The reduction of low-density lipoprotein cholesterol (LDL-C) levels is a key element for the prevention of cardiovascular diseases (CVD), but the target level is still a matter of debate among experts. New lipid guidelines from the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) have recommended that LDL-C levels should be lowered as much as possible to prevent CVD, especially in high and very high-risk patients.1 The new guidelines were released on August 31st at the European Society of Cardiology Congress 2019 at Paris, France, and simultaneously published in the European Heart Journal.1
New guidelines are instrumental for further reducing the risk of ASCVD
CVD is responsible for 31% of all deaths annually worldwide.2 Atherosclerotic cardiovascular disease (ASCVD), is the main type of disease among CVD.1 The 2019 ESC/EAG guidelines provide recommendations on how to modify plasma lipid levels through lifestyle and medications to reduce the risk of ASCVD.
“Although it is only three years since the previous ESC/EAS Guidelines on the management of dyslipidemias were published, a substantial body of new evidence has accumulated,” stressed Prof. Heinz Drexel, Guideline Review Coordinator for the European Atherosclerosis Society (EAS), University Hospital of Bern, Bern, Switzerland.3
He further emphasized the importance of updated guidelines mentioning, “New up-to-date ESC/EAS guidelines are needed to help physicians provide the very best approaches to efficiently and safely modify lipid levels and reduce the risk of ASCVD as far as possible.”3
Emerging evidence has confirmed that the key initiating event in atherogenesis is the retention of LDL, LDL-C and other cholesterol-rich apolipoprotein B (ApoB) containing lipoproteins within the arterial wall.4 Furthermore, recent placebo-controlled clinical studies have shown that the addition of either ezetimibe or anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) to statin therapy provides a further reduction in ASCVD risk.5 The ASCVD risk reduction is directly and positively correlated with the incrementally achieved absolute LDL-C reduction.6
Prof. Colin Baigent, task force chairperson and Director of the Medical Research Council Population Health Research Unit, University of Oxford, UK, outlined, “There is now overwhelming evidence from experimental, epidemiological, genetic studies, and randomized clinical trials, that higher LDL-C is a potent cause of heart attack and stroke.” Additionally, Prof Baigent highlighted the benefits of lowering LDL-C saying, “Lowering LDL-C reduces risk irrespective of the baseline concentration. It means that in people at very high risk of heart attack or stroke, reducing LDL-C is effective even if they have below average starting levels.”3
There is no lower limit of LDL-C that is known to be unsafe. The guidelines aim to ensure that the available drugs (statins, ezetimibe and PCSK9 inhibitors) are used as effectively as possible to lower the levels in those most at risk. The comparison of changes in the recommendations of 2016 and 2019 guidelines are presented in Figure 1.1
Primary and secondary prevention of ASCVD
One of the major changes in the new guidelines is the removal of the distinction between primary and secondary prevention of ASCVD. Prof. Baigent explained the reason for this change, “What we’ve done is to make sure the recommendations are similar for a same level of risk regardless of whether a patient has had a previous event.”7 Although the risk is not distinguished between the primary and secondary prevention, the risk is always assessed as the previous version of guidelines in both settings.
Prof. Baigent further clarified, “While with secondary prevention, patients will normally be at higher risk, patients with primary prevention could still be at high risk if they have multiple risk factors, and data showed that the benefits of statins do not differ between primary and secondary prevention per se rather, it is the level of risk that is important.”7
However, there is an exception for the elderly over 75 years. Prof. Baigent highlighted, “While we have strengthened the recommendation for use of statins in the elderly in general, we have given a slightly weaker recommendation for those patients aged over 75 with primary prevention.”7
New recommendations on high-risk categories
Risk stratification categories have been revised in the new guidelines, so that patients with ASCVD, diabetes with target organ damage, familial hypercholesterolemia, and severe chronic kidney disease are all categorized as very high-risk patients.1 Therefore, intensive LDL-C lowering therapy is recommended for these patients. The treatments aim for a particular category of risk despite the history of patients having a heart attack or stroke.1
The need to estimate total cardiovascular (CV) risk, including all CV risk factors, not only LDL-C, is also reinforced in the 2019 ESC/EAS Guidelines. Prof. Drexel explained the concern regarding other lipids, “There has been much interest in the effects of omega-3 polyunsaturated fatty acids to reduce the elevated triglyceride levels, but there has been some inconclusive evidence. However, based on the results of recent REDUCE-IT trial, icosapent ethyl (2g twice a day) should now be considered in combination with a statin in high-risk (or above) patients with triglyceride levels from 1.5 to 5.6mmol/L (135–499mg/dL) despite statins.”7
2019 ESC/EAS guidelines recommended both a ≥50% LDL-C reduction from baseline and an absolute LDL-C treatment goal of <1.4mmol/L (< 55mg/dL) for very high-risk patients.1 Specifically, for patients at high-risk, a ≥50% LDL-C reduction and an LDL-C goal of <1.8mmol/L (<70mg/dL) are recommended.1 Moreover, a high-intensity statin is suggested up to the highest tolerated dose to achieve specified goals. In addition, PCSK9 inhibitor could be prescribed in patients at very high risk who are not achieving treatment goals on a maximum tolerated dose of a statin and ezetimibe.1
Prof. Alberico L. Catapano, the task force chairperson and Professor of the Department of Pharmacological and Biomolecular Sciences at the University of Milan, Italy, remarked, “This is to ensure that high- or very high-risk patients receive intensive LDL cholesterol lowering therapy irrespective of their baseline level.” He further highlighted that, “patients who are already close to their target on current treatment will be offered additional treatment that provides a further minimum 50% reduction.”8
New revisions to statin therapy
Statin ‘intolerance’ is one of the latest inclusions to the 2019 ESC/EAS guidelines. In a number of observational studies, statin-associated muscle symptoms have been frequently encountered, although the experts are questioning whether this is due to the “placebo effect”.9
“Statins are very well tolerated, and true ‘statin intolerance’ is uncommon. Most patients can take a statin regimen,” stated Prof. François Mach, the task force chairperson and the Head of the Department of Cardiology, Geneva University Hospital, Switzerland. Furthermore, he explained, “statins have very few side-effects. These include an increased risk of developing diabetes, and they may rarely cause myopathy. But the benefits of statins greatly outweigh their hazards, even among those at low risk of ASCVD.”7
However, in the 2019 ESC/EAS guidelines, statins are not recommended in pre-menopausal women considering pregnancy or not using adequate contraception.1 Although statins have not been shown to cause fetal malformations when unintentionally used in the first trimester of pregnancy, due to the lack of formal evidence, it was suggested that women needing a statin should avoid them during any period when they might conceive.1
Furthermore, the evidence available for statin therapy is limited in patients over 75 years old. The guidelines recommended taking the level of risk, baseline LDL-C, health status, and the risk of drug interactions into account when deciding whether statins are appropriate in those aged above 75.1
Other significant recommendations
The new ESC/EAS guidelines stated that ApoB measurement should be considered at least once in a person’s lifetime, if possible, to identify people who have very high inherited levels (>180mg/dL [>430nmol/L]) and who may have a very high ASCVD risk.1 ApoB measurement should also be considered in selected patients with a family history of premature ASCVD, and for reclassification in people who are borderline between moderate and high risk. Prof. Baigent highlighted, “assessment should be done around 40 years of age to identify people before they have a heart attack or stroke.”7
Other new ways to evaluate the risk and risk-classification include non-invasive CV imaging. For example, arterial ultrasonography is now recommended for the plaque burden assessment, while computed tomography is used to assess the coronary artery calcium score. These non-invasive imaging techniques can now be considered as risk modifiers in the individuals at low or moderate risk.1
Fish oil supplements (particularly icosapent ethyl) are recommended in combination with a statin for patients with hypertriglyceridemia despite statin treatment.1 In these patients, supplements could reduce the risk of ASCVD events, including heart attack and stroke, by about one-quarter.
The guidelines also advocated a lifetime approach to CV risk.1 This means that people of all ages and risk levels should be encouraged to adopt and sustain a healthy lifestyle. The main requirements are a healthy diet, avoidance of cigarette smoking and regular exercise.
The new 2019 ESC/EAS dyslipidemia guidelines advocating “lower is better” for LDL-C were well received by the experts all over the world. Furthermore, the revisions of the treatment protocol for high-risk patients were warmly welcomed by the clinicians. The fundamental next steps will be an appropriate implementation in the clinical practice, together with ensuring the effective treatment adherence among patients.
1. Mach F, Baigent C, Catapano AL et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular riskThe Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2019 Aug 31. doi:10.1093/eurheartj/ehz455
2. Cardiovascular diseases. World Health Organization. (Accessed September 21, 2019, at https://www.who.int/westernpacific/health-topics/cardiovascular-diseases)
3. Lipid modification to reduce cardiovascular risk: 2019 ESC/EAS Clinical Practice. ESCardio.org, (Accessed September 21, 2019, at https://www.escardio.org/Congresses-&-Events/ESC-Congress/Congress-resources/Congress-news/lipid-modification-to-reduce-cardiovascular-risk-2019-esc-eas-clinical-practice-guidelines-for-the-management-of-dyslipidaemias)
4. Sun Y, Hou XH, Wang DD et al. Apolipoprotein B/AI ratio as an independent risk factor for intracranial atherosclerotic stenosis. Aging 2019 Sep 3;11(17):6851-6862.
5. S Sabatine MS, Wiviott SD, Im K et al. Efficacy and Safety of Further Lowering of Low-Density Lipoprotein Cholesterol in Patients Starting With Very Low Levels: A Meta-analysis. JAMA Cardiol. 2018 Sep 1;3(9):823-828.
6. Silverman MG, Ference BA, Im K et al. Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis. JAMA. 2016 Sep 27;316(12):1289-97.
7. New European Lipid Guidelines Take Aggressive Approach. Medscape.com (Accessed September 21, 2019, at https://www.medscape.com/viewarticle/917551)
8. Drive LDL as Low as Possible, ESC Says. Medpage Today. (Accessed September 21,2019, at https://www.medpagetoday.com/meetingcoverage/esc/81919)
9. Algharably EA, Filler I, Rosenfeld S et al. Statin intolerance – a question of definition. Expert Opin Drug Saf. 2017 Jan;16(1):55-63.