Feature article

Managing dyslipidaemia for the primary prevention of cardiovascular disease

Aidan Ryan, academic clinical fellow1, Simon Heath, partner2, Paul Cook, consultant in chemical pathology and metabolic medicine1


What you need to know

  • Assess lipid status as part of an overall cardiovascular risk assessment using a risk calculator

  • Routinely record a family history of premature cardiovascular disease, and consider an underlying familial dyslipidaemia

  • Explain to patients their cardiovascular risk and the benefits and harms of treatment

Sources and selection criteria

We carried out an electronic search through PubMed and Cochrane database of systematic reviews using the following search terms: “primary prevention,” “dyslipidaemia,” “cardiovascular disease,” “statins,” “statin intolerance,” “ezetimibe,” “PCSK9,” “hypercholesterolaemia diagnosis and treatment.” We also interrogated relevant dyslipidaemia guidelines and personal archives for supporting evidence as discussed and as referenced.

Cardiovascular disease (CVD) is the most common underlying cause of death worldwide, accounting for 17.3 million of 54 million total deaths per year. Of these, 8.2 million were caused by ischaemic heart disease and 6.5 million by stroke.1 Mean total cholesterol, calculated low density lipoprotein (LDLc), and triglyceride concentrations have declined over the last 20 years. However, some observational cohort evidence suggests that long term exposure to even modestly elevated cholesterol concentrations is associated with CVD in later life.12

Cholesterol made in the liver and from the diet is transported to peripheral cells by apoB-containing lipoproteins in the blood (fig 1). In a fasting sample, the LDL particles constitute most of the circulating apoB lipoproteins. However, in clinical practice LDL is not measured directly but is calculated (LDLc) (box 1). LDLc has become a metric for treatment success and for diagnosis.

Fig 1

Apolipoprotein B, non-HDL lipid transport, and atherosclerosis. Lipoproteins involved in cholesterol are transported from gut and liver to the peripheral tissues, providing fuel, membrane structure, and hormones. Lipoproteins carrying apolipoprotein B (apart from chylomicrons) have the potential to be atherogenic. APOE: apoliprotein ε receptor; Chol: cholesterol; FA: fatty acids; IDL: intermediate density lipoprotein; TG: triglyceride; C: chylomicron; CR: chylomicron remnant; LDL: low density lipoprotein; LDLR: LDL receptor; LRP: LDL relation protein receptor; LPL: lipoprotein lipase; NPL1C1: Niemann-Pick C1-like 1; PCSK9 ab: Proprotein convertase subtilisin/kexin type 9 antibody; V: very low density lipoprotein; T: tissue

bmj-360-bmj-k946-F1.jpg
Box 1

Lipid calculations

  • Friedwald equation:

  • LDLc=total cholesterol−high density lipoprotein (HDL)−triglyceride/2.2

  • (Note: triglycerides are divided by 5 if units are in mg/dL rather than 2.2 when in mmol/L)

  • Non-HDL=total cholesterol−HDL (units can be in mg/dL or mmol/L)

  • Remnant cholesterol=total cholesterol−HDL−LDL (units can be in mg/dL or mmol/L)

This article reviews the management of dyslipidaemia in adults for primary prevention of cardiovascular disease and highlights recent changes in lipid guidelines, particularly focusing on diagnosis and the evidence behind therapeutic intervention (see accompanying article doi:10.1136/bmj.k835).

What are the risks of dyslipidaemia?

High LDLc is strongly associated with a risk of cardiovascular disease based on meta-analysis of cohort studies and clinical trial data.34 Evidence from randomised controlled trial data, however, has shown that the risk of CVD events associated with any given LDL concentration is strongly influenced by overall cardiovascular disease risk.45678 Hence guidelines have moved away from absolute LDL thresholds towards assessing cardiovascular disease risk overall using risk calculators.5678

This has led to the use of the term dyslipidaemia in guidelines, which is a general term applied to any lipoprotein abnormality but without pre-specified values such as an LDL cut-off. In this article we use dyslipidaemia to indicate mainly LDL abnormalities, and, where the term hypercholesterolaemia is used, cut-off values are indicated.

How is dyslipidaemia assessed as a risk factor for CVD?

Risk calculators have been based on large cohort studies such as Framingham or UK-based general practice cohorts, which have evaluated risk factors over time associated with CVD.56

This information is then used to generate a risk score (see accompanying 10-Minute Consultation doi:10.1136/bmj.k835 for more detailed discussion of how to use QRISK2 calculator). Data input to the risk calculator includes total cholesterol/HDL ratio and other risk factors. The risk score generated indicates the risk of CVD over 10 years, which then determines a threshold for statin prescription. The UK National Institute for Health and Care Excellence (NICE) guidelines recommend using the QRISK2 calculator and a 10% threshold. US based guidelines use 7.5%, and the European Society of Cardiology uses a 10% threshold, but modified by pre-treatment LDLc.5-7

For QRISK2, the factors associated with highest CVD risk were atrial fibrillation, type 2 diabetes, family history coronary disease, current cigarette smoker, age (older), sex (male), renal disease, and being on blood pressure medication.9 The risk factors with the two lowest hazard ratios in QRISK2 were lipid profile and body mass index (BMI). Furthermore, it is possible to reach a risk threshold based on age alone: 60 for men and 67 or more for women, with a recent cross-sectional study estimating that 95% of people over the age of 60 were eligible for statins without any other of the traditional CVD risk factors (such as hypertension, diabetes mellitus, or dyslipidaemia).10

There is agreement that use of such calculators is not appropriate for people with cardiovascular disease, type 1 diabetes mellitus, or chronic kidney disease, or for those with suspected familial hypercholesterolaemia. These people are already high risk and should be offered active management of all cardiovascular risk factors, including statin therapy.

Who should be offered lipid testing?

Across the guidelines for primary prevention, a common recommendation is to assess the cardiovascular risk of all people over 40, outside the high risk groups discussed above.5678 In keeping with the assessment of dyslipidaemia in the context of overall CVD risk, other risk factors are also checked at the same visit.

What to measure in a lipid profile

Laboratories routinely calculate the LDL, having directly measured total cholesterol, high density lipoprotein, and triglyceride (box 1). The gold standard for measuring cholesterol is ultra-centrifugation, which gives the lipoprotein fractions described in figure 1. However, this is not widely available and is expensive.11

The Friedwald equation, based on more than 400 fasting patients, assumes a fixed ratio between very low density lipoprotein (VLDL) and triglycerides to calculate LDL. However, this calculation is not valid for those with high triglycerides or very low LDLc.11 A novel estimate of LDL has been developed that shows good correlation with ultra-centrifugation and more precision than Friedwald across different ranges of triglycerides but also at very low LDL. This could be of therapeutic relevance given the arrival of PCSK9 antibody therapy, which might be associated with LDLs below the lowest LDL (1.6 mmol/L) used for the original Friedwald equation.11

Do patients need to fast before a lipid profile?

Fasting for a lipid profile is no longer routinely recommended.567 Previously, the fasting profile was regarded as standard. However, there are now population based data showing that, for most patients, eating a standard meal does not have a major effect.12 For those with triglycerides >4.5 mmol/L there is likely to be a highly variable response to food intake and fasting is therefore recommended in this group.8

How to identify familial dyslipidaemias?

Patients with familial dyslipidaemias are at higher risk of CVD. Heterozygous familial hypercholesterolaemia has an estimated prevalence of 1 in 250 and is inherited in an autosomal dominant manner. It is deemed an ischaemic heart disease equivalent due to lifelong exposure to elevated LDL. Historically, where the condition was left untreated, at least 50% of men developed ischaemic heart disease by 50 and 30% of women by 60.13 LDLc >4.9 mmol/L is a red flag in many guidelines5678 (box 2).

Box 2

Familial dyslipidaemias associated with premature CVD

• Heterozygous familial hypercholesterolaemia is defined as an LDLc >4.9 mmol/L in index case plus either the same lipid profile in a first or second degree relative or premature ischaemic heart disease in same relative (Simon Broome criteria).

• Familial combined hyperlipidaemia: triglyceride >1.5 mmol/L plus apoB >1.2 g/L plus premature ischaemic heart disease in a first degree relative plus similar lipid profile

Familial combined hyperlipidaemia is estimated to occur in 1 in 100 and is an important cause of premature ischaemic heart disease.14 It is defined by a triglyceride >1.5 mmol/L plus premature ischaemic heart disease in a first degree relative with a similar triglyceride in that relative.6 Confirmatory testing with apoB is undertaken in secondary care.

How should dyslipidaemia be managed?

Interventions for primary prevention of CVD

Patients not classified as high risk (based on risk calculators) do not require lipid lowering medication but can be offered diet and lifestyle advice and further assessment at regular intervals after the age of 40. For those patients deemed at high risk of CVD (based on risk calculators or existing risk factors), offer a combination of diet, lifestyle, and statin therapy to reduce this risk. High intensity statin therapy such as atorvastatin 20 mg has become the initial statin of choice for primary prevention of CVD6 (box 3). The aim is to achieve a non-HDL reduction of 40%.

Box 3

Lipid lowering medication: mechanism of action (see also figure 1).

Statins inhibit HMG-CoA reductase, the rate limiting enzyme in cholesterol synthesis. This leads to an increase in a transcription factor that upregulates LDL receptor expression in the liver, which leads to lower LDL cholesterol.

Ezetimibe acts to inhibit cholesterol absorption from the gut via NPL1C1.

PCSK9 antibodies act by binding to PCSK9 in the extracellular space and preventing the binding of PCSK9 to the LDL receptor complex. This prevents LDLR degradation, which in turn remains on the liver surface available to remove LDL-C from the bloodstream.

To date there is limited evidence regarding lipid targets, as these have generally focused on fixed dose medication rather than on dose titration to achieve a target LDL. Guidance towards cholesterol lowering varies (box 4).5678 Other analysis recommends a more flexible approach, with those at higher risk (within the high risk category) thought to benefit more from LDL targets and those with lower risk from a fixed dose strategy.15

Box 4

Statin based treatment strategy: international guidelines

  • Statin intensity definitions vary: for the American Heart Association, high intensity is an LDL reduction of >50%; for NICE, this is defined by a reduction of >40%.

  • NICE: High intensity statin aiming for 40% reduction in non-HDL cholesterol6

  • US: Moderate to high intensity statin aims for 30% to 50% LDL reduction5

  • European Society of Cardiology: Aim for LDLc <1.8 mmol/L in very high risk or <2.6 mmol/L in high risk, or at least a 50% LDLc reduction.7

  • Based on NICE guidance:

    • High intensity: Atorvastatin 20 mg (and above); rosuvastatin 10 mg (and above);

    • Medium intensity (31% to 40% LDL reduction): Atorvastatin 10 mg, rosuvastatin 5 mg, simvastatin 20-40 mg;

    • Low intensity (20-30% LDL reduction): Pravastatin 10-40 mg, simvastatin 10 mg. (Statin intensity NICE guidelines)

There is potential for over and under treatment of various groups. For example, use of CVD risk calculators to determine statin prescription might result in over treatment on age/sex alone. However, these calculators are based on cohort data, not clinical trial data, tend to underestimate the risk for those with elevated BMI and dyslipidaemia, and those under 50.

Incorporating clinical trial data into cardiovascular disease risk calculators has been proposed as one method of resolving this discrepancy.1617 However, this would require further validation (to derive a risk score) including an economic evaluation and the consideration of treating more younger patients for longer and the implications of this approach.

What are the benefits and harms of statin medication?

The US Preventive Services Task Force has undertaken a detailed meta-analysis on randomised clinical trial data on statins and primary prevention of CVD.18 The pooled analysis absolute risk reduction and number needed to treat are shown in table 1. The systematic review concluded that the benefits of statins in the primary prevention of cardiovascular disease were maintained regardless of demographic (age, race, sex) and clinical (hypertension, diabetes mellitus, renal dysfunction) subgroups.18 Trial numbers for these were small, and the authors found insufficient evidence to determine benefits or harms of initiating statin therapy for primary prevention for over 75s.18

Table 1

US Preventive Services Task Force statin primary prevention absolute risk reduction and number needed to treat

Absolute risk reduction (%)Number needed to treat
All cause mortality0.4250
Cardiovascular disease mortality0.54233
Stroke0.37263
Myocardial infarction0.73123

At present we have no way of knowing who will experience the benefits or harms of statin therapy before starting medication, and for some patients this will be difficult to accept or understand.

The benefits of statin therapy are 500 fewer cardiovascular disease events in a statin patient group of 10 000 treated for five years. The potential harms in the same group are one rhabdomyolysis, five myopathies, and 75 new cases of diabetes mellitus.

Statins are contraindicated in pregnancy and during breast feeding.6 Muscle symptoms associated with statins are the most common side effect, with mild myalgia estimated to affect 5% to 10% of statin users. More severe muscle related injury, such as rhabdomyolysis, is rare.19

The exact prevalence of statin associated muscular symptoms has been the subject of debate due to lack of standardisation and imbalance between trial and observational data. Diagnosis of statin related muscular symptoms depends on clinical features and laboratory testing, including measurement of creatine kinase and checking for alternative causes such as hypothyroidism or acute illness.20

Alternative evidence suggests that statins increase fasting blood glucose marginally, although overall the benefits of treatment outweigh this risk of diabetes mellitus, and, furthermore, statin medication does not substantially affect glycaemic control in known diabetics (number needed to harm 255 over four years for one new case of diabetes mellitus).18

The implications of cardiovascular disease guidelines in lowering the threshold for statin eligibility are that, potentially, more patients might be on statin medication for longer. There is uncertainty regarding the long term side effects and the lack of trials in people over 80.1018 The West of Scotland Coronary Prevention Study reported a 20 year follow-up that showed no increase in either cancers or diabetes mellitus compared with placebo. However, detail of statin use and follow-up was limited over the last 10 years.21

Baseline liver function tests are recommended in all relevant lipid guidelines, but follow-up testing at eight weeks and 12 months is only recommended by NICE.5678 Raised levels of alanine transaminase occur in 0.5% to 2.0% of statins users, particularly in those with hepatic fat, and is not associated with hepatotoxicity when only mildly raised.7 One task force has provided a proposed structured framework for managing this, and if the serum alanine transaminase is <3 times the upper limit of normal then the statin can continue, with anything above this requiring more detailed investigation and statin cessation until investigation of the causes is completed.22

Non-statin pharmacological therapy

Outside statin therapy there are limited clinical trial data for medication for primary prevention of cardiovascular disease in people with or without dyslipidaemia. For ezetimibe there are currently only clinical trial outcome data showing efficacy for secondary prevention, and current guidelines recommend the drug as second line in primary prevention or in those who are intolerant of statins.67 Ezetimibe is also contraindicated during pregnancy and breast feeding. Ezetimibe, like statins, can cause asymptomatic liver enzyme elevation and myalgia.

A consensus document seeking to review evidence on the use of proprotein convertase subtilisin/kexin type 9 inhibitors concluded that at present there are limited efficacy and long term safety data on these drugs and they should not be used in primary prevention in those who do not have familial hypercholesterolaemia.23

Diet and lifestyle

Nutritional factors are believed to play a role in CVD by either directly influencing atherogenesis or via risk factors such as glucose, hypertension, or lipids. The quality of this evidence is variable, and is mainly based on observational rather than clinical trial data 24 Across the guidance, there is a consensus that recommendations such as the “Dietary approach to stopping hypertension” or the “Primary prevention of cardiovascular disease with a Mediterranean diet” are preferable to single nutrient strategies, as patients will find these interventions easier to undertake, and, therefore, they might be of benefit in lowering CVD risk.5678

There is no evidence that exercise or smoking directly impact lipid levels and any lifestyle advice regarding these risk factors would be based on their general impact on overall CVD.

Education into practice

  • How do you discuss management options for people with dyslipidaemia?

  • Can you note one or some things you would do differently in your practice having read this article?

Notes

  1. Contributors: AR, SH, PC all contributed to the creation and drafting of this paper. AR undertook the literature review and is the guarantor.
  2. Competing interests: We have read and understood The BMJ policy on declaration of interests and declare the following interests: none.
  3. Provenance and peer review: Encouraged, externally peer reviewed.

References

  1. EJ BenjaminMJ BlahaSE ChiuveAmerican Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics 2017 update: a report from the American Heart Association. Circulation2017;135:e146-603. 10.1161/CIR.0000000000000485 28122885
  2. AM Navar-BogganED PetersonRB D’Agostino SrB NeelyAD SnidermanMJ Pencina. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation2015;131:451-8. 10.1161/CIRCULATIONAHA.114.012477 25623155
  3. BA FerenceHN GinsbergI Graham. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J2017;38:2459-72. 10.1093/eurheartj/ehx144 28444290
  4. B MihaylovaJ EmbersonL BlackwellCholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet2012;380:581-90. 10.1016/S0140-6736(12)60367-5 22607822
  5. NJ StoneJG RobinsonAH LichtensteinAmerican College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation2014;129(Suppl 2):S1-45. 10.1161/01.cir.0000437738.63853.7a 24222016
  6. S RabarM HarkerN O’FlynnAS WierzbickiGuideline Development Group. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. BMJ2014;349:g4356. 10.1136/bmj.g4356 25035388
  7. AL CatapanoI GrahamG De BackerAuthors/Task Force Members. 2016 ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis2016;253:281-344. 10.1016/j.atherosclerosis.2016.08.018 27594540
  8. TJ AndersonJ GrégoireGJ Pearson. 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol2016;32:1263-82. 10.1016/j.cjca.2016.07.510 27712954
  9. J Hippisley-CoxC CouplandY Vinogradova, et al. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.BMJ. 2008;336(7659):1475-82. 17615182
  10. P UedaTW LungP ClarkeG Danaei. Application of the 2014 NICE cholesterol guidelines in the English population: a cross-sectional analysis. Br J Gen Pract2017;67:e598-608. 10.3399/bjgp17X692141 28760741
  11. R QuispeA HendraniMB Elshazly. Accuracy of low-density lipoprotein cholesterol estimation at very low levels. BMC Med2017;15:83. 10.1186/s12916-017-0852-2 28427464
  12. BG Nordestgaard. A test in context: lipid profile, fasting versus nonfasting. J Am Coll Cardiol2017;70:1637-46. 10.1016/j.jacc.2017.08.006 28935041
  13. BG NordestgaardMJ ChapmanSE HumphriesEuropean Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J2013;34:3478-90a. 10.1093/eurheartj/eht273 23956253
  14. AL CatapanoI GrahamG De BackerESC Scientific Document Group. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J2016;37:2999-3058. 10.1093/eurheartj/ehw272 27567407
  15. H SoranS AdamPN Durrington. Are recent statin recommendations to employ fixed doses and abandon targets effective for treatment of hypercholesterolaemia? Investigation based on number needed to treat. Eur J Prev Cardiol2017;24:76-83. 10.1177/2047487316667785 27609614
  16. PM RidkerL RoseNR Cook. A proposal to incorporate trial data into a hybrid ACC/AHA algorithm for the allocation of statin therapy in primary prevention. J Am Coll Cardiol2015;65:942-8. 10.1016/j.jacc.2014.12.028 25744012
  17. G ThanassoulisK WilliamsKK AltobelliMJ PencinaCP CannonAD Sniderman. Individualized statin benefit for determining statin eligibility in the primary prevention of cardiovascular disease. Circulation2016;133:1574-81. 10.1161/CIRCULATIONAHA.115.018383 26945047
  18. K Bibbins-DomingoDC GrossmanSJ CurryUS Preventive Services Task Force. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services task force recommendation statement. JAMA2016;316:1997-2007. 10.1001/jama.2016.15450 27838723
  19. PD ThompsonG PanzaA ZaleskiB Taylor. Statin-associated side effects. J Am Coll Cardiol2016;67:2395-410. 10.1016/j.jacc.2016.02.071 27199064
  20. ES StroesPD ThompsonA CorsiniEuropean Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society consensus panel statement on assessment, aetiology and management. Eur Heart J2015;36:1012-22. 10.1093/eurheartj/ehv043 25694464
  21. I FordH MurrayC McCowanCJ Packard. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy: 20-year follow-up of West of Scotland Coronary Prevention Study. Circulation2016;133:1073-80. 10.1161/CIRCULATIONAHA.115.019014 26864092
  22. H BaysDE CohenN ChalasaniSA HarrisonThe National Lipid Association’s Statin Safety Task Force. The National Lipid Association’s statin safety task force. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol2014;8(suppl):S47-57. 10.1016/j.jacl.2014.02.011 24793441
  23. U LandmesserMJ ChapmanM FarnierEuropean Society of Cardiology (ESC)European Atherosclerosis Society (EAS). European Society of Cardiology/European Atherosclerosis Society Task Force consensus statement on proprotein convertase subtilisin/kexin type 9 inhibitors: practical guidance for use in patients at very high cardiovascular risk. Eur Heart J2017;38:2245-55.27789571
  24. Mozaffarian DDietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive reviewCirculation. 2016;133(2):187-225. doi: 10.1161/CIRCULATIONAHA.115.018585. 27789571

Journal Information

Article Information

Author Affiliations

MEDICAL DISCLAIMER NOTICE: To the fullest extent permitted by law, the material and information displayed in The BMJ is provided "as is" without any guarantees, conditions or warranties as to accuracy. We rely on our authors of articles, contractors and third party data providers to confirm the accuracy of information and advertisements presented and to describe generally accepted practices and therefore we as the publisher and editors cannot warrant its accuracy. Differences may occur also between the print and online text of articles and advertisements. Readers should be aware that professionals in the field may have different opinions. Because of this fact and also because of regular advances in medical research we strongly recommend that readers independently verify any information that they chose to rely upon. Ultimately it is the reader's responsibility to make their own professional judgements. Opinions posted on Rapid Responses, the Advice Zone, International Experience and any other parts of the sites are those of the individuals posting them and not the views of BMJ.


This article was written by BMJ from The BMJ and was legally licensed through the NewsCred publisher network. Please direct all licensing questions to legal@newscred.com.