ORIGINAL ARTICLE

Heart, Lung and Circulation (2015) 24, 495–502 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2014.12.009

Clinical Guidelines on Hyperlipidaemia: Recent Developments, Future Challenges and the Need for an Australian Review D.R. Sullivan a*, G.F. Watts b, S.J. Nicholls c, P. Barter d, R. Grenfell e, C.K. Chow f, A. Tonkin g, A. Keech h a

Department of Chemical Pathology, Royal Prince Alfred Hospital, Camperdown, NSW Department of Medicine, University of Western Australia, Perth, WA South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, SA d Centre for Vascular Research, University of NSW, Sydney NSW e National Heart Foundation Director of Cardiovascular Health, Melbourne Vic f The George Institute for International Health, University of Sydney, Camperdown, Sydney NSW g Cardiovascular Research Unit, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic h NHMRC Clinical Trials Centre, University of Sydney and Royal Prince Alfred Hospital, University of Sydney, NSW b c

Online published-ahead-of-print 25 December 2014

Large reductions in cardiovascular disease (CVD) mortality have been achieved over the last 50 years in developed countries. The health policies that have contributed so much to this success have largely been coordinated by means of expert guidelines for the management of the classic modifiable risk factors such as blood pressure, diabetes and blood lipids. National and international guidelines for lipid management have demonstrated a high degree of consistency between numerous sets of recommendations. It has been argued that some important components of the consensus that has been established over the past decade have been challenged by the latest guidelines of the American Heart Association - American College of Cardiologists (AHA-ACC). Clinicians can be reassured that continued reliance on extensive scientific evidence has reaffirmed the importance of lipid metabolism as a modifiable risk factor for atherosclerotic cardiovascular disease. On the other hand, the recent AHA-ACC guidelines suggest changes in the strategies by which metabolic risk factors may be modified. This small number of important changes should not be sensationalised because these differences usefully reflect the need for guidelines to evolve to accommodate different contexts and changing perspectives as well as emerging issues and new information for which clinical trial evidence is incomplete. This article will consider the recent policies and responses of national and supranational organisations on topics including components of CVD risk assessment, sources of CVD risk information and re-appraisal of lipid-lowering interventions. Timely review of Australian lipid management guidelines will require consideration of these issues because they are creating a new context within which new guidelines must evolve. Keywords

Cardiovascular disease  Guidelines  Blood lipids  Lipid-lowering therapy  Australia

Introduction The recent release of the AHA-ACC Lipid Guidelines [1] has stimulated much discussion, and has prompted strong responses from both supporters and opponents. There has

also been much discussion of how these AHA-ACC guidelines differ from the European Society of Cardiology – European Atherosclerosis Society (ESC-EAS) Guidelines [2] and the International Atherosclerosis Society (IAS) recommendations [3]. Despite the unfortunate focus on differences in

*Corresponding author at: Department of Chemical Pathology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown NSW 2050 Australia. Tel.: +61 2 95158832; fax: +61 2 95156186/+61 427952996(Mob)., Email: [email protected] © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.

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many of these discussions, it is important to note that the recommendations from all three groups agree on almost all important points, with the remaining differences representing fine-tuning rather than major disagreements. This article will examine these issues from an Australasian perspective. The aetiology underlying atherosclerotic CVD is multi-factorial. Overarching guidelines which address all major modifiable CVD risk factors are required as the basis for an integrated primary care strategy. The Australian National Vascular Disease Prevention Alliance (NVDPA) guidelines allow general practitioners to engage with CVD prevention without the need to refer to three or four separate (and possibly conflicting) risk factor-specific guidelines [4]. The NVDPA primary prevention guidelines provide a patient-centred approach that is based on the impact of all major CVD risk factors on an individual’s absolute risk of a CVD event within a five-year timeframe. The resultant emphasis on individuals at greatest risk favours cost-effective CVD prevention in primary care. Individual risk factors for CVD such as hypertension, hyperglycaemia and hyperlipidaemia are continuous, so the paradigm of a group of separate disease states at levels above arbitrary cutpoints is outdated. Consequently, full implementation of a multi-factorial approach still requires substantial reorganisation of the current system in which single risk factor clinics predominate. On the other hand, single risk factor-specific guidelines remain necessary to meet the requirement amongst nonexpert clinicians and specialists from other fields for greater expertise in particular circumstances. Furthermore, risk factors such as dyslipidaemia may take on particular significance in population subgroups including the elderly, children, women of child-bearing age, patients receiving anti-retroviral therapy, transplant recipients and others. Logistically, clinical lipid management needs to be provided by cardiologists, hypertension physicians and diabetologists, and to some extent by renal physicians, vascular surgeons and interested primary care and occupational health doctors. The evolution of successive generations of Australian lipid management guidelines has reflected an extensive and advancing body of evidence based on a foundation of experimental investigations, epidemiological and observational studies and culminating in Level A meta-analyses [5] and systematic reviews of randomised controlled trials. These lines of evidence confirm that effective recognition and management of lipid disorders is fundamental to the prevention of CVD [6]. Lipid guidelines have been at the forefront of the use of absolute risk assessment in patient management. Despite efforts to promote a multiple risk factor approach to CVD prevention, suboptimal professional awareness has meant that patients have not always received appropriate management [7]. Even greater understanding of lipid metabolism and management principles will become necessary as newly developed lipid-modifying drugs become available. The National Heart Foundation (NHF) updated their Guidelines for Lipid Management in 2005 [8] and although many components of the NHF Guidelines remain robust, a comprehensive review of

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new developments and emerging issues is appropriate. In an era of limited resources it is instructive to consider the conclusions reached by expert groups in other developed countries that have recently undertaken the exhaustive process of guideline development based on essentially identical bodies of evidence [1–3,9]. Topics that have arisen include a) components of CVD risk assessment, such as ethnicity, family history, alternatives to low-density lipoprotein cholesterol (LDL-C), novel biomarkers and non-invasive imaging; b) sources of CVD risk information, such as reference populations, qualifying events and time-frames; and c) re-appraisal of lipid-lowering interventions in terms of target levels, non-statin drugs, costs and side effects. An appraisal of the similarities and differences that identify important guiding principles in a changing clinical environment [10].

Scope and Foundations for Lipid Management Guidelines Lipid management guidelines need to address all forms of dyslipidaemia that affect diverse groups of people and that result from disturbances in the metabolism of low-density lipoproteins (LDL), triglyceride-rich lipoproteins and highdensity lipoproteins (HDL). The aim is to identify and diagnose these disorders and recommend safe and cost-effective treatment to mitigate risk of end-organ damage, including CVD, pancreatitis and hepatic steatosis. Integration of all available evidence should be used to make graded recommendations, based on the quality of evidence, to best inform the medical consultation with the patient. With respect to coronary disease and CVD, the data may derive from several sources, including cell biology, animal experiments, genetic studies, case series, epidemiological observations and intervention trials employing imaging techniques and clinical endpoints, as well as integrated assessments such as systematic reviews and meta-analyses. Given that intervention trials cannot be undertaken to cover all clinical scenarios and are only carried out over a short period in the life of a patient, the totality of evidence needs to be considered. Lipid management guidelines must relate specifically to the population in which they will be employed.

Components of CVD Risk Assessment It has been suggested that since clinical trials of statins have not employed estimates of global risk as a criterion for recruitment, such estimates may be unnecessary in deciding whether to introduce drug therapy. On the other hand, the event rates in the placebo arms of clinical trials have provided estimates of risk in these studies. Guidelines for the prevention of prevalent problems, such as CVD, need to be directed towards the population in question. It has become evident that data obtained in a particular population or era may not be fully applicable in other circumstances [11]. There

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are population trends in the prevalence of obesity, smoking, and other health-related habits. Consequently, the weighting of risk factors may change with time. In addition, individual and population-wide genetic traits may strongly influence the impact of risk factors. Family history and ethnicity: Clinical evaluation includes family history of CVD. In some instances it is the only demonstrable risk factor. Information about family history may be difficult to obtain in sufficient detail so it has been omitted from traditional methods for calculation of absolute CVD risk. This deficiency has been addressed in the some calculators which weight a positive family history of onset of CVD in early life in affected first degree relatives [12]. Likewise, Canadian guidelines double risk estimated by Framingham-based calculators if family history is positive [9]. Family history may also indicate the presence of the important monogenic lipid disorder Familial Hypercholesterolaemia (FH) [13]. The recognition of this powerfully prognostic diagnosis varies widely between countries [14]. Collection and follow-up of family history may be influenced by aspects of the prevailing healthcare system, and systematic detection of FH-affected relatives may vary accordingly. Future guidelines will provide an opportunity to support the implementation of cost-effective strategies such as Family Cascade Screening [15]. The recognition of socio-economic status and ethnicity as CVD risk modifiers presents similar opportunities and challenges, and will be discussed later. The recent AHA-ACC guidelines attempted to provide an ethnic-specific risk calculator [1]. An alternative approach provided by the ESC-EAS involves country-specific risk tables [2]. These developments illustrate the realisation that absolute risk assessment must be calibrated to relevant populations to reflect the prevalence of CVD in the target population [16]. Non-HDL cholesterol: The calculation of CVD risk has traditionally involved the use of total and high density lipoprotein cholesterol (HDL-C), often in the form of the total:HDL-C ratio. Importantly, Mendelian randomisation studies emphasise the CVD impact of alleles that affect atherogenic lipoproteins rather than those that modulate HDL [17]. Treatment targets have been based on LDL-C levels that have been selected with regard to the results of intervention trials. The simple calculation of non-HDL cholesterol (N-HDLC: Total – HDL-C = N-HDLC) offers several practical benefits that have resulted in its widespread inclusion as an alternative to LDL-C in several recent guidelines [2,3,9,18]. Indeed the theoretical superiority of N-HDLC compared to LDL-C in the presence of hypertriglyceridaemia has been noted by some [19]. Whereas total cholesterol is confounded by the presence of atherogenic and non-atherogenic fractions, N-HDLC provides a convenient estimate of all potentially atherogenic lipoproteins. Furthermore, changes in the composition of LDL mediated by the action of cholesterol ester transfer protein in the presence of triglyceride-rich lipoproteins may cause LDL-C levels to under-estimate CVD risk [19]. Evidence suggests that NHDLC is superior to LDL-C for assessment of both CVD risk and response to treatment [20,21]. N-HDLC may be calculated simply, even on non-fasting samples and N-HDLC levels may

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be set by adding 0.5 - 0.8 mmol/l to the LDL-C target until clinical trial data can be re-analysed to confirm appropriate levels. Canadian guidelines note that in comparison with LDLC, N-HDLC is more concordant with apolipoprotein B (Apo B) levels. One apo B molecule is present on each atherogenic lipoprotein particle and evidence suggests that its association with CVD risk is stronger than LDL-C, especially in hypertriglyceridaemia, where LDL size is decreased [22,23]. Whilst apo B remains more expensive and less accessible than NHDLC, it is likely that N-HDLC will feature more prominently in future guidelines, but it should be noted that apo B and NHDL-C may not be equivalent estimates of risk in individual patients. Up until now clinical awareness of the utility of NHDL-C has not kept pace with guideline recommendations concerning its expanded use. Novel biomarkers and non-invasive tests: Reliance on historical data from sources such as Framingham also limits the incorporation of information concerning novel risk factors. Lipoprotein (a) (Lp(a)) is a unique lipoprotein consisting of an LDL particle which is covalently bonded to apolipoprotein (a). Lp (a) has many potentially atherogenic features including a tendency to adhere to connective tissue, a capacity to inhibit plasminogen and a prominent role in the transport of oxidised phospholipids [23]. Lp (a) and apolipoprotein (a) are mainly determined by genetic factors and studies suggest that the top 20% of the Lp(a) distribution are at increased risk of CVD [24]. A case could be made for the inclusion of Lp (a) measurement in CVD risk assessment because novel agents such as antiPCSK9 inhibitors and CETP inhibitors reduce Lp (a) levels. On the other hand, it may be difficult to determine whether or not targeting of Lp (a) as a separate lipid moiety for intervention is warranted until specific therapies such as anti-lipoprotein (a) mRNA antisense oligonucleotides undergo clinical trials. In the case of inflammatory biomarkers, the competition between numerous candidates has yet to identify a compelling case for inclusion of any of the contenders. Independent predictors of CVD risk include myeloperoxidase [25] and lipoprotein associated phospholipase A2 (LpPLA2) [26], both of which may influence the atherosclerotic process. Pharmacological inhibition of phospholipase A2 did not achieve reduction in CVD in the recent STABILITY trial [27] although the total coronary events (a pre-specified secondary endpoint) was reduced by darapladib. These results fall short of support for a causative role for LpPLA2, but they need not detract from potential utility of LpPLA2 measurements in the assessment of CVD risk. The situation is reminiscent of homocysteine, which fell from favour as a CVD risk marker after negative intervention trials. It remains uncertain whether the inflammatory marker C-reactive protein (CRP) plays a causative role in CVD, but inclusion of high-sensitivity CRP measurement as a discriminator in intermediate risk patients is supported by Canadian guidelines [9]. An alternative approach is illustrated by guidelines that highlight the risk associated with inflammatory conditions such as psoriasis, periodontitis or systemic lupus. The British Joint Societies’ (BJS) guidelines flag the presence of rheumatoid arthritis as a CVD risk factor [28].

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Left ventricular hypertrophy or silent myocardial infarction on ECG, both of which are strongly associated with risk of future CVD, are often unavailable for inclusion in calculation of CVD risk. Indicators of subclinical myocardial damage such as Troponins T and I, or B-type natriuretic peptide are amongst the most predictive of the so-called biomarkers. Perhaps they represent more quantitative surrogates for the information previously provided by ECG. As in the case of inflammatory biomarkers, the number needed to screen in order to achieve a downstream reduction in events is large and the most promising application is for reclassification of patients in the intermediate risk category. A similar general principle applies to the use of new noninvasive imaging techniques. In particular, coronary calcium score acquired with low-dose computerised tomography (CT) has demonstrated considerable promise with evidence of a close relationship between calcium score and risk of future CVD events [29,30]. By comparison, CT angiography, which sometimes tends to overestimate the degree of stenosis, may be superfluous to requirements for CVD risk assessment. Most guidelines mention the use of CT calcium score to re-classify intermediate risk patients, but in principle this technology could transform CVD risk assessment. Coronary calcium score (CCS) may accurately identify the subgroup of symptom-free patients who have subclinical coronary disease [31]. The needs of this subgroup of patients are likely to be intermediate between primary and secondary prevention. As a result they may warrant more aggressive treatment than they would receive if their CCS was not indicative of subclinical CVD. Under these circumstances, the important issues are whether or not a low CCS can be used to ‘‘rule out’’ the risk of a coronary event in the short to medium term, whether there is a threshold above which CCS identifies a ‘‘coronary equivalent risk’’, and whether the test can be used and interpreted in a serial fashion. This is clearly an area in which practice is ahead of the evidence, but the rapid increase in the availability and affordability of this test makes the development of tentative guidelines an urgent priority.

Sources of CVD Risk Information Limitations of traditional sources of CVD risk information: A consistent feature of published guidelines for management in asymptomatic individuals without a history of CVD has been allocation of treatment according to absolute CVD risk. The 2013 AHA-ACC guidelines advocate major treatment decisions such as the introduction of lifelong use of statins, purely on the estimated risk using a calculator compounded of data from Framingham, the UK’s Joint Recommendations (a Framingham-derived calculator) and more recent Scottish data based on general practice records [1]. This dependence solely on a statistical estimate of risk bypasses clinical assessment and judgment that includes more nuanced consideration of risk factors. The AHA-ACC’s suggested risk calculator was subject to immediate criticism [18] on the grounds that it appears to overestimate risk by up to 150%

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[32]. Estimation of risk using the Framingham study and its derived risk equations relies on data collected from a single population over 30 years ago. Although classic risk factors continue to account for the much of the attributable risk [33], the overall risk of CVD and the related risk factors are likely to differ in other populations and at the present time. Socioeconomic [34,35] and ethnic differences exist between populations (e.g. the high risk in South Indian families [11] recognised in the UK recommendations and excess mortality in Australian Aboriginals reflected in NVDPA guidelines [4]). Life expectancy has increased and health-related behaviour has changed over time: for example smoking has decreased and obesity / glucose intolerance / diabetes have increased. Hence risk calculators require periodic updating, and region-specific data are desirable. Variation in expressing CVD risk estimates: Comparison of absolute CVD risk factor levels can be confusing due to differences in clinical outcomes and the duration of follow-up. The new AHA-ACC risk thresholds for treatment apply to risk of both coronary and non-coronary CVD whereas previous risk thresholds referred to risk of coronary disease alone. This requires clinicians to change their perception of the percentage levels involved. Previous US and several overseas outcomes are limited to coronary disease, whereas Australian guidelines reflect all atherosclerotic CVD, including stroke. These differences are important in terms of patient preferences and treatment selection. For example, the prevention of CVD, which includes stroke, may place more emphasis on blood pressure control whilst coronary disease prevention may favour lipid control. The timeframe is also variable. Australian guidelines reflect a five-year timeframe whereas some overseas guidelines represent a 10-year interval. These differences partially reflect separate sources of data within the Framingham dataset, but they also indicate conscious decisions based on anticipated patient perception and discounting of health benefits. Recent IAS and BJS guidelines have taken a different approach known as ‘‘lifetime risk’’ which assesses the accumulated risk at an older age [36]. Lifetime risk has the advantage of diminishing the overwhelming effect of age on risk assessment [36]. As a result, greater impetus may be given to identifying younger patients who may warrant treatment earlier whilst limiting over-aggressive treatment of elderly patients. Although this alternative approach to CVD risk is being promulgated internationally, the methodology employed needs further validation. It therefore remains controversial and more research is required to assess which interpretation of absolute risk is most suitable for future guidelines.

Re-appraisal of Lipid-lowering Interventions Target levels in lipid-lowering: In the case of pharmacological intervention, consensus concerning a common risk threshold for initiation of therapy avoids inconsistency between the

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approaches for major modifiable risk factors such as hypertension, diabetes and dyslipidaemia. Despite this use of absolute risk of CVD as the main determinant of intervention, no guidelines recommend absolute CVD risk levels as targets to guide the intensity of therapy. To do so would probably exacerbate the current overwhelming influence of age on estimated risk. Traditionally, each major risk factor guideline has specified target levels to which the relevant risk factor should be reduced. Cholesterol Treatment Trialists’ Collaboration evidence estimated that standard statin therapy reduces LDL-C by approximately 1 mmol/l with a subsequent 22% reduction in relative risk in the ensuing five years and that greater absolute risk reduction will be achieved amongst patients with the highest baseline absolute risk [5]. Traditionally, lipid guidelines have recommended dosage titration to intensify therapy to achieve the desired target level. The AHA-ACC guidelines point out that no controlled trial has been reported that was specifically designed to compare particular target levels of plasma LDL-C; in their example, there is to date no trial of CVD event rates to compare targets of 70 mg/100 ml and 100 mg/100 mL (1.8 and 2.6 mmol/L) in secondary prevention of CVD. The authors concluded that it was not appropriate to employ target levels in the followup and treatment of elevated CVD risk; they advised instead that the maximum tolerated dose of a statin be generally employed [1]. The only quantitative guidance was the suggestion that LDL-C levels should be reduced by 50%, but this may be insufficient for those at highest risk or patients with Familial Hypercholesterolaemia. Conversely, it may be unnecessarily aggressive for those with LDL-C < 3.4 mmol/l prior to treatment. Furthermore, angiographic studies suggest that attainment of LDL-C < 1.8 mmol/l favourably affects plaque remodelling in most, but not all patients with CHD [37]. Omission of targets has proved to be controversial, having been a feature of most if not all previous sets of recommendations. The concept of a target level for atherogenic (LDL or non-HDL) cholesterol is based on evidence derived from clinical endpoint trials, coronary imaging studies, human genetic disorders of lipid metabolism and experimental investigations in animal models of atherosclerosis. The importance of target lipid levels has been embraced and re-asserted by all international expert bodies, including most recently the IAS and National Lipid Association. Treating to a target allows an individualised approach: it offers (probabilistically) an expected reduction in risk. Since there is considerable individual variation in responsiveness to therapy, it allows for dose titration to achieve this goal; and if the target is not reached, the physician has the option of changing to a more potent drug or of adding a second lipidlowering agent. More generally, target levels provide for upward titration of dosage, permitting use of the minimum effective dose of statin with major implications for costs and avoidance of side effects. In addition, dose titration permits an early assessment of compliance, responsiveness and tolerability; the poor responder may change to a more potent

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agent whilst an intolerant patient may require an alternative therapy. These advantages are persuasive, so future guidelines should not lightly discard the use of treatment target levels. The safety and the benefits of extreme reduction of LDL-C have been questioned. Trials with more intensive therapy showed that additional reduction of LDLC to 1-2 mmol/L (about 40-80 mg/dl) led to further reduction in major CVD events, without evidence of an increase in any category of non-cardiovascular events [38]. Physiological human lipid levels are undefined, but mean N-HDLC in a population in rural China was 1.04 mmol;/L (40 mg/dL) and modern day ‘‘Paleolithic’’ populations have similarly low levels [39]. Both are lower than any lipid targets advocated in recent recommendations. When more safety data emerge, particularly with the advent of more efficacious drugs, future guidelines are highly likely to recommend lower targets than at present, i.e. less than 1.8 mmol/L (70 mg/dL). An undesirable consequence of risk factor treatment targets for individual patients is the possibility that lower targets may encourage polypharmacy. Non-statin lipid-lowering agents: Lipid guidelines maximise response to statins by instituting appropriate lifestyle advice as the first intervention [40] in all instances. When statin therapy is insufficient, second line non-statin therapy requires consideration. The AHA-ACC guideline interpretation of clinical trials involving non-statin lipid lowering drugs was very narrow. Early studies of non-statin drugs were limited by inadequate long-term compliance and efficacy [41] as well as selection of participants who lacked the appropriate pattern of lipid disturbance for the drug in question. The subsequent success of statins has created an ethical pre-requisite for statin therapy against which it has been difficult to demonstrate independent protection against CVD by second line LDLC-lowering agents. Indeed, the ability of drugs such as niacin or fibrates to prevent cardiovascular events seems to have waned since treatment progressed from the pre-statin to the post-statin era. Consequently, recent AHA-ACC guidelines provided little encouragement for the use of drugs other than statins. The potential benefits of the use of fibrates in patients with high triglyceride and low HDL [42], and the addition of niacin in the setting of statin intolerance or inadequate response were largely overlooked [1]. Niacin’s failure to live up to hopes based on the evidence of earlier clinical trials [43] may reflect study designs that sacrificed the possibility of broad clinical utility in order to examine a theoretical question about lipid metabolism (is HDL-raising protective?). Trials of new drugs such as cholesterol ester transfer protein inhibitors, which are capable of massively increasing HDL-C levels, will only partially resolve uncertainty concerning the role of HDLC-raising therapies because they also reduce LDL-C and Lp(a). The AHA-ACC guideline’s reliance on statins implies acceptance of the so-called ‘‘pleiotropic effects’’ of statins over the LDL-C-lowering capacity of agents such as ezetimibe. The validity of this approach is now in question. The recently reported, but as yet unpublished results of the

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IMPROVE IT Trial, in which addition of ezetimibe to simvastatin revealed significant CVD benefit in patients who reduced LDL-C to 1.4 mmol/l [44] will inform the debate concerning the role of LDL-lowering drugs. The efficacy of ezetimibe is consistent with the lower CVD risk associated with genetic variations affecting cholesterol absorption. Benefits in CVD risk are also associated with genetic variations in the target for new agents known as PCSK9 inhibitors [45], which powerfully reduce LDL-C (andLp (a)). Consequently clinical guidelines should maintain a strong emphasis on the importance of lowering LDL-C and N-HDLC levels. Costs and side-effects of lipid-lowering therapy: The recent AHA-ACC guidelines reduced the recommended risk threshold for commencement of statin treatment to an estimated risk of CVD of 7.5% in 10 years (with discretion to treat those above 5% risk). It has been claimed that 40-50% of those men to whom these recommendations apply would qualify for a statin and that at least 13 million more American adults would be identified for treatment [46]. This change is explained in part by the recognition that statin therapy has become cost-effective in these lower risk categories, and that the therapeutic ratio is favourable due to a low incidence of serious side effects. Inclusion in a so-called ‘‘polypill’’ is likely to enhance cost-effectiveness [47]. The accurate assessment of the incidence of side-effects in the post-marketing phase is fraught with difficulty [48]. Recent studies suggest that many patients may tolerate statin therapy after all, or that perceived side-effects may be poorly correlated with drug exposure [49]. On the other hand, the increased risk of new-onset diabetes, particularly in insulin resistant patients, appears to be a consistent finding [50]. Ongoing efforts to refine the balance between the cardiovascular benefits versus the costs and side-effects of therapy will be pivotal for future guidelines. Future CVD guidelines should also highlight measures which sustain medical management and promote adherence with therapy. New policy directions: The multifactorial aetiology of dyslipidaemia and CVD reflects a complex interaction between genetic and environmental factors. New evidence justifies reappraisal of the measurement and treatment of lipids and lipoproteins other than cholesterol and LDL-C. Lipid guidelines should include plasma triglyceride because severely elevated levels may pose a risk of acute pancreatitis and hepatic steatosis. The role of triglyceride as a risk factor for CVD has been uncertain. However studies suggest that measurement of non-fasting triglyceride, especially at the four-hour postprandial time-point, actually enhances the sensitivity of triglyceride measurement as a risk factor for coronary and total mortality [51]. It is vital that future sets of guidelines emphasise the importance of environmental influences such as diet and physical activity which determine the level of CVD risk at the population level. Dietary recommendations have been less impressively adopted than, for example, anti-smoking guidance. The rising prevalence of obesity reflects an increase in the consumption of ‘junk’ foods such as high sugar content soft drinks. The increased caloric intake has led to energy imbalance because it has not been matched

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by increased levels of activity. Guidelines need to be augmented with social interventions which target healthy patterns of diet and exercise as a consequence of planning, publicity and possibly legislation. Collective pressure by practicing clinicians and their organisations may expedite such policies, and reference to planning, administrative and legislative measures therefore deserves a place in future sets of recommendations. As suggested by current NICE guidelines [52], future research should anticipate and evaluate the cost-benefit proposition that guidelines offer to the healthcare system. Whilst the cost-benefit analysis of statin therapy is generally favourable, it is very sensitive to the absolute risk level of the patients selected for therapy. Cost-benefit analysis of the development and implementation of guidelines is less frequently reported and this represents a potential area for improvement [53]. The differences between the AHA-ACC, ESC-EAS, and IAS recommendations are relatively minor. It will be most unfortunate if these minor differences create a level of confusion that obscures the major points of agreement between all recommendations. We need to focus on the most important aspects of the respective guidelines – those commonalities outlined above – all of which will most benefit patients in Australia. It is noteworthy that the American Guidelines are directed towards America and the European Guidelines are for management in Europe. New Zealand, which has been a world leader in the development of CVD prevention guidelines, is likely to view these and other issues from the perspective of subtle local differences. This paper has been prepared to inform the preparation of lipid management guidelines for use in Australia.

Acknowledgements No financial assistance was provided towards the preparation of this paper. The authors thank Professor B Lewis for his insightful discussion and assistance with a preliminary draft manuscript. Dr Sullivan has received research funding from Amgen, Abbott Products, AstraZeneca, Merck, Sharp and Dohme, and Sanofi Aventis; funding for educational programs from Abbott Products, AstraZeneca, Merck Sharp and Dohme, Pfizer Australia, and Roche; travel support from Merck, Sharp, and Dohme; and advisory boards fees from Amgen, Abbott Products, Merck, Sharp, and Dohme, and Pfizer Australia.

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