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National Institute for Health and Care Excellence guidelines for lipid management
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  1. Jaimini Cegla
  1. Division of Diabetes Endocrinology and Metabolism, Imperial College London, London, UK
  1. Correspondence to Dr Jaimini Cegla, Imperial College London Division of Diabetes Endocrinology and Metabolism, London, UK; j.cegla{at}ic.ac.uk

Abstract

This article provides a summary of the available lipid-lowering therapies in the UK and how they fit into national guidelines. In addition, comparison is made between the current National Institute for Health and Care Excellence lipid modification guidelines and international guidance such as those published by the European Society of Cardiology/European Atherosclerosis Society and American Heart Association/American College of Cardiology.

  • hyperlipidemias

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Introduction

Despite advances in treatment, atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide. Cardiovascular disease (CVD) prevention is a long-term priority for the National Health Service. Effective lipid management is a key component of this.1 Large observational studies and randomised controlled trials have shown that lipid therapies improve cardiovascular outcomes, with each 1 mmol/L reduction in low-density lipoprotein (LDL) cholesterol reducing the risk of ASCVD by about a fifth, irrespective of baseline cholesterol concentration.2 Despite this, there is still a considerable variability in the clinical use and patient acceptance of these therapies. This article summarises the main available lipid-lowering therapies in the UK and how they fit into national guidelines.

NICE clinical guideline CG181

In 2014, the National Institute for Health and Care Excellence (NICE) published its clinical guideline, ‘Cardiovascular disease: risk assessment and reduction, including lipid modification (CG181)’, which it subsequently updated in 2016.3 The core premise of CG181 is based on estimation of 10-year CVD risk to guide decision-making regarding the use of statin therapy for primary prevention, as calculated by the prediction algorithm QRISK2 (now superseded by QRISK3).4 It is not to be used in patients over the age of 84 or with type 1 diabetes, estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 or albuminuria, familial hypercholesterolaemia or other inherited disorders of lipid metabolism. It is also acknowledged that risk is underestimated in patients with some underlying medical conditions (including HIV, serious mental health problems, systemic inflammatory disorders, recently stopped smoking, obesity and hypertriglyceridaemia) or who take certain medications (eg, antipsychotic drugs, corticosteroids or immunosuppressants). Of course, ASCVD risk is not related solely to the plasma concentration of LDL-c; therefore, QRISK also incorporates age, gender, postcode, history of smoking, diabetes and hypertension, family history of CVD, height and weight.

NICE CG181 recommends that those with a 10-year risk of an ASCVD event greater than 10% should be offered atorvastatin 20 mg per day to lower their CVD risk. By contrast, patients with established ASCVD, whose risk of (recurrent) events is higher, should commence 80 mg of atorvastatin per day. Since the publication of NICE CG181, clinical trial evidence for the use of additional lipid-lowering agents has accumulated and resulted in the publication of several NICE technology appraisals5–10 that give guidance on individual treatment options. However, a unifying clinical pathway for the practical use of general clinicians was lacking. NHS England, via the Accelerated Access Collaborative, therefore developed NICE-endorsed lipid management pathways for both primary and secondary prevention of CVD. These were first published in April 2020 and updated most recently in April 2022. They provide guidance on how to approach lipid management for individual patients.11

What to measure?

Debate concerning the lipid biomarker of choice has focused on the pros and cons of low-density lipoprotein cholesterol (LDL-c) versus non-high-density lipoprotein cholesterol (non-HDL-c). Most lipidologists and epidemiologists, however, agree that apolipoprotein B (ApoB) should actually be the preferred measurand, as it consistently outperforms LDL-c and non-HDL-c in prediction of ASCVD.12 However, its utility is limited due to additional cost, lack of familiarity among clinicians and less widespread availability. The vast majority of clinical trials employed change in plasma concentration of LDL-c as their main biochemical endpoint. Furthermore, laboratories across the globe can readily calculate LDL-c using the Friedewald formula or other novel equations. This is far from perfect as calculated LDL-c requires a fasting sample and its accuracy is diminished in patients with high triglyceride concentration. Non-HDL-c is also a calculated parameter (total cholesterol minus HDL-cholesterol) and is an estimation of cholesterol in all the ApoB-containing lipoproteins. Measurement of non-HDL-c does not require fasting and is superior to LDL-c in estimation of ASCVD risk in large epidemiological studies.13 It was for this reason that NICE decided to incorporate non-HDL-c, rather than LDL-c, as the lipid parameter of choice in estimation of ASCVD risk. However, this approach has not been consistent and, in more recent NICE technology appraisals, LDL-c thresholds have been employed to assess eligibility for medicines such as evolocumab, alirocumab and inclisiran. This was because the industry submissions of evidence for the technology appraisals were based on LDL-c. In addition, the diagnosis of familial hypercholesterolaemia is made predominantly on LDL-c concentration, the disease being characterised as a disorder of LDL metabolism. Thus, both non-HDL-c and LDL-c measurements are currently required to assess the dyslipidaemic patient appropriately.

Targets

NICE CG181 does not recommend a specific lipid target. Instead, the advice is to repeat measurement of non-HDL-c at 3 months and that, for patients who do not achieve a non-HDL-c reduction of greater than 40%, a discussion around adherence should be undertaken with consideration of dose escalation. Patients taking 20 mg of atorvastatin daily are expected, on average, to achieve a 43% reduction in LDL-c. The evidence shows that randomised controlled trials with high intensity, compared with medium-intensity statins, gave significantly better outcomes. Therefore, patients should be treated with drug and dose combinations expected to achieve LDL-C reduction of greater than 40%, which equates to high-intensity statin therapy. It was agreed that response should be assessed by non-fasting non-HDL-C and if 40% reduction was not achieved, concordance should be checked and/or lower doses titrated up.

In contrast, for those with established CVD, the Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3), also published in 2014, recommended an absolute non-HDL-c target of 2.5 mmol/L (broadly equivalent to an LDL-c of 1.8 mmol/L) with a ‘lower the better’ approach, based on data from the Cholesterol Treatment Trialists’ Collaborators.2 14 These data showed that among 170 000 in 26 randomised trials, those who achieved a serum LDL-c concentration ≤1.8 mmol/L suffered fewer cardiovascular events than those who achieved higher levels.

Lipid-lowering therapies

The armamentarium of available lipid-lowering therapies has rapidly expanded in recent years with the discovery of new therapeutic targets and technology to harness them. These approaches are summarised in figure 1.

Figure 1

Therapeutic approaches to reducing LDL-c using small molecules, monoclonal antibodies and siRNA. ACL, ATP-citrase lyase; CoA, coenzyme A; HMG, 3-hydroxy-3-methylglutaryl; LDL, low-density lipoprotein; LDL-c, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; mRNA, messenger RNA; NPC1L1, Niemann–Pick C1-like one protein; PCSK9, proprotein convertase subtilisin/kexin type 9; siRNA, small interfering ribonucleic acid. Adapted from Nordestgaard et al. Nat Rev Cardiol, 2018.29

Statins

In the early 1970s, Akira Endo speculated that some fungi might produce antibiotics to inhibit a key enzyme, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, in the cholesterol biosynthesis pathway and upregulate the LDL receptor. Through the screening of over 6000 fungal extracts, compactin (mevastatin) was the first potent inhibitor of 3-HMG-CoA reductase to be discovered and has led to the development of seven commercially available statins. Five of these are licensed in the UK (table 1).

Table 1

Licensed statins in the UK and extent of LDL-c lowering by statin and dose

Statins remain the bedrock of lipid-lowering therapy to reduce ASCVD risk, both in primary and secondary prevention, supported by a vast body of evidence.2 These medicines have been hugely underused, predominantly due to misinformation and bad press regarding adverse effects. Despite the evidence base for the safety and efficacy of these medicines, subjectively perceived statin intolerance remains a major problem. To help clinicians address this, NHS England have devised a Statin Intolerance Algorithm to provide a structured approach for managing patients with statin intolerance.15 Strategies may include stopping the statin and trying again when the symptoms have resolved to check if the symptoms are related to the statin, reducing the dose within the same intensity group or changing the statin to a lower intensity group.

Ezetimibe

By targeting the Niemann–Pick C1-like 1 (NPC1L1) protein, ezetimibe reduces absorption of cholesterol from the intestine and interrupts enterohepatic recirculation of bile. In 2015, the IMPROVE-IT trial demonstrated that, in patients with recent acute coronary syndrome, with a baseline LDL-c of 1.8 mmol/L, ezetimibe added to simvastatin led to greater reduction in LDL-c and also reduced cardiovascular events when compared with simvastatin alone.16 This was the first trial to show a significant reduction in cardiovascular outcomes with a non-statin agent, used in combination with a statin and was pivotal in supporting the LDL-c hypothesis. Thus, a NICE technology appraisal (TA385), published in 2016, recommended the use of ezetimibe in patients with statin intolerance/contraindication and as combination therapy with statin where LDL-c could not be appropriately controlled by statin alone.9

Bempedoic acid

Bempedoic acid is an inhibitor of ATP–citrate lyase, a key enzyme in the cholesterol synthesis pathway acting upstream of HMG-CoA reductase, the target for statins. Bempedoic acid is a prodrug and requires activation by an enzyme which is present in the liver but absent in most peripheral tissues. Therefore, an important feature differentiating bempedoic acid from statins is its liver-specific action.17 The Clear Harmony Trial demonstrated that bempedoic acid with maximally tolerated statin led to an additional 18% reduction in LDL-c compared with statin alone without increasing overall adverse events. The incidence of gout was slightly higher in patients who were randomised to receive bempedoic acid, which increases plasma levels of uric acid. The drug is available in a fixed dose combined formulation with ezetimibe which NICE recommends if statins are contraindicated or not tolerated and ezetimibe alone does not control LDL-c.10 There is currently no CVD outcome data available for bempedoic acid, with or without ezetimibe.

Monoclonal antibodies targeting PCSK9

Proprotein convertase subtilisin–kexin type 9 (PCSK9) is a protein that binds the LDL receptor and directs it to destruction in the lysosome. The appreciation that carriage of PCSK9 loss-of-function alleles was associated with reduced LDL-c and protection against ASCVD led to PCSCK9 becoming an attractive therapeutic target. Both evolocumab and alirocumab, monoclonal antibodies to PCSK9, reduce LDL-c by approximately 60% and have demonstrated reduction in major adverse cardiovascular events.18 19 They are self-administered as a subcutaneous injection every 2 weeks. In 2016, both evolocumab and alirocumab were approved by NICE; however, based on their clinical benefits and cost, both agents have strict LDL-c thresholds and clinical criteria for eligibility7 8 (table 2). Currently, NICE recommend specialist initiation.

Table 2

NICE eligibility criteria for PCSK9 monoclonal antibody therapy (NICE Technology Appraisals 393 and 394)7 8

Small interfering ribonucleic acid (siRNA) targeting PCSK9

Inclisiran is a double-stranded small interfering RNA (siRNA) that suppresses PCSK9 translation in the liver, leading to sustained reductions in LDL-c by approximately 50% with twice-yearly dosing.5 Inclisiran uses a triantennary N-acetylgalactosamine ligand to allow for targeted delivery of the siRNA to the hepatocyte. It is the first licensed siRNA-based therapy for cardiovascular disease; indeed, other licensed siRNA-based treatments cover much rarer indications such as acute intermittent porphyria and hereditary transthyretin-mediated amyloidosis. Therefore, the collection of long-term safety data with this novel agent is important. Orion-4, a phase III cardiovascular outcomes trial of inclisiran, is still ongoing.20 NICE have approved the use of inclisiran in adults with a history of a cardiovascular event and LDL-c persistently 2.6 mmol/L or more, despite maximum tolerated lipid-lowering therapy.5 It is prescribable in both primary and secondary care and is given as a subcutaneous injection by a healthcare professional.

Icosapent ethyl

Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA). The data supporting the use of omega-3 fatty acid compounds, EPA and docosahexaenoic acid (DHA ) for the prevention of CVD have been highly controversial over the last few decades.21 22 Icosapent ethyl was recently assessed in the REDUCE-IT trial and found to lower CV outcomes in patients with previous CVD or at high risk of developing CVD, with elevated triglyceride levels despite the use of statins.23 This resulted in the publication of a NICE technology appraisal on icosapent ethyl as an option for reducing the risk of cardiovascular events in adults.6 It is recommended if they have established cardiovascular disease and raised fasting triglycerides (1.7 mmol/L or above) and are taking statins, with LDL-c levels between 1.04 mmol/L and 2.60 mmol/L, as per the REDUCE-IT trial. This latest NICE guidance is not yet reflected in the NHS England lipid management pathway.

Other therapies

There are several other lipid-lowering therapies that are currently used in clinical practice but are either not incorporated into NICE guidelines/technology appraisals or are used in more specialist settings. Some of these are outlined as follows:

Fibrates: Of the main classes of lipid-lowering therapies, the fibrates are the longest established. They promote lipolysis by stimulating lipoprotein lipase via peroxisome proliferator-activated receptor (PPAR) α in the liver and PPAR γ in adipose tissue, thus effectively improving hypertriglyceridaemia and raising HDL-c, with modest LDL-c lowering. However, trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk and therefore NICE CG181 does not recommend the routine use of fibrates for CVD prevention.3 Meta-analysis does suggest that fibrates may have a role in reducing CV risk, particularly in those with mixed dyslipidaemia.24 In the ACCORD study, individuals with both a low HDL-c and high triglycerides were the subset in whom the greatest proportional risk reduction was achieved (relative risk reduction of 28%).25

Bile acid sequestrants: These agents, as an adjunct or alternative to statins, have largely been superseded by the other therapies described previously. NICE recommends that they should be initiated by specialists and limited to cases of familial hypercholesterolemia (FH).26 However, colesevelam is designated by the FDA as category B (no risk to pregnancy in animal studies) and may be used in place of other drugs for women in pregnancy or while breastfeeding.

Lipoprotein apheresis: Extracorporeal removal of ApoB-containing lipoproteins is the mainstay of treatment for homozygous FH, both in children and adults. In heterozygous FH, NICE CG71 recommends that, in exceptional instances such as when there is progressive, symptomatic coronary heart disease, despite maximal tolerated lipid-modifying drug therapy, healthcare professionals should consider offering lipoprotein apheresis. This should take place in a specialist centre on a case-by-case basis and data recorded in an appropriate registry.26

Using the NHS England lipid management pathway to guide lipid lowering

With several guidelines and technology appraisals having been published by NICE in the last few years, it has become challenging for clinicians to keep abreast of advances in the field of lipidology. Hence, NHS England, via the Accelerated Access Collaborative, decided to create simple diagrammatic lipid management pathways to provide clinicians with guidance on how to approach lipid management for the individual (figures 2 and 3).

Figure 2

Summary of lipid-lowering guidance for the primary prevention of atherosclerotic cardiovascular disease as recommended by the NHS England Accelerated Access Collaborative (AAC) pathway.11 aAdditional risk factor could be over 40 years old, diabetes for more than 10 years, nephropathy or another atherosclerotic cardiovascular disease risk factor. bConsider comorbidities, frailty and life expectancy. cAdditional risk factors such as treated for HIV, severe mental illness, taking medicines that cause dyslipidaemia, systemic inflammatory disorders, impaired fasting glycaemia or a recent change in risk factors. dAgree the use of higher doses with a renal specialist if eGFR is less than 30 mL/min/1.73 m2. DM, diabetes mellitus; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HDL-c, high-density lipoprotein cholesterol; OD, once daily.

Figure 3

Summary of lipid-lowering guidance for the secondary prevention of atherosclerotic cardiovascular disease as recommended by the NHS England Accelerated Access Collaborative (AAC) pathway.11 Secondary prevention includes angina, previous myocardial infarction, revascularisation, stroke or transient ischaemic attack or symptomatic peripheral arterial disease. aUse a lower dose of atorvastatin if there is a potential drug interaction, high risk of or experiencing adverse effects, or patient preference. Offer atorvastatin 20 mg if eGFR <60 mL/min/1.73 m2. eGFR, estimated glomerular filtration rate; OD, once daily; PCSK9 mab, monoclonal antibodies to PCSK9.

The primary prevention pathway takes a risk-based approach, recommending 20 mg of atorvastatin as first-line pharmacotherapy. The patient is then assessed 3 months later. If 40% reduction in non-HDL-c is not achieved, discussion around adherence and lifestyle is advised, with the possibility of increasing the statin dose. Another option is the addition of ezetimibe. The Statin Intolerance Algorithm should be used in those who cannot tolerate high-intensity statin. Specialist referral to lipid clinic is advised if a clinical diagnosis of FH is made or the patient has severe hypertriglyceridaemia (>10 mmol/L).

In secondary prevention, the prescribing of atorvastatin 80 mg once daily should not be delayed unless there is a specific clinical reason. If non-HDL-c is not reduced by 40% at 3 months, ezetimibe or injectable therapies can be added in. For evolocumab, alirocumab and inclisiran, specific NICE eligibility criteria apply.

How do NICE guidelines compare with ESC/EAS and ACC/AHA guidance?

NICE guidelines differ intrinsically from those published by specialist societies such as the Joint British Societies14 and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS)27 as they are not purely based on the current science and expert opinion, but also take into account the cost-effectiveness of treatments and health economics. In addition, NICE guidance tends to be very focused on evidence from randomised clinical trials within specific cohorts of patients and there is little scope to extend this for more generalisability to other patient cohorts who may also benefit. The American Heart Association/American College of Cardiology (AHA/ACC) guidelines28 do take into account the cost of therapies and are therefore more conservative than the European guidelines, but more liberal than NICE.

This has led to some very clear differences in policy between NICE and the specialist society statements (table 3). One stark difference is the use of non-HDL-c as the lipid biomarker of choice by NICE whereas the Europeans and Americans have stayed with LDL-c. The European LDL-c targets are much more stringent than the American ones. NICE does not recommend imaging of subclinical atherosclerosis whereas the ESC/EAS and AHA/ACC do. ESC/EAS have much broader eligibility criteria for some of the more costly agents. For example, under NICE, patients without FH, being treated for primary prevention, would not qualify for PCSK9 monoclonals; however, they would under the ESC guidelines if considered ‘very-high risk’.

Table 3

Comparison of NICE guidelines with ESC/EAS and ACC/AHA guidelines3 5–10 26–28

The 2018 AHA/ACC guidelines and the 2019 ESC/EAS guidelines for lipid management were published within 9 months of each other. These guidelines therefore have not advised on the use of some of the newer therapies such as inclisiran, bempedoic acid and icosapent ethyl. One of the advantages of the NICE approach is that each new agent is assessed as part of the technology appraisal process with the intent for them to become ‘live guidelines’.

Future perspectives

For the primary prevention of ASCVD, 10-year CVD risk is used to guide clinical decision-making. Moving forward, lifetime risk should be considered and this is especially pertinent to young patients with strong family history of ASCVD whose 10-year risk may be very low, but lifetime risk is very high. Other established risk factors, such as lipoprotein(a), should be incorporated into QRISK3, to refine risk stratification. Lipoprotein(a) is already recognised in the European and American guidelines, and both consider those patients with elevated lipoprotein(a) to be at higher risk of ASCVD.27 28 Finally, clinicians, particularly in primary care, find percentage reduction in non-HDL-c challenging to implement and audit. Patients often find this a tricky concept to grasp. In practice, many lipidologists and cardiologists employ absolute targets to guide clinical care. The use of non-HDL-c in NICE CG181 and LDL-c in the NICE technology appraisals further confuses the matter. The practicality of guidelines should be taken into account in future iterations.

Conclusion

In conclusion, the NICE guidance, summarised by the NHS England lipid management pathway, provides up-to-date guidance on the use of lipid -lowering therapies.

Ethics statements

Patient consent for publication

Ethics approval

Not applicable.

Acknowledgments

The author would like to thank G.R. Thompson and R. D. G. Neely for reviewing the draft manuscript.

References

Footnotes

  • Contributors JC is sole author of this manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests JC has received speaker/advisory board fees from Amgen, Sanofi, Amyrt, Pfizer, Novartis, Akcea and Ionis. JC has received research grants from Amgen, Amyrt, Novartis and Silence Therapeutics. JC is a member of the Medical, Scientific and Research committee of HEART UK, the Cholesterol Charity.

  • Provenance and peer review Commissioned; externally peer reviewed.