Article

How Do We Approach Low High-density Lipoprotein Cholesterol in 2011?

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.
Average (ratings)
No ratings
Your rating

Abstract

The prevalence of obesity and of the metabolic syndrome is increasing worldwide, and the management of global cardiovascular disease (CVD) risk requires strategies for the treatment of complex, pro-atherogenic dyslipidaemia. Considerable evidence provides a scientific rationale for the role of high-density lipoprotein (HDL) in atheroprotection. Although HDL function can become altered in pathological states, the quantitative evaluation of HDL cholesterol (HDL-C) in addition to total cholesterol (TC) levels improves the accuracy of CVD risk prediction, and is therefore a component of most global CVD risk assessment models. Non-pharmacological lifestyle interventions, such as diet and exercise for weight loss and smoking cessation, are the mainstay of raising HDL in clinical practice. Several HDL-raising medications are available but, beyond statin therapy, evidence of an incremental clinical benefit is limited. Potent novel HDL therapeutics are emerging that not only increase HDL-C levels but may also improve HDL function. Early data have restored some confidence in the potential of new cholesteryl ester transfer protein (CETP) antagonists in clinical practice. It is essential that clinical trials address vascular burden and patient outcomes, and data from large outcome trials are eagerly awaited.

Keywords

High-density lipoprotein, dyslipidaemia, obesity, atherosclerosis, cardiovascular risk assessment, lipid-lowering therapy,

Disclosure:Julian PJ Halcox received consulting and speaker fees from Abbott, AstraZeneca, Merck Sharp and Dohme, Pfizer and Roche. Esther Godfrey has no conflicts of interest to declare.

Received:

Accepted:

DOI:https://doi.org/10.15420/ecr.2011.7.4.257

Correspondence Details:Julian PJ Halcox, Sir Geraint Evans Wales Heart Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. E: halcoxjp@cardiff.ac.uk

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Atherosclerotic cardiovascular disease (CVD) is a global epidemic. As life expectancy has increased, chronic degenerative diseases have become a significant healthcare burden, affecting developed and developing countries alike,1 with atherosclerotic disease the leading cause of death according to the WHO.2 The development of effective strategies for the prevention of cardiovascular events at individual and population levels should reduce premature morbidity and mortality and have a significant global impact.1 To manage cardiovascular risk, it is prudent to understand the pathophysiological mechanisms of atherosclerosis and target the modifiable factors that contribute to CVD. Traditional risk factors for CVD include age, male gender, smoking, blood pressure, diabetes and cholesterol. These factors contribute to CVD risk through a complex interplay of many pathophysiological mechanisms, including endothelial injury, oxidative stress and induction of inflammatory pathways. Cholesterol is a key driving force involved in initiating vascular dysfunction and inflammation, an essential component of atherosclerotic plaque and thus an attractive and important target for disease prevention.3 The balance between cholesterol entry to, and removal from, the subintima is mediated by the interaction between cells in the vessel wall and lipid carriers called lipoproteins, which are highly relevant in the pathophysiology of atherosclerosis.

We hope this article will provide an up-to-date and comprehensive assessment of the role of high-density lipoprotein (HDL) in CVD for practising clinicians. This article will provide a summary, rather than a detailed biochemical examination, of the aspects of HDL biology that are relevant to atherogenesis. We will also focus on the relevance and utility of the measurement of HDL in patients with, and at risk of, CVD, particularly with regard to the estimation of cardiovascular risk and the current evidence base for HDL as a therapeutic target.

High-density Lipoprotein Biology
Atherogenesis

Atherosclerosis is a chronic inflammatory process affecting the vasculature, characterised by lipid deposition and formation of plaques within the arterial wall.4 Cholesterol transport to and from the arterial intima is key to this process; net deposition of cholesterol in excess of its removal from the arterial wall helps create a local environment that favours lipid oxidation and uptake into cells of the monocyte/macrophage lineage; this in turn drives inflammation and atherosclerosis via the release of inflammatory mediators and attraction of further inflammatory cells, together with endothelial activation and dysfunction.3

Lipoprotein Physiology

Lipoproteins are water-soluble structures that bind fat-soluble cholesterol and triglyceride (TG), thus enabling lipid carriage within the bloodstream. The lipoprotein family has been described and characterised by the size, density and electrophoretic mobility of its different subtypes.5 Those include large, TG-rich chylomicrons, very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs) and HDLs.

LDL particles and, to a lesser extent, IDL, VLDL and chylomicron remnants provide the supply of cholesterol that enters the vascular wall and is ‘captured’ through interaction between apoprotein-B (Apo-B) and the scavenger receptor on the surface of monocytic lineage cells. These become activated and transform into macrophages and eventually into the cholesterol-laden foam cells, which further influence vascular inflammation and are the hallmark of the atherosclerotic plaque. In contrast, HDL mediates removal of cholesterol from peripheral tissues, primarily via interaction between apoprotein-A1 (Apo-A1) on smaller, discoid ‘pre-β’ HDL particles and the adenosine triphosphate-binding cassette transporter-A1 (ABCA1) cholesterol transporter on the cell surface, thus initiating the process of reverse cholesterol transport. Several other factors promote the flow of cholesterol through HDL in this process, including lecithin cholesterol acyltransferase (LCAT), phospholipase transfer protein (PLTP) and cholesteryl ester transfer protein (CETP), with factors such as scavenger receptor-B1 (SR-B1) and the adenosine triphosphate-binding cassette-G1 (ABCG1) transporter also facilitating transfer of additional cholesterol from peripheral tissues into more mature forms of HDL.4 Thus HDL promotes efflux of cholesterol from cholesterol-rich macrophages or foam cells, eventually allowing delivery of cholesterol to the liver for elimination. This limits oxidative damage caused by macrophage activation/foam cell formation and prevents atherogenic inflammatory responses induced by oxidised LDL cholesterol (LDL-C). Indeed, adding HDL to experimental arterial wall models reduces intimal LDL-C deposition, decreasing lipid oxidation and production of pro-inflammatory and pro-atherogenic cytokines.6 Some of the biological functions and effects of HDL are shown in Figures 1–3.

HDL particles are complex in structure and composition. It is increasingly appreciated that HDL has a variety of physiological functions and is involved in the acute-phase response, complement regulation and cytokine-mediated pathways.7–9 HDL reduces expression of adhesion molecules, which has downstream consequences, including inhibition of neutrophil chemotaxis and reduction of reactive oxygen species generation within the arterial wall.8,9

HDL also acts to protect vascular endothelium in part through activation of nitric oxide-dependent pathways. Lysophospholipids carried by HDL activate endothelial nitric oxide synthase, which results in vasodilatation via nitric oxide release and relaxation of vascular smooth muscle cells within the arterial wall.3 Together with reverse cholesterol transport, these anti-inflammatory, antioxidant and vasodilatory properties of HDL may all contribute to an atheroprotective influence.3,6,8,9 The functions of HDL are summarised in Table 1.

Clinical Applications of High Density Lipoprotein

Considerable research effort has focused on establishing the mechanisms by which HDL might protect against atherosclerosis, and a large body of scientific evidence demonstrates several ways in which it may do so. However, HDL biology is not yet fully understood and the assays used to assess its multiple functions are not currently suitable for use outside the research setting. None the less, useful clinical evidence can be obtained simply by measuring HDL cholesterol (HDL-C) levels, particularly with regard to quantifying cardiovascular risk. The role of HDL as a treatment target in contemporary practice is more controversial, particularly in patients being treated with statins, as there is a relative paucity of outcome studies examining the incremental impact, on major clinical events, of the addition of agents that affect HDL to regimens that contain statins as background therapy.

Extensive research into factors associated with cardiovascular risk and the development of risk estimation systems has enabled us to identify high-risk populations who are most likely to benefit from evidence-based preventive interventions. This approach can help those responsible for developing and paying for systems of care to prioritise resource allocation most appropriately on the basis of both clinical effectiveness and cost-effectiveness; it can also limit the over-medicalisation of lower-risk individuals who are less likely to gain an appreciable clinical benefit from more intensive pharmacological approaches.10,11 Thus cardiovascular risk estimation has now become an essential component of the management of arterial disease.

High-density Lipoprotein in Cardiovascular Risk Assessment
Global Risk Assessment

Atherosclerotic CVD develops as a consequence of a complex interplay of multiple risk factors, with no single risk factor carrying enough weight in isolation for accurate prediction of risk. Therefore, models have been developed to estimate ‘global risk’ by accounting for the respective influence of those multiple risk factors. The output is typically presented as a patient’s 10-year risk of suffering a major clinical CVD event or CVD mortality, and is generally used to assess risk in individuals between the ages of 40 and 75 years. Risk estimation is not felt to be necessary in elderly (>75 years) or diabetic patients, nor in secondary prevention; these patient groups are all considered to be at high risk of cardiovascular events and should benefit from a more intensive approach to risk factor management.12

Much of our current knowledge of cardiovascular risk factors is derived from the Framingham Heart Study, which specifically identified low HDL-C as a CVD risk factor.13 Data from that study have been used to generate the Framingham Risk Score (FRS), the best-established and most widely used model, which uses systolic blood pressure, smoking status, total cholesterol (TC):HDL ratio, age, gender and the presence of diabetes mellitus and electrocardiographic left ventricular hypertrophy to estimate CVD risk.14,15

More recently, extensive European outcome data were used to generate the Systemic Coronary Risk Estimation (SCORE) system, a relative risk chart that incorporates similar variables to the Framingham model, but, in its initial iteration, only used TC levels and did not consider HDL.16 At the time, it was felt that the practical simplicity of using this single marker of lipid risk only outweighed any additional advantage conferred by knowledge of the patient’s more detailed lipid profile. However, a more recent analysis of the SCORE data suggests that the importance of HDL-C in risk estimation might have been underestimated. Inclusion of HDL values and use of the TC:HDL ratio commonly reclassifies patients into higher- or lower-risk categories, regardless of gender and baseline risk, and is likely to result in more accurate clinical decision-making; this approach has been recommended in the recent European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS) lipid management guidelines and will be recommended in the forthcoming joint European CVD prevention guidance.17,18 Indeed, the US National Cholesterol Education Program (NCEP) and UK National Institute for Health and Clinical Excellence (NICE) recommend assessment of HDL-C values when calculating CVD risk.19Figure 4 illustrates the impact of variations in HDL level on the global cardiovascular mortality risk using the European SCORE model.

Risk Assessment beyond High-density Lipoprotein

Clinical practice favours the simplicity of both the Framingham and SCORE systems. However, these systems focus on traditional risk factors and do not formally allow for increased CVD risk in cases of positive family history, treated hypertension, social deprivation or obesity, which are all recognised to have an important influence on CVD risk. Obesity is becoming increasingly common, and the clustering of risk factors such as hypertension, dyslipidaemia and diabetes is commonly seen in obese individuals, particularly those with a central/visceral pattern of weight gain.21,22 This is an important factor contributing to CVD risk at individual and population levels, where an increasing prevalence of obesity is offsetting the benefits gained through improvements in CVD risk management elsewhere.23

Recently developed systems aim to improve the accuracy of risk estimation by incorporating additional risk factors. For example, the QRISK2 cardiovascular disease risk calculator developed from a large UK primary care dataset estimates CVD risk using the following additional risk factors: family history of early CVD, existing antihypertensive treatment, social deprivation, body mass index, ethnicity, presence of rheumatoid arthritis, chronic kidney disease and atrial fibrillation.24 The Reynolds Risk Score, developed in the US, estimates risk using a combination of high sensitivity C-reactive protein (CRP), non-HDL-C (TC-HDL), glycated haemoglobin (HbA1c) percentage and family history of premature myocardial infarction alongside traditional factors;25 it has been shown to provide incremental ability to predict risk compared with the FRS, but is not currently used in Europe, as it has not been validated in European populations, where routine CRP testing is not universally supported.

Although systems that incorporate additional risk factors demonstrate efficacy and can reclassify patients into higher- or lower-risk categories, they require information on a larger number of variables, or perhaps on newer variables. There are less extensive data supporting their use, somewhat limiting their utility in clinical practice. HDL is readily available on lipid profiling and can improve diagnostic accuracy without the practitioner having to request additional information, and it is likely to be both pragmatic and cost-effective to use risk scoring systems based on HDL levels.

Limitations of High-density Lipoprotein Cholesterol Levels in Risk Assessment

There has been much debate over the lipid parameters measured for the optimal assessment of CVD risk. Research has also focused on assessing the value of biomarkers for CVD, with the hope of elucidating which ones most accurately predict CVD risk.

Apo-A1 and Apo-B are the main surface proteins on LDL and HDL, respectively, and it has been argued that their levels provide a more reliable estimate of the amount of these lipoproteins than the levels of LDL-C and HDL-C and improve the accuracy of CVD risk prediction.26,27 However, an extensive recent meta-analysis suggests that lipid fractions are equally valuable in assessing risk in a general population. Clinical practice should be guided by which system is most pragmatic, cost-effective and relevant for local use.28

Lipid biology is complex, with much interplay between lipid fractions. Although low HDL and hypertriglyceridaemia are epidemiologically associated with CVD,13,29–33 debate has continued over whether both HDL and TG are independently associated with CVD following adjustment for other risk factors. Recent evidence from the Emerging Risk Factors Collaboration has reinforced information from previous studies,33 demonstrating that most of the predictive value of TG is lost following adjustment for other common risk factors. In contrast, the predictive value of HDL remains consistent following risk factor adjustment.34

It has been suggested that HDL-C may be less predictive of cardiovascular risk in patients achieving very low concentrations of LDL-C as a result of high-dose statin therapy,35,36 and recent data from the Justification for the use of statins in primary prevention: an intervention trial evaluating rosuvastatin (JUPITER) study have demonstrated that levels of HDL-C do not correlate with residual cardiovascular risk in patients with high CRP and low LDL-C receiving potent statin therapy.37 However, a recent meta-analysis of 20 randomised controlled trials, including the JUPITER study, has shown that low levels of HDL are clearly associated with CHD risk at all levels of LDL-C and that this relationship is not changed appreciably by statin therapy.38 Indeed, HDL remains an important predictor of progression of coronary atheroma, even in patients achieving very low levels of LDL on statin therapy.39,40

Currently, HDL-C together with non-HDL-C or TC within a multifactorial risk model appears to be sufficient for contemporary cardiovascular risk assessment without the need for TG values. Therefore, testing can be carried out without fasting, reducing the need for delayed or additional testing due to patient oversight.28 Apolipoproteins A and B demonstrate similar merit to HDL and non-HDL-C levels for risk prediction at a population level, although additional information might be provided by more detailed assessment of apolipoprotein levels in some individuals. Cost and practicality should guide lipid test selection for routine risk assessment, with conventional lipid profiling adequate for most individuals. Whether further functional assays of HDL might enhance the evaluation remains a subject of investigation.

Although individuals with low HDL-C frequently have dysfunctional HDL, recent evidence has demonstrated that levels alone do not always correlate with HDL function,3,41 emphasising the complex relationship that exists between HDL and atherosclerosis. Genetic and environmental host factors can influence the function of HDL – for example, certain inflammatory states reduce reverse cholesterol transport and anti-inflammatory function without altering the levels of HDL-C.42

A small number of individuals originating from the Italian village of Limone sul Garda were found to express a variant of Apo-A1 known as Apo-A1 Milano. Those with this mutation demonstrate a very low risk of ischaemic heart disease despite very low plasma levels of HDL-C.43 Although the mechanism of benefit has not yet been fully elucidated, Apo-A1 Milano appears to promote very rapid cholesterol efflux and reverse cholesterol transport in experimental models. It also has enhanced antioxidant and anti-inflammatory properties, with parenteral infusion of Apo-A1 Milano mediating plaque regression within weeks in patients with coronary atheroma.44,45

HDL function is affected by a variety of host factors, including the acute-phase response to stress and infection, rheumatological disease, diabetes mellitus and impaired glucose tolerance.42 Importantly, individuals with abdominal obesity commonly have altered HDL function46 and it appears that intensive dietary and lifestyle modification can modulate HDL-C from a pro-inflammatory to an anti-inflammatory state.47

It has been proposed that the pharmaceutical industry ought to focus on developing agents that improve HDL function and assays to measure this functionality, in addition to simply focusing on increasing levels of HDL-C.48 Given the strong independent relationship between HDL-C levels and CVD, and the beneficial impact of HDL on disease progression in animal models, therapeutics that target HDL-C ought to provide clinical benefit.28

Low High-density Lipoprotein as a Therapeutic Target – High-density Lipoprotein-modifying agents

Individuals with low levels of HDL-C, who often have elevated TG and dysfunctional HDL, have increased CVD risk even when receiving statins, particularly those with diabetes mellitus.49–51 Indeed, statins confer only a modest benefit once LDL-C levels have been reduced to very low levels, have only a modest impact on HDL levels (3–10 %); and some agents reduce serum HDL-C, suggesting that combination therapies may be of benefit.32,52

Niacin

Niacin (nicotinic acid) has been used in clinical practice for many years and has notable effects on all aspects of atherogenic dyslipidaemia, with effects on HDL-C, LDL-C, TG and lipoprotein(a) [Lp(a)]. It increases HDL-C levels by 15–35 %53,54 and protects HDL from metabolic consumption by reducing the breakdown of its main structural component, Apo-A1. Despite a good safety profile, niacin commonly causes flushing in the initial stages of therapy. This may indicate good response to therapy55 and tends to settle over time, but remains problematic for many patients and is a common reason for non-compliance.53,56,57 It is otherwise well tolerated, significantly increases serum HDL-C levels and appears to result in improved patient outcomes and recovery of the atheroprotective effects of HDL.19,57

Recent evidence suggests that niacin therapy demonstrates both quantitative and qualitative effects on HDL, increasing plasma levels and improving molecule function. Trials have demonstrated that the additional use of extended-release niacin alongside conventional statin therapy improves several lipid fractions – LDL-C, non-HDL-C, TG, HDL-C, Lp(a), CRP – when compared with simvastatin monotherapy53,54,56 and, in a recent study, the administration of niacin to diabetic subjects has been shown to increase the protective effects of HDL on vascular endothelium, with improved endothelial repair, nitric oxide production and resultant endothelial-dependent vasodilatation.58

Effects of Niacin on Outcomes

In addition to improvements in lipid fractions and functionality, combination therapy using niacin has shown favourable results regarding patient outcomes. Niacin therapy (in combination) appears to improve coronary atherosclerosis on angiography (0.4 % regression) and reduces long-term mortality (11 %), cardiovascular morbidity (27 % reduced non-fatal re-infarction) and the need for surgical revascularisation (60 %) when compared with placebo.57,59–63

Niacin seems to be both efficacious and safe and is frequently considered for use in high-risk patients with dyslipidaemia (in particular low HDL-C) refractory to statin monotherapy.19 Unfortunately, the majority of studies so far have focused on statin–niacin combination therapy versus placebo. Two large trials are addressing whether niacin has additional benefits on top of statin use: the Atherothrombosis intervention in metabolic syndrome with low HDL cholesterol/high triglyceride and impact on global health outcomes (AIM-HIGH) and the Heart protection study-2 treatment of HDL to reduce the incidence of vascular events (HPS-2 THRIVE) trials.

It is disappointing to note the recent discontinuation of the AIM-HIGH trial in coronary disease patients with low HDL, due to a safety analysis suggesting clinical futility with regard to the likelihood of achieving the primary endpoint and perhaps even a small increased risk of stroke.64,65 It is most likely that the AIM-HIGH trial was too small and therefore underpowered to address the main outcome measure(s) in the light of the observed event rate in the study population, but further insights will be provided when the full manuscript is published. The considerably larger HPS-2 THRIVE study is ongoing and should hopefully provide a more definitive answer.

Peroxisome Proliferator-activated Receptor-α Agonists

Fibrates activate peroxisome proliferator-activated receptor-α (PPAR-α), which alters expression of apolipoproteins and has downstream effects on many aspects of dyslipidaemia. Substantial reductions in TG are seen, alongside reductions in LDL-C and moderately increased HDL-C (10 %).66 Fibrate monotherapy has improved outcomes in patients with coronary disease and low HDL,67 but not in those with diabetes mellitus, although some subgroups may benefit.68,69 There is some reluctance to use fibrates in combination with statins, due to worries regarding increased adverse events (muscle aches, rhabdomyolysis). While genuine concerns exist for gemfibrozil, which inhibits statin metabolism and may increase the adverse effects of statins on muscle tissue,70 fenofibrate does not interact with statins and combination therapies demonstrate a good safety profile,71 with similar efficacy to niacin combination therapies.

The Action to control cardiovascular risk in diabetes (ACCORD) trial evaluated the effect of statin monotherapy versus combination therapy with fenofibrate on clinical outcomes in patients with type 2 diabetes mellitus without selecting for those with low HDL and/or elevated TG. Overall, patient outcomes were no better with the additional use of fenofibric acid, but subgroup analysis suggested a markedly beneficial effect on patient outcomes in those with high baseline TG and low HDL-C. Thus it might be appropriate to consider fenofibric acid–statin combination therapy to address residual lipid risk in diabetic patients with this characteristic dyslipidaemic lipid profile who are already on statin therapy.72

Cholesteryl Ester Transfer Protein Antagonists

CETP antagonists are a novel therapeutic class in HDL modification. CETP activity promotes neutral lipid exchange, in particular the delivery of cholesterol into Apo-B-containing atherogenic lipoproteins, and it also promotes HDL remodelling, which regenerates the pre-β HDL that has major importance in the initial stage of reverse cholesterol transport. CETP antagonists reduce HDL-C clearance and are the most potent therapeutic agents that increase the levels of HDL-C.73,74

Despite marked improvements in serum HDL-C, the CETP antagonist torcetrapib demonstrated increased risk of morbidity and mortality, which resulted in the discontinuation of the Investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial.75 It is postulated that the failure of torcetrapib may be due to significant off-target effects, resulting in activation of the renin–angiotensin–aldosterone system and increased blood pressure in treated subjects. However, much controversy exists regarding the mechanisms underlying the adverse effects demonstrated, and the reasons for higher mortality and morbidity remain unclear.75 It is now hoped that the adverse effects of torcetrapib are not due to a ‘class’ effect.76 Indeed, these off-target effects are not seen with the more selective agent anacetrapib. Recent data from the Determining the efficacy and tolerability of CETP inhibition with anacetrapib (DEFINE) trial are reassuring, pointing towards an impressive effect on HDL values (138 % increase versus placebo) alongside a good safety profile, with no significant effect on morbidity and mortality.77,78 Dalcetrapib also shows promise, despite less potent CETP modulation and smaller increases in serum HDL-C levels (36 %) when compared with torcetrapib and anacetrapib. Unlike anacetrapib and torcetrapib, this molecule does not inhibit CETP-induced pre-β HDL formation,79 which may have clinical importance, as pre-β HDL is a key component of reverse cholesterol transport.79

Reassuring study results point towards improved safety profiles of the newer CETP agents anacetrapib and dalcetrapib.80 It is hoped that the encouraging early results will translate into improved outcomes in the large clinical trials currently in progress. Several pivotal trials will assess the efficacy of dalcetrapib: dal-PLAQUE will assess atherosclerosis and inflammation, dal-VESSEL endothelial function and blood pressure, and dal-ACUTE and dal-OUTCOMES the effect of dalcetrapibdalcetrapib on adverse clinical events in patients with acute coronary syndromes. Similarly, the Randomised evaluation of the effects of anacetrapib through lipid modification (REVEAL) HPS-3 TIMI-55 trial will assess the impact of anacetrapib on morbidity and mortality in 30,000 patients with known CVD.81–83

New Agents

Novel HDL agents show early promise and aim to optimise HDL function in addition to improving serum HDL-C values. Apo-A1 mimetic compounds appear to confer atheroprotection via antioxidant properties in addition to increasing HDL-C formation, particle maturation and reverse cholesterol transport. Liver X receptor (LXR) agonists are thought to promote reverse cholesterol transport by modulating expression of membrane transporter ABCA1, which promotes delivery of lipids to nascent HDL particles. Although experimental animal and early clinical models have demonstrated the efficacy of these novel therapeutic agents,84–87 considerable further clinical research is needed to confirm their efficacy and safety.

Conclusions

There is growing evidence in favour of the use of additional therapeutic agents in combination with statins for the treatment of atherogenic dyslipidaemia. Niacin and fibrates have a good safety profile when used appropriately and lead to significantly improved levels of HDL-C. Current guidelines suggest that the additional use of a fibrate or niacin to statin therapy may be appropriate in high-risk patients with low HDL-C and/or hypertriglyceridaemia.32 Newer pharmacological therapies, such as CETP antagonists, Apo-A1 analogues and HDL mimetics, show early promise, but further investigation into their efficacy, safety and impact on cardiovascular events is needed before they can be licensed and recommended for use in clinical practice.

Non-pharmacological treatment remains fundamental to the management of cardiovascular risk. Healthy dietary intake and regular exercise have antiatherogenic effects through reduction in blood pressure and atherogenic dyslipidaemia,88 improved insulin sensitivity and glycaemic control.89 Recent data also suggest that dietary and lifestyle modification alone can convert HDL-C from a pro-inflammatory to an anti-inflammatory state.47 However, it is particularly difficult for patients to make long-term changes to lifestyle, and cost-effective support systems are elusive.90 Population-level interventions impacting dietary and other lifestyle choices may hold greater promise. Current recommendations – e.g., those of the NCEP-Adult Treatment Panel III – suggest that practitioners continue to advocate non-pharmacological strategies, including healthy diet, moderate daily exercise and smoking cessation, alongside the use of pharmacotherapeutics in certain high-risk individuals.32

Considerable evidence supports HDL as an atheroprotective agent and, as such, HDL is highly relevant to our understanding of CVD. HDL testing demonstrates value in cardiovascular risk estimation by accurately reclassifying patients into higher- or lower-risk categories, and its use is currently recommended by national and European guidelines. However, the clinical impact of medications addressing HDL as a treatment target remains controversial, and outcome data from large randomised clinical trials demonstrating an incremental impact of HDL-modifying agents in combination with background statin therapies are essential to justify their routine use. The results of these trials are eagerly awaited.

References

  1. Yusuf S, Ounpuu S, Anand S, The global epidemic of atherosclerotic cardiovascular disease, Med Princ Pract, 2002;11(Suppl. 2):3–8.
    Crossref | PubMed
  2. Mackay J, Mensah G, Atlas of heart disease and stroke, Geneva: World Health Organization, 2004;112.
  3. Navab M, Anantharamaiah GM, Reddy ST, et al., HDL as a biomarker, potential therapeutic target, and therapy, Diabetes, 2009;58(12):2711–7.
    Crossref | PubMed
  4. Badimón JJ, Ibáñez B, Increasing high-density lipoprotein as a therapeutic target in atherothrombotic disease, Rev Esp Cardiol, 2010;63(3):323–33.
    Crossref | PubMed
  5. Hegele RA, Plasma lipoproteins: genetic influences and clinical implications, Nat Rev Genet, 2009;10(2):109–21.
    Crossref | PubMed
  6. Navab M, Imes SS, Hama SY, et al., Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein, J Clin Invest, 1991;88(6):2039–46.
    Crossref | PubMed
  7. Nofer JR, van der Giet M, Tölle M, et al., HDL induces NOdependent vasorelaxation via the lysophospholipid receptor S1P3, J Clin Invest, 2004;113(4):569–81.
    Crossref | PubMed
  8. Lesnik P, Chapman MJ, A new dimension in the vasculoprotective function of HDL: progenitor-mediated endothelium repair, Arterioscler Thromb Vasc Biol, 2006;26(5):965–7.
    Crossref | PubMed
  9. Bursill CA, Castro ML, Beattie DT, et al., High-density lipoproteins suppress chemokines and chemokine receptors in vitro and in vivo, Arterioscler Thromb Vasc Biol, 2010;30(9):1773–8.
    Crossref | PubMed
  10. Pearson TA, Blair SN, Daniels SR, et al., AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee, Circulation, 2002;106(3):388–91.
    Crossref | PubMed
  11. De Backer G, Ambrosioni E, Borch-Johnsen K, et al., European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts), Eur J Cardiovasc Prev Rehabil, 2003;10(4):S1–S10.
    Crossref | PubMed
  12. Graham IM, Cooney MT, Dudina A, Squarta S, What is my risk of developing cardiovascular disease?, Eur J Cardiovasc Prev Rehabil, 2009;16(Suppl. 2):S2–7.
    Crossref | PubMed
  13. Gordon T, Castelli WP, Hjortland MC, et al., High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study, Am J Med, 1977;62(5):707–14.
    Crossref | PubMed
  14. Barzi F, Patel A, Gu D, et al., Cardiovascular risk prediction tools for populations in Asia, J Epidemiol Community Health, 2007;61(2):115–21.
    Crossref | PubMed
  15. Hippisley-Cox J, Coupland C, Vinogradova Y, et al., Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: prospective open cohort study, BMJ, 2007;335(7611):136.
    Crossref | PubMed
  16. Conroy RM, Pyörälä K, Fitzgerald AP, et al., Estimation of tenyear risk of fatal cardiovascular disease in Europe: the SCORE project, Eur Heart J, 2003;24(11):987–1003.
    Crossref | PubMed
  17. Cooney MT, Dudina A, De Bacquer D, et al., How much does HDL cholesterol add to risk estimation? A report from the SCORE Investigators, Eur J Cardiovasc Prev Rehabil, 2009;16(3):304–14.
    Crossref | PubMed
  18. Cooney MT, Dudina A, De Bacquer D, et al., HDL cholesterol protects against cardiovascular disease in both genders, at all ages and at all levels of risk, Atherosclerosis, 2009;206(2):611–6.
    Crossref | PubMed
  19. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report, Circulation, 2002;106(25):3143–3421.
    PubMed
  20. Reiner Z, Catapano AL, De Backer G, et al., ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS), Eur Heart J, 2011;32(14):1769–1818.
    Crossref | PubMed
  21. Bhatti MS, Akbri MZ, Shakoor M, Lipid profile in obesity, J Ayub Med Coll Abbottabad, 2001;13(1):31–3.
    PubMed
  22. Brehm A, Pfeiler G, Pacini G, et al., Relationship between serum lipoprotein ratios and insulin resistance in obesity, Clin Chem, 2004;50(12):2316–22.
    Crossref | PubMed
  23. Murray CJ, Lopez AD, Regional patterns of disability-free life expectancy and disability-adjusted life expectancy: global Burden of Disease Study, Lancet, 1997;349(9062):1347–52.
    Crossref | PubMed
  24. Hippisley-Cox J, Coupland C, Vinogradova Y, et al., Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2, BMJ, 2008;336(7659):1475–82.
    Crossref | PubMed
  25. Ridker PM, Buring JE, Rifai N, Cook NR, Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA, 2007;297(6):611–9.
    Crossref | PubMed
  26. Parish S, Peto R, Palmer A, et al., The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls, Eur Heart J, 2009;30(17):2137–46.
    Crossref | PubMed
  27. McQueen MJ, Hawken S, Wang X, et al., Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study, Lancet, 2008;372(9634):224–33.
    Crossref | PubMed
  28. Erqou S, Kaptoge S, Perry PL, et al., Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality, JAMA, 2009;302(4):412–23.
    Crossref | PubMed
  29. Kannel WB, High-density lipoproteins: epidemiologic profile and risks of coronary artery disease, Am J Cardiol, 1983;52(4):9B–12B.
    Crossref | PubMed
  30. DeGoma EM, Leeper NJ, Heidenreich PA, Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol, J Am Coll Cardiol, 2008;51(1):49–55.
    Crossref | PubMed
  31. Castelli WP, Cholesterol and lipids in the risk of coronary artery disease--the Framingham Heart Study, Can J Cardiol, 1988;4(Suppl. A):5A–10A.
    PubMed
  32. Grundy SM, Cleeman JI, Merz CN, et al., Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines, J Am Coll Cardiol, 2004;44(3):720–32.
    Crossref | PubMed
  33. Sarwar N, Danesh J, Eiriksdottir G, et al., Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies, Circulation, 2007;115(4):450–8.
    Crossref | PubMed
  34. Di Angelantonio E, Sarwar N, Perry P, et al., Major lipids, apolipoproteins, and risk of vascular disease, JAMA, 2009;302(18):1993–2000.
    Crossref | PubMed
  35. Barter P, Gotto AM, LaRosa JC, et al., HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events, N Engl J Med, 2007;357(13):1301–10.
    Crossref | PubMed
  36. Ray KK, Cannon CP, Cairns R, et al., Prognostic utility of apoB/AI, total cholesterol/HDL, non-HDL cholesterol, or hs- CRP as predictors of clinical risk in patients receiving statin therapy after acute coronary syndromes: results from PROVE IT-TIMI 22, Arterioscler Thromb Vasc Biol, 2009;29(3):424–30.
    Crossref | PubMed
  37. Ridker PM, Genest J, Boekholdt SM, et al., HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial, Lancet, 2010;376(9738):333–9.
    Crossref | PubMed
  38. Jafri H, Alsheikh-Ali AA, Karas RH, Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk, Ann Intern Med, 2010;153(12):800–8.
    Crossref | PubMed
  39. Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ, Metaanalysis of comparative efficacy of increasing dose of Atorvastatin versus Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids (from VOYAGER), Am J Cardiol, 2010;105(1):69–76.
    Crossref | PubMed
  40. Bayturan O, Kapadia S, Nicholls SJ, et al., Clinical predictors of plaque progression despite very low levels of low-density lipoprotein cholesterol, J Am Coll Cardiol, 2010;55(24):2736–42.
    Crossref | PubMed
  41. Frikke-Schmidt R, Nordestgaard BG, Stene MC, et al., Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease, JAMA, 2008;299(21):2524–32.
    Crossref | PubMed
  42. Van Lenten BJ, Hama SY, de Beer FC, et al., Antiinflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures, J Clin Invest, 1995;96(6):2758–67.
    Crossref | PubMed
  43. Sirtori CR, Calabresi L, Franceschini G, et al., Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study, Circulation, 2001;103(15):1949–54.
    Crossref | PubMed
  44. Rader DJ, Regulation of reverse cholesterol transport and clinical implications, Am J Cardiol, 2003;92(4A):42J–49J.
    Crossref | PubMed
  45. Nissen SE, Tsunoda T, Tuzcu EM, et al., Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial, JAMA, 2003;290(17):2292–2300.
    Crossref | PubMed
  46. Perségol L, Vergès B, Gambert P, Duvillard L, Inability of HDL from abdominally obese subjects to counteract the inhibitory effect of oxidized LDL on vasorelaxation, J Lipid Res, 2007;48(6):1396–1401.
    Crossref | PubMed
  47. Roberts CK, Ng C, Hama S, et al., 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;101(6):1727–32.
    Crossref | PubMed
  48. Briel M, Ferreira-Gonzalez I, You JJ, et al., Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis, BMJ, 2009;338:b92.
    Crossref | PubMed
  49. Downs JR, Clearfield M, Weis S, et al., Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study, JAMA, 1998;279(20):1615–22.
    Crossref | PubMed
  50. Sever PS, Dahlöf B, Poulter NR, et al., Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial, Lancet, 2003;361(9364):1149–58.
    Crossref | PubMed
  51. Cziraky MJ, Watson KE, Talbert RL, Targeting low HDLcholesterol to decrease residual cardiovascular risk in the managed care setting, J Manag Care Pharm, 2008; 14(8 Suppl.):S3–28; quiz S30–1.
    PubMed
  52. Hayward RA, Hofer TP, Vijan S, Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem, Ann Intern Med, 2006;145(7):520–30.
    Crossref | PubMed
  53. Ballantyne CM, Davidson MH, McKenney J, et al., 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;101(10): 1428–36.
    Crossref | PubMed
  54. Ballantyne CM, Davidson MH, McKenney JM, et al., Comparison of the efficacy and safety of a combination tablet of niacin extended-release and simvastatin with simvastatin 80 mg monotherapy: the SEACOAST II (high-dose) study, J Clin Lipidol, 2008;2(2):79–90.
    Crossref | PubMed
  55. Taylor AJ, Stanek EJ, Flushing and the HDL-C response to extended-release niacin, J Clin Lipidol, 2008;2(4):285–8.
    Crossref | PubMed
  56. Kashyap ML, McGovern ME, Berra K, et al., Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia, Am J Cardiol, 2002;89(6):672–8.
    Crossref | PubMed
  57. McKenney J, New perspectives on the use of niacin in the treatment of lipid disorders, Arch Intern Med, 2004;164(7):697–705.
    Crossref | PubMed
  58. Sorrentino SA, Besler C, Rohrer L, et al., Endothelialvasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy, Circulation, 2010;121(1):110–22.
    Crossref | PubMed
  59. Knopp RH, Ginsberg J, Albers JJ, et al., Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism of action of niacin, Metabolism, 1985;34(7):642–50.
    Crossref | PubMed
  60. Brown BG, Zhao XQ, Chait A, et al., Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease, N Engl J Med, 2001;345(22):1583–92.
    Crossref | PubMed
  61. Jin FY, Kamanna VS, Kashyap ML, Niacin decreases removal of high-density lipoprotein apolipoprotein A-I but not cholesterol ester by Hep G2 cells. Implication for reverse cholesterol transport, Arterioscler Thromb Vasc Biol, 1997;17(10):2020–8.
    Crossref | PubMed
  62. Shepherd J, Packard CJ, Patsch JR, et al., Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein A metabolism, J Clin Invest, 1979;63(5):858–67.
    Crossref | PubMed
  63. Clofibrate and niacin in coronary heart disease, JAMA, 1975;231(4):360–81.
    Crossref | PubMed
  64. US National Institutes of Health, NIH stops clinical trial on combination cholesterol treatment [press release], 2011. Available at: www.nih.gov/news/health/may2011/nhlbi- 26.htm (accessed 21 October 2011).
  65. US Food and Drug Administration, FDA statement on the AIM-HIGH trial, 2011. Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInform ationforPatientsandProviders/ucm256841.htm (accessed 21 October 2011).
  66. Gross B, Staels B, PPAR agonists: multimodal drugs for the treatment of type-2 diabetes, Best Pract Res Clin Endocrinol Metab, 2007;21(4):687–710.
    Crossref | PubMed
  67. Goldenberg I, Boyko V, Tennenbaum A, et al., Long-term benefit of high-density lipoprotein cholesterol-raising therapy with bezafibrate: 16-year mortality follow-up of the bezafibrate infarction prevention trial, Arch Intern Med, 2009;169(5):508–14.
    Crossref | PubMed
  68. Keech A, Simes RJ, Barter P, et al., 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;366(9500):1849–61.
    Crossref | PubMed
  69. Keech AC, Mitchell P, Summanen PA, et al., Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial, Lancet, 2007;370(9600):1687–97.
    Crossref | PubMed
  70. Davidson MH, Combination therapy for dyslipidemia: safety and regulatory considerations, Am J Cardiol, 2002;90(10B):50K–60K.
    Crossref | PubMed
  71. Jones PH, Davidson MH, Kashyap ML, et al., Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: a phase 3 study, Atherosclerosis, 2009;204(1):208–15.
    Crossref | PubMed
  72. Elam M, Lovato LC, Ginsberg H, Role of fibrates in cardiovascular disease prevention, the ACCORD-Lipid perspective, Curr Opin Lipidol, 2011;22(1):55–61.
    Crossref | PubMed
  73. Sharma RK, Singh VN, Reddy HK, Thinking beyond lowdensity lipoprotein cholesterol: strategies to further reduce cardiovascular risk, Vasc Health Risk Manag, 2009;5:793–9.
    Crossref | PubMed
  74. Brousseau ME, Schaefer EJ, Wolfe ML, et al., Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol, N Engl J Med, 2004;350(15):1505–15.
    Crossref | PubMed
  75. Barter PJ, Caulfield M, Eriksson M, et al., Effects of torcetrapib in patients at high risk for coronary events, N Engl J Med, 2007;357(21):2109–22.
    Crossref | PubMed
  76. Krishna R, Anderson MS, Bergman AJ, et al., Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies, Lancet, 2007;370(9603):1907–14.
    Crossref | PubMed
  77. Cannon CP, Dansky HM, Davidson M, et al., Design of the DEFINE trial: determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib, Am Heart J, 2009;158(4):513–9.e3.
    Crossref | PubMed
  78. Cannon CP, Shah S, Dansky HM, et al., Safety of anacetrapib in patients with or at high risk for coronary heart disease, N Engl J Med, 2010;363(25):2406–15.
    Crossref | PubMed
  79. Niesor EJ, Magg C, Ogawa N, et al., Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport, J Lipid Res, 2010;51(12):3443–54.
    Crossref | PubMed
  80. Stein EA, Roth EM, Rhyne JM, et al., Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial, Eur Heart J, 2010;31(4):480–8.
    Crossref | PubMed
  81. Schwartz GG, Olsson AG, Ballantyne CM, et al., Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome, Am Heart J, 2009;158(6):896–901.e3.
    Crossref | PubMed
  82. Hoffman La Roche, A Randomized, Placebo-controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease (CHD) Including Patients With Other CHD Risk Factors. Identifier: NCT00655473, 2008. Available at: www.clinicaltrials.gov/ct2/show/NCT00655473 (accessed 20 October 2011).
  83. Hoffman La Roche, A Multi-Center, Double-blind, Randomized, Placebo Controlled, Parallel Group Study of the Effect of Dalcetrapib on Atherosclerotic Disease Progression As Measured by Coronary Intravascular Ultrasound, Carotid B-Mode Ultrasound and Coronary Angiography. Identifier: NCT01059682, 2010. Available at: www.clinicaltrials.gov/ct2/show/NCT01059682 (accessed 20 October 2011).
  84. Collins JL, Fivush AM, Watson MA, et al., Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines, J Med Chem, 2002;45(10):1963–6.
    Crossref | PubMed
  85. Navab M, Anantharamaiah GM, Hama S, et al., D-4F and statins synergize to render HDL antiinflammatory in mice and monkeys and cause lesion regression in old apolipoprotein Enull mice, Arterioscler Thromb Vasc Biol, 2005;25(7):1426–32.
    Crossref | PubMed
  86. White CR, Datta G, Mochon P, et al., Vasculoprotective Effects of Apolipoprotein Mimetic Peptides: An Evolving Paradigm In Hdl Therapy (Vascular Disease Prevention, In Press.), Vasc Dis Prev, 2009;6:122–30.
    Crossref | PubMed
  87. Chen X, Burton C, Song X, et al., An apoA-I mimetic peptide increases LCAT activity in mice through increasing HDL concentration, Int J Biol Sci, 2009;5(5):489–99.
    Crossref | PubMed
  88. Esposito K, Marfella R, Ciotola M, et al., Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial, JAMA, 2004;292(12):1440–6.
    Crossref | PubMed
  89. Thomas DE, Elliott EJ, Naughton GA, Exercise for type 2 diabetes mellitus, Cochrane Database Syst Rev, 2006;3:CD002968.
    Crossref | PubMed
  90. Chiuve SE, McCullough ML, Sacks FM, Rimm EB, Healthy lifestyle factors in the primary prevention of coronary heart disease among men: benefits among users and nonusers of lipid-lowering and antihypertensive medications, Circulation, 2006;114(2):160–7
    Crossref | PubMed
Previous Volume Article Next Volume Article