidemiology, genetics, and intervention trials).237 For elevated LDL-C, the consensus is definite causality. The Panel contends, on the basis of available evidence, that elevated TRL and their remnants combined with low HDL-C may also play a causal role in premature atherosclerosis, whereas insufficient data are currently available for assessing the causality of TRL and remnants alone. The clinical relevance of isolated low HDL-C to CVD also remains unclear.238

Table 5

Evidence supporting the contention that elevated LDL-C, elevated fasting or non-fasting TRL and their remnants, and subnormal HDL-C alone and/or together play causal roles in CVD

Type of evidence Elevated LDL-C Elevated TRL, their remnants or low HDL-C 
Human epidemiology Direct association between LDL-C and CVD in numerous studies Direct association between TG and CVD in numerous studies; association lost on correction for non-HDL-C and HDL-C in ERFC93 
Strong inverse association between low HDL-C and CVD in numerous studies; association maintained after correction for TG and non-HDL-C in ERFC93 
Mechanistic studies Definitive mechanistic evidence; LDL accumulate in arterial intima and promote atherosclerosis Arterial accumulation of TRL and their remnants to promote atherosclerosis like LDL, with potential pro-inflammatory and pro-thrombotic/anti-fibrinolytic effects 
In vitro and ex vivo evidence for potential anti-inflammatory vasculoprotective, anti-thrombotic and cytoprotective effects of HDL particles; central implication of cholesterol acceptor activity 
Animal models Pro-atherogenic effect in numerous studies Pro-atherogenic and pro-inflammatory effects for TRL and their remnants 
Atheroprotection exerted by elevated HDL or apo A-I levels 
Human genetic studies Direct causal association in numerous studies, and notably in familial hypercholesterolaemia Dysbetalipoproteinaemia (remnant hyperlipidaemia , apo E2/E2) provides causal evidence for the atherogenicity of elevated TRL and their remnants 
Lack of definitive insight for HDL-C, potentially due to the complexity of HDL metabolism 
Human intervention studies Statin trials provided conclusive proof of causality Imaging trials reveal that fibrate therapy may impact atherosclerosis progression but fails to slow intima–media thickening; see Supplementary material online, Table S2 
Meta-analysis of fibrate trials (+statin) show clinical benefit limited to non-fatal CV events.208 Subgroup analyses reveal major reduction in CV events in patients with high TG and low HDL-C211 
Niacin imaging trials showed consistent stabilization and/or regression of atherosclerosis or intima–media thickening in monotherapy or in combination; see Supplementary material online, Table S1 
Reduction in CV events and total mortality with niacin monotherapy183,184 
Interpretation 2010a Definite causality Evidence suggestive of a strong causal association of atherogenic dyslipidaemia, i.e. elevated TRL and their remnants combined with low HDL-C 
Insufficient evidence for TRL and their remnants alone 
Insufficient evidence for low HDL-C alone 
Type of evidence Elevated LDL-C Elevated TRL, their remnants or low HDL-C 
Human epidemiology Direct association between LDL-C and CVD in numerous studies Direct association between TG and CVD in numerous studies; association lost on correction for non-HDL-C and HDL-C in ERFC93 
Strong inverse association between low HDL-C and CVD in numerous studies; association maintained after correction for TG and non-HDL-C in ERFC93 
Mechanistic studies Definitive mechanistic evidence; LDL accumulate in arterial intima and promote atherosclerosis Arterial accumulation of TRL and their remnants to promote atherosclerosis like LDL, with potential pro-inflammatory and pro-thrombotic/anti-fibrinolytic effects 
In vitro and ex vivo evidence for potential anti-inflammatory vasculoprotective, anti-thrombotic and cytoprotective effects of HDL particles; central implication of cholesterol acceptor activity 
Animal models Pro-atherogenic effect in numerous studies Pro-atherogenic and pro-inflammatory effects for TRL and their remnants 
Atheroprotection exerted by elevated HDL or apo A-I levels 
Human genetic studies Direct causal association in numerous studies, and notably in familial hypercholesterolaemia Dysbetalipoproteinaemia (remnant hyperlipidaemia , apo E2/E2) provides causal evidence for the atherogenicity of elevated TRL and their remnants 
Lack of definitive insight for HDL-C, potentially due to the complexity of HDL metabolism 
Human intervention studies Statin trials provided conclusive proof of causality Imaging trials reveal that fibrate therapy may impact atherosclerosis progression but fails to slow intima–media thickening; see Supplementary material online, Table S2 
Meta-analysis of fibrate trials (+statin) show clinical benefit limited to non-fatal CV events.208 Subgroup analyses reveal major reduction in CV events in patients with high TG and low HDL-C211 
Niacin imaging trials showed consistent stabilization and/or regression of atherosclerosis or intima–media thickening in monotherapy or in combination; see Supplementary material online, Table S1 
Reduction in CV events and total mortality with niacin monotherapy183,184 
Interpretation 2010a Definite causality Evidence suggestive of a strong causal association of atherogenic dyslipidaemia, i.e. elevated TRL and their remnants combined with low HDL-C 
Insufficient evidence for TRL and their remnants alone 
Insufficient evidence for low HDL-C alone 

aFor an interpretation of causality given the data available in 2010, all five types of evidence should favour causality and all three types of human studies (epidemiology, genetics, and intervention trials) must be consistent; this is clearly the case for elevated LDL-C.

Guidance for clinical management

The EAS Consensus Panel believes that targeting a high triglyceride/low HDL-C phenotype is likely to be beneficial in patients with CVD or at high risk of CVD, especially those with cardiometabolic abnormalities. The therapeutic needs of these patients are likely to exceed LDL-C lowering by statin monotherapy.239 The recommended steps for managing these patients after achieving LDL-C goal, as defined by the most recent European guidelines,4 are summarized in Figure 6. The Panel proposes triglycerides as a marker for TRL and their remnants. Elevated triglycerides (≥1.7 mmol/L or 150 mg/dL, consistent with European guidelines4) and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) are triggers for considering further treatment in both men and women. HDL-C levels <1.0 mmol/L (40 mg/dL) in men and <1.2 mmol/L (45 mg/dL) in women are also considered a CV risk factor in current European guidelines.4 It is noteworthy that in ACCORD Lipid, a cutoff for triglycerides of ≥2.3 mmol/L identified statin-treated patients at high CV risk, who may respond to fibrates.107 For simplicity and convenience, measurement of non-fasting plasma lipids is recommended, supported by data from the ERFC,93 but care should be taken when interpreting triglyceride levels in individuals who have recently consumed a high-fat meal.

The Panel stresses that lifestyle modifications (Box 5) should underpin the management of all patients at increased CV risk, especially those with elevated triglycerides (≥1.7 mmol/L or 150 mg/dL) and/or low plasma levels of HDL-C (<1.0 mmol/L or 40 mg/dL). As non-compliance can be a significant issue, addressing its causes and identifying solutions, including improvement in physician–patient alliance is essential. Secondary causes of dyslipidaemia, including poor glycaemic control, obesity, diets high in refined carbohydrates, alcohol excess, lack of exercise, and smoking must be addressed. Despite adherence to lifestyle interventions, it is likely that many of these patients with atherogenic dyslipidaemia will require pharmacotherapy. At least 50% of all high-risk patients on a statin may require optimization of treatment to further lower LDL-C,240 and about 10–15%107 may need additional treatment for elevated triglycerides and/or low HDL-C. In these patients, clinicians may consider adding niacin or a fibrate, while taking into account potential safety issues, as discussed in this paper.

Box 5
Recommended basic lifestyle interventions to lower triglycerides and increase HDL-C

• Stop smoking: all smokers at high cardiovascular risk unable to quit smoking should be referred to specialized smoking cessation clinics

• Increase physical activity: aim for at least 30 min of moderate aerobic activity (activity producing a heart rate of 60–75% of age-related maximum heart rate) for at least 5 days per week

• Adopt a Mediterranean-type diet characterized by high monounsaturated and low saturated fatty acids, and low-carbohydrate content. Avoid refined sugar and fructose rich diets which aggravate dyslipidaemia. Increase intake of complex carbohydrates, viscous fibre, and whole-grains

• Lose weight: obese and overweight subjects should adopt a calorie restriction diet, aiming to achieve optimal weight or at least to lose 10% of body weight

• Restrict alcohol intake to less than 30 g per day (<20 g/day in women). Avoid alcohol consumption in case of high triglyceride levels

In view of its broad spectrum lipid-modulating actions in atherogenic dyslipidaemia (Box 2), niacin may be of special value for reducing TRL and their remnants concomitant with raising HDL-C levels among patients with cardiometabolic abnormalities, particularly those with insulin resistance. However, definitive data from AIM-HIGH and HPS2-THRIVE are needed. Niacin is also unique in lowering Lp(a) levels.35 Treatment with niacin is supported by clinical evidence of stabilization or regression of atherosclerosis in clinical trials (see Niacin subsection). In practice, plasma glucose and urate levels should be monitored regularly for the possibility of hyperglycaemia and hyperuricaemia, respectively, and liver function tests should be monitored to exclude hepatotoxicity. In patients with impaired fasting glucose or impaired glucose tolerance, lifestyle modification is the first option to control glucose, and if niacin is introduced glucose levels should be monitored.

The current level of evidence for clinical outcomes benefits and safety suggests that fenofibrate may be the preferred fibrate for combination with a statin, and may also have particular value in T2DM patients with mild-to-moderate retinopathy.216,217 From a safety perspective, pre-treatment serum transaminases, creatine (phospho)kinase, and creatinine should be measured. Creatine (phospho)kinase should be repeated if myalgia is reported, or there are known risk factors for myopathy, and treatment discontinued if levels exceed five times the upper limit of normal and/or symptoms are severe. Alanine and aspartate transaminases should be monitored 3 months after starting therapy and annually thereafter, but more frequently if the dose of statin is uptitrated. Serum creatinine should be monitored with statin–fenofibrate combinations.

If patients are intolerant of both niacin and fenofibrate, a high dose of omega-3 fatty acids ethyl esters may be considered. In patients with very high triglycerides (>5.5 mmol/L or 490 mg/dL), fenofibrate, niacin, or high-dose omega-3 fatty acids (3–4 g/day), together with a very low fat diet (<10% of calorie intake) and reduced alcohol intake, are recommended to prevent acute pancreatitis consistent with current guidelines.4

The Panel believes there is insufficient evidence to permit definition of targets for triglycerides or HDL-C for these high-risk patients. Instead, the Panel proposes that treatment should be tailored to the individual to achieve desirable levels below (for triglycerides or non-HDL-C) or above (for HDL-C) the recommended cut-offs (Box 6). The Panel acknowledges that other expert bodies recommend apo B as a secondary therapeutic target in hypertriglyceridaemic patients,18.19 but considers that the precise clinical yield of this approach has yet to be demonstrated. The Panel also recognizes the limitations of the current evidence base for fibrates, niacin, and omega-3 fatty acids, including the lack of hard outcome data for statin–niacin and statin–omega-3 fatty acid combination therapies. Clearly, there is a need for well-defined trials to evaluate the efficacy and safety of these therapeutic combinations in high-risk patients at LDL-C goal with elevated triglycerides and/or low HDL-C.

Box 6
Desirable lipid levels in patients at high risk of CVD, according to recent European guidelines4
LDL-C <2.5 mmol/L (100 mg/dL) in high risk; <2.0 mmol/L (80 mg/dL) in very high risk 
Triglycerides <1.7 mmol/L (150 mg/dL) 
HDL-C >1.0 mmol/L (40 mg/dL) in men; >1.2 mmol/l (45 mg/dL) in women 
Non-HDL-C <2.5 mmol/L (100 mg/dL) 
LDL-C <2.5 mmol/L (100 mg/dL) in high risk; <2.0 mmol/L (80 mg/dL) in very high risk 
Triglycerides <1.7 mmol/L (150 mg/dL) 
HDL-C >1.0 mmol/L (40 mg/dL) in men; >1.2 mmol/l (45 mg/dL) in women 
Non-HDL-C <2.5 mmol/L (100 mg/dL) 

Conclusions

The EAS Consensus Panel believes that adoption of these recommendations for clinical management of elevated triglycerides, a marker of TRL and their remnants, and/or low concentrations of HDL-C, supported by appraisal of the current evidence, will facilitate reduction in the substantial CV risk that persists in high-risk patients at LDL-C goal, especially those with cardiometabolic abnormalities (Box 7).

Box 7
Key messages

• High-risk individuals, especially with cardiometabolic disease, who achieve LDL-C goals remain at high risk of CV events

• Appraisal of the current evidence base implicates elevated triglycerides, a marker of TRL and their remnants, and low levels of HDL-C in this excess CV risk

• In clinical intervention studies using surrogate outcome measures, the addition of niacin to statin reduced atherosclerosis progression in high-risk patients with low LDL-C and elevated triglycerides and/or low HDL-C. Subgroup analyses also showed additional reduction in CV events with fibrate therapy, either alone or in combination with a statin, in patients with atherogenic dyslipidaemia

• Consistent with European guidelines,4 elevated triglycerides (≥1.7 mmol/L or 150 mg/dL) and/or low HDL-C levels (<1.0 mmol/L or 40 mg/dL) should be triggers for considering further treatment in high-risk individuals

• Lifestyle intervention and addressing compliance and secondary causes of dyslipidaemia constitutes the first step in management

• Adding niacin or a fibrate, or intensifying LDL-C lowering, are suggested options for correction of atherogenic dyslipidaemia

Authors’ contribution

European Atherosclerosis Society Consensus Panel:

Co-chairs: John Chapman and Henry Ginsberg.

The EAS Consensus Panel met four times during the preparation of this manuscript. At the first meeting, members of the Panel critically reviewed the available evidence based on the published literature and at subsequent meetings scrutinized the draft manuscript. All members of the EAS Consensus Panel were involved in the writing of the manuscript and approved the final manuscript before submission.

Supplementary material

Supplementary material is available at European Heart Journal online.

Funding

This work including Consensus Panel meetings were supported by unrestricted educational grants to the EAS from Merck, Kowa, Roche, and AstraZeneca. This funding also supported the Open Access publication charges for this article. These companies were not present at the Consensus Panel meetings, had no role in the design or content of the Consensus Statement, and had no right to approve or disapprove of the final document.

Conflict of interest: several of the Consensus Panel members have received lecture honoraria, consultancy fees, and/or research funding from Abbott (A.L.C., O.S.D., H.G., B.G.N., K.R., Z.R., L.T., G.W.); Astra Zeneca (F.A., J.B., A.L.C., J.C., O.S.D., E.F., H.G., P.T.K., L.M., B.G.N., K.R., Z.R., L.T., G.W.); Bayer (F.A.); Boehringer Ingelheim (F.A., A.L.C., B.G.N., M.R.T., G.W.); Bristol-Myers Squibb (F.A., K.R., L.T.); Daiichi–Sankyo (F.A., K.R., L.T.); Glaxo-Welcome (G.W.); Karo Bio (B.G.N.); Kowa (L.M., M.R.T.); Lilly (F.A., K.R., M.R.T.); Menarini (K.R., L.T.); Merck (F.A., J.B., A.L.C., J.C., O.S.D., E.F., H.G., P.T.K., L.M., K.R., Z.R., L.T., R.T., G.W.); Novartis (L.M., K.R., L.T., M.R.T., L.M., G.W.); Pfizer (F.A., J.B., A.L.C., J.C., O.S.D., H.G., P.T.K., B.G.N., K.R., Z.R., L.T., G.W.), Sanofi-Aventis (A.L.C., J.B., O.S.D., B.G.N., K.R., L.T., M.R.T., G.W.); Takeda (E.F., M.R.T.).

Acknowledgements

Jane Stock provided outstanding editorial support to the Consensus Panel.

References

1
European Cardiovascular Disease Statistics
2008
 
2
Annual Report of the EHN activities and its members in 2008
 
3
Shaw
JE
Sicree
RA
Zimmet
PZ
Global estimates of the prevalence of diabetes for 2010 and 2030
Diabetes Res Clin Pract
 , 
2010
, vol. 
87
 (pg. 
4
-
14
)
4
Graham
I
Atar
D
Borch-Johnsen
K
Boysen
G
Burell
G
Cifkova
R
Dallongeville
J
De Backer
G
Ebrahim
S
Gjelsvik
B
Herrmann-Lingen
C
Hoes
A
Humphries
S
Knapton
M
Perk
J
Priori
SG
Pyorala
K
Reiner
Z
Ruilope
L
Sans-Menendez
S
Scholte op Reimer
W
Weissberg
P
Wood
D
Yarnell
J
Zamorano
JL
Walma
E
Fitzgerald
T
Cooney
MT
Dudina
A
European Society of Cardiology (ESC) Committee for Practice Guidelines (CPG)
European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts)
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
2375
-
2414
)
5
Grundy
SM
Cleeman
JI
Merz
CN
Brewer
HB
Jr
Clark
LT
Hunninghake
DB
Pasternak
RC
Smith
SC
Jr
Stone
NJ
Coordinating Committee of the National Cholesterol Education Program
Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines
Arterioscler Thromb Vasc Biol
 , 
2004
, vol. 
24
 (pg. 
e149
-
e161
)
6
Wiviott
SD
Braunwald
E
McCabe
CH
Montalescot
G
Ruzyllo
W
Gottlieb
S
Neumann
FJ
Ardissino
D
De Servi
S
Murphy
SA
Riesmeyer
J
Weerakkody
G
Gibson
CM
Antman
EM
TRITON-TIMI 38 Investigators
Prasugrel versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
 , 
2007
, vol. 
357
 (pg. 
2001
-
2015
)
7
Wallentin
L
Becker
RC
Budaj
A
Cannon
CP
Emanuelsson
H
Held
C
Horrow
J
Husted
S
James
S
Katus
H
Mahaffey
KW
Scirica
BM
Skene
A
Steg
PG
Storey
RF
Harrington
RA
Freij
A
Thorsén
M
PLATO Investigators
Ticagrelor versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
1045
-
1057
)
8
Ray
KK
Cannon
CP
McCabe
CH
Cairns
R
Tonkin
AM
Sacks
FM
Jackson
G
Braunwald
E
PROVE IT-TIMI 22 Investigators
Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial
J Am Coll Cardiol
 , 
2005
, vol. 
46
 (pg. 
1405
-
1410
)
9
Ahmed
S
Cannon
CP
Murphy
SA
Braunwald
E
Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial
Eur Heart J
 , 
2006
, vol. 
27
 (pg. 
2323
-
2329
)
10
Deedwania
P
Barter
P
Carmena
R
Fruchart
JC
Grundy
SM
Haffner
S
Kastelein
JJ
LaRosa
JC
Schachner
H
Shepherd
J
Waters
DD
Treating to New Targets Investigators
Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study
Lancet
 , 
2006
, vol. 
368
 (pg. 
919
-
928
)
11
Miller
M
Cannon
CP
Murphy
SA
Qin
J
Ray
KK
Braunwald
E
PROVE IT-TIMI 22 Investigators
Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial
J Am Coll Cardiol
 , 
2008
, vol. 
51
 (pg. 
724
-
730
)
12
Barter
P
Gotto
AM
LaRosa
JC
Maroni
J
Szarek
M
Grundy
SM
Kastelein
JJ
Bittner
V
Fruchart
JC
Treating to New Targets Investigators
HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events
N Engl J Med
 , 
2007
, vol. 
357
 (pg. 
1301
-
1310
)
13
Olsson
AG
Schwartz
GG
Szarek
M
Sasiela
WJ
Ezekowitz
MD
Ganz
P
Oliver
MF
Waters
D
Zeiher
A
High-density lipoprotein, but not low-density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndrome: results from the MIRACL trial
Eur Heart J
 , 
2005
, vol. 
26
 (pg. 
890
-
896
)
14
Wolfram
RM
Brewer
HB
Xue
Z
Satler
LF
Pichard
AD
Kent
KM
Waksman
R
Impact of low high-density lipoproteins on in-hospital events and one-year clinical outcomes in patients with non-ST-elevation myocardial infarction acute coronary syndrome treated with drug-eluting stent implantation
Am J Cardiol
 , 
2006
, vol. 
98
 (pg. 
711
-
717
)
15
Turner
RC
Millns
H
Neil
HA
Stratton
IM
Manley
SE
Matthews
DR
Holman
RR
Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23)
BMJ
 , 
1998
, vol. 
316
 (pg. 
823
-
828
)
16
Rydén
L
Standl
E
Bartnik
M
Van den Berghe
G
Betteridge
J
de Boer
MJ
Cosentino
F
Jönsson
B
Laakso
M
Malmberg
K
Priori
S
Ostergren
J
Tuomilehto
J
Thrainsdottir
I
Vanhorebeek
I
Stramba-Badiale
M
Lindgren
P
Qiao
Q
Priori
SG
Blanc
JJ
Budaj
A
Camm
J
Dean
V
Deckers
J
Dickstein
K
Lekakis
J
McGregor
K
Metra
M
Morais
J
Osterspey
A
Tamargo
J
Zamorano
JL
Deckers
JW
Bertrand
M
Charbonnel
B
Erdmann
E
Ferrannini
E
Flyvbjerg
A
Gohlke
H
Juanatey
JR
Graham
I
Monteiro
PF
Parhofer
K
Pyörälä
K
Raz
I
Schernthaner
G
Volpe
M
Wood
D
Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC), European Association for the Study of Diabetes (EASD)
Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD)
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
88
-
136
)
17
American Diabetes Association
Standards of medical care in diabetes-2008
Diabetes Care
 , 
2008
, vol. 
31
 
Suppl. 1
(pg. 
S12
-
S54
[Updated 2009: Executive summary: standards of medical care in diabetes-2009. Diabetes Care 2009;32(Suppl. 1):S6–S12
18
Brunzell
JD
Davidson
M
Furberg
CD
Goldberg
RB
Howard
BV
Stein
JH
Witztum
JL
American Diabetes Association, American College of Cardiology Foundation
Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation
Diabetes Care
 , 
2008
, vol. 
31
 (pg. 
811
-
821
)
19
Genest
J
McPherson
R
Frohlich
J
Anderson
T
Campbell
N
Carpentier
A
Couture
P
Dufour
R
Fodor
G
Francis
GA
Grover
S
Gupta
M
Hegele
RA
Lau
DC
Leiter
L
Lewis
GF
Lonn
E
Mancini
GB
Ng
D
Pearson
GJ
Sniderman
A
Stone
JA
Ur
E
2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations
Can J Cardiol
 , 
2009
, vol. 
25
 (pg. 
567
-
579
)
20
Ginsberg
HN
New perspectives on atherogenesis. Role of abnormal triglyceride-rich lipoprotein metabolism
Circulation
 , 
2002
, vol. 
106
 (pg. 
2137
-
2142
)
21
Twickler
TB
Dallinga-Thie
GM
Cohn
JS
Chapman
MJ
Elevated remnant-like particle cholesterol concentration: a characteristic feature of the atherogenic lipoprotein phenotype
Circulation
 , 
2004
, vol. 
109
 (pg. 
1918
-
1925
)
22
Vergeer
M
Holleboom
AG
Kastelein
JJ
Kuivenhoven
JA
The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?
J Lipid Res
 , 
2010
, vol. 
51
 (pg. 
2058
-
2073
)
23
Rye
KA
Bursill
CA
Lambert
G
Tabet
F
Barter
PJ
The metabolism and anti-atherogenic properties of HDL
J Lipid Res
 , 
2009
, vol. 
50
 
uppl
(pg. 
S195
-
S200
)
24
Havel
RJ
Triglyceride-rich lipoproteins and plasma lipid transport
Arterioscler Thromb Vasc Biol
 , 
2010
, vol. 
30
 (pg. 
9
-
19
)
25
Lassel
TS
Guerin
M
Auboiron
S
Guy-Grand
B
Chapman
MJ
Evidence for a cholesteryl ester donor activity of LDL particles during alimentary lipemia in normolipidemic subjects
Atherosclerosis
 , 
1999
, vol. 
147
 (pg. 
41
-
48
)
26
Chan
DC
Watts
GF
Dyslipidaemia in the metabolic syndrome and type 2 diabetes: pathogenesis, priorities, pharmacotherapies
Expert Opin Pharmacother
 , 
2011
, vol. 
12
 (pg. 
13
-
30
)
27
Fisher
EA
GPIHBP1: lipoprotein lipase's ticket to ride
Cell Metab
 , 
2010
, vol. 
12
 (pg. 
1
-
2
)
28
Kontush
A
Chapman
MJ
Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidaemia, inflammation, and atherosclerosis
Pharmacol Rev
 , 
2006
, vol. 
58
 (pg. 
342
-
374
)
29
Horowitz
BS
Goldberg
IJ
Merab
J
Vanni
T
Ramakrishnan
R
Ginsberg
HN
Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol
J Clin Invest
 , 
1993
, vol. 
91
 (pg. 
1743
-
1776
)
30
Brunzell
JD
Clinical practice. Hypertriglyceridemia
N Engl J Med
 , 
2007
, vol. 
357
 (pg. 
1009
-
1017
)
31
Brouwers
MC
de Graaf
J
van Greevenbroek
MM
Schaper
N
Stehouwer
CD
Stalenhoef
AF
Novel drugs in familial combined hyperlipidemia: lessons from type 2 diabetes mellitus
Curr Opin Lipidol
 , 
2010
, vol. 
21
 (pg. 
530
-
538
)
32
Goldstein
JL
Schrott
HG
Hazzard
WR
Bierman
EL
Motulsky
AG
Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia
J Clin Invest
 , 
1973
, vol. 
52
 (pg. 
1544
-
1568
)
33
Wijsman
EM
Rothstein
JH
Igo
RP
Jr
Brunzell
JD
Motulsky
AG
Jarvik
GP
Linkage and association analyses identify a candidate region for apoB level on chromosome 4q32.3 in FCHL families
Hum Genet
 , 
2010
, vol. 
127
 (pg. 
705
-
719
)
34
Williams
KJ
Tabas
I
The response-to-retention hypothesis of early atherogenesis
Arterioscler Thromb Vasc Biol
 , 
1995
, vol. 
15
 (pg. 
551
-
561
)
35
European Atherosclerosis Society Consensus Panel
Lipoprotein(a) as a cardiovascular risk factor: current status
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
2844
-
2853
)
36
Smith
EB
Slater
RS
The microdissection of large atherosclerotic plaques to give morphologically and topographically defined fractions for analysis. 1. The lipids in the isolated fractions
Atherosclerosis
 , 
1972
, vol. 
15
 (pg. 
37
-
56
)
37
Rohrer
L
Ohnsorg
PM
Lehner
M
Landolt
F
Rinninger
F
von Eckardstein
A
High-density lipoprotein transport through aortic endothelial cells involves scavenger receptor BI and ATP-binding cassette transporter G1
Circ Res
 , 
2009
, vol. 
104
 (pg. 
1142
-
1150
)
38
Nordestgaard
BG
Stender
S
Kjeldsen
K
Reduced atherogenesis in cholesterol-fed diabetic rabbits. giant lipoproteins do not enter the arterial wall
Arteriosclerosis
 , 
1988
, vol. 
8
 (pg. 
421
-
428
)
39
Rapp
JH
Lespine
A
Hamilton
RL
Colyvas
N
Chaumeton
AH
Tweedie-Hardman
J
Kotite
L
Kunitake
ST
Havel
RJ
Kane
JP
Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque
Arterioscler Thromb Vasc Biol
 , 
1994
, vol. 
14
 (pg. 
1767
-
1774
)
40
Daugherty
A
Lange
LG
Sobel
BE
Schonfeld
G
Aortic accumulation and plasma clearance of β-VLDL and HDL: effects of diet-induced hypercholesterolemia in rabbits
J Lipid Res
 , 
1985
, vol. 
26
 (pg. 
955
-
963
)
41
Proctor
SD
Mamo
JCL
Retention of fluorescent-labelled chylomicron remnants within the intima of the arterial wall—evidence that plaque cholesterol may be derived from post-prandial lipoproteins
Eur J Clin Invest
 , 
1998
, vol. 
28
 (pg. 
497
-
504
)
42
Goldstein
JL
Ho
YK
Brown
MS
Innerarity
TL
Mahley
RW
Cholesteryl ester accumulation in macrophages resulting from receptor-mediated uptake and degradation of hypercholesterolemic canine beta-very low density lipoproteins
J Biol Chem
 , 
1980
, vol. 
255
 (pg. 
1839
-
1848
)
43
Pitas
RE
Innerarity
TL
Mahley
RW
Foam cells in explants of atherosclerotic rabbit aortas have receptors for beta-very low density lipoproteins and modified low density lipoproteins
Arteriosclerosis
 , 
1983
, vol. 
3
 (pg. 
2
-
12
)
44
Alaupovic
P
Mack
WJ
Knight-Gibson
C
Hodis
HN
The role of triglyceride-rich lipoprotein families in the progression of atherosclerotic lesions as determined by sequential coronary angiography from a controlled clinical trial
Arterioscler Thromb Vasc Biol
 , 
1997
, vol. 
17
 (pg. 
715
-
722
)
45
Grønholdt
ML
Nordestgaard
BG
Nielsen
TG
Sillesen
H
Echolucent carotid artery plaques are associated with elevated levels of fasting and postprandial triglyceride-rich lipoproteins
Stroke
 , 
1996
, vol. 
27
 (pg. 
2166
-
2172
)
46
Zheng
XY
Liu
L
Remnant-like lipoprotein particles impair endothelial function: direct and indirect effects on nitric oxide synthase
J Lipid Res
 , 
2007
, vol. 
48
 (pg. 
1673
-
1680
)
47
Giannattasio
C
Zoppo
A
Gentile
G
Failla
M
Capra
A
Maggi
FM
Catapano
A
Mancia
G
Acute effect of high-fat meal on endothelial function in moderately dyslipidemic subjects
Arterioscler Thromb Vasc Biol
 , 
2005
, vol. 
25
 (pg. 
406
-
410
)
48
Zilversmit
DB
Atherogenesis: a postprandial phenomenon
Circulation
 , 
1979
, vol. 
60
 (pg. 
473
-
485
)
49
Alipour
A
van Oostrom
AJ
Izraeljan
A
Verseyden
C
Collins
JM
Frayn
KN
Plokker
TW
Elte
JW
Castro Cabezas
M
Leukocyte activation by triglyceride-rich lipoproteins
Arterioscler Thromb Vasc Biol
 , 
2008
, vol. 
28
 (pg. 
792
-
797
)
50
Ting
HJ
Stice
JP
Schaff
UY
Hui
DY
Rutledge
JC
Knowlton
AA
Passerini
AG
Simon
SI
Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-alpha
Circ Res
 , 
2007
, vol. 
100
 (pg. 
381
-
390
)
51
Wang
L
Gill
R
Pedersen
TL
Higgins
LJ
Newman
JW
Rutledge
JC
Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation
J Lipid Res
 , 
2009
, vol. 
50
 (pg. 
204
-
213
)
52
Davies
MJ
Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995
Circulation
 , 
1996
, vol. 
94
 (pg. 
2013
-
2020
)
53
Falk
E
Shah
PK
Fuster
V
Coronary plaque disruption
Circulation
 , 
1995
, vol. 
92
 (pg. 
657
-
671
)
54
Sambola
A
Osende
J
Hathcock
J
Degen
M
Nemerson
Y
Fuster
V
Crandall
J
Badimon
JJ
Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity
Circulation
 , 
2003
, vol. 
107
 (pg. 
973
-
977
)
55
Moyer
MP
Tracy
RP
Tracy
PB
van't Veer
C
Sparks
CE
Mann
KG
Plasma lipoproteins support prothrombinase and other procoagulant enzymatic complexes
Arterioscler Thromb Vasc Biol
 , 
1998
, vol. 
18
 (pg. 
458
-
465
)
56
Kohler
HP
Grant
PJ
Plasminogen-activator inhibitor type 1 and coronary artery disease
N Engl J Med
 , 
2000
, vol. 
342
 (pg. 
1792
-
1801
)
57
Grant
PJ
Diabetes mellitus as a prothrombotic condition
J Intern Med
 , 
2007
, vol. 
262
 (pg. 
157
-
172
)
58
Rütti
S
Ehses
JA
Sibler
RA
Prazak
R
Rohrer
L
Georgopoulos
S
Meier
DT
Niclauss
N
Berney
T
Donath
MY
von Eckardstein
A
Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells
Endocrinology
 , 
2009
, vol. 
150
 (pg. 
4521
-
4530
)
59
Fryirs
MA
Barter
PJ
Appavoo
M
Tuch
BE
Tabet
F
Heather
AK
Rye
KA
Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion
Arterioscler Thromb Vasc Biol
 , 
2010
, vol. 
30
 (pg. 
1642
-
1648
)
60
Getz
GS
Reardon
CA
High-density lipoprotein function in regulating insulin secretion: possible relevance to metabolic syndrome
Arterioscler Thromb Vasc Biol
 , 
2010
, vol. 
30
 (pg. 
1497
-
1499
)
61
Mineo
C
Deguchi
H
Griffin
JH
Shaul
PA
Endothelial and antithrombotic actions of HDL
Circ Res
 , 
2006
, vol. 
98
 (pg. 
1352
-
1364
)
62
Tso
C
Martinic
G
Fan
WH
Rogers
C
Rye
KA
Barter
PJ
High-density lipoproteins enhance progenitor-mediated endothelium repair in mice
Arterioscler Thrombosis Vasc Biol
 , 
2006
, vol. 
26
 (pg. 
1144
-
1149
)
63
Murphy
AJ
Woollard
KJ
Hoang
A
Mukhamedova
N
Stirzaker
RA
McCormick
SP
Remaley
AT
Sviridov
D
Chin-Dusting
J
High-density lipoprotein reduces the human monocyte inflammatory response
Arterioscler Thromb Vasc Biol
 , 
2008
, vol. 
28
 (pg. 
2071
-
2077
)
64
Wilhelm
AJ
Zabalawi
M
Grayson
JM
Weant
AE
Major
AS
Owen
J
Bharadwaj
M
Walzem
R
Chan
L
Oka
K
Thomas
MJ
Sorci-Thomas
MG
Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity
Arterioscler Thromb Vasc Biol
 , 
2009
, vol. 
29
 (pg. 
843
-
849
)
65
Rosenson
RS
Brewer
HB
Jr
Chapman
MJ
Fazio
S
Hussain
MM
Kontush
A
Krauss
RM
Otvos
JD
Remaley
AT
Schaefer
EJ
HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events
Clin Chem
 , 
2011
, vol. 
57
 (pg. 
392
-
410
)
66
Epand
RM
Stafford
A
Leon
B
Lock
PE
Tytler
EM
Segrest
JP
Anantharamaiah
GM
HDL and apolipoprotein A-I protect erythrocytes against the generation of procoagulant activity
Arterioscler Thromb
 , 
1994
, vol. 
14
 (pg. 
1775
-
1783
)
67
Griffin
JH
Kojima
K
Banka
CL
Curtiss
LK
Fernández
JA
High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C
J Clin Invest
 , 
1999
, vol. 
103
 (pg. 
219
-
227
)
68
Nofer
JR
Walter
M
Kehrel
B
Wierwille
S
Tepel
M
Seedorf
U
Assmann
G
HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs via decreased production of phosphoinositide-derived second messengers 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate
Arterioscler Thromb Vasc Biol
 , 
1998
, vol. 
18
 (pg. 
861
-
869
)
69
Patel
S
Drew
BG
Nakhla
S
Duffy
SJ
Murphy
AJ
Barter
PJ
Rye
KA
Chin-Dusting
J
Hoang
A
Sviridov
D
Celermajer
DS
Kingwell
BA
Reconstituted high-density lipoprotein increases plasma high-density lipoprotein anti-inflammatory properties and cholesterol efflux capacity in patients with type 2 diabetes
J Am Coll Cardiol
 , 
2009
, vol. 
53
 (pg. 
962
-
971
)
70
Calkin
AC
Drew
BG
Ono
A
Duffy
SJ
Gordon
MV
Schoenwaelder
SM
Sviridov
D
Cooper
ME
Kingwell
BA
Jackson
SP
Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux
Circulation
 , 
2009
, vol. 
120
 (pg. 
2095
-
2104
)
71
Khera
AV
Cuchel
M
de la Llera-Moya
M
Rodrigues
A
Burke
MF
Jafri
K
French
BC
Phillips
JA
Mucksavage
ML
Wilensky
RL
Mohler
ER
Rothblat
GH
Rader
DJ
Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis
N Engl J Med
 , 
2011
, vol. 
364
 (pg. 
127
-
135
)
72
Rubin
EM
Krauss
RM
Spangler
EA
Verstuyft
JG
Clift
SM
Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI
Nature
 , 
1991
, vol. 
353
 (pg. 
265
-
267
)
73
Badimon
JJ
Badimon
L
Fuster
V
Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit
J Clin Invest
 , 
1990
, vol. 
85
 (pg. 
1234
-
1241
)
74
Chiesa
G
Monteggia
E
Marchesi
M
Lorenzon
P
Laucello
M
Lorusso
V
Di Mario
C
Karvouni
E
Newton
RS
Bisgaier
CL
Franceschini
G
Sirtori
CR
Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks
Circ Res
 , 
2002
, vol. 
90
 (pg. 
974
-
980
)
75
Spieker
LE
Sudano
I
Hürlimann
D
Lerch
PG
Lang
MG
Binggeli
C
Corti
R
Ruschitzka
F
Lüscher
TF
Noll
G
High-density lipoprotein restores endothelial function in hypercholesterolemic men
Circulation
 , 
2002
, vol. 
105
 (pg. 
1399
-
1402
)
76
Nissen
SE
Tsunoda
T
Tuzcu
EM
Schoenhagen
P
Cooper
CJ
Yasin
M
Eaton
GM
Lauer
MA
Sheldon
WS
Grines
CL
Halpern
S
Crowe
T
Blankenship
JC
Kerensky
R
Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial
JAMA
 , 
2003
, vol. 
290
 (pg. 
2292
-
2300
)
77
Tardif
JC
Gregoire
J
L'Allier
PL
Ibrahim
R
Lesperance
J
Heinonen
TM
Kouz
S
Berry
C
Basser
R
Lavoie
MA
Guertin
MC
Rodes-Cabau
J
Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial
JAMA
 , 
2007
, vol. 
297
 (pg. 
1675
-
1682
)
78
Shaw
JA
Bobik
A
Murphy
A
Kanellakis
P
Blombery
P
Mukhamedova
N
Woollard
K
Lyon
S
Sviridov
D
Dart
AM
Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque
Circ Res
 , 
2008
, vol. 
103
 (pg. 
1084
-
1091
)
79
Nicholls
SJ
Tuzcu
EM
Sipahi
I
Grasso
AW
Schoenhagen
P
Hu
T
Wolski
K
Crowe
T
Desai
MY
Hazen
SL
Kapadia
SR
Nissen
SE
Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis
JAMA
 , 
2007
, vol. 
297
 (pg. 
499
-
508
)
80
Taskinen
MR
Type 2 diabetes as a lipid disorder
Curr Mol Med
 , 
2005
, vol. 
5
 (pg. 
297
-
308
)
81
Hodoğlugil
U
Williamson
DW
Mahley
RW
Polymorphisms in the hepatic lipase gene affect plasma HDL-cholesterol levels in a Turkish population
J Lipid Res
 , 
2010
, vol. 
51
 (pg. 
422
-
430
)
82
Mahley
RW
Palaogiu
KE
Atak
Z
Dawaon-Pepin
J
Langlois
A-M
Cheung
V
Onat
H
Fulks
P
Mahley
LL
Vakar
F
Ozbayrakq
S
Giikdemir
O
Winkler
W
Turkish Heart Study: lipids, lipoproteins, and apolipoproteins
J Lipid Res
 , 
1995
, vol. 
36
 (pg. 
839
-
859
)
83
Sanisoglu
SY
Oktenli
C
Hasimi
A
Yokusoglu
M
Ugurlu
M
Prevalence of metabolic syndrome-related disorders in a large adult population in Turkey
BMC Public Health
 , 
2006
, vol. 
6
 pg. 
92
  
doi:10.1186/1471-2458-6-92
84
Eriksson
M
Zethelius
B
Eeg-Olofsson
K
Nilsson
PM
Gudbjörnsdottir
S
Cederholm
J
Eliasson
B
Blood lipids in 75 048 type 2 diabetic patients: a population-based survey from the Swedish National diabetes register
Eur J Cardiovasc Prev Rehab
 , 
2011
, vol. 
18
 (pg. 
97
-
105
)
85
Kotseva
K
Wood
D
De Backer
G
De Bacquer
D
Pyörälä
K
Keil
U
EUROASPIRE Study Group
EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries
Eur J Cardiovasc Prev Rehabil
 , 
2009
, vol. 
16
 (pg. 
121
-
137
)
86
Assmann
G
Cullen
P
Schulte
H
Non-LDL-related dyslipidemia and coronary risk: a case-control study
Diab Vasc Dis Res
 , 
2010
, vol. 
7
 (pg. 
204
-
212
)
87
Austin
MA
Plasma triglyceride and coronary heart disease
Arterioscler Thromb
 , 
1991
, vol. 
11
 (pg. 
2
-
14
)
88
Hokanson
JE
Austin
MA
Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies
J Cardiovasc Risk
 , 
1996
, vol. 
3
 (pg. 
213
-
219
)
89
Nordestgaard
BG
Benn
M
Schnohr
P
Tybjærg-Hansen
A
Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women
JAMA
 , 
2007
, vol. 
298
 (pg. 
299
-
308
)
90
Freiberg
JJ
Tybjærg-Hansen
A
Jensen
JS
Nordestgaard
BG
Nonfasting triglycerides and risk of ischemic stroke in the general population
JAMA
 , 
2008
, vol. 
300
 (pg. 
2142
-
2152
)
91
Gordon
DJ
Probstfield
JL
Garrison
RJ
Neaton
JD
Castelli
WP
Knoke
JD
Jacobs
DR
Jr
Bangdiwala
S
Tyroler
HA
High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies
Circulation
 , 
1989
, vol. 
79
 (pg. 
8
-
15
)
92
Jacobs
DR
Jr
Mebane
IL
Bangdiwala
SI
Criqui
MH
Tyroler
HA
High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study
Am J Epidemiol
 , 
1990
, vol. 
131
 (pg. 
32
-
47
)
93
The Emerging Risk Factors Collaboration
Major lipids, apolipoproteins, and risk of vascular disease
JAMA
 , 
2009
, vol. 
302
 (pg. 
1993
-
2000
)
94
Mahley
RW
Rall
SC
Jr.
Scriver
C
Beaudet
A
Sly
W
Valle
D
Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism
The Metabolic and Molecular Bases of Inherited Disease
 , 
2001
8th ed.
New York
McGraw-Hill Inc
(pg. 
2705
-
2960
)
95
Benlian
P
De Gennes
JL
Foubert
L
Zhang
H
Gagné
SE
Hayden
M
Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene
N Engl J Med
 , 
1996
, vol. 
335
 (pg. 
848
-
854
[Erratum in: N Engl J Med 1997;336:451]
96
Weinstein
MM
Yin
L
Tu
Y
Wang
X
Wu
X
Castellani
LW
Walzem
RL
Lusis
AJ
Fong
LG
Beigneux
AP
Young
SG
Chylomicronemia elicits atherosclerosis in mice—brief report
Arterioscler Thromb Vasc Biol
 , 
2010
, vol. 
30
 (pg. 
20
-
23
)
97
Nordestgaard
BG
Zilversmit
DB
Large lipoproteins are excluded from the arterial wall in diabetic cholesterol-fed rabbits
J Lipid Res
 , 
1988
, vol. 
29
 (pg. 
1491
-
1500
)
98
Amarenco
P
Goldstein
LB
Messig
M
O'Neill
BJ
Callahan
A
3rd
Sillesen
H
Hennerici
MG
Zivin
JA
Welch
KM
SPARCL Investigators
Relative and cumulative effects of lipid and blood pressure control in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial
Stroke
 , 
2009
, vol. 
40
 (pg. 
2486
-
2492
)
99
Baigent
C
Keech
A
Kearney
PM
Blackwell
L
Buck
G
Pollicino
C
Kirby
A
Sourjina
T
Peto
R
Collins
R
Simes
R
Cholesterol Treatment Trialists' (CTT) Collaborators
Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins
Lancet
 , 
2005
, vol. 
366
 (pg. 
1267
-
1278
)
100
Cholesterol Treatment Trialists' Ctt Collaboration
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials
Lancet
 , 
2010
, vol. 
376
 (pg. 
1670
-
1681
)
101
Briel
M
Ferreira-Gonzalez
I
You
JJ
Karanicolas
PJ
Akl
EA
Wu
P
Blechacz
B
Bassler
D
Wei
X
Sharman
A
Whitt
I
Alves da Silva
S
Khalid
Z
Nordmann
AJ
Zhou
Q
Walter
SD
Vale
N
Bhatnagar
N
O'Regan
C
Mills
EJ
Bucher
HC
Montori
VM
Guyatt
GH
Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis
BMJ
 , 
2009
, vol. 
338
 pg. 
b92
 
102
Ridker
PM
Genest
J
Boekholdt
SM
Libby
P
Gotto
AM
Nordestgaard
BG
Mora
S
MacFadyen
JG
Glynn
RJ
Kastelein
JJP
for the JUPITER Trial Study Group
HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial
Lancet
 , 
2010
, vol. 
376
 (pg. 
333
-
339
)
103
Pedersen
TR
Olsson
AG
Faergeman
O
Kjekshus
J
Wedel
H
Berg
K
Wilhelmsen
L
Haghfelt
T
Thorgeirsson
G
Pyörälä
K
Miettinen
T
Christophersen
B
Tobert
JA
Musliner
TA
Cook
TJ
Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)
Circulation
 , 
1998
, vol. 
97
 (pg. 
1453
-
1460
)
104
Faergeman
O
Holme
I
Fayyad
R
Bhatia
S
Grundy
SM
Kastelein
JJ
LaRosa
JC
Larsen
ML
Lindahl
C
Olsson
AG
Tikkanen
MJ
Waters
DD
Pedersen
TR
Steering Committees of IDEAL and TNT Trials
Plasma triglycerides and cardiovascular events in the Treating to New Targets and Incremental Decrease in End-Points through Aggressive Lipid Lowering trials of statins in patients with coronary artery disease
Am J Cardiol
 , 
2009
, vol. 
104
 (pg. 
459
-
463
)
105
Kastelein
JJ
van der Steeg
WA
Holme
I
Gaffney
M
Cater
NB
Barter
P
Deedwania
P
Olsson
AG
Boekholdt
SM
Demicco
DA
Szarek
M
LaRosa
JC
Pedersen
TR
Grundy
SM
TNT Study Group, IDEAL Study Group
Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment
Circulation
 , 
2008
, vol. 
117
 (pg. 
3002
-
3009
)
106
Scott
R
O'Brien
R
Fulcher
G
Pardy
C
D'Emden
M
Tse
D
Taskinen
MR
Ehnholm
C
Keech
A
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study Investigators
Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study
Diabetes Care
 , 
2009
, vol. 
32
 (pg. 
493
-
498
)
107
Ginsberg
HN
Elam
MB
Lovato
LC
Crouse
JR
3rd
Leiter
LA
Linz
P
Friedewald
WT
Buse
JB
Gerstein
HC
Probstfield
J
Grimm
RH
Ismail-Beigi
F
Bigger
JT
Goff
DC
Jr
Cushman
WC
Simons-Morton
DG
Byington
RP
ACCORD Study Group
Effects of combination lipid therapy in type 2 diabetes mellitus
N Eng J Med
 , 
2010
, vol. 
362
 (pg. 
1563
-
1574
)
108
Taskinen
MR
Barter
PJ
Ehnholm
C
Sullivan
DR
Mann
K
Simes
J
Best
JD
Hamwood
S
Keech
AC
on behalf of the FIELD Study Investigators
Ability of traditional lipid ratios and apolipoprotein ratios to predict cardiovascular risk in people with type 2 diabetes
Diabetologia
 , 
2010
, vol. 
53
 (pg. 
1846
-
1855
)
109
Hegele
RA
Plasma lipoproteins: genetic influences and clinical implications
Nat Rev Genet
 , 
2009
, vol. 
10
 (pg. 
109
-
121
)
110
Wittrup
HH
Tybjærg-Hansen
A
Nordestgaard
BG
Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease: a meta-analysis
Circulation
 , 
1999
, vol. 
99
 (pg. 
2901
-
2907
)
111
Hokanson
JE
Lipoprotein lipase gene variants and risk of coronary disease: a quantitative analysis of population-based studies
Int J Clin Lab Res
 , 
1997
, vol. 
27
 (pg. 
24
-
34
)
112
Johansen
CT
Wang
J
Lanktree
MB
Cao
H
McIntyre
AD
Ban
MR
Martins
RA
Kennedy
BA
Hassell
RG
Visser
ME
Schwartz
SM
Voight
BF
Elosua
R
Salomaa
V
O'Donnell
CJ
Dallinga-Thie
GM
Anand
SS
Yusuf
S
Huff
MW
Kathiresan
S
Hegele
RA
Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia
Nat Genet
 , 
2010
, vol. 
42
 (pg. 
684
-
687
)
113
Hu
Y
Liu
W
Huang
R
Zhang
X
A systematic review and metaanalysis of the relationship between lipoprotein lipase Asn291Ser variant and diseases
J Lipid Res
 , 
2006
, vol. 
47
 (pg. 
1908
-
1914
)
114
Thompson
A
Di Angelantonio
E
Sarwar
N
Erqou
S
Saleheen
D
Dullaart
RPF
Keavney
B
Ye
Z
Danesh
J
Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk
JAMA
 , 
2008
, vol. 
299
 (pg. 
2777
-
2788
)
115
Teslovich
TM
Musunuru
K
Smith
AV
Edmondson
AC
Stylianou
IM
Koseki
M
Pirruccello
JP
Ripatti
S
Chasman
DI
Willer
CJ
Johansen
CT
Fouchier
SW
Isaacs
A
Peloso
GM
Barbalic
M
Ricketts
SL
Bis
JC
Aulchenko
YS
Thorleifsson
G
Feitosa
MF
Chambers
J
Orho-Melander
M
Melander
O
Johnson
T
Li
X
Guo
X
Li
M
Shin Cho
Y
Jin Go
M
Jin Kim
Y
Lee
JY
Park
T
Kim
K
Sim
X
Twee-Hee Ong
R
Croteau-Chonka
DC
Lange
LA
Smith
JD
Song
K
Hua Zhao
J
Yuan
X
Luan
J
Lamina
C
Ziegler
A
Zhang
W
Zee
RY
Wright
AF
Witteman
JC
Wilson
JF
Willemsen
G
Wichmann
HE
Whitfield
JB
Waterworth
DM
Wareham
NJ
Waeber
G
Vollenweider
P
Voight
BF
Vitart
V
Uitterlinden
AG
Uda
M
Tuomilehto
J
Thompson
JR
Tanaka
T
Surakka
I
Stringham
HM
Spector
TD
Soranzo
N
Smit
JH
Sinisalo
J
Silander
K
Sijbrands
EJ
Scuteri
A
Scott
J
Schlessinger
D
Sanna
S
Salomaa
V
Saharinen
J
Sabatti
C
Ruokonen
A
Rudan
I
Rose
LM
Roberts
R
Rieder
M
Psaty
BM
Pramstaller
PP
Pichler
I
Perola
M
Penninx
BW
Pedersen
NL
Pattaro
C
Parker
AN
Pare
G
Oostra
BA
O'Donnell
CJ
Nieminen
MS
Nickerson
DA
Montgomery
GW
Meitinger
T
McPherson
R
McCarthy
MI
McArdle
W
Masson
D
Martin
NG
Marroni
F
Mangino
M
Magnusson
PK
Lucas
G
Luben
R
Loos
RJ
Lokki
ML
Lettre
G
Langenberg
C
Launer
LJ
Lakatta
EG
Laaksonen
R
Kyvik
KO
Kronenberg
F
König
IR
Khaw
KT
Kaprio
J
Kaplan
LM
Johansson
A
Jarvelin
MR
Cecile
JW
Janssens
A
Ingelsson
E
Igl
W
Kees Hovingh
G
Hottenga
JJ
Hofman
A
Hicks
AA
Hengstenberg
C
Heid
IM
Hayward
C
Havulinna
AS
Hastie
ND
Harris
TB
Haritunians
T
Hall
AS
Gyllensten
U
Guiducci
C
Groop
LC
Gonzalez
E
Gieger
C
Freimer
NB
Ferrucci
L
Erdmann
J
Elliott
P
Ejebe
KG
Döring
A
Dominiczak
AF
Demissie
S
Deloukas
P
de Geus
EJ
de Faire
U
Crawford
G
Collins
FS
Chen
YD
Caulfield
MJ
Campbell
H
Burtt
NP
Bonnycastle
LL
Boomsma
DI
Boekholdt
SM
Bergman
RN
Barroso
I
Bandinelli
S
Ballantyne
CM
Assimes
TL
Quertermous
T
Altshuler
D
Seielstad
M
Wong
TY
Tai
ES
Feranil
AB
Kuzawa
CW
Adair
LS
Taylor
HA
Jr
Borecki
IB
Gabriel
SB
Wilson
JG
Holm
H
Thorsteinsdottir
U
Gudnason
V
Krauss
RM
Mohlke
KL
Ordovas
JM
Munroe
PB
Kooner
JS
Tall
AR
Hegele
RA
Kastelein
JJ
Schadt
EE
Rotter
JI
Boerwinkle
E
Strachan
DP
Mooser
V
Stefansson
K
Reilly
MP
Samani
NJ
Schunkert
H
Cupples
LA
Sandhu
MS
Ridker
PM
Rader
DJ
van Duijn
CM
Peltonen
L
Abecasis
GR
Boehnke
M
Kathiresan
S
Biological, clinical and population relevance of 95 loci for blood lipids
Nature
 , 
2010
, vol. 
466
 (pg. 
707
-
713
)
116
Sarwar
N
Sandhu
MS
Ricketts
SL
Butterworth
AS
Di Angelantonio
E
Boekholdt
SM
Ouwehand
W
Watkins
H
Samani
NJ
Saleheen
D
Lawlor
D
Reilly
MP
Hingorani
AD
Talmud
PJ
Danesh
J
Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration
Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies
Lancet
 , 
2010
, vol. 
375
 (pg. 
1634
-
1639
)
117
Andersen
RV
Wittrup
HH
Tybjærg-Hansen
A
Steffensen
R
Schnohr
P
Nordestgaard
BG
Hepatic lipase mutations, elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease
J Am Coll Cardiol
 , 
2003
, vol. 
41
 (pg. 
1972
-
1982
)
118
van Acker
BA
Botsma
GJ
Zwinderman
AH
Kuivenhoven
JA
Dallinga-Thie
GM
Sijbrands
EJ
Boer
JM
Seidell
JC
Jukema
JW
Kastelein
JJ
Jansen
H
Verhoeven
AJ
REGRESS Study Group
High HDL cholesterol does not protect against coronary artery disease when associated with combined cholesteryl ester transfer protein and hepatic lipase gene variants
Atherosclerosis
 , 
2008
, vol. 
200
 (pg. 
161
-
167
)
119
Johannsen
TH
Kamstrup
P
Andersen
RV
Jensen
GB
Sillesen
H
Tybjærg-Hansen
A
Nordestgaard
BG
Hepatic lipase, genetically elevated high-density lipoprotein, and risk of ischemic cardiovascular disease
J Clin Endocrinol Metab
 , 
2009
, vol. 
94
 (pg. 
1264
-
1273
)
120
Frikke-Schmidt
R
Nordestgaard
BG
Stene
MCA
Sethi
AA
Remaley
AT
Schnohr
P
Grande
P
Tybjærg-Hansen
A
Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease
JAMA
 , 
2008
, vol. 
299
 (pg. 
2524
-
2532
)
121
Kathiresan
S
Melander
O
Guiducci
C
Surti
A
Burtt
NP
Rieder
MJ
Cooper
GM
Roos
C
Voight
BF
Havulinna
AS
Wahlstrand
B
Hedner
T
Corella
D
Tai
ES
Ordovas
JM
Berglund
G
Vartiainen
E
Jousilahti
P
Hedblad
B
Taskinen
MR
Newton-Cheh
C
Salomaa
V
Peltonen
L
Groop
L
Altshuler
DM
Orho-Melander
M
Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans
Nat Genet
 , 
2008
, vol. 
40
 (pg. 
189
-
197
)
122
Willer
CJ
Sanna
S
Jackson
AU
Scuteri
A
Bonnycastle
LL
Clarke
R
Heath
SC
Timpson
NJ
Najjar
SS
Stringham
HM
Strait
J
Duren
WL
Maschio
A
Busonero
F
Mulas
A
Albai
G
Swift
AJ
Morken
MA
Narisu
N
Bennett
D
Parish
S
Shen
H
Galan
P
Meneton
P
Hercberg
S
Zelenika
D
Chen
WM
Li
Y
Scott
LJ
Scheet
PA
Sundvall
J
Watanabe
RM
Nagaraja
R
Ebrahim
S
Lawlor
DA
Ben-Shlomo
Y
Davey-Smith
G
Shuldiner
AR
Collins
R
Bergman
RN
Uda
M
Tuomilehto
J
Cao
A
Collins
FS
Lakatta
E
Lathrop
GM
Boehnke
M
Schlessinger
D
Mohlke
KL
Abecasis
GR
Newly identified loci that influence lipid concentrations and risk of coronary disease
Nat Genet
 , 
2008
, vol. 
40
 (pg. 
161
-
169
)
123
Maeda
K
Noguchi
Y
Fukui
T
The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis
Prev Med
 , 
2003
, vol. 
37
 (pg. 
283
-
290
)
124
Dattilo
AM
Kris-Etherton
PM
Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis
Am J Clin Nutr
 , 
1992
, vol. 
56
 (pg. 
320
-
328
)
125
Kodama
S
Tanaka
S
Saito
K
Shu
M
Sone
Y
Onitake
F
Suzuki
E
Shimano
H
Yamamoto
S
Kondo
K
Ohashi
Y
Yamada
N
Sone
H
Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta-analysis
Arch Intern Med
 , 
2007
, vol. 
167
 (pg. 
999
-
1008
)
126
Tambalis
K
Panagiotakos
DB
Kavouras
SA
Sidossis
LS
Responses of blood lipids to aerobic, resistance, and combined aerobic with resistance exercise training: a systematic review of current evidence
Angiology
 , 
2009
, vol. 
60
 (pg. 
614
-
632
)
127
Roberts
CK
Ng
C
Hama
S
Eliseo
AJ
Barnard
RJ
Effect of a short-term diet and exercise intervention on inflammatory/anti-inflammatory properties of HDL in overweight/obese men with cardiovascular risk factors
J Appl Physiol
 , 
2006
, vol. 
101
 (pg. 
1727
-
1732
)
128
Magkos
F
Basal very low-density lipoprotein metabolism in response to exercise: mechanisms of hypotriacylglycerolemia
Prog Lipid Res
 , 
2009
, vol. 
48
 (pg. 
171
-
190
)
129
Magkos
F
Tsekouras
YE
Prentzas
KI
Basioukas
KN
Matsama
SG
Yanni
AE
Kavouras
SA
Sidossis
LS
Acute exercise-induced changes in basal VLDL-triglyceride kinetics leading to hypotriglyceridemia manifest more readily after resistance than endurance exercise
J Appl Physiol
 , 
2008
, vol. 
105
 (pg. 
1228
-
1236
)
130
Wang
Y
Simar
D
Fiatarone Singh
MA
Adaptations to exercise training within skeletal muscle in adults with type 2 diabetes or impaired glucose tolerance: a systematic review
Diabetes Metab Res Rev
 , 
2009
, vol. 
25
 (pg. 
13
-
40
)
131
Kelley
GA
Kelley
KS
Impact of progressive resistance training on lipids and lipoproteins in adults: a meta-analysis of randomized controlled trials
Prev Med
 , 
2009
, vol. 
48
 (pg. 
9
-
19
)
132
Gaziano
JM
Buring
JE
Breslow
JL
Goldhaber
SZ
Rosner
B
Van Denburgh
M
Willett
W
Hennekens
CH
Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction
N Engl J Med
 , 
1993
, vol. 
329
 (pg. 
1829
-
1834
)
133
Crouse
JR
Grundy
SM
Effects of alcohol on plasma lipoproteins and cholesterol and triglyceride metabolism in man
J Lipid Res
 , 
1984
, vol. 
25
 (pg. 
486
-
496
)
134
Ginsberg
H
Olefsky
J
Farquhar
JW
Reaven
GM
Moderate ethanol ingestion and plasma triglyceride levels. A study in normal and hypertriglyceridemic persons
Ann Intern Med
 , 
1974
, vol. 
80
 (pg. 
143
-
149
)
135
Mensink
RP
Zock
PL
Kester
AD
Katan
MB
Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials
Am J Clin Nutr
 , 
2003
, vol. 
77
 (pg. 
1146
-
1155
)
136
Appel
LJ
Sacks
FM
Carey
VJ
Obarzanek
E
Swain
JF
Miller
ER
3rd
Conlin
PR
Erlinger
TP
Rosner
BA
Laranjo
NM
Charleston
J
McCarron
P
Bishop
LM
OmniHeart Collaborative Research Group
Effects of protein, monosaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial
JAMA
 , 
2005
, vol. 
294
 (pg. 
2455
-
2464
)
137
Nicholls
SJ
Lundman
P
Harmer
JA
Cutri
B
Griffiths
KA
Rye
KA
Barter
PJ
Celermajer
DS
Consumption of saturated fat impairs the anti-inflammatory properties of high-density lipoproteins and endothelial function
J Am Coll Cardiol
 , 
2006
, vol. 
48
 (pg. 
715
-
720
)
138
Wong
S
Nestel
PJ
Eicosapentaenoic acid inhibits the secretion of triacylglycerol and of apoprotein B and the binding of LDL in Hep G2 cells
Atherosclerosis
 , 
1987
, vol. 
64
 (pg. 
139
-
146
)
139
Denmacker
PN
Reijnen
IG
Katan
MB
Stuyt
PM
Stalenhoef
AF
Increased removal of remnants of triglyceride-rich lipoproteins on a diet rich in polyunsaturated fatty acids
Eur J Clin Invest
 , 
1991
, vol. 
21
 (pg. 
197
-
203
)
140
Zheng
C
Khoo
C
Furtado
J
Ikewaki
K
Sacks
FM
Dietary monounsaturated fat activates metabolic pathways for triglyceride-rich lipoproteins that involve apolipoproteins E and C-III
Am J Clin Nutr
 , 
2008
, vol. 
88
 (pg. 
272
-
281
)
141
Chelland Campbell
S
Moffatt
RJ
Stamford
BA
Smoking and smoking cessation—the relationship between cardiovascular disease and lipoprotein metabolism: a review
Atherosclerosis
 , 
2008
, vol. 
201
 (pg. 
225
-
235
)
142
Facchini
FS
Hollenbeck
CB
Jeppesen
J
Chen
YD
Reaven
GM
Insulin resistance and cigarette smoking
Lancet
 , 
1992
, vol. 
339
 (pg. 
1128
-
1130
)
143
The Look AHEAD Research Group
Reduction in weight and cardiovascular risk factors in individuals with type 2 diabetes
Diabetes Care
 , 
2007
, vol. 
30
 (pg. 
1374
-
1383
)
144
The Look AHEAD Research Group
Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus
Arch Intern Med
 , 
2010
, vol. 
170
 (pg. 
1566
-
1575
)
145
Ilanne-Parikka
P
Eriksson
JG
Lindström
J
Peltonen
M
Aunola
S
Hämäläinen
H
Keinänen-Kiukaanniemi
S
Laakso
M
Valle
TT
Lahtela
J
Uusitupa
M
Tuomilehto
J
Finnish Diabetes Prevention Study Group
Effect of lifestyle intervention on the occurrence of metabolic syndrome and its components in the Finnish Diabetes Prevention Study
Diabetes Care
 , 
2008
, vol. 
31
 (pg. 
805
-
807
)
146
Uusitupa
M
Peltonen
M
Lindström
J
Aunola
S
Ilanne-Parikka
P
Keinänen-Kiukaanniemi
S
Valle
TT
Eriksson
JG
Tuomilehto
J
Finnish Diabetes Prevention Study Group
Ten-year mortality and cardiovascular morbidity in the Finnish Diabetes Prevention Study—secondary analysis of the randomized trial
PLoS ONE
 , 
2009
, vol. 
4
 pg. 
e5656
 
147
Sigal
RJ
Kenny
GP
Boulé
NG
Wells
GA
Prud'homme
D
Fortier
M
Reid
RD
Tulloch
H
Coyle
D
Phillips
P
Jennings
A
Jaffey
J
Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial
Ann Intern Med
 , 
2007
, vol. 
147
 (pg. 
357
-
369
)
148
Jeon
CY
Lokken
RP
Hu
FB
Van Dam
RM
Physical activity of moderate intensity and risk of type 2 diabetes. A systematic review
Diabetes Care
 , 
2007
, vol. 
30
 (pg. 
744
-
752
)
149
Schuler
G
Hambrecht
R
Schlierf
G
Niebauer
J
Hauer
K
Neumann
J
Hoberg
E
Drinkmann
A
Bacher
F
Grunze
M
Regular physical exercise and low-fat diet. Effects on progression of coronary artery disease
Circulation
 , 
1992
, vol. 
86
 (pg. 
1
-
11
)
150
Watts
GF
Lewis
B
Brunt
JN
Lewis
ES
Coltart
DJ
Smith
LD
Mann
JI
Swan
AV
Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS)
Lancet
 , 
1992
, vol. 
339
 (pg. 
563
-
569
)
151
Ornish
D
Brown
SE
Scherwitz
LW
Billings
JH
Armstrong
WT
Ports
TA
McLanahan
SM
Kirkeeide
RL
Brand
RJ
Gould
KL
Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial
Lancet
 , 
1990
, vol. 
336
 (pg. 
129
-
133
)
152
Hjermann
I
Velve Byre
K
Holme
I
Leren
P
Effect of diet and smoking intervention on the incidence of coronary heart disease. Report from the Oslo Study Group of a randomised trial in healthy men
Lancet
 , 
1981
, vol. 
2
 (pg. 
1303
-
1310
)
153
Burr
ML
Fehily
AM
Gilbert
JF
Rogers
S
Holliday
RM
Sweetnam
PM
Elwood
PC
Deadman
NM
Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART)
Lancet
 , 
1989
, vol. 
2
 (pg. 
757
-
761
)
154
de Lorgeril
M
Renaud
S
Mamelle
N
Salen
P
Martin
JL
Monjaud
I
Guidollet
J
Touboul
P
Delaye
J
Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease
Lancet
 , 
1994
, vol. 
343
 (pg. 
1454
-
1459
)
155
Brown
BG
Stukovsky
KH
Zhao
XQ
Simultaneous low-density lipoprotein-C lowering and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials
Curr Opin Lipidol
 , 
2006
, vol. 
17
 (pg. 
631
-
636
)
156
Chapman
MJ
Redfern
JS
McGovern
ME
Giral
P
Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk
Pharmacol Ther
 , 
2010
, vol. 
126
 (pg. 
314
-
345
)
157
Bays
HE
Tighe
AP
Sadovsky
R
Davidson
MH
Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications
Exp Rev Cardiovasc Ther
 , 
2008
, vol. 
6
 (pg. 
391
-
409
)
158
Kamanna
VS
Kashyap
ML
Mechanism of action of niacin
Am J Cardiol
 , 
2008
, vol. 
101
 (pg. 
20B
-
26B
)
159
Gille
A
Bodor
ET
Ahmed
K
Offermanns
S
Nicotinic acid: pharmacological effects and mechanisms of action
Ann Rev Pharmacol Toxicol
 , 
2008
, vol. 
48
 (pg. 
79
-
106
)
160
Lamon-Fava
S
Diffenderfer
MR
Barrett
PH
Buchsbaum
A
Nyaku
M
Horvath
KV
Asztalos
BF
Otokozawa
S
Ai
M
Matthan
NR
Lichtenstein
AH
Dolnikowski
GG
Schaefer
EJ
Extended-release niacin alters the metabolism of plasma apolipoprotein (Apo) A-I and ApoB-containing lipoproteins
Arterioscler Thromb Vasc Biol
 , 
2008
, vol. 
28
 (pg. 
1672
-
1678
)
161
Watts
GF
Chan
DC
Of mice and men: blowing away the cobwebs from the mechanism of action of niacin on HDL metabolism
Arterioscler Thromb Vasc Biol
 , 
2008
, vol. 
28
 (pg. 
1892
-
1895
)
162
Chan
DC
Watts
GF
Ooi
EM
Ji
J
Johnson
AG
Barrett
PH
Atorvastatin and fenofibrate have comparable effects on VLDL-apolipoprotein C-III kinetics in men with the metabolic syndrome
Arterioscler Thromb Vasc Biol
 , 
2008
, vol. 
28
 (pg. 
1831
-
1837
)
163
Watts
GF
Barrett
PH
Ji
J
Serone
AP
Chan
DC
Croft
KD
Loehrer
F
Johnson
AG
Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome
Diabetes
 , 
2003
, vol. 
52
 (pg. 
803
-
811
)
164
Chan
DC
Watts
GF
Ooi
EM
Rye
KA
Ji
J
Johnson
AG
Barrett
PH
Regulatory effects of fenofibrate and atorvastatin on lipoprotein A-I and lipoprotein A-I:A-II kinetics in the metabolic syndrome
Diabetes Care
 , 
2009
, vol. 
32
 (pg. 
2111
-
2113
)
165
Guerin
M
Bruckert
E
Dolphin
PJ
Turpin
G
Chapman
MJ
Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia
Arterioscler Thromb Vasc Biol
 , 
1996
, vol. 
16
 (pg. 
763
-
772
)
166
Chapman
MJ
Le Goff
W
Guerin
M
Kontush
A
Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
149
-
164
)
167
Park
Y
Harris
WS
Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance
J Lipid Res
 , 
2003
, vol. 
44
 (pg. 
455
-
463
)
168
Wang
H
Chen
X
Fisher
EA
N-3 fatty acids stimulate intracellular degradation of apoprotein B in rat hepatocytes
J Clin Invest
 , 
1993
, vol. 
91
 (pg. 
1380
-
1389
)
169
Nestel
PJ
Connor
WE
Reardon
MF
Connor
S
Wong
S
Boston
R
Suppression by diets rich in fish oil of very low density lipoprotein production in man
J Clin Invest
 , 
1984
, vol. 
74
 (pg. 
82
-
89
)
170
Chan
DC
Watts
GF
Nguyen
MN
Barrett
PH
Factorial study of the effect of n-3 fatty acid supplementation and atorvastatin on the kinetics of HDL apolipoproteins A-I and A-II in men with abdominal obesity
Am J Clin Nutr
 , 
2006
, vol. 
84
 (pg. 
37
-
43
)
171
Sorrentino
SA
Besler
C
Rohrer
L
Meyer
M
Heinrich
K
Bahlmann
FH
Mueller
M
Horváth
T
Doerries
C
Heinemann
M
Flemmer
S
Markowski
A
Manes
C
Bahr
MJ
Haller
H
von Eckardstein
A
Drexler
H
Landmesser
U
Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy
Circulation
 , 
2010
, vol. 
121
 (pg. 
110
-
122
)
172
Wu
BJ
Yan
L
Charlton
F
Witting
P
Barter
PJ
Rye
KA
Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids
Arterioscler Thromb Vasc Biol
 , 
2010
, vol. 
30
 (pg. 
968
-
975
)
173
Yvan-Charvet
L
Kling
J
Pagler
T
Li
H
Hubbard
B
Fisher
T
Sparrow
CP
Taggart
AK
Tall
AR
Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib
Arterioscler Thromb Vasc Biol
 , 
2010
, vol. 
30
 (pg. 
1430
-
1438
)
174
Blankenhorn
DH
Nessim
SA
Johnson
RL
Sanmarco
ME
Azen
SP
Cashin-Hemphill
L
Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts
JAMA
 , 
1987
, vol. 
257
 (pg. 
3233
-
3240
)
175
Brown
G
Albers
JJ
Fisher
LD
Schaefer
SM
Lin
JT
Kaplan
C
Zhao
XQ
Bisson
BD
Fitzpatrick
VF
Dodge
HT
Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B
N Engl J Med
 , 
1990
, vol. 
23
 (pg. 
1289
-
1298
)
176
Kane
JP
Malloy
MJ
Ports
TA
Phillips
NR
Diehl
JC
Havel
RJ
Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens
JAMA
 , 
1990
, vol. 
264
 (pg. 
3007
-
3012
)
177
Brown
BG
Zhao
XQ
Chait
A
Fisher
LD
Cheung
MC
Morse
JS
Dowdy
AA
Marino
EK
Bolson
EL
Alaupovic
P
Frohlich
J
Albers
JJ
Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease
N Engl J Med
 , 
2001
, vol. 
345
 (pg. 
1583
-
1592
)
178
Whitney
EJ
Krasuski
RA
Personius
BE
Michalek
JE
Maranian
AM
Kolasa
MW
Monick
E
Brown
BG
Gotto
AM
Jr.
A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events
Ann Intern Med
 , 
2005
, vol. 
142
 (pg. 
95
-
104
)
179
Taylor
AJ
Sullenberger
LE
Lee
HJ
Lee
JK
Grace
KA
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
 , 
2004
, vol. 
110
 (pg. 
3512
-
3517
)
180
Taylor
AJ
Lee
HJ
Sullenberger
LE
The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3
Curr Med Res Opin
 , 
2006
, vol. 
22
 (pg. 
2243
-
2250
)
181
Taylor
AJ
Villines
TC
Stanek
EJ
Devine
PJ
Griffen
L
Miller
M
Weissman
NJ
Turco
M
Extended-release niacin or ezetimibe and carotid intima-media thickness
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
2113
-
2122
)
182
Lee
JM
Robson
MD
Yu
LM
Shirodaria
CC
Cunnington
C
Kylintireas
I
Digby
JE
Bannister
T
Handa
A
Wiesmann
F
Durrington
PN
Channon
KM
Neubauer
S
Choudhury
R
Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
1787
-
1794
)
183
The Coronary Drug Project Group
Clofibrate and niacin in coronary heart disease
JAMA
 , 
1975
, vol. 
231
 (pg. 
360
-
381
)
184
Canner
PL
Berge
KG
Wenger
NK
Stamler
J
Friedman
L
Prineas
RJ
Friedewald
W
Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin
J Am Coll Cardiol
 , 
1986
, vol. 
8
 (pg. 
1245
-
1255
)
185
Canner
PL
Furberg
CD
Terrin
ML
McGovern
ME
Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project)
Am J Cardiol
 , 
2005
, vol. 
95
 (pg. 
254
-
257
)
186
Canner
PL
Furberg
CD
McGovern
ME
Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project)
Am J Cardiol
 , 
2006
, vol. 
97
 (pg. 
477
-
479
)
187
Bruckert
E
Labreuche
J
Amarenco
P
Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis
Atherosclerosis
 , 
2010
, vol. 
210
 (pg. 
353
-
361
)
188
Elam
MB
Hunninghake
DB
Davis
KB
Garg
R
Johnson
C
Egan
D
Kostis
JB
Sheps
DS
Brinton
EA
Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. Arterial Disease Multiple Intervention Trial
JAMA
 , 
2000
, vol. 
284
 (pg. 
1263
-
1270
)
189
Grundy
SM
Vega
GL
McGovern
ME
Tulloch
BR
Kendall
DM
Fitz-Patrick
D
Ganda
OP
Rosenson
RS
Buse
JB
Robertson
DD
Sheehan
JP
Diabetes Multicenter Research Group
Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial
Arch Intern Med
 , 
2002
, vol. 
162
 (pg. 
1568
-
1576
)
190
McKenney
JM
Jones
PH
Bays
HE
Knopp
RH
Kashyap
ML
Ruoff
GE
McGovern
ME
Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study)
Atherosclerosis
 , 
2007
, vol. 
192
 (pg. 
432
-
437
)
191
Ballantyne
CM
Davidson
MH
McKenney
J
Keller
LH
Bajorunas
DR
Karas
RH
Comparison of the safety and efficacy of a combination tablet of niacin extended release and simvastatin vs simvastatin monotherapy in patients with increased non-HDL cholesterol (from the SEACOAST I study)
Am J Cardiol
 , 
2008
, vol. 
101
 (pg. 
1428
-
1436
)
192
Gleim
G
Ballantyne
CM
Liu
N
Thompson-Bell
S
McCrary Sisk
C
Pasternak
RC
Mitchel
Y
Paolini
JF
Efficacy and safety profile of co-administered ER niacin/laropiprant and simvastatin in dyslipidaemia
Br J Cardiol
 , 
2009
, vol. 
16
 (pg. 
90
-
97
)
193
Lai
E
De Lepeleire
I
Crumley
TM
Liu
F
Wenning
LA
Michiels
N
Vets
E
O'Neill
G
Wagner
JA
Gottesdiener
K
Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype1
Clin Pharmacol Ther
 , 
2007
, vol. 
81
 (pg. 
49
-
57
)
194
Shah
S
Ceska
IR
Gil-Extremera
B
Paolini
JF
Giezek
H
Vandormael
K
Mao
A
McCrary Sisk
C
Maccubbin
D
Efficacy and safety of extended-release niacin/laropiprant plus statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia
Int J Clin Pract
 , 
2010
, vol. 
64
 (pg. 
727
-
738
)
195
Maclean
A
McKenney
JM
Scott
R
Brinton
E
Bays
H
Mitchel
YB
Paoloni
JF
Giezek
H
Vandormael
K
Ruck
RA
Gibson
K
McCrary Sisk
C
Maccubbin
DL
Efficacy and safety of extended-release niacin/laropiprant in patients with type 2 diabetes mellitus
Br J Cardiol
 , 
2011
, vol. 
18
 (pg. 
37
-
45
)
196
Ericsson
CG
Hamsten
A
Nilsson
J
Grip
L
Svane
B
de Faire
U
Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients
Lancet
 , 
1996
, vol. 
347
 (pg. 
849
-
853
)
197
Frick
MH
Syvänne
M
Nieminen
MS
Kauma
H
Majahalme
S
Virtanen
V
Kesäniemi
YA
Pasternack
A
Taskinen
MR
Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group
Circulation
 , 
1997
, vol. 
96
 (pg. 
2137
-
2143
)
198
DAIS Investigators
Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study
Lancet
 , 
2001
, vol. 
357
 (pg. 
905
-
910
)
199
Elkeles
RS
Diamond
JR
Poulter
C
Dhanjil
S
Nicolaides
AN
Mahmood
S
Richmond
W
Mather
H
Sharp
P
Feher
MD
Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study
Diabetes Care
 , 
1998
, vol. 
21
 (pg. 
641
-
648
)
200
Zhu
S
Su
G
Meng
QH
Inhibitory effects of micronized fenofibrate on carotid atherosclerosis in patients with essential hypertension
Clin Chem
 , 
2006
, vol. 
52
 (pg. 
2036
-
2042
)
201
Hiukka
A
Westerbacka
J
Leinonen
ES
Watanabe
H
Wiklund
O
Hulten
LM
Salonen
JT
Tuomainen
TP
Yki-Järvinen
H
Keech
AC
Taskinen
MR
Long-term effects of fenofibrate on carotid intima-media thickness and augmentation index in subjects with type 2 diabetes mellitus
J Am Coll Cardiol
 , 
2008
, vol. 
52
 (pg. 
2190
-
2197
)
202
Oliver
MF
Heady
JA
Morris
J
Cooper
J
A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Report from the Committee of Principal Investigators
Br Heart J
 , 
1978
, vol. 
40
 (pg. 
1069
-
1118
)
203
Coronary Drug Project Research Group
Clofibrate and niacin in coronary heart disease
JAMA
 , 
1975
, vol. 
231
 (pg. 
360
-
381
)
204
Frick
MH
Elo
O
Haapa
K
Heinonen
OP
Heinsalmi
P
Helo
P
Huttunen
JK
Kaitaniemi
P
Koskinen
P
Manninen
V
Mäenpää
H
Mälkönen
M
Mänttäri
M
Norola
S
Pasternack
A
Pikkarainen
J
Romo
M
Sjöblom
T
Nikkilä
EA
Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease
N Engl J Med
 , 
1987
, vol. 
317
 (pg. 
1237
-
1245
)
205
Rubins
HB
Robins
SJ
Collins
D
Fye
CL
Anderson
JW
Elam
MB
Faas
FH
Linares
E
Schaefer
EJ
Schectman
G
Wilt
TJ
Wittes
J
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
 , 
1999
, vol. 
341
 (pg. 
410
-
418
)
206
The BIP Study Group
Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. The Bezafibrate Infarction Prevention (BIP) Study
Circulation
 , 
2000
, vol. 
102
 (pg. 
21
-
27
)
207
Keech
A
Simes
RJ
Barter
P
Best
J
Scott
R
Taskinen
MR
Forder
P
Pillai
A
Davis
T
Glasziou
P
Drury
P
Kesäniemi
YA
Sullivan
D
Hunt
D
Colman
P
d'Emden
M
Whiting
M
Ehnholm
C
Laakso
M
FIELD study investigators
Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial
Lancet
 , 
2005
, vol. 
366
 (pg. 
1849
-
1861
)
208
Jun
M
Foote
C
Lv
J
Neal
B
Patel
A
Nicholls
SJ
Grobbee
DE
Cass
A
Chalmers
J
Perkovic
V
Effects of fibrates on cardiovascular outcomes: a systemic review and meta-analysis
Lancet
 , 
2010
, vol. 
375
 (pg. 
1875
-
1884
)
209
Manninen
V
Tenkanen
L
Koskinen
P
Huttunen
JK
Mänttäri
M
Heinonen
OP
Frick
MH
Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment
Circulation
 , 
1992
, vol. 
85
 (pg. 
37
-
45
)
210
Robins
SJ
Collins
D
Wittes
JT
Papademetriou
V
Deedwania
PC
Schaefer
EJ
McNamara
JR
Kashyap
ML
Hershman
JM
Wexler
LF
Rubins
HB
VA-HIT Study Group
Veterans Affairs High-Density Lipoprotein Intervention Trial. Relation of gemfibrozil treatment and lipid levels with major coronary events
JAMA
 , 
2001
, vol. 
285
 (pg. 
1585
-
1591
)
211
Sacks
FM
Carey
VJ
Fruchart
JC
Combination lipid therapy in type 2 diabetes
N Engl J Med
 , 
2010
, vol. 
363
 (pg. 
692
-
694
)
212
Derosa
G
Cicero
AE
Bertone
G
Piccinni
MN
Ciccarelli
L
Roggeri
DE
Comparison of fluvastatin + fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial
Clin Ther
 , 
2004
, vol. 
26
 (pg. 
1599
-
1607
)
213
Athyros
VG
Papageorgiou
AA
Athyrou
VV
Demitriadis
DS
Kontopoulos
AG
Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia
Diabetes Care
 , 
2002
, vol. 
25
 (pg. 
1198
-
1202
)
214
Koh
KK
Quon
MJ
Han
SH
Chung
WJ
Ahn
JY
Seo
YH
Choi
IS
Shin
EK
Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia
J Am Coll Cardiol
 , 
2005
, vol. 
45
 (pg. 
1649
-
1653
)
215
Grundy
SM
Vega
GL
Yuan
Z
Battisti
WP
Brady
WE
Palmisano
J
Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial)
Am J Cardiol
 , 
2005
, vol. 
95
 (pg. 
462
-
468
)
216
The ACCORD Study Group and ACCORD Eye Study Group
Effects of medical therapies on retinopathy progression in type 2 diabetes
New Engl J Med
 , 
2010
, vol. 
363
 (pg. 
233
-
244
)
217
Keech
AC
Mitchell
P
Summanen
PA
O'Day
J
Davis
TM
Moffitt
MS
Taskinen
MR
Simes
RJ
Tse
D
Williamson
E
Merrifield
A
Laatikainen
LT
d'Emden
MC
Crimet
DC
O'Connell
RL
Colman PG, FIELD study investigators
Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial
Lancet
 , 
2007
, vol. 
370
 (pg. 
1687
-
1697
)
218
Davidson
MH
Armani
A
McKenney
JM
Jacobson
TA
Safety considerations with fibrate therapy
Am J Cardiol
 , 
2007
, vol. 
99
 
suppl
(pg. 
3C
-
18C
)
219
Health Sciences Authority
Increased myopathy with combination use of ER niacin/laropiprant (Tredaptive®) and simvastatin 40mg in Chinese patients
 
220
Davis
TM
Ting
R
Best
JD
Donoghoe
MW
Drury
PL
Sullivan
DR
Jenkins
AJ
O'Connell
RL
Whiting
MJ
Glasziou
PP
Simes
RJ
Kesäniemi
YA
Gebski
VJ
Scott
RS
Keech
AC
on behalf of the FIELD Study investigators
Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study
Diabetologia
 , 
2011
, vol. 
54
 (pg. 
280
-
290
)
221
Forsblom
C
Hiukka
A
Leinonen
ES
Sundvall
J
Groop
PH
Taskinen
MR
Effects of long-term fenofibrate treatment on markers of renal function in type 2 diabetes: the FIELD Helsinki substudy
Diabetes Care
 , 
2010
, vol. 
33
 (pg. 
215
-
220
)
222
Taskinen
MR
Sullivan
DR
Ehnholm
C
Whiting
M
Zannino
D
Simes
RJ
Keech
AC
Barter
PJ
FIELD study investigators
Relationships of HDL cholesterol, ApoA-I, and ApoA-II with homocysteine and creatinine in patients with type 2 diabetes treated with fenofibrate
Arterioscler Thromb Vasc Biol
 , 
2009
, vol. 
29
 (pg. 
950
-
955
)
223
Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico
Lancet
 , 
1999
, vol. 
354
 (pg. 
447
-
455
)
224
Yokoyama
M
Origasa
H
Matsuzaki
M
Matsuzawa
Y
Saito
Y
Ishikawa
Y
Oikawa
S
Sasaki
J
Hishida
H
Itakura
H
Kita
T
Kitabatake
A
Nakaya
N
Sakata
T
Shimada
K
Shirato
K
Japan EPA lipid intervention study (JELIS) Investigators
Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis
Lancet
 , 
2007
, vol. 
369
 (pg. 
1090
-
1098
)
225
Kromhout
D
Giltay
EJ
Geleijnse
JM
for the Alpha Omega Trial Group
n–3 Fatty acids and cardiovascular events after myocardial infarction
N Engl J Med
 , 
2010
, vol. 
363
 (pg. 
2015
-
2026
)
226
Leaf
A
Omega-3 fatty acids and prevention of arrhythmias
Curr Opin Lipidol
 , 
2007
, vol. 
18
 (pg. 
31
-
34
)
227
Holman
RR
Paul
S
Farmer
A
Tucker
L
Stratton
IM
Neil
HAW
on behalf of the AFORRD Study Group
Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes (AFORRD): a randomized controlled trial
Diabetologia
 , 
2009
, vol. 
52
 (pg. 
50
-
59
)
228
Grover
SA
Kaouache
M
Joseph
L
Barter
P
Davignon
J
Evaluating the incremental benefits of raising high-density lipoprotein cholesterol levels during lipid therapy after adjustment for the reductions in other blood lipid levels
Arch Intern Med
 , 
2009
, vol. 
169
 (pg. 
1
-
7
)
229
Robinson
JG
Dalcetrapib: a review of Phase II data
Expert Opin Investig Drugs
 , 
2010
, vol. 
19
 (pg. 
795
-
805
)
230
Barter
PJ
Caulfield
M
Eriksson
M
Grundy
SM
Kastelein
JJP
Komajda
M
Lopez-Sendon
J
Mosca
L
Tardif
J-C
Waters
DD
Shear
CL
Revkin
JH
Buhr
KA
Fisher
MR
Tall
AR
Brewer
HB
Effects of torcetrapib in patients at high risk for coronary events
N Engl J Med
 , 
2007
, vol. 
357
 (pg. 
2109
-
2122
)
231
Hu
X
Dietz
JD
Xia
C
Knight
DR
Loging
WT
Smith
AH
Yuan
H
Perry
DA
Keiser
J
Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition
Endocrinology
 , 
2009
, vol. 
150
 (pg. 
2211
-
2219
)
232
Forrest
MJ
Bloomfield
D
Briscoe
RJ
Brown
PN
Cumiskey
AM
Ehrhart
J
Hershey
JC
Keller
WJ
Ma
X
McPherson
HE
Messina
E
Peterson
LB
Sharif-Rodriguez
W
Siegl
PK
Sinclair
PJ
Sparrow
CP
Stevenson
AS
Sun
SY
Tsai
C
Vargas
H
Walker
M
3rd
West
SH
White
V
Woltmann
RF
Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone
Br J Pharmacol
 , 
2008
, vol. 
154
 (pg. 
1465
-
1473
)
233
Catalano
G
Julia
Z
Frisdal
E
Vedie
B
Fournier
N
Le Goff
W
Chapman
MJ
Guerin
M
Torcetrapib differentially modulates the biological activities of HDL2 and HDL3 particles in the reverse cholesterol transport pathway
Arterioscler Thromb Vasc Biol
 , 
2009
, vol. 
29
 (pg. 
268
-
275
)
234
Yvan-Charvet
L
Matsuura
F
Wang
N
Bamberger
MJ
Nguyen
T
Rinninger
F
Jiang
XC
Shear
CL
Tall
AR
Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL
Arterioscler Thromb Vasc Biol
 , 
2007
, vol. 
27
 (pg. 
1132
-
1138
)
235
Stein
EA
Roth
EM
Rhyne
JM
Burgess
T
Kallend
D
Robinson
JG
Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
480
-
488
)
236
Cannon
CP
Shah
S
Dansky
HM
Davidson
M
Brinton
EA
Gotto
AM
Stepanavage
M
Liu
SX
Gibbons
P
Ashraf
TB
Zafarino
J
Mitchel
Y
Barter
P
the DEFINE Investigators
Safety of anacetrapib in patients with or at high risk for coronary heart disease
N Engl J Med
 , 
2010
, vol. 
363
 (pg. 
2406
-
2415
)
237
Nordestgaard
BG
Does elevated C-reactive protein cause human atherothrombosis? Novel insights from genetics, intervention trials, and elsewhere
Curr Opin Lipidol
 , 
2009
, vol. 
20
 (pg. 
393
-
401
)
238
Frikke-Schmidt
R
Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population
Atherosclerosis
 , 
2010
, vol. 
208
 (pg. 
305
-
316
)
239
Reiner
Ž
Combined therapy in the treatment of dyslipidemia
Fundam Clin Pharmacol
 , 
2010
, vol. 
24
 (pg. 
19
-
28
)
240
Kontos
MC
Joyner
SE
Roberts
CS
Anderson
FP
Ornato
JP
Tatum
JL
Jesse
RL
Implication of the new low-density lipoprotein goals in dyslipidemia management of patients with acute coronary syndrome
Mayo Clin Proc
 , 
2007
, vol. 
82
 (pg. 
551
-
555
)
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