Comments on the 2019 ESC/EAS Guidelines on Dyslipidemias

Cardiovascular risk evaluation

The definition of high and very high-risk subjects is close to the one found in the 2016 Guidelines.

Very high-risk subjects:

Atherosclerotic cardiovascular disease –ASCVD-, either clinical or unequivocal on imaging (CT scan included in these guidelines); diabetes mellitus with target organ damage, long standing duration (>20 years), or associated with other risk factors; eGFR <30 mL/min/1.73 m²; Familial Hypercholesterolemia (FH) with ASCVD or with another major risk factor; SCORE>10%. 

High risk subjects:

markedly elevated single risk factors, including Low-Density-Lipoprotein cholesterol (LDL-c)

>190mg/dl, FH without other risk factors, diabetes with a duration >10years or with another risk factor; eGFR 30-59 mL/min/1.73 m²; calculated SCORE >5% and <10%.

Moderate/low risk subjects:

The concept of risk modifier factors is confirmed in the 2019 Guidelines, possibly leading to reclassification of global risk if some laboratory or clinical characteristic such as social deprivation, immune-inflammatory diseases, atrial fibrillation, family history of premature cardiovascular disease, are present. CT Calcium Score may be useful in treatment strategies when LCL-c goal is not achieved by lifestyle Intervention.

LDL-c

The first key message is reinforcing the strength of recommendations of the 2016 ESC/EAS Guidelines about the need to achieve the lowest LDL-c possible levels by intensifying treatment, mainly in patients at high or very high cardiovascular risk (‘lower is better without no lower threshold’).  

New lower LDL-c goals are recommended in selected populations with the indication to treat with the maximally tolerated dose of statins, and, if the goals are not achieved, to add Ezetimibe and  thenProprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9i). Indeed, the guidelines set a new goal of LDL-c level <55mg/dL both in primary and secondary prevention in very high risk subjects, recommending the goal of <70mg/dL for high risk subjects. These ambitious new goals cannot surprise the medical community and are indicated with compelling recommendations due to recent unquestionable scientific evidence.

More intensive reduction of LDL-c than the one suggested previously should be considered in the moderate risk (<100mg/dL) whereas a goal of <116mg/dL may be considered in low risk subjects. These latter goals underline the urgency to act at a population level (first through lifestyle interventions) to obtain relevant event reduction through lowering LDL-c.

In patients with acute coronary syndrome, high dose statin treatment should be initiated as early as possible, regardless baseline LDL-c levels, and if the patient is not at LDL-c goal of <55mg/dL and he/she is already taking statin plus Ezetimibe, a PCSK9i should be considered quickly, whereas Ezetimibe and a PCSK9i should be added if the goal is not achieved after 4-6 weeks. These indications prompt to the responsibility of medical doctors to tightly target the challenging new LDL-c goals as early as possible.  

It is stated clearly that no known adverse events have been linked to very low LDL-c levels.

Moreover, the indication to treat the elders as the younger population in secondary prevention and in primary prevention when £75 years, and to consider to initiate statin therapy if high risk or above also at ages > 75years.  Caution is recommended in older subjects: start treatment with a low dose and then up-titrate to the goal. 

Lipid profile and other risk considerations

Apolipoprotein B

The use of Apolipoprotein B (ApoB) in risk stratification may be useful when LDL-c underestimates the risk as in high triglycerides (TG) conditions, diabetes mellitus, obesity, or very low LDL-c. The identification of ApoB as secondary goals  < 65, 80, and 100 mg/dL for very-high, high-, and moderate-risk people, respectively, could become relevant in near future, particularly in the view of newer drugs targeting TG.

According to the acquired concept that ApoB-containing lipoproteins has a causal role in ASCVD, these guidelines establish the use of statins as drugs of first choice to reduce TG in patients at high risk with hypertrigliceridemia >200mg/dL (class I recommendation), being the use of n-3 PUFAs and fibrates other potential pharmacological interventions to be considered. For very high TG levels (associated with genetic causes and bearing the risk of acute pancreatitis) restriction of calories and fat content, alcohol abstinence, and initiation of fibrate therapy possibly in association with n-3 fatty acids should be obtained.

 Lp (a)

As a new indication for lipid profile assessment, a one-off measurement of Lp(a) may be useful to identify the low number of subjects with extremely high values >180mg/dL at high risk of ASCVD.

Other lipids treatments issues

The guidelines put into evidence that there is a frequent problem in clinical use of statins due to reported adverse effects, and that practitioners may have difficulty to manage this so called ‘intolerance’ to statins; however the use of statins is supported even when adverse effects, in particular statin-associated-muscle symptoms, are reported. The focus on this issue is shown only in supplement data through a possible algorithm (in part derived from a previously published -2015- EAS consensus) to be used in case muscular symptoms during statin treatment whereas other strategies such as reduction of dosages or different administration schedules (alternate day or 2-3 times a week therapy)  are only indicated in the supplementary figure 6 and in the text. The substantial lack of evidence on clinical endpoints has possibly limited the focus on these points. Indeed, in the clinical setting, a large number of subjects is not adherent to statin treatment and most of the patients who stop statins increase dramatically their risk of events.

Nutraceuticals and phytosterols  may be considered as light suggestion, though the use of Ezetimibe and PCSK9i is strongly supported throughout these guidelines to reach the LDL-c targets in adjunct of statins or as drugs of choice in statin intolerant patients at high risk.

'What to do’ and ‘What not to do’ messages

The striking messages (IA recommendations) from these guidelines  rise from the strong awareness that the maximally achievable reduction of LDL-c and ApoB lead to the maximally attainable reduction of vascular events and push the medical community towards intensification of LDL-lowering therapy, particularly in higher risk categories of patients. Moreover these guidelines are a call to stop the delay on treatment actions even at a population level,  due to  cost-effectiveness of LDL-c focused treatment.

It is recommended that the risk scores developed for the general population have not to be used in patients who are already defined as being at high/very high risk because of the underlying disease such as  diabetes mellitus or FH, patients with previous stroke, with peripheral artery diseases and carotid diseases, and in severe mental illnesses. Statins have not to be used in fertile women, in patients with heart failure  without any other indications, in patients with Chronic Inflammatory Immuno-mediated Diseases alone,  in aortic stenosis to delay progression (though patients with aortic stenosis often need lipid lowering therapy because of concomitant cardiovascular risk factors and high SCORE) and in patients with dialysis-dependent chronic kidney disease free of ASCVD.

Access the 2019 Guidelines on the Management of Dyslipidaemias

Authors

From the Univsersity of Insubria, Varese, Italy

• Luigina Guasti
• Giovanni Gaudio
• Riccardo Asteggiano