What is New in the Most Recent Guidelines for the Management of Dyslipidemias of the European Society of Cardiology and the European Atherosclerosis Society?

In August 2019, the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) published their joint Guidelines for the Management of Dyslipidemias that introduced important novelties in cardiovascular prevention and management. (1) The main change introduced was based on the results of two large clinical studies that demonstrated robust benefits in patients with confirmed atherosclerotic cardiovascular disease (ASCVD) and acute coronary syndrome (ACS) when LDL cholesterol (LDL-C) was reduced even further by adding a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) to intensive statin therapy. It was demonstrated that there is no LDL-C concentration that is too low, i.e. that every reduction in LDL-C has clinical benefits. (2, 3)

The guidelines pay special attention to ASCVD prevention by: 1) promoting healthy lifestyle habits in the community, 2) assessing the total cardiovascular risk (CVR) of an individual by analyzing their risk factors, in particular LDL-C concentration, 3) undertaking individually tailored preventive and therapeutic measures, the intensity of which should be proportional to the patient’s total CVR.

The new guidelines have slightly modified patient classification according to CVR levels. A portion of patients with diabetes mellitus (DM) has been reclassified into categories of less severe risk, leaving some patients in the very high risk category from the previous guidelines, and moving others into the high risk category. (4) Also, a portion of patients categorized as high-risk according to the previous guidelines has now been moved to the moderate-risk category, which did not previously include patients with diabetes. The new guidelines also added patients with familial hypercholesterolemia (FH) and another additional risk factor or already present ASCVD to the very high risk category.

The very high risk category now includes patients with: 1) ASCVD that has been documented either clinically or by imaging (the new guidelines include CT coronarography (5)); 2) long-term diabetes mellitus (>20 years) or burdened with ≥3 additional major risk factors, or complicated target organ damage; 3) severe chronic kidney disease (eGFR 2); 4) familial hypercholesterolemia with another additional major risk factor or complicated with ASCVD.

The high risk category includes patients with: 1) at least one risk factor markedly elevated (e.g. total cholesterol (TC) >8 mmol/L, LDL-C >4.9 mmol/L, arterial blood pressure ≥180/110 mmHg); 2) diabetes mellitus duration ≥10 years or another additional risk factor; 3) chronic kidney disease (eGFR 30-59 mL/min/1.73 m2); 4) familial hypercholesterolemia without other additional risk factors or without documented ASCVD.

The moderate risk category includes young patients with diabetes mellitus (type 1 DM <35 years, type 2 DM <50 years) duration <10 years, without other risk factors.

The category of CV risk in apparently healthy people (men aged >40 and women >50 years or postmenopausal) should be evaluated using the SCORE system, which calculates the 10-year cumulative risk of the first fatal cardiovascular event based on age, gender, smoking, systolic blood pressure values, and TC. Persons with risk values of ≥10% belong to the very high risk category, 5-9% to the high risk category, 1-4% to the moderate risk category, and 2.3 mmol/L, since the risk then increased.

Instead of calculating the absolute CVR, an estimate of the relative CVR and the so-called calculated CV risk age is suggested for young people for a better idea of their CV risk and also to motivate individuals to change their lifestyle habits. Namely, even if a young person has a low absolute CVR, the SCORE relative risk chart may indicate that their relative risk is actually significantly high. The risk age of a person corresponds to the age of a person with the same CVR but with an ideal risk profile, meaning that they are a non-smoker, with a TC of 100 in CT coronarography, to raise the risk category in individuals with low or moderate CV risk, which can, for example, be important in making a decision on introducing statins into therapy.

The approach to prevention and treatment allows flexibility, and if optimal control of one risk factor is not achieved, total risk should be reduced by strong action against the other factors. The SCORE chart can be used to predict the impact of reducing one risk factor on total CVR. For example, giving up smoking reduces CVR by half. In addition to recognizing and treating persons with high and very high risk, it is also essential to provide professional advice to persons with moderate CVR regarding the benefits of modifying their lifestyle habits and even recommend drug treatment in some cases.

Lipids and lipoproteins

The guidelines emphasize the atherogenic properties of lipoprotein particles containing apolipoprotein B (ApoB), i.e. LDL, VLDL, and residual particles. (7) Routine measurement of TC and HDL-C, required to calculate the risk using the SCORE system, is still recommended, as well as LDL-C measurement, which is the primary lipid target for screening, diagnosis, and treatment, and finally triglyceride measurement. The new guidelines attribute more importance to measuring non-HDL-C and ApoB in order to evaluate the risk in people with high triglycerides, diabetes mellitus, obesity, and very low values of LDL-C.

A novelty is that ESC now recommends measuring Lp(a): 1) in adults, at least once in their lifetime; 2) in persons with family history of premature CVD (men 430 nmol/L is considered to increase the risk of ASCVD to a level equal to that in people with heterozygous familial hypercholesterolaemia. (9) There are no clear recommendations on treating persons with elevated Lp(a), but PCSK9i is recommended in addition to intense statin and ezetimibe therapy, and certain patients can be treated with apheresis. (1, 8)

Taking into consideration the strong evidence for the continued reduction of CVR proportionate to the reduction of serum levels of LDL-C, the ESC Guidelines suggest therapeutic strategies based on the level of risk and LDL-C concentration in each individual. However, it is advised to avoid overtreatment in elderly persons based on their high SCORE risk just because of their high age, when their other risk factors are relatively low.

Treatment goals, lifestyle modifications, and drugs for treatment of dyslipidemias

The basic approach for the prevention and treatment of CVD involves lifestyle modifications, arterial pressure control, and reduction of LDL-C due to its key role in the development of atherosclerosis. With the exception of persons with low CVR, target values of LDL-C have been significantly reduced in all other risk categories (Table 1). Unlike the 2016 Guidelines, the new guidelines differentiate between the recommended LDL-C values in persons with low and moderate risk. Non-HDL-C and ApoB are recommended as secondary therapeutic goals for the lipid profiles of people with moderate to very high risk: non-HDL-C <2.2 mmol/L and ApoB <65 g/L for persons with very high risk; non-HDL-C <2.6 mmol/L and ApoB <80 mg/dL for persons with high risk; non-HDL-C <3.4 mmol/L and ApoB <100 mg/dL for persons with moderate risk.

Even the introduction to the 2019 Guidelines already emphasizes the clinical importance of lowering LDL-C according to the principle “the lower, the better”, i.e. without a defined lower limit of LDL-C value, and the non-existence of evidence of any complications caused by LDL-C being “too low”. With each reduction in LDL-C by 1 mmol/L, we reduce the relative risk of cardiovascular complications by approximately 20%. (10)

These high-set therapeutic goals require more intense therapeutic measures, and thereby also a frequent need to combine hypolipemic agents. Because of the above, the guidelines suggest algorithms and tables with practical recommendations depending on the patient’s risk category, baseline LDL-C level, and its expected reduction with certain types of hypolipemic drugs. The effect of treatment with hypolipemic drugs should be evaluated after 1-3 months or in the same interval after treatment intensification, until the therapeutic goal is reached.

Great importance is attributed to lifestyle modifications, Mediterranean diet, especially using extra virgin olive oil, daily physical activity for ≥30 min, reduced intake of saturated fats and food and beverages with added sugar, and completely avoiding trans fats in one’s diet, although the latter measure lowers TC and LDL-C and increases HDL-C by a mere 5-10%. The expected effect of weight loss on the reduction of serum triglycerides in obese persons has been reduced.

The basic medicinal products for the treatment of dyslipidemias are statins, cholesterol absorption inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), and fibrates. The guidelines advise a cascade therapeutic strategy starting with a high-intensity statin. If target LDL-C is not achieved, we enhance it by adding ezetimibe and finally a PCSK9 inhibitor.

Statins

Statins have the capacity to lower LDL-C by up to 50%. A reduction of LDL-C concentration by 1 mmol/L with statin therapy reduces the risk of major adverse CV events by 22%, coronary incidents by 23%, and the total 5-year mortality by 10%. Statins are effective even in people older than 75. Statins have not demonstrated benefits in patients on hemodialysis or patients with heart failure. Although they show class effect, the choice of statins depends on the desired therapeutic target; however, the potential interactions with other drugs and associated diseases should also be considered. According to the intensity of LDL-C reduction, we can differentiate between high-intensity statin therapy (atorvastatin 40-80 mg, rosuvastatin 20-40 mg), which achieves a reduction by approximately 50%, and moderate intensity therapy, which achieves a reduction by approximately 30%. Although statins demonstrate pleiotropic effects, the benefit of their use depends primarily on the achieved LDL-C reduction. Statins slightly reduce Lp(a), mildly increase HDL-C (by 1-10%), and lower triglycerides only slightly more in the case of intensive therapy (by 10-20%). (11)

The most important adverse reaction to treatment is rhabdomyolysis. Measuring creatine kinase (CK) before introducing the drug is recommended. Routine monitoring of CK is not necessary, except in myalgia. If CK increases by 10 times, statin therapy should be discontinued and creatinine and CK should be monitored every two weeks. Drug treatment can continue if the patient shows no symptoms but CK has increased by <10 times, and CK should be measured again in 2-6 weeks. It is recommended to routinely measure ALT before starting statin treatment. This should be repeated again 8-12 weeks after introducing treatment or increasing the dose. If ALT increases by ≥3 times, the statin dose should be lowered or the treatment should be discontinued and ALT re-evaluated after 4-6 weeks. Re-attempting statin treatment is possible after ALT normalizes.

The new guidelines highlight a significantly larger benefit of reducing CVR vs. mildly increased risk of diabetes with statin treatment. (13) Because of the above, regular monitoring of serum HbA1c or glucose is recommended when prescribing high statin doses or in persons with increased risk, including the elderly, persons with obesity, and persons with other evidence of insulin resistance.

Cholesterol absorption inhibitors

Ezetimibe is still the only drug in this class. The benefit of the synergistic effect of ezetimibe with statins, bile acid sequestrants, and PCSK9 inhibitors is emphasized. The new guidelines attribute more importance (class I recommendation) to ezetimibe in prescribing therapy after the maximum tolerable statin dose has failed to achieve the set goal, unlike the previous guidelines (class IIa).

Proprotein convertase subtilisin/kexin type 9 inhibitors

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have been shown to be very effective in reducing CV events in patients with very high risk. Other than lowering LDL-C concentration by up to 60%, they also act by reducing serum Lp(a) by 25-30%. (2, 3) The new guidelines assigned a higher class of recommendation (I A) to PCSK9i for secondary prevention of CVD and for primary prevention in patients with familial hypercholesterolemia and another additional major risk factor who failed to achieve target LDL-C value despite taking the maximum tolerable dose of statins and ezetimibe. The use of PCSK9i for primary prevention in persons with very high risk without familial hypercholesterolemia was assigned a lower class of recommendation (IIb).

Fibrates

The guidelines still question the benefits of treatment with fibrates, although studies reporting CVR reduction proportionate to the achieved non-HDL-C reduction are mentioned. The new guidelines give less importance to adverse effects of fibrates, including the risk of increased creatinine and homocysteine. Fibrates can be prescribed (recommendation class IIb) to persons with high CV risk who achieved their target LDL-C levels with statins, but still have serum triglycerides at >2.3 mmol/L.

n-3 fatty acids

The guidelines mention the result of a Cochrane meta-analysis that did not confirm the effect of n-3 fatty acids on CV mortality and morbidity, except in coronary events. (14) The guidelines comment on the results of REDUCE-IT, a study showing benefits of this therapy for the reduction of CV events frequency in high-risk patients with elevated triglycerides despite receiving statin treatment. (15) In comparison with fibrates, the use of icosapent ethyl at the dosage of 2×2 g per day received a higher class of recommendation (IIa) for the treatment of hypertriglyceridemia in persons with high or very high risk with a triglycerides concentration of 1.5-5.6 mmol/L despite receiving statin therapy.

Treatment of dyslipidemias in different clinical settings

Familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (FH) is described as a relatively frequent cause of premature atherosclerotic disease. FH should be suspected in diagnosing CVD in men aged 5 mmol/L, children with LDL-C >4 mmol/L, persons with tendinous xanthomata, or persons with relatives suffering from FH, premature CVD, or tendinous xanthomata. Diagnosis is established using the Dutch Lipid Clinic Network criteria, which take into consideration data from familial and personal medical history, physical examination, pre-treatment LDL-C values, and the potentially available results of genetic analysis. The score sum reflects the probability of this diagnosis. If possible, diagnosis should be confirmed by genetic testing because a confirmed mutation can be used for a cascade screening of other family members. Early screening for FH in children is recommended at the age of ≥5 years. In persons with FH and another additional major risk factor, and especially if they have already developed ASCVD, it is useful to introduce PCSK9i treatment if target LDL-C was not achieved with intensive statin and ezetimibe therapy. Persons with “isolated” FH are treated like any other persons with high CV risk.

Homozygous FH is a rare, but very severe form of the disease, characterized by very high LDL-C concentration (>13 mmol/L), early and progressive ASCVD, and often ending with death at the age of <30 years. It is treated with intense hypolipemic therapy and apheresis. Addition of lomitapide can reduce LDL-C by up to 50%, reducing the frequency of the need for apheresis. (16)

Persons with diabetes mellitus

The new guidelines reclassified persons with diabetes mellitus according to CV risk categories and made their target LDL-C values stricter. Non-HDL-C and ApoB are recommended as secondary therapeutic goals in these patients as good indicators of burden with triglyceride-rich lipoproteins and residual particles. Statins are the first choice of treatment, but ezetimibe has been shown as very effective, causing a greater reduction in CV risk in persons with very high CV risk with diabetes mellitus vs. those without diabetes mellitus. (17) PCSK9i in persons with diabetes mellitus also cause an additional reduction of absolute risk for 3-year major CV events of 2.7% vs. people without diabetes mellitus. All of this is a consequence of increased absolute risk in this patient population. Persons with type 1 diabetes mellitus and good glycemic control sometimes have a “supernormal” lipid profile with low triglycerides and LDL-C, with HDL-C being at the upper limit of normal values or even slightly elevated. This is a consequence of subcutaneous insulin injections that promote the activity of lipoprotein lipase in adipose tissue and muscles, accelerating the rate of VLDL particle turnover. However, the changed composition of the resulting HDL and LDL particles can increase their atherogenic potential. (18) Statin treatment can be prescribed in young persons with type 1 and 2 diabetes mellitus (≤30 years) if there is evidence of target organ damage and/or LDL-C is >2.5 mmol/L, except in women planning to become pregnant.

Persons with acute coronary syndrome

The guidelines emphasize the importance of intensive and prolonged high-intensity statin treatment in patients with acute coronary syndrome (ACS), with the goal of a quick relative reduction of LDL-C by at least 50% and an absolute reduction of LDL-C <1.4 mmol/L. Ezetimibe should be added to statin treatment if this is not achieved with the maximum tolerable statin dosage within 4-6 weeks. If the set goal is not reached after an additional 4-6 weeks, addition of PCSK9i should be considered. If the patient was on the maximum tolerable dose of statin and ezetimibe even before ACS, PCSK9i introduction should be considered during hospital stay.

In case of vascular event recurrence in the patient during the next two years (not necessarily ACS recurrence!), it is advisable to reduce LDL-C to <1.0 mmol/L. After hospitalization, patients with ACS should be referred to cardiovascular rehabilitation, which achieves better control of risk factors and significantly reduces mortality through a wholesome approach to reduction of total cardiovascular risk by exercising and educating patients on CVD, changing unhealthy lifestyle habits, and appropriate diet. (19)

Ischemic stroke

After suffering an ischemic stroke or transitory ischemic attack, patients have the same therapeutic goals as people with very high CV risk. With each reduction of LDL-C by 1 mmol/L, we reduce the risk of recurrent neurological events, myocardial infarction, and CV death by 12%. (20)

Peripheral artery disease

Based on the results of the FOURIER study, the new guidelines introduced PCSK9i into the therapeutic recommendations. (21) The benefits of using fenofibrate for the reduction of amputations in this population as well as for diabetic retinopathy progression are briefly mentioned. (22)

Elderly persons

Statin treatment of patients with ASCVD aged >65 is equally recommended as in young people. There is insufficient evidence to confirm the benefits of using statins in primary prevention in people older than 75, although the guidelines allow for that possibility in people with high or very high risk (IIb). (23) In case of kidney insufficiency or risk of interactions with other medicinal products, we should start with a low dose of statins and titrate it carefully.

Conclusion

The new guidelines for the treatment of dyslipidemias give priority to the clinical benefits of reducing LDL-C quickly and intensely, according to the principle of “the lower, the better”, especially in persons with high and very high cardiovascular risk. With such ambitious goals, combining basic hypolipemic drugs, high-intensity statins, ezetimibe, and PCSK9 inhibitors becomes more important. We are now tasked with putting extra effort into implementing these recommendations in our daily clinical practice and achieving good patient adherence with the prescribed therapy, in order to translate these excellent results from clinical trials to the real world.