Lipid metabolism disorders: clinical guidelines

Applies toadults2023 editionE78.0, E78.1, E78.2, E78.3…

Clinical Guidelines of the Russian Ministry of Health, adults. 2023 edition, ICD-10 codes: E78.0, E78.1, E78.2, E78.3….

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Brief for Practice

WhiteCoat Pro editorial summary of the clinical guideline text, 2023 edition. Each point links to the original section — consult it before prescribing.

Dyslipidemias are conditions involving altered blood lipid and lipoprotein concentrations, which can be hereditary or acquired. The guideline describes diagnostics, cardiovascular risk assessment, target LDL-C levels, and the sequence of lifestyle modification and lipid-lowering therapy.

Key points

Dyslipidemias are classified as primary, including familial genetic forms, and secondary; it is important to distinguish them before choosing treatment, as the management differs. → in the text
In adults older than 40 years, a lipid profile screening is performed and LDL-C is determined; HDL-C determination is recommended for all patients. In high or very high risk, non-HDL-C is additionally determined. → in the text
In asymptomatic individuals older than 40 years without CVD, diabetes mellitus, CKD, or familial hypercholesterolemia with LDL-C <4.9 mmol/L, risk is assessed using SCORE2. With established CVD, familial hypercholesterolemia, diabetes mellitus, stage 3–5 CKD, very high SCORE2 risk, or LDL-C >4.9 mmol/L, the patient is classified into the high or very high risk group. → in the text
Target LDL-C: <3.0 mmol/L at low risk, <2.6 mmol/L at moderate risk, <1.8 mmol/L at high risk, and <1.4 mmol/L at very high risk; in high and very high risk, a reduction of at least 50% from baseline is also required. → in the text
All patients with dyslipidemia are prescribed a statin at the dose required to achieve the target LDL-C. If the maximum tolerated dose is insufficient, ezetimibe is added, and if the target remains unachieved in very high-risk patients, alirocumab, evolocumab, or inclisiran is added. → in the text
In hypertriglyceridemia, the target TG level is <1.7 mmol/L. On statin therapy with TG of 1.7–2.3 mmol/L in high and very high-risk patients, omega-3 PUFAs up to 2 g twice daily are added; with TG >2.3 mmol/L, fenofibrate or omega-3 PUFAs are used, and with TG >5.0 mmol/L, fenofibrate and omega-3 PUFAs. → in the text
After initiating or changing the dose of lipid-lowering therapy, lipids are monitored in 8±4 weeks until the target is reached, then annually. ALT, AST, bilirubin, and CK are checked 4–6 weeks after therapy modification; once the target is reached, routine monitoring of these parameters is unnecessary in the absence of relevant symptoms. → in the text

Diagnostics

Take medical history: inquire about coronary artery disease, arterial hypertension, diabetes mellitus, peripheral artery disease, familial hypercholesterolemia, metabolic syndrome, obesity, and CKD; separately check for early CVD in first-degree relatives. → in the text
Evaluate symptoms and signs of atherosclerosis across different vascular beds: angina, dyspnea, and palpitations; cerebrovascular symptoms; intermittent claudication or resting leg pain. → in the text
Perform physical examination: inspect skin and eyes for xanthelasma, xanthomas, and corneal arcus, palpate major arteries, assess pulse, perform heart and vascular auscultation, and measure waist circumference. → in the text
Investigate venous blood lipid profile with calculation of LDL-C and non-HDL-C. In dyslipidemia, additionally determine glucose, creatinine, urea, bilirubin, ALT, AST, CK, and perform a complete blood count; in patients with hypertriglyceridemia, blood for lipids should be drawn fasting. → in the text
Assess cardiovascular risk using SCORE2 in eligible asymptomatic patients; in CVD, familial hypercholesterolemia, diabetes mellitus, stage 3–5 CKD, or LDL-C >4.9 mmol/L, the scale is not used, as the patient is already in the high or very high risk category. → in the text
Screen for subclinical atherosclerosis: perform duplex scanning of brachiocephalic arteries in all patients with dyslipidemia; the presence of plaques in carotid or femoral arteries or an Agatston calcium score >100 units may upgrade the risk category. → in the text
When familial hypercholesterolemia is suspected, use the DLCN criteria in adults; clinical suspicion is particularly high with total cholesterol ≥8 mmol/L or LDL-C ≥5 mmol/L untreated, early atherosclerotic CVD, xanthomas, or sudden cardiac death in a relative. → in the text

Treatment

The foundation of lifestyle modification is a diet rich in vegetables, fruits, whole grains, fiber, nuts, fish, and vegetable oils, while limiting sweets, sugary drinks, and red meat. To lower triglycerides, weight reduction, alcohol abstention in hypertriglyceridemia, physical exercise for at least 30 minutes daily, and limiting rapidly digestible carbohydrates are required. → in the text
All patients with dyslipidemia are prescribed a statin at a dose sufficient to achieve the target LDL-C. In case of intolerance to high-intensity therapy, the dose is reduced and tolerability is reassessed. → in the text
If the target is not met on the maximum tolerated statin dose, ezetimibe is added; rosuvastatin/ezetimibe and atorvastatin/ezetimibe fixed-dose combinations are registered. For intolerance to any statin dose, ezetimibe is used. → in the text
In very high risk with persistently elevated LDL-C despite statin plus ezetimibe, alirocumab, evolocumab, or inclisiran is added. → in the text
For TG of 1.7–2.3 mmol/L in high and very high-risk patients on statin therapy, omega-3 PUFAs up to 2 g twice daily are added. For TG >2.3 mmol/L, fenofibrate or omega-3 PUFAs are added; for TG >5.0 mmol/L, fenofibrate and omega-3 PUFAs are prescribed. → in the text
In acute coronary syndrome, high-dose statin is initiated or continued as early as possible regardless of baseline LDL-C. After 4–6 weeks, achievement of a 50% LDL-C reduction and a level <1.4 mmol/L is checked; if the target is not met, ezetimibe is added, followed by alirocumab or evolocumab. → in the text
In ischemic stroke or transient ischemic attack, most patients are prescribed a high-intensity statin: atorvastatin 40–80 mg/day or rosuvastatin 20–40 mg/day. In patients older than 75 years, moderate-intensity therapy is initiated: atorvastatin 10–20 mg/day, rosuvastatin 5–10 mg/day, or pitavastatin 4 mg; if the target is not reached after 4–12 weeks, ezetimibe is added. → in the text

When to refer and how to monitor

Plasmapheresis and plasmosorption are performed only in specialized hospital and clinic departments. → in the text
Extracorporeal removal of atherogenic lipoproteins is considered if the target LDL-C is not achieved after 6 months of combination therapy at maximum tolerated doses, as well as in the specified forms of familial hypercholesterolemia and high levels of LDL-C or Lp(a). → in the text
Planned and emergency hospitalization for dyslipidemia are not provided for in the guidelines. → in the text

Frequently asked questions

Who should be assessed using SCORE2?

Asymptomatic adults older than 40 years without CVD, diabetes mellitus, CKD, and familial hypercholesterolemia with LDL-C <4.9 mmol/L. In the presence of these conditions or LDL-C >4.9 mmol/L, the patient is assigned to the high or very high risk category without calculating SCORE2. → in the text

What target LDL-C levels should be used?

The target is <3.0 mmol/L at low risk, <2.6 mmol/L at moderate risk, <1.8 mmol/L at high risk, and <1.4 mmol/L at very high risk. In high and very high risk, a reduction of LDL-C by at least 50% from baseline is also required. → in the text

Is it necessary to have a fasting lipid profile?

This is optional for screening. In hypertriglyceridemia, evaluation of severe dyslipidemia, and subsequent follow-up, lipids are recommended to be determined fasting. → in the text

What to do if a statin does not lead to the target LDL-C or is poorly tolerated?

If the effect of the maximum tolerated statin dose is insufficient, ezetimibe is added. In case of intolerance to any dose, ezetimibe is used, and if the target is not reached, alirocumab, evolocumab, or inclisiran is added. → in the text

Status: Applied · approved by the Scientific and Practical Council of the Russian Ministry of Health
Database ID: 752, edition 1 (ID 752_1)
Publication date: February 14, 2023
Age category: adults
ICD-10 codes: E78.0 E78.1 E78.2 E78.3 E78.4
Specialties: Cardiology Endocrinology Internal Medicine Geriatrics Medical Rehabilitation
Developers: All-Russian Public Organization "Russian Society of Cardiology"
Russian Association of Endocrinologists
All-Russian Public Organization "Russian Scientific Medical Society of Internal Medicine Physicians"
National Association for Atherosclerosis Research (Autonomous Non-Profit Organization)
All-Russian Public Organization "Russian Association of Gerontologists and Geriatricians"
Eurasian Association of Therapists
Russian Society for Cardiosomatic Rehabilitation and Secondary Prevention (RosOKR)
Eurasian Association of Cardiology
Official text: Ministry of Health Guidelines — 752_1

List of Abbreviations

AH arterial hypertension

BP blood pressure

ALT alanine aminotransferase

ASB atherosclerotic plaque

AST aspartate aminotransferase

ASCVD atherosclerotic cardiovascular disease

ULN upper limit of normal

DLP dyslipidemia

HeFH heterozygous familial hypercholesterolemia

HoFH homozygous familial hypercholesterolemia

HTG hypertriglyceridemia

HC hypercholesterolemia

CI confidence interval

DLP dyslipidemia

ESC European Society of Cardiology

EAS European Society of Atherosclerosis

VITAL Essential Drugs

CHD coronary heart disease

MI myocardial infarction

BMI body mass index

CAC calcium score

CT computed tomography

CKD creatine phosphokinase

HDL high-density lipoproteins

LDL low-density lipoproteins

Lp(a) lipoprotein(a)

IDL intermediate-density lipoproteins

VLDL very low-density lipoproteins

siRNA small interfering ribonucleic acid

non-HDL non-high-density lipoproteins

omega-3 PUFA omega-3 triglycerides, including other esters and acids

ACS acute coronary syndrome

RR relative risk

TC total cholesterol

RNA ribonucleic acid

FH familial hypercholesterolemia

DM diabetes mellitus

eGFR estimated glomerular filtration rate

CVD cardiovascular disease

CVE cardiovascular events

TG triglycerides

TIA transient ischemic attack

US ultrasound

RF risk factors

CKD chronic kidney disease

CM chylomicrons

C cholesterol

TL target level

LDLR low-density lipoprotein receptor

APOB apolipoprotein B gene

DLCN Dutch Lipid Clinic Network

LDLR low-density lipoprotein receptor gene

PCSK9 proprotein convertase subtilisin/kexin type 9 (C10AX Other lipid-modifying agents)

SCORE Systemic Coronary Risk Evaluation

Terms and Definitions

Dyslipidemias (DLP) are conditions where blood lipid and lipoprotein concentrations fall outside the normal range.

Evidence-based medicine — the conscientious, explicit, and judicious use of current best evidence (clinical research results) in combination with individual clinical expertise, taking into account patient values and preferences in making decisions about the patient's health and care [1].

Disease is a condition arising from the impact of pathogenic factors, representing a disruption of bodily function, working capacity, and the ability to adapt to changing environmental and internal conditions, accompanied by alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms [2].

Outcome is any possible result arising from exposure to a causative factor, preventive or therapeutic intervention, or any established changes in health status resulting from an intervention [3].

Clinical trial is any investigation conducted with human subjects to identify or verify clinical and/or pharmacological effects of investigational products, and/or to identify adverse reactions to investigational products, and/or to study their absorption, distribution, metabolism, and excretion with the aim of assessing their safety and/or efficacy [4].

Conflict of interest — a situation in which a medical or pharmaceutical worker, in the exercise of their professional activities, has a personal interest, either directly or through a representative of a company, in obtaining material gain or other advantage that influences or may influence the proper performance of their professional duties due to a contradiction between the personal interest of the medical or pharmaceutical worker and the interests of the patient [2].

Medicinal products — pharmacological agents in the form of dosage forms used for the prevention, diagnosis, and treatment of disease, rehabilitation, and for the maintenance, prevention, or termination of pregnancy [5].

Medical intervention encompasses types of medical examinations and/or medical procedures performed by a medical worker or other personnel authorized to engage in medical activity, affecting a person's physical or mental state and aimed at prevention, diagnosis, treatment, rehabilitation, or research, as well as artificial termination of pregnancy [2].

Lifestyle modification measures aimed at normalizing weight, diet, and physical activity with the goal of reducing cardiovascular risk.

Patient — an individual who receives medical care or who applies for medical care regardless of the presence of a disease and their condition [2].

Elderly patients — patients aged 60 to 75 years.

Working group for the development/updating of clinical guidelines — a team of specialists working together and in coordination to develop/update clinical guidelines and bearing joint responsibility for the results of this work.

Syndrome — a stable set of a number of symptoms with a common pathogenesis [6].

Condition — changes in the body arising from the influence of pathogenic and/or physiological factors and requiring medical care [2].

Level of evidence — the degree of certainty that the observed effect of a medical intervention is true [7].

Level of confidence of the recommendations — the degree of certainty in the validity of the intervention's effect and that following the recommendations will bring more benefit than harm in a specific situation [7].

Chronic kidney disease — a supra-nosological concept uniting all patients with signs of renal damage and/or decreased function assessed by the glomerular filtration rate, persisting for 3 months or more.

Target level — the level of a particular laboratory, instrumental, or clinical indicator, varying for different groups of patients with a given disease, the achievement of which during treatment allows for the most favorable benefit-to-risk (adverse effects) ratio (reduction of cardiovascular risk).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Dyslipidemia (DLP) — conditions where blood lipid and lipoprotein concentrations fall outside the normal range, which can be caused by both acquired (secondary) and hereditary (primary) factors [8].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Primary dyslipidemias have a genetic nature and develop as a result of anomalies in genes that regulate the functions of receptors, enzymes, or transport proteins involved in lipid metabolism. In these cases, they manifest as familial (hereditary) lipid metabolism disorders and belong to primary monogenic dyslipidemias. FH is a hereditary autosomal dominant disease caused by mutations in genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), and the proprotein convertase subtilisin/kexin type 9 proenzyme (PCSK9), accompanied by a persistent increase in low-density lipoprotein cholesterol (LDL-C) levels and the early development of atherosclerosis. The disease manifests in two forms: a less severe heterozygous form and a more severe homozygous form [9]. However, in the vast majority of cases, they develop as primary polygenic dyslipidemias, i.e., they are the consequence of a combination of minor genetic influences with environmental factors: smoking, dietary disturbances, and a sedentary lifestyle. The most atherogenic dyslipidemias are isolated hypercholesterolemia (HCH) (phenotype IIa), represented by familial and polygenic HCH, and combined hyperlipidemia (various hyperlipidemia phenotypes in a family). Isolated hypertriglyceridemia (HTG) (phenotype IV or V) is less atherogenic. Fasting HTG can be associated with a number of external and internal factors. External factors contributing to the development of HTG and, accordingly, its high prevalence in the population include overeating with a predominance of fatty foods, simple carbohydrates with a high glycemic index (sugar, glucose), as well as excessive alcohol consumption and the long-term use of certain medications, primarily glucocorticoids and non-selective beta-blockers. Secondary HTG is significantly more common than primary HTG and can be caused primarily by insulin resistance and related conditions: type 2 diabetes mellitus, metabolic syndrome, and obesity. Metabolic factors contributing to the formation of HTG include low activity of lipolytic enzymes, in particular, peripheral lipoprotein lipase (LPL), which is determined either by the genetic characteristics of the enzyme or by an increase in the content of LPL inhibitors in lipoproteins, primarily apoCIII [10, 11]. Among the primary causes of elevated TG, hereditary mechanisms should be mentioned (overproduction of VLDL, TG hydrolysis defect, defect in the clearance of TG remnants in the liver) [12]. The main causes of secondary dyslipidemias are diabetes mellitus (DM), hypothyroidism, and chronic kidney disease (CKD).

Pathogenesis of atherosclerosis associated with DLP

Atherosclerosis manifests as thickening of the vascular wall and the formation of atherosclerotic plaques. This is a dynamic process characterized by both progression and regression of changes in the arterial wall. However, over time, atherosclerosis progresses, ultimately leading to the clinical manifestations of the disease. To date, a clear understanding of atherosclerosis has emerged as a multifactorial disease based on complex disorders in biochemical, immunological, and molecular-genetic processes. Today, two hypotheses of the development and establishment of atherosclerosis dominate: the "response-to-injury" hypothesis and the lipid-infiltration hypothesis. The "response-to-injury" hypothesis places integrity loss of the endothelium at the forefront as the initiating factor of the atherosclerotic process. Factors causing endothelial injury are quite diverse, but the most common are carbon monoxide entering the blood during active and "passive" smoking, elevated blood pressure, dyslipidemia, especially HCH caused either by familial predisposition or bad habits, primarily dietary errors. Modified (oxidized, desialylated) lipoproteins and a number of other both endogenous and exogenous factors can act as damaging agents. Monocyte and platelet adhesion occurs at the site of endothelial injury, accompanied by monocyte migration into the intima. Progressive thickening of the intima leads to the development of hypoxia inside the plaque and in adjacent areas of the vessel. Hypoxia is a possible cause of necrotic changes in the plaque core and enhanced vascularization of the plaque from the vasa vasorum system of the adventitia. These vessels in the plaque core are the source of microhemorrhages (apoplexy) within it, which in turn leads to an increase in its thrombogenic activity. As a result of the weakening of the muscular-elastic layer of the vessel in the coronary arteries, they remodel with dilation, and the internal diameter of the vessel lumen is maintained "normal" for some time, until the progressive growth of the plaque exceeds the compensatory capabilities of the medial layer of the artery and leads to progressive narrowing of its lumen. It is at this stage that plaques acquire the character of unstable ones and play a major role in the development of complications of atherosclerosis. In addition, there is a change in the phenotype of smooth muscle cells, which upon vascular wall injury transitions from a contractile to a secretory state with the release of pro-inflammatory cytokines and activation of adhesion molecules.

The lipid theory of atherosclerosis posits that the initiating event in the development of atherosclerosis is the infiltration of the intima and subendothelium by lipids and lipoproteins. As lipids accumulate in the core of the plaque, its size increases, causing the fibrous cap of the plaque to thin under the action of specific enzymes (elastases, matrix metalloproteinases) and, under certain conditions (increased blood pressure, significant physical exertion), rupture. The rupture is accompanied by the activation of the blood coagulation cascade and platelet aggregation with thrombus formation, blocking the vascular lumen. Clinically, depending on the localization, this process manifests as unstable angina, myocardial infarction (MI), or ischemic stroke.

1.3 Epidemiology of the Disease or Condition

The most relevant data on the prevalence of lipid metabolism disorders in the Russian Federation were obtained during the multicenter ESSE-RF study conducted in 13 regions of the RF involving 21,048 individuals [13]. The prevalence of hypercholesterolemia (total cholesterol (TC) level ≥5.0 mmol/L) averaged 58.4±0.34%. No significant differences in cholesterol levels were found between men and women. With age, the prevalence of hypercholesterolemia increases almost 2-fold: from 37.7±0.73% in the 25–34 age group to 74.5±0.54% among individuals aged 55 to 64 years (p <0.01). Regardless of gender, rural residents experience hypercholesterolemia more frequently than urban residents (63.2±0.82 and 57.4±0.38%, respectively; p <0.001). Atherogenic shifts in the lipid profile in the form of hypercholesterolemia are mainly due to elevated (≥3.0 mmol/L) LDL-C levels. A significantly higher prevalence of elevated LDL-C levels among rural residents compared to urban residents (62.4±0.60% vs. 59.2±0.38%; p<0.05) is primarily driven by higher values of this indicator among women (61.3±1.08% vs. 56.5±0.48%; p<0.05). An elevated triglyceride (TG) level was found in 30.2±0.52% of men in the total sample, which is significantly higher than in women (20.1±0.34%; p<0.0001). The prevalence of high TG levels is age-related, particularly characteristic of women: 8.8±0.59% in the younger age group (25–34 years) and 34.4±0.71% among women aged 55–64 years (p<0.0001). At the same time, the frequency of hypertriglyceridemia is significantly higher in men with a low socioeconomic status compared to men with a high socioeconomic status (30.9±0.66% vs. 23.8±3.41%; p<0.05). Among rural residents, the prevalence of hypertriglyceridemia is slightly, but significantly, higher than among urban residents (p<0.05 for all cases). A low HDL-C level (less than 1.0 mmol/L for men and 1.2 mmol/L for women) was found in 19.5% of cases.

Furthermore, the results of the ESSE-RF study showed that 23% of the population had a pronounced increase in TC levels >6.2 mmol/L, while a pronounced increase in LDL-C levels >4.2 mmol/L occurred in 20.6% [152].

Relationship between DLP and the risk of cardiovascular events

The largest prospective study was the MRFIT (Multiple Risk Factor Intervention Trial). In 361,662 examined men aged 35–57 years, major risk factors for coronary artery disease (CAD), including serum lipids, were determined. For the first time, a threshold level of TC (5.2 mmol/L) was established, starting from which a significant increase in CAD mortality is registered. The absolute risk of CAD at the highest population-average TC values was 20 times higher than at the lowest levels of 4.7 mmol/L [14].

A meta-analysis of 4 prospective epidemiological studies (Framingham, MRFIT, Coronary Primary Prevention Trial, Lipid Research Clinic) revealed an association between a 1 mg/dL increase in HDL-C and a 2–3% decrease in CAD risk, regardless of other risk factors, including LDL-C [15].

A meta-analysis of 17 prospective population-based studies showed that a 1 mmol/L increase in serum TGs is associated with a 32% increase in new CAD events in men and 76% in women [15]. According to the largest epidemiological study (Framingham Study), a TG level greater than 1.7 mmol/L implies a significantly higher risk of cardiovascular events (CVEs) [15]. When reaching the target level (TL) of LDL-C <1.8 mmol/L, the risk of CVEs in patients with HDL-C <1.0 mmol/L is 64% higher than in patients with HDL-C ≥1.4 mmol/L [16]. Elevated TG levels and low HDL-C synergistically increase the risk of cardiovascular events in patients who have already achieved LDL-C target levels (<2.1 mmol/L) [17]. It has been shown that in patients with TGs greater than 2.3 mmol/L and concurrently HDL-C less than 0.8 mmol/L, the risk of CVEs increases 10-fold compared to patients with normal TG and HDL-C values [17, 18].

1.4 Features of Coding the Disease or Condition

E78.0 Pure hypercholesterolemia

Familial hypercholesterolemia

Fredrickson hyperlipoproteinemia, type IIa

Hyperbetalipoproteinemia

Hyperlipidemia, group A

Low-density lipoprotein hyperlipoproteinemia

E78.1 Pure hyperglyceridemia

Endogenous hyperglyceridemia

Fredrickson hyperlipoproteinemia, type IV

Hyperlipidemia, group B

Hyper-pre-beta-lipoproteinemia

Very-low-density-lipoprotein type hyperlipoproteinemia

E78.2 Mixed hyperlipidemia

Broad- or floating-beta-lipoproteinemia

Fredrickson hyperlipoproteinemia, type IIb or III

Hyperbetalipoproteinemia with pre-betalipoproteinemia

Hypercholesterolemia with endogenous hyperglyceridemia

Hyperlipidemia, group C

Tuberoeruptive xanthoma

Tuberous xanthoma

E78.3 Hyperchylomicronemia

Fredrickson hyperlipoproteinemia, type I or V

Hyperlipidemia, group D

Mixed hyperglyceridemia

E78.4 Other hyperlipidemias

Familial combined hyperlipidemia

1.5 Classification of the disease or condition

DLP is classified depending on which specific lipids and lipoproteins are abnormal. It is critically important to differentiate primary and secondary dyslipidemias, as treatment strategies differ fundamentally in these cases. Currently, the WHO has adopted the Fredrickson classification (1976), which distinguishes several phenotypes (Table 1, Appendix A3). It should be emphasized that this classification does not establish a diagnosis, but merely identifies the DLP phenotype, regardless of whether it is acquired or inherited. The classification also allows determining the risk of developing atherosclerosis depending on the DLP type. Thus, types IIa, IIb, and III are atherogenic, while types I, IV, and V are "relatively" atherogenic. The classification of inherited (familial) dyslipidemias is presented in Table 2, Appendix A3.

Principles of Diagnostic Formulation

Examples of Diagnostic Formulation

Hyperlipidemia (Hyperlipoproteinemia - HLP) type IIa. Hyperlipoproteinemia(a).

Mixed hyperlipidemia.

1.6 Clinical presentation of the disease or condition

The clinical manifestations of the disease result from the progression of the atherosclerotic process caused by DLP. The symptom and syndrome complex varies widely depending on the predominantly affected vascular bed. The main complication of coronary artery atherosclerosis is CAD, which clinically manifests as angina pectoris and MI, often leading to chronic heart failure. Lesions of major cerebral arteries manifest as symptoms of chronic cerebral ischemia, followed by the development of atherosclerotic encephalopathy and/or stroke. Atherosclerosis of the lower extremity arteries presents clinically with intermittent claudication. Without appropriate treatment, the disease progresses and may result in lower extremity gangrene.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

The diagnosis of DLP based on lipid parameters is established according to the cut-off values specified in Table 2, Appendix A3.

The current diagnostic algorithm consists of the following key steps:

identification of major risk factors (RF) (Table 3, Appendix A3)
identification of clinical symptoms of atherosclerosis (interview and physical examination data);
determination of lipid profile (venous blood) with calculation of LDL-C, non-HDL-C;
cardiovascular risk assessment using the SCORE2 scale;
exclusion/verification of subclinical and clinically significant atherosclerosis (instrumental diagnostic methods).

2.1 Complaints and Anamnesis

Many patients with elevated serum lipid levels may be completely asymptomatic. Symptoms depend on the localization of the atherosclerotic process—specifically, the vascular bed predominantly involved. Involvement of the coronary bed leads to left-sided chest pain or retrosternal pain upon exertion or at rest, cardiac arrhythmias (complaints of irregular, markedly rapid heartbeat, or sensations of "skipping beats" or "heart palpitations"), shortness of breath, and lower extremity edema. When the atherosclerotic process is localized primarily in the cerebrovascular bed, complaints of headache, subjective dizziness, decreased memory, attention, and work capacity, as well as "tinnitus" and a "noise in the head," predominate. The development of obliterating atherosclerosis of the lower extremity arteries leads to intermittent claudication, and in severe cases, intense lower extremity pain at rest, worsening at night while the patient is in a horizontal position (pain intensity may decrease after the patient sits or stands up).

At the initial stage of examination, a medical history is taken to determine whether the patient has coronary artery disease (CAD), hypertension (HTN), diabetes mellitus (DM), peripheral artery disease, familial hypercholesterolemia (FH), metabolic syndrome, obesity, or chronic kidney disease (CKD). When taking a family history, special attention should be paid to early manifestations of cardiovascular disease (CVD) in first-degree relatives.

2.2 Physical Examination

To identify clinical signs of lipid metabolism disorders and associated conditions/diseases, all patients are recommended to undergo a physical examination including: inspection (corneal arcus in individuals under 45 years of age, xanthelasma, xanthomas); palpation of major main arteries of the upper and lower extremities and carotid arteries; assessment of pulse characteristics; auscultation of the heart and major vessels; and waist circumference measurement [153-154].

ESC/EAS: no (CGR C, LOC 5)

Comments. Xanthomas are focal lesions of varying color (from normal to yellowish-brown, orange, or pink); they are most frequently localized in the area of tendons, joints, palms, soles, buttocks, and thighs. Histologically, xanthomas represent accumulations of xanthoma (foam) cells, which are macrophages loaded with lipids. Xanthoma cells typically have a single nucleus, although multinucleated foreign body-type cells (Touton giant cells) can also be found; histiocytes and lymphoid cells may be present among them. Fibrosis is usually absent. In older lesions, fibroblasts and newly formed collagen fibers surrounding groups of foam cells predominate. Over time, fibrous tissue replaces the foam cells. There are four clinical varieties of xanthomas: flat, multiple nodular (eruptive xanthomas), tuberous, and tendinous. Flat xanthomas (xanthoma planes) are more commonly observed in elderly individuals, appearing as yellowish-orange flat or slightly raised bands in the creases of the palms and fingers. Eruptive xanthomas (syn.: xanthoma papulosum multiplex, multiple nodular xanthomas) are characterized by multiple flat or hemispherical papules 2 to 6 mm in diameter, yellowish or yellowish-orange in color with a pinkish-bluish halo at the base. The rash elements may be scattered over the entire skin surface, but most frequently appear on the extensor surfaces of the extremities, in the area of joints, back, and buttocks. Tuberous xanthomas (syn.: xanthoma tuberosum, tuberous xanthoma, nodular xanthoma) are found in patients with familial hypercholesterolemia on the extensor surfaces of the knee and elbow joints, and on the buttocks. The lesions are symmetrical—painless, dense nodules ranging from 1.5 to 3.5 cm in diameter, yellowish in color with a brownish or bluish tint. Tendinous xanthomas (syn.: xanthoma tendineum, tendon xanthoma) are dense, slowly enlarging, tumor-like yellowish formations located in the region of the Achilles tendons and finger extensor tendons.

Xanthelasmas are flat, yellow lesions on the skin of the eyelids. Their size ranges from a few millimeters to 3-5 cm or more.

Corneal arcus has diagnostic significance in individuals younger than 40-45 years.

2.3 Laboratory Diagnostics

Screening is recommended for all individuals older than 40 years, including biochemical blood analysis of lipid metabolism disorders (lipid profile) for the purpose of cardiovascular risk stratification using the SCORE2 scale [50, 241]. ESC/EAS I C (CGR C, LOC 5)

Patients with dyslipidemia are recommended to undergo laboratory testing including blood glucose, creatinine, urea, total bilirubin, ALT, AST, CK, and a complete blood count (CBC) [154].

ESC/EAS I C (CGR C, LOC 5)

Determination of blood HDL-C levels is recommended for all patients to provide additional risk assessment within the SCORE2 system [50, 241].

ESC/EAS I C (CGR C, LOC 5)

In all patients older than 40 years, determining the LDL-C level is recommended as the primary indicator for assessing cardiovascular risk [19, 20, 21].

ESC/EAS I C (CGR C, LOC 4)

In patients at high/very high risk, determining non-HDL-C in addition to LDL-C is recommended [155, 156].

ESC/EAS IIa C (CGR B, LOC 2)

In patients with hypertriglyceridemia (HTG), diabetes mellitus, obesity, or metabolic syndrome, laboratory evaluation of non-HDL-C is recommended for a more accurate cardiovascular risk assessment [20, 21, 22].

ESC/EAS I C (CGR A, LOC 1)

In cases where the interpretation of cardiovascular risk is difficult or questionable, particularly in patients with HTG, diabetes mellitus, obesity, or metabolic syndrome, laboratory assessment of atherogenic apolipoprotein B100 is recommended [20].

ESC/EAS I C (CGR C, LOC 5)

Measuring blood Lp(a) levels is recommended at least once in a lifetime for every adult. A Lp(a) value >180 mg/dL is equivalent in risk to heterozygous familial hypercholesterolemia [20].

ESC/EAS IIa C (CGR C, LOC 5)

Measuring blood Lp(a) levels is recommended in patients with a positive family history. An Lp(a) level >50 mg/dL is associated with an increased cardiovascular risk [20].

ESC/EAS IIa C (CGR C, LOC 5)

Comments. Principles of determining serum lipid levels: traditionally, blood samples for lipid analysis are drawn fasting, although recent studies indicate that plasma lipid concentration fluctuations are minimal regardless of food intake [23, 24]. However, blood collection is recommended to be performed fasting in individuals with hypertriglyceridemia.

The reference method for determining LDL-C levels is multi-stage:

1) ultracentrifugation at a density of 1.006 g/mL for 18 hours to remove triglyceride-rich lipoproteins (chylomicrons and VLDL);

2) isolation of the bottom fraction (density 1.006 g/mL) and precipitation of apoB-containing lipoproteins within it using a mixture of heparin and MnCl2 to isolate HDL;

3) determination of cholesterol concentration in the bottom fraction and supernatant using a reference cholesterol method (modified Abell-Kendall method);

4) calculation of LDL-C as the difference between cholesterol values in the bottom fraction and HDL-C. Preparative isolation by ultracentrifugation in a salt solution of a specific density allows for the isolation of LDL and the determination of their composition.

The duration and labor-intensive nature of ultracentrifugation led to the development of methods more accessible for laboratory practice. The most common method for determining LDL-C levels in clinical laboratories is calculation. In this case, it is necessary to determine total cholesterol, triglycerides, and HDL-C in the blood, as well as the HDL-C concentration in the supernatant after precipitation of apoB-containing lipoproteins (VLDL and LDL), and calculate the LDL-C concentration using the Friedewald formula:

LDL-C (in mg/dL) = total cholesterol – HDL-C – TG/5

LDL-C (in mmol/L) = total cholesterol – HDL-C – TG/2.2

This formula is based on two assumptions: 1) the majority of plasma triglycerides are located in VLDL; 2) the triglyceride/cholesterol mass ratio in VLDL is 5:1.

The Friedewald formula yields LDL-C values comparable to those obtained by the reference method when TG < 200 mg/dL, whereas calculations may be subject to error at concentrations of 200–400 mg/dL. Using this formula at TG concentrations > 400 mg/dL, in the presence of chylomicrons (CM), or type III DLP leads to an overestimation of VLDL-C and an underestimation of LDL-C, failing to produce comparable results. Currently, direct methods for LDL isolation have been developed that are suitable for clinical diagnostic laboratories [5]. Lipid profiling for screening to assess risk does not strictly require a fasting state. However, determining lipid levels in the non-fasting state may underestimate risk in patients with diabetes mellitus, as one study demonstrated that diabetes patients had LDL-C levels 0.6 mmol/L lower postprandially [8]. Subsequently, fasting lipid profiling is recommended for the detailed characterization and further evaluation of severe DLPs, as well as for patient monitoring.

In patients with clinical manifestations of HeFH (CVD in men younger than 55 years and women younger than 60 years, xanthomatosis, hypercholesterolemia [LDL-C > 5 mmol/L in adults, > 4 mmol/L in children]), the Dutch Lipid Clinic Network (DLCN) diagnostic criteria (Table 3/A3) are recommended to establish a clinical diagnosis of HeFH [50, 153].

ESC/EAS I C (RRR C, LVE 5)

2.4 Instrumental Diagnostics

Non-invasive imaging methods can detect the presence, evaluate the severity, and assess the clinical consequences of atherosclerotic vascular damage. Coronary computed tomography (CT) angiography and duplex scanning of the extracranial brachiocephalic arteries are informative for detecting atherosclerotic arterial lesions. Detection of coronary artery calcification using non-contrast CT provides a good estimate of atherosclerotic burden and is closely associated with CVD events. CT angiography has a high sensitivity of 95–99% and specificity of 64–83% for diagnosing CAD [25]. The coronary artery calcium (CAC) score, determined by CT according to Agatston [26], can be used for coronary atherosclerosis screening. This test provides additional risk stratification [27], is less costly, and does not require intravenous contrast administration (Table 4, Appendix A3). The use of the CAC score improves both discrimination and reclassification of risk categories [28, 29]. Assessment of atherosclerotic plaques in the carotid or femoral arteries using ultrasound is a predictor of cardiovascular events comparable to the CAC score [30, 31], whereas measurement of carotid intima-media thickness is inferior to the CAC score and carotid plaque presence [32, 33] and is not used as a risk stratifier.

In asymptomatic individuals at moderate risk, a CAC score > 100 Agatston units and the presence of atherosclerotic plaques in the carotid or femoral arteries on duplex scanning may reclassify them into a higher risk category. However, the CAC score is low and has low specificity in patients younger than 45 years with severe HeFH, including homozygous HeFH (HoFH).

Duplex scanning of the brachiocephalic arteries is recommended for all patients with dyslipidemia [34].

ESC/EAS IIaB (RRR A, LVE 1)

In patients with identified atherosclerotic plaques in the carotid or femoral arteries on duplex scanning, reclassifying the risk category from low and moderate to high is recommended for the effective management of risk-driving factors [34, 35, 50].

ESC/EAS IIaB (RRR A, LVE 1)

In patients with coronary atherosclerosis and a CAC score > 100 units on cardiac CT, reclassifying the risk category from low and moderate to high is recommended for the effective correction of risk factors [36, 33].

ESC/EAS IIaB (BRP B, LoE 2)

2.5 Other Procedures

No other diagnostic tests are stipulated for the diagnosis of DLP; expanding the diagnostic workup is permitted at the physician's discretion based on the clinical situation and the patient's condition.

Cardiovascular Risk Assessment

All asymptomatic adults older than 40 years without CVD, diabetes mellitus, CKD, or HeFH, and with an LDL-C < 4.9 mmol/L, should undergo screening for total risk assessment using the SCORE2 scale [50, 241, 254].

ESC/EAS IC (RRR C, LVE 5)

Patients with previously established CVD, HeFH, diabetes mellitus, stage 3–5 CKD, very high risk according to the SCORE2 scale, or an LDL-C level > 4.9 mmol/L should be classified into the high or very high-risk category for the effective management of risk factors [8, 50].

ESC/EAS IC (RRR C, LVE 5)

Comments. In Russia the SCORE2 scale for high cardiovascular risk countries should be used to calculate the 10-year percentage risk of fatal and non-fatal cardiovascular events (Appendix G2) [254]. To assess risk using the SCORE2 scale, select the box corresponding to the patient's sex, age, and smoking status. Within the selected box, locate the cell that best matches the patient's systolic blood pressure and non-HDL-C levels. Risk assessment using the SCORE2 scale is not recommended in individuals with confirmed CVD, diabetes mellitus, CKD, a single severe risk factor (e.g., severe hypertension), or HeFH. Such patients are automatically categorized into the high and very high cardiovascular risk groups and require intensive risk factor correction. The presence of stenosis greater than 50% in major arteries of any vascular bed according to any instrumental imaging method, even in the absence of clinical symptoms, also reclassifies the patient into the very high-risk category.

Cardiovascular risk categories harmonized with the SCORE2 scale are presented in Appendix G2.

Special attention should be paid to identifying the extreme-risk category within the very-high-risk category. Extreme risk should include: the presence of 2 or more cardiovascular events within 2 years, despite optimal lipid-lowering therapy and/or achieving an LDL-C level <1.4 mmol/L.

Atherosclerotic cardiovascular disease (ASCVD) is defined as all manifestations of coronary artery disease (CAD), ischemic stroke or transient ischemic attack, and lower extremity artery atherosclerosis.

Patients with HeFH and ASCVD are recommended to be classified into the very-high-risk category for the purpose of effective management of determining risk factors [37].

ESC/EAS IC (Reliability of Evidence Level C, Reliability of Evidence Grade 2)

Patients with HeFH without ASCVD are recommended to be classified into the high-risk category for the purpose of effective management of determining risk factors [37].

ESC/EAS IC (Reliability of Evidence Level C, Reliability of Evidence Grade 2)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

It is recommended to decide on the treatment strategy depending on the baseline level of cardiovascular risk. The strategy of lifestyle modification and pharmacotherapy is summarized in Table 1, Appendix B4.

3.1 Target LDL-C Levels

In very-high-risk patients, it is recommended to achieve a target LDL-C level of <1.4 mmol/L and a reduction of at least 50% from baseline at 8±4 weeks of therapy for both primary and secondary prevention of cardiovascular events [39, 42, 50].

ESC/EAS IC (Reliability of Evidence Level C, Reliability of Evidence Grade 5)

In patients with confirmed ASCVD who have experienced a recurrent vascular event within 2 years (in any vascular bed) despite taking the maximally tolerated dose of a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, a target LDL-C level of <1.0 mmol/L is recommended [40, 41, 50].

ESC/EAS IIbB (Reliability of Evidence Level C, Reliability of Evidence Grade 5)

In high-risk patients, a target LDL-C level of <1.8 mmol/L and a reduction of at least 50% from baseline are recommended [39, 42, 50].

ESC/EAS IA (Reliability of Evidence Level C, Reliability of Evidence Grade 5)

In moderate-risk patients, a target LDL-C level of <2.6 mmol/L is recommended for primary prevention of CVD [39, 50].

ESC/EAS IIaA (Reliability of Evidence Level C, Reliability of Evidence Grade 5)

In low-risk patients, a target LDL-C level of <3.0 mmol/L is recommended [42, 50].

ESC/EAS IIbA (Reliability of Evidence Level C, Reliability of Evidence Grade 5)

Comments. Statins - C10AA HMG-CoA reductase inhibitors.

3.2 Non-pharmacological Treatment of Dyslipidemia

For CVD prevention, a diet [44] high in fruits, vegetables, whole grains and fiber, nuts, fish, poultry and low-fat dairy products, with limited consumption of sweets, sugary beverages and red meat, has proven its benefit. It is recommended to use fats from vegetable oils. Such a diet is an effective means of primary and secondary prevention of atherosclerosis [45]. In particular, the multicenter randomized PREDIMED trial, conducted in Spain in high-risk individuals without CVD, demonstrated a 28-31% reduction in the incidence of major CV events (MI, stroke, or cardiovascular death) with daily consumption of olive oil or nuts [46]. Observational studies support recommendations that fish consumption at least twice a week and low-dose omega-3 polyunsaturated fatty acids as a dietary supplement may reduce the risk of cardiovascular death and stroke in primary prevention without affecting plasma lipoprotein metabolism [47]. Evaluation of dietary supplements and functional foods must include not only evidence of beneficial effects on the lipid profile and atherosclerosis, but also good tolerability. An important factor is the manufacturing standard for such products, ensuring standardization and quality. Dietary supplements affecting the lipid profile include red yeast rice (monacolin), whose action, like that of statins, is related to inhibition of HMG-CoA reductase. In a large study conducted in China in patients with coronary artery disease, monacolin reduced the incidence of CV events by 45% [48]. A hypocholesterolemic effect (a 15-25% reduction in LDL-C) is observed with daily intake of monacolin K at a dose of 10 mg [49]. Given its proven clinical efficacy and safety, monacolin K may be used in low- and moderate-risk individuals with moderately elevated LDL-C who have no indications for statin therapy. The effects of lifestyle modification on lipid levels and dietary recommendations for improving the overall lipoprotein profile are presented in Appendix B (“Patient Information”) and Table S2, Appendix B4.

Non-pharmacological methods for reducing TG include reducing excess body weight [BMI 20–25 kg/m2, waist circumference <94 cm (men) and <80 cm (women)], reducing alcohol consumption (patients with hypertriglyceridemia should completely abstain from alcohol), increasing regular physical activity (exercise for at least 30 minutes every day), and restricting the intake of readily absorbable carbohydrates [50].

3.3 Pharmacotherapy of Dyslipidemia

3.3.1 General Principles of Pharmacotherapy

Comments: when planning lipid-lowering therapy, it is recommended to follow this algorithm:

- assess the total risk of developing CVD;

- discuss CVD prevention specifics with the patient;

- determine the LDL-C target level in accordance with the risk category;

- calculate the percentage reduction in LDL-C levels required to achieve the target value;

- select a statin from the group that can provide this level of LDL-C reduction;

-the efficacy and tolerability of statin therapy are variable, therefore titration of the drug dose may be required;

- if statin monotherapy fails to achieve the target, combination therapy should be considered, including a statin with ezetimibe, preferably as a single pill or capsule (rosuvastatin+ezetimibe and atorvastatin+ezetimibe are registered) (in individuals at very high risk, lipid-lowering therapy may be initiated directly with a statin-ezetimibe combination).

- the physician must convince the patient of the need for continuous (lifelong) lipid-lowering therapy.

3.3.2 Main Drug Classes for Dyslipidemia Treatment

Agents used to correct dyslipidemia include statins, ezetimibe, fibrates, and other lipid-lowering drugs (ezetimibe, omega-3 triglycerides, including other esters and acids (omega-3 PUFAs), alirocumab**, evolocumab**, inclisiran**).

Statins are among the most thoroughly studied classes of drugs in cardiovascular disease prevention. The results of numerous clinical trials indicate that statins significantly reduce cardiovascular morbidity and mortality in both primary and secondary prevention across all age groups, in both men and women. In clinical trials, statins slowed the progression and even induced regression of atherosclerotic plaques. The largest meta-analysis of 19 trials involving various statins showed a 14% reduction in all-cause mortality, a 27% reduction in cardiovascular events, a 27% reduction in non-fatal and fatal coronary events, and a 22% reduction in stroke per 1.0 mmol/L reduction in LDL-C[51]. The relative risk reduction in primary prevention is comparable to that in secondary prevention. Available data suggest that the clinical effect largely depends not on the specific drug, but on the magnitude of LDL-C reduction. In the Russian Federation, the available agents (in descending order of lipid-lowering effect) are rosuvastatin in doses of 5, 10, 15, 20, and 40 mg; atorvastatin** at 10, 20, 30, 40, and 80 mg/day; pitavastatin at 1, 2, and 4 mg; and simvastatin** at 10, 20, and 40 mg. Maximum LDL-C reductions of 50–55% can be achieved with high doses of rosuvastatin and atorvastatin**. Statins differ in their absorption, bioavailability, plasma protein binding, elimination, and solubility characteristics. Drug absorption varies from 20 to 98%. Most statins undergo significant hepatic metabolism via cytochrome P450 isoenzymes, with the exception of pravastatin, rosuvastatin, and pitavastatin. Drugs with potential interactions with statins are listed in Table P3, Appendix G4[52, 53, 54, 55, 56, 57, 58, 59, 60]. It is important to note that a meta-analysis published in 2014 of 8 major randomized clinical trials with statins (n=38,153, 6,286 CV events in 5,387 individuals) demonstrated a lower incidence of cardiovascular events at LDL-C levels <1.3 mmol/L (50 mg/dL). When compared with participants having LDL-C levels >4.5 mmol/L (175 mg/dL), a progressive reduction in the relative risk of cardiovascular complications was observed according to LDL-C levels: 2.0–2.6 mmol/L (75–100 mg/dL), 1.3–2.0 mmol/L (50–75 mg/dL), and <1.3 mmol/L (50 mg/dL), showing 0.56 (95% CI 0.46–0.67), 0.51 (0.42–0.62), and 0.44 (0.35–0.55), respectively[61]. Currently, to achieve LDL-C targets and reduce the risk of cardiovascular events, the use of four statins is justified: rosuvastatin, atorvastatin**, pitavastatin, and simvastatin.

Fibrates. Their mechanism of action involves the activation of peroxisome proliferator-activated receptors alpha (PPARα) located in the liver, muscles, adipose tissue, heart, kidneys, macrophages, and platelets. The primary role of PPARα receptors is the regulation of lipid and lipoprotein metabolism, inflammation, and endothelial function. Activated PPARα receptors bind to specific DNA sequences, stimulating or inhibiting key genes encoding metabolic processes. It should be noted that among the fibrate class, only fenofibrate** may be used in combination with statins [44]. Fenofibrate** increases the synthesis of apoA1 and apoA2, enhances lipoprotein lipase (LPL) activity, and reduces the synthesis of apoCIII and apoB100, as well as the concentration of small dense LDL particles by 50%. This leads to a 10–30% increase in HDL-C levels, accelerates the conversion of chylomicrons into their remnants, reduces LDL-C levels by 25%, and decreases the synthesis of triglycerides and VLDL. Triglyceride levels can be reduced by up to 50% [62, 63]. In addition to its effects on lipid metabolism, fenofibrate** reduces uric acid levels by an average of 25%, fibrinogen by 21%, and C-reactive protein by 34% [62, 63].

Cholesterol absorption inhibitors. Ezetimibe inhibits the intestinal absorption of cholesterol derived from both the diet and bile, without affecting the absorption of other fat-soluble nutrients. By inhibiting cholesterol absorption at the brush border of the small intestine (through interaction with the NPC1L1 protein), ezetimibe reduces the amount of cholesterol delivered to the liver. In response to this decreased cholesterol delivery, the liver upregulates LDL receptors on its surface, leading to increased clearance of LDL-C from the blood. In clinical trials, ezetimibe monotherapy resulted in a 15–22% reduction in LDL-C levels. The combination of ezetimibe with statins provided an additional 15–20% reduction in LDL-C levels. In the SHARP (Study of Heart and Renal Protection) trial in patients with CKD, the incidence of cardiovascular disease in the active treatment group receiving ezetimibe combined with simvastatin** was reduced by 17% compared to the placebo group [64]. The IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) is the largest and longest-running randomized clinical trial of ezetimibe, involving 18,144 patients hospitalized for acute coronary syndrome [38]. At baseline, patients were not receiving ezetimibe or the maximum dose of any statin, but were required to have relatively low LDL-C levels (1.3–3.2 mmol/L or 50–125 mg/dL). The follow-up period reached up to 7 years. At 1 year of follow-up, the mean LDL-C level in the ezetimibe group was 1.4 mmol/L (54 mg/dL), which was 0.4 mmol/L (14 mg/dL) lower than in the simvastatin group. The combination therapy group demonstrated a significant 6.4% reduction in the composite endpoint of cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary revascularization, and stroke (hazard ratio [HR] = 0.936; 95% confidence interval [CI] = 0.89–0.99, p = 0.016), with an absolute risk reduction of 2.0% [38]. Thus, ezetimibe can be used as a second-line agent in combination with statins when statin monotherapy fails to achieve the target level even at maximum doses, as well as in cases of statin intolerance or contraindications.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors Alirocumab** and evolocumab** (ATX classification: C10AX Other lipid-modifying agents) are inhibitors of (monoclonal antibodies against) PCSK9, a protein that regulates the expression of hepatocyte LDL-C receptors[65]. Elevated PCSK9 levels/function decrease LDL receptor expression and increase plasma LDL-C concentrations, whereas reduced PCSK9 levels/function lead to a decrease in plasma LDL-C[66]. Alirocumab** at doses of 75 and 150 mg and evolocumab** at a dose of 140 mg subcutaneously every 2 weeks have been shown in clinical trials to reduce LDL-C levels by 60% and the risk of cardiovascular events by 15% in patients with ASCVD when combined with moderate- to high-intensity statin therapy. The FOURIER (Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) trial included 27,564 patients with atherosclerotic disease in various vascular beds: 22,040 patients (81%) had a history of prior myocardial infarction (of whom 5,500 had an event 4 weeks to 1 year prior to enrollment), 5,330 (19%) had a history of non-hemorrhagic stroke, and 3,640 (13%) had peripheral artery disease. Patients were receiving adequate lipid-lowering therapy: 69.2% received high-intensity statins and 30.4% moderate-intensity statins, with 5.1% receiving ezetimibe in addition to a statin. Patients randomized to the active treatment group received subcutaneous evolocumab** at a dose of 140 mg every 2 weeks or 420 mg monthly, whereas control patients received subcutaneous placebo throughout the trial[40]. The median follow-up in the trial was 2.2 years. The potent lipid-lowering efficacy of evolocumab** was confirmed: LDL-C levels decreased by 59% from 2.40 mmol/L to 0.78 mmol/L. For the first time, a positive effect of evolocumab** therapy on cardiovascular outcomes was demonstrated: the primary endpoint event rate was 15% lower in the evolocumab** group (HR = 0.85, 95% CI = 0.79–0.92, p < 0.001), and the secondary endpoint rate was 20% lower (HR = 0.80, 95% CI = 0.73–0.88, p < 0.001) compared to the placebo group. Shortly thereafter, results of an additional pre-specified analysis were presented, aimed at determining the relationship between the thresholds and magnitude of LDL-C reduction and the frequency of MACE[67]. This analysis included 25,982 individuals (94% of the total randomized cohort, 13,013 on evolocumab**, 12,969 on placebo). Patients were categorized based on LDL-C levels achieved at week 4 into 5 subgroups: < 0.5 mmol/L (n = 2,669), 0.5–1.3 mmol/L (n = 8,003), 1.4–1.8 mmol/L (n = 3,444), 1.9–2.6 mmol/L (n = 7,471), and > 2.6 mmol/L (n = 4,395). It was observed that lowering LDL-C down to 0.2 mmol/L (7.7 mg/dL) reduced the frequency of cardiovascular events without increasing the risk of adverse reactions. However, a statistically significant reduction in primary and secondary endpoint events was shown only in the two lowest LDL-C subgroups (i.e., less than 0.5 and 1.3 mmol/L): by 24% and 15% [HR = 0.76 (0.64–0.90) and 0.85 (0.76–0.96)] for the primary endpoint, and by 31% and 25% [0.69 (0.56–0.85)] and [0.75 (0.64–0.86)] for the secondary endpoint, respectively. Based on these data, the authors noted the rationale for revising LDL-C targets in current guidelines for individuals at very high cardiovascular risk. The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, involving 18,924 patients with a prior ACS 1–12 months earlier, demonstrated that alirocumab** statistically significantly reduced the risk of major adverse cardiovascular events. These events occurred in 903 patients (9.5%) in the alirocumab** group and 1,052 patients (11.1%) in the placebo group, representing a 15% relative risk reduction (HR 0.85; 95% CI, 0.78–0.93; p < 0.001). Furthermore, alirocumab** reduced all-cause mortality risk by 15%. Patients with a higher baseline LDL-C level (≥ 100 mg/dL / 2.6 mmol/L) treated with alirocumab** experienced a more pronounced reduction in the risk of cardiovascular events by 24% (HR 0.76; 95% CI, 0.65–0.87) and all-cause mortality by 29% (HR 0.71; 95% CI, 0.56–0.90) compared to placebo[41].

Inclisiran** is a chemically modified double-stranded small interfering ribonucleic acid (siRNA). In hepatocytes, inclisiran** utilizes the RNA interference mechanism to target PCSK9 messenger RNA and trigger its degradation, thereby increasing LDL receptor recycling and surface expression, followed by enhanced LDL uptake and reduced blood LDL-C levels [157–160]. Inclisiran** is administered subcutaneously 3 times in the first year, and biannually thereafter.

The ORION (A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease) clinical trial program (9, 10, 11) confirmed the long-term lipid-lowering efficacy of inclisiran** in the following patient populations: HeFH, ASCVD, and cardiovascular risk equivalents such as type 2 diabetes, HeFH, or a 10-year CVD risk > 20% by the Framingham risk score or equivalent. It was established that administration of inclisiran leads to a 50–58% reduction in LDL-C levels in these patient categories, both in the short and long term [161, 162]. The safety profile of inclisiran** is comparable to placebo [161, 162], with no reports of specific treatment-emergent serious adverse events [50]. A meta-analysis of three randomized clinical trials demonstrated a 24% reduction in the incidence of major adverse cardiovascular events (hazard ratio = 0.76; 95% confidence interval, 0.61–0.92) [252].

Omega-3 PUFAs are currently considered the primary drugs for lowering triglyceride (TG) levels. The recently completed REDUCE-IT (Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia) trial involving 8,179 patients demonstrated the effect of omega-3 PUFAs on hard endpoints [68]. Inclusion criteria were: a history of CVD (~70% of patients) or type 2 diabetes + >1 risk factor, TG levels ≥2.3 mmol/L and <5.6 mmol/L, and achieved target LDL-C levels >1.03 mmol/L and ≤2.6 mmol/L. The primary endpoint was the time from randomization to the first occurrence of: cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, revascularization, or unstable angina. A 25% relative risk reduction in major adverse cardiovascular events (p <0.001) was demonstrated in patients receiving omega-3 PUFAs (icosapent ethyl 4 g/day) compared to placebo. Thus, omega-3 triglycerides, including other esters and acids, can be used to treat hypertriglyceridemia at a dose of 2–4 g/day.

A comparison of the efficacy of statins, fibrates, and ezetimibe is presented in Table P4, Appendix G4.

Summary data on the efficacy, doses, and adverse effects of lipid-lowering drugs are given in Table P8, Appendix G4.

3.3.3 Pharmacotherapy of Dyslipidemia to Achieve Target LDL-C Level

All patients with dyslipidemia are recommended statin therapy at doses necessary to achieve the target LDL-C level [39, 69, 70].

Comments: statin doses for intensive and moderate LDL-C reduction are shown in Table P4, Appendix B3. In case of intolerance to high-intensity statin therapy, a dose reduction should be considered, followed by re-evaluation of tolerability.

ESC/EAS I A (LoE B, GoR 1)

Patients who do not reach the target LDL-C level on maximally tolerated statin doses should be considered for combination therapy, including a statin with ezetimibe, preferably in a single pill or capsule (rosuvastatin+ezetimibe and atorvastatin+ezetimibe are approved) [38].

ESC/EAS I B (LoE A, GoR 2)

In very high-risk patients who fail to achieve the target LDL-C level on maximally tolerated statin doses combined with ezetimibe, it is recommended to add alirocumab** (ESC/EAS I A), evolocumab** (ESC/EAS I A), or inclisiran** (ESC/EAS not available) for secondary prevention of CVD [40, 41, 67, 243].

(LoE A, GoR 1)

In case of a significant increase in LDL-C levels in very high-risk patients (above 4.0 mmol/L), it is recommended to consider initial combination therapy with a statin and ezetimibe, preferably in a single pill or capsule (rosuvastatin+ezetimibe and atorvastatin+ezetimibe are approved) [244].

ESC/EAS not available (LoE A, GoR 1)

In case of a significant increase in LDL-C levels in extreme or very high-risk patients (above 5.0 mmol/L), it is recommended to consider initial therapy with a statin at the maximally tolerated dose + ezetimibe + a PCSK9 inhibitor: alirocumab** (ESC/EAS I A), evolocumab** (ESC/EAS I A), or inclisiran** (ESC/EAS not available) [243, 245, 246, 255].

(LoE A, GoR 1)

In very high-risk patients without FH, who do not achieve the target LDL-C level on maximally tolerated statin doses with or without ezetimibe, it is recommended to add alirocumab**, evolocumab**, or inclisiran** [40, 41, 67, 243] for primary prevention of CVD.

ESC/EAS IIbC (BRP A, LoE 2)

Patients with intolerance to any dose of a statin are recommended ezetimibe [71, 72].

ESC/EAS IIaC (BRP A, LoE 2)

In patients with intolerance to any statin dose who, while on ezetimibe therapy, have not achieved the target LDL-C level, it is recommended to add alirocumab**, evolocumab**, or inclisiran** to therapy [71, 72, 73, 243].

ESC/EAS IIbC (BRP A, LoE 2)

Comments: the degree of LDL-C reduction with various lipid-lowering regimens is specified in Table A3.11. The algorithm of pharmacotherapy to achieve target LDL-C levels is given in Appendix B2.

3.3.4 Pharmacotherapy of Hypertriglyceridemia

Patients in any risk category are recommended a target TG level <1.7 mmol/L [16, 156, 163].

ESC/EAS IIaC (BRP B, LoE 2)

Comments: Important causes of residual risk are high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Even when target low-density lipoprotein cholesterol (LDL-C) levels are achieved, patients retain a residual cardiovascular risk (CVR). According to the largest epidemiological study (Framingham Study), a TG level <1.7 mmol/L (< 150 mg/dL) indicates a lower risk of cardiovascular events, while higher levels indicate the need to investigate causes for the elevated TG. Elevated TG and low HDL-C levels synergistically increase cardiovascular risk in patients who have already achieved their LDL-C target levels [16, 156, 163].

For high- and very-high-risk patients who achieve a TG level of 1.7–2.3 mmol/L on statin therapy, it is recommended to add an omega-3 polyunsaturated fatty acid (PUFA) preparation at a dose of up to 2 g twice daily [68].

ESC/EAS IIaB (BRP B, LoE 2)

For patients with a TG level > 2.3 mmol/L on statin therapy, it is recommended to add fenofibrate** (preferably as a single-pill combination, rosuvastatin+fenofibrate is registered) or an omega-3 PUFA preparation at a dose of up to 2 g twice daily [68, 77, 78, 79].

Comments: In the ECLIPSE-REAL study, by the end of 12 weeks of therapy with a combination of fenofibrate** and a statin, total cholesterol, TG, LDL-C, and very-low-density lipoprotein cholesterol (VLDL-C) were significantly reduced, with the reduction being greater and statistically significant in the group receiving the combination of rosuvastatin and fenofibrate** [164–166].

ESC/EAS IIaB (Level of Consensus, LoC C; Level of Evidence, LoE 5)

For patients with a TG level > 5.0 mmol/L, it is recommended to prescribe fenofibrate** and an omega-3 PUFA preparation at a dose of up to 2 g twice daily [242].

ESC/EAS IIaB (BRP B, LoE 2)

The algorithm for choosing drug therapy for hypertriglyceridemia is presented in Appendix B1.

3.4 Apheresis Treatment of Dyslipidemia

Refers to extracorporeal methods for the removal of atherogenic lipoproteins such as plasmapheresis and plasmasorption. They are prescribed to patients who fail to achieve target LDL-C levels after 6 months of combined lipid-lowering therapy at maximum tolerated doses. In addition, plasmapheresis and plasmasorption are performed according to the following indications: homozygous familial hypercholesterolemia (FH) and LDL-C >7.8 mmol/L, or heterozygous FH and LDL-C >7.8 mmol/L + 1 additional cardiovascular risk factor, or heterozygous FH and LDL-C > 5.0 mmol/L + 2 risk factors, or Lp(a) level >50 mg/dL; heterozygous FH and LDL-C >4.1 mmol/L in individuals at very high risk; FH when lipid-lowering therapy is discontinued due to pregnancy in the presence of a high risk of cardiovascular complications [8].

Plasmapheresis and plasmasorption are performed weekly or once every two weeks. During the procedure, up to 80% of the LDL-C level is removed from the patient's blood plasma, while the concentration of LDL-C in the patient's blood plasma decreases by 70–80%, depending on the volume of processed plasma. Currently, there are a number of methods for LDL-C plasmapheresis and plasmasorption: cascade membrane filtration, heparin-induced extracorporeal LDL precipitation (HELP), affinity plasma and hemisorption of lipoproteins, and LDL immunoadsorption.

Plasmapheresis and plasmasorption are performed only in specialized hospital and clinic departments.

Indications for LDL and Lp(a) plasmapheresis and plasmasorption are given in Table P3 of Appendix B.

3.5 Treatment of Dyslipidemia in Specific Clinical Situations

3.5.1 Familial Hypercholesterolemia

Definition. Epidemiology

Familial hypercholesterolemia (FH) is a genetically determined monogenic lipid metabolism disorder with a predominantly autosomal dominant inheritance pattern, accompanied by a significant increase in blood LDL-C levels and, consequently, the premature development and progressive course of atherosclerosis, typically at a young age [9, 220]. Two forms are distinguished: heterozygous (HeFH) and homozygous (HoFH). Among monogenic dyslipidemias, HeFH ranks first in prevalence, averaging 1 in 200–250 individuals [9, 220]. According to the results of an epidemiological study conducted in several regions of the Russian Federation, the prevalence of HeFH ranges from 1:108 to 1:173 individuals [221]. HoFH is much rarer, with a prevalence of 1 case per 160,000–300,000 of the European population [222].

Etiology and pathogenesis

Genetic basis of the disease

The development of FH is caused by defects in genes encoding proteins involved in lipoprotein metabolism, which disrupts the cellular uptake of LDL particles and increases blood LDL-C levels [223, 224].

The most frequent genetic cause of FH is a mutation in the low-density lipoprotein receptor gene (LDLR), which is located primarily on the surface of hepatocytes and plays a key role in the binding and clearance of circulating LDL particles from the bloodstream [225, 226]. To date, more than 1,600 LDLR mutations are known that can impair receptor function and cause the development of FH. Mutations in the LDLR gene account for 85 to 90% of FH cases [227].

The second most frequent cause is a mutation in the apolipoprotein B gene (APOB), which encodes the apoB-100 protein that is part of LDL particles and is responsible for LDL binding to the receptor. As a result of changes in the gene, half of the LDL particles are unable to bind to the LDL receptor [228]. Mutations in the APOB gene account for 5 to 10% of HeFH cases [229]. It has been shown that carriers of LDLR gene mutations have higher levels of TC and LDL-C and more pronounced manifestations of arterial atherosclerosis than carriers of APOB gene mutations [230].

The third gene whose mutations can lead to HeFH development is the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease involved in the degradation of the LDL receptor [231, 232, 233]. Mutations in the PCSK9 gene account for less than 5% of HeFH cases [227]. LDL-C levels in carriers of PCSK9 missense mutations vary widely from relatively moderate to very high [234].

Diagnostic criteria of the disease

The potential probability of HeFH should be assessed in the following cases [235, 236]:

TC ≥8 mmol/L and/or LDL-C ≥5 mmol/L without therapy for adults, and TC >6.7 mmol/L or LDL-C ≥3.5 mmol/L in children,
Early onset of atherosclerotic CVD (in men <55 years; in women <60 years),
Cutaneous / tendon xanthomas,
A case of sudden cardiac death in a family member.

Due to genetic predisposition, rapid progression of atherosclerosis in patients with HeFH leads to an early onset of atherosclerotic CVD, most commonly CHD. The prolonged asymptomatic course of the disease necessitates relying primarily on laboratory parameters and family history when identifying new cases of HeFH for timely initiation of therapy within the primary prevention setting.

For clinical diagnosis of the disease, it is advisable to use specialized criteria developed for adults and children with HeFH and for patients with HoFH. It is extremely crucial to conduct additional examinations to exclude secondary dyslipidemias and their contribution to elevated LDL-C values in individuals with suspected HeFH.

Diagnostic criteria for HeFH

Ø For the diagnosis of HeFH in adult patients aged 18 years and older, it is recommended to use the Dutch Lipid Clinic Network (DLCN) diagnostic criteria (Appendix G1) [50, 235].

ESC/EAS I C (LoE C, GoR 5)

The diagnosis is established based on the sum of points obtained in each category. Within a category, points are not summed; only a single feature yielding the maximum number of points within each category is taken into account.
According to the total score, HeFH can be definite, probable, or possible. Furthermore, the diagnosis of HeFH is established only in the presence of a definite or probable form.
To determine the 95th percentile of the LDL-C level depending on sex and age, the values given in Table P6/A3 (Population parameters of LDL-C depending on sex and age, according to the ESSE-RF study) should be used [152].

Ø For the diagnosis of HeFH in adult patients aged 18 years and older only in cases where LDL-C determination is not available, as well as in children , it is recommended to use the Simon Broome Registry diagnostic criteria (Table 7/A3) [235, 237].

ESC/EAS I C (LoE C, GoR 5)

Ø The diagnosis of HeFH is established if the patient meets the criteria for a definite or probable diagnosis of FH.

Diagnostic criteria for HoFH

Ø For the diagnosis of HoFH in both adults and children , it is recommended to use the criteria proposed by the European Atherosclerosis Society experts (Table 8/A3) [222].

ESC/EAS I C (LoE A, GoR 3)

According to these criteria, the diagnosis of HoFH is established in children and adults in the presence of one of two conditions.

Thus, the diagnosis of FH is possible without performing molecular genetic testing based on clinical criteria; however, identifying a specific mutation significantly facilitates the diagnosis of FH and subsequent cascade screening, and also allows for more accurate cardiovascular risk stratification [238].

Performing molecular genetic testing to verify FH is indicated for individuals with a score of 6 or more according to the DLCN clinical criteria or when diagnosing HeFH according to the Simon Broome criteria [239, 240].

ESC/EAS I C (LoE A, GoR 2)

Cascade screening

Cascade screening is recommended for first-, second-, and, if possible, third-degree relatives of a patient with an established diagnosis of FH. If a pathogenic or likely pathogenic nucleotide sequence variant in the LDLR, APOB, PCSK9 genes is detected in the proband, genetic cascade screening should be performed in the proband's relatives to determine the presence or absence of this genetic variant. If the presence of pathogenic or likely pathogenic variants is confirmed in a relative, the diagnosis of FH is recommended even if the LDL-C level is lower than the diagnostic values according to clinical criteria [235, 237].

ESC/EAS I C (LoE C, GoR 5)

Treatment

LDL-C target levels

In very high-risk patients with FH, it is recommended to achieve an LDL-C target level of <1.4 mmol/L and a reduction of at least 50% from baseline for primary prevention of CVD events [37, 43, 50]

ESC/EAS IIa C (LoE C, GoR 5)

In very high-risk patients with FH and ASCVD, it is recommended to achieve an LDL-C target level of <1.4 mmol/L and a reduction of at least 50% from baseline for secondary prevention of CVD events [37, 43]

ESC/EAS I C (LoE C, GoR 5)

In high-risk patients with FH, it is recommended to achieve an LDL-C target level of <1.8 mmol/L and a reduction of at least 50% from baseline [39, 42, 50].

ESC/EAS IA (Reliability of Evidence Level C, Reliability of Evidence Grade 5)

Drug therapy

Lipid-lowering therapy is recommended to be initiated immediately after diagnosis establishment.

All patients with FH are recommended to receive statin therapy at doses necessary to achieve the LDL-C target level [39, 69, 70].

ESC/EAS I A (LoE B, GoR 1)

Comments: statin doses for intensive and moderate LDL-C reduction are given in Table 4, Appendix B3. In case of intolerance to high-intensity statin therapy, a dose reduction should be considered followed by re-evaluation of tolerability.

Patients who have not reached the LDL-C target level on maximally tolerated statin doses, are recommended combination therapy with a statin and ezetimibe, preferably in a single pill (rosuvastatin+ezetimibe and atorvastatin+ezetimibe are registered) [38].

ESC/EAS I B (LoE A, GoR 2)

In very high-risk patients who have not achieved the LDL-C target level on maximally tolerated statin doses in combination with ezetimibe, it is recommended to add alirocumab** (ESC/EAS I A), inclisiran** (ESC/EAS not specified), or evolocumab** (ESC/EAS I A) for secondary prevention of CVD [40, 41, 67, 243].

(LoE A, GoR 2)

Patients with intolerance to any statin dose are recommended to take ezetimibe to achieve the LDL-C target level [71, 72].

ESC/EAS IIaC (BRP A, LoE 2)

Patients with intolerance to any statin dose who have not achieved the LDL-C target level while taking ezetimibe are recommended to add alirocumab** (ESC/EAS IIbC), inclisiran** (ESC/EAS not specified), or evolocumab** (ESC/EAS IIbC) to therapy [71, 72, 73, 243]

ESC/EAS IIbC (LoE A, GoR 1)

In very high-risk patients with FH who have not achieved the LDL-C target level on maximally tolerated statin doses in combination with ezetimibe, it is recommended to add alirocumab** (ESC/EAS I C), inclisiran** (ESC/EAS not specified), or evolocumab** (ESC/EAS I C) to therapy [9, 74, 75, 243, 247]

(LoE A, GoR 1)

3.5.2 Dyslipidemia and Diabetes Mellitus

In patients with type 2 diabetes mellitus and very high-risk category, an LDL-C reduction of ≥50% and <1.4 mmol/L is recommended [39, 80, 81].

ESC/EAS I A (LoE B, GoR 1)

In patients with type 2 diabetes mellitus and high-risk category, an LDL-C reduction of ≥50% and <1.8 mmol/L is recommended [50, 80, 167].

ESC/EAS I A (LoE C, GoR 5)

Patients with type 1 diabetes mellitus and high/very high risk are recommended statin therapy [50, 82].

ESC/EAS I A (LoE C, GoR 5)

Patients with diabetes mellitus who have started HMG-CoA reductase inhibitor therapy but have not reached the LDL-C target level are recommended therapy intensification [50].

ESC/EAS IIa C (LoE C, GoR 5)

In patients with type 2 diabetes mellitus receiving statin therapy but with a TG level of ≥2.3 mmol/L, it is recommended to add fenofibrate** to statin therapy, preferably in a single pill (rosuvastatin+fenofibrate is registered) [79, 167].

ESC/EAS IIa B (LoE B, GoR 2)

Comments: long-term follow-up of diabetic patients receiving combination therapy with fenofibrate** and a statin has proven the validity of this strategy regarding long-term prognosis—a reduction in overall and cardiovascular mortality was revealed. Across all three time points, a significant reduction in major adverse cardiovascular events by 34–36% was obtained [248].

For patients with DM in whom the target LDL-C level is not achieved after intensification of statin therapy, adding ezetimibe to the statin is recommended [38, 83], including a statin combined with ezetimibe in a single tablet or capsule (rosuvastatin+ezetimibe and atorvastatin+ezetimibe are registered).

ESC/EAS IA (GGR A, LE 2)

It is recommended to prescribe other lipid-lowering agents, such as PCSK9 inhibitors — alirocumab**, evolocumab**, or inclisiran** — to all patients with type 2 DM at high and very high cardiovascular risk with insufficient LDL-C reduction on maximally tolerated doses of statins and ezetimibe, in order to achieve LDL-C target levels and reduce the risk of cardiovascular events [50, 249].

ESC/EAS I A (LoE C, GoR 5)

Female patients with DM before menopause who are planning pregnancy or are not using contraceptives are not recommended to receive statin therapy [8, 50].

ESC/EAS IIIC (GGR C, LE 5)

For patients with type 1 DM and type 2 DM aged ≤30 years with target organ damage and/or LDL-C >2.5 mmol/L, statin therapy is recommended [8, 50, 81].

ESC/EAS IIbC (GGR C, LE 5)

Comments. According to the Russian Clinical Practice Guidelines for the Treatment of Diabetes Mellitus 2019 (9th revision) and the 2019 ESC Guidelines for the management of dyslipidaemias, therapy for ASCVD combined with type 2 DM should be initiated with sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. In patients with type 2 DM and cardiovascular disease who are at very high and high cardiovascular risk, empagliflozin** is recommended as glucose-lowering therapy to reduce the risk of new cardiovascular events, or dapagliflozin** to reduce the risk of hospitalization for heart failure [87].

To manage patients with CVD for the purpose of reducing cardiovascular risk, the following are recommended:

Sodium-glucose cotransporter 2 inhibitors: empagliflozin**, dapagliflozin**. Glucagon-like peptide-1 receptor agonists (GLP-1 RA): liraglutide, dulaglutide, semaglutide.
Biguanides: metformin** (as a second-line drug).

Sodium-glucose cotransporter 2 inhibitors

Following the EMPA-REG OUTCOME trial, empagliflozin(**) demonstrated a 14% reduction in the incidence of the primary composite endpoint (p=0.038), while the results for individual components of the composite endpoint varied: all-cause mortality decreased by 32% (p<0.001), and cardiovascular mortality by 38% (p<0.0001) [84].

GLP-1 receptor agonists. In 2016, the results of the LEADER trial on the efficacy and safety of liraglutide were published. This multicenter, double-blind, placebo-controlled trial was conducted across 410 centers in 32 countries and included 9,340 patients, of whom 4,668 were randomized to the liraglutide group and 4,672 to the placebo group. The incidence of cardiovascular death was lower in the liraglutide group (4.7%) than in the placebo group (6.0%, HR 0.78, CI 0.66–0.93, p=0.007), and all-cause mortality was 8.2% and 9.6%, respectively (HR 0.85, CI 0.74–0.97, p=0.02). A 13% reduction in the risk of achieving the primary composite 3-point endpoint was demonstrated, along with a 22% reduction in cardiovascular death, a 20% reduction in the composite endpoint (coronary revascularization, unstable angina, hospitalization for heart failure), a 15% reduction in all-cause mortality risk, and a 22% increase in the time to onset of a microvascular event (nephropathy) [85]. The effect of semaglutide therapy on cardiovascular outcomes was evaluated in the SUSTAIN-6 trial. A total of 3,297 patients with type 2 DM and high cardiovascular risk were randomized to semaglutide (0.5 or 1 mg once weekly) or placebo in addition to standard antidiabetic and cardiovascular therapy. Of the enrolled patients, 83% had established cardiovascular disease and/or stage III–V CKD. The follow-up duration was 104 weeks. Semaglutide treatment was associated with a 26% reduction in the risk of the 3-point composite endpoint and a 38% reduction in strokes; however, the drug did not reduce all-cause or cardiovascular mortality, non-fatal myocardial infarction, or hospitalization for heart failure [86].

To reduce the number of cardiovascular events and improve the prognosis of patients with type 2 DM, priority should be given to drugs with proven cardiovascular benefits. Given the available evidence of the favorable effects of empagliflozin** and liraglutide on cardiovascular events, these agents should be considered, along with metformin**, as first-line therapy for patients with type 2 DM at high and very high risk. In the presence of heart failure, preference is given to empagliflozinu**.

In patients with type 2 DM and CVD at very high and high cardiovascular risk, empagliflozin** or dapagliflozin** are recommended as glucose-lowering therapy to reduce the risk of new cardiovascular events [87].

ESC/EAS IA (GGR A, LE 1)

In patients with type 2 DM and CVD, empagliflozin** is recommended as glucose-lowering therapy to reduce the risk of death [88].

ESC/EAS IB (GGR A, LE 1)

In patients with type 2 DM and CVD at very high and high cardiovascular risk, liraglutide is recommended as glucose-lowering therapy to reduce the risk of both new cardiovascular events and death [85].

ESC/EAS IB (GGR A, LE 2)

In patients with type 2 DM without CVD, metformin** is recommended to reduce cardiovascular risk [89].

ESC/EAS IIaC (GGR A, LE 2)

3.5.3 Dyslipidemia and Chronic Kidney Disease

In the early stages of CKD, triglyceride levels are elevated, and HDL-C levels are reduced. CKD is characterized by elevated Lp(a) levels. Patients with stage 3–5 CKD are at high or very high cardiovascular risk [90, 91].

In dialysis-independent patients with stage 3–5 CKD, the use of a statin or a statin/ezetimibe combination is recommended [92, 93, 94, 95].

ESC/EAS I A (LoE B, GoR 1)

In patients with stage 5 CKD and atherosclerotic CVD who are already receiving a statin, ezetimibe, or a statin/ezetimibe combination upon initiation of dialysis, it is recommended to continue the baseline lipid-lowering therapy [92, 93, 96, 97, 98].

ESC/EAS IIaC IA (GGR B, LE 1)

For patients with stage 1–4 CKD and triglyceride levels >1.7 mmol/L, prescribing omega-3 polyunsaturated fatty acids should be considered to reduce triglyceride levels [168–170].

ESC/EAS IIaB (GGR A, LE 2)

In patients with dialysis-dependent CKD without atherosclerotic CVD, initiating statin therapy is not recommended [99, 100].

ESC/EAS IIIA (GGR A, LE 2)

3.5.4 Dyslipidemia and Acute Coronary Syndrome / Percutaneous Coronary Interventions

In all patients with acute coronary syndrome (ACS) in the absence of contraindications or documented intolerance, high-intensity statin therapy should be initiated or continued as early as possible, regardless of baseline LDL-C levels [101, 102, 103].

ESC/EAS IA (GGR A, LE 2)

All patients should be evaluated 4–6 weeks after ACS for achievement of LDL-C target levels (a 50% reduction from baseline and <1.4 mmol/L), safety of statin therapy, and dosage adjustment if necessary [8, 50, 101, 102, 171].

ESC/EAS IIaC (GGR A, LE 1)

Patients who fail to achieve LDL-C target levels 4–6 weeks after ACS while on maximally tolerated statin doses are recommended a combination of statin and ezetimibe [38], including a statin with ezetimibe in a single tablet or capsule (rosuvastatin+ezetimibe and atorvastatin+ezetimibe are registered).

ESC/EAS IA (GGR A, LE 2)

In patients after ACS who do not reach LDL-C target levels after 4–6 weeks on maximally tolerated doses of a statin with or without ezetimibe, adding alirocumab** or evolocumab** is recommended [40, 41, 250–252].

ESC/EAS I B (LoE A, GoR 2)

Patients with contraindications to statin therapy or confirmed statin intolerance are recommended ezetimibe therapy [71, 72].

ESC/EAS IIaC (GGR A, LE 2)

In patients with ACS who present with LDL-C levels above the target despite therapy with maximally tolerated doses of a statin and ezetimibe, early initiation (during hospitalization for the coronary event) of alirocumab** or evolocumab** is recommended [104, 105].

ESC/EAS IIaC (GGR A, LE 2)

Comment: if LDL-C levels remain significantly elevated (>2.5 mmol/L) despite therapy with maximally tolerated statin doses, PCSK9 inhibitors may be considered without prior use of ezetimibe.

3.5.5 Dyslipidemia in the Elderly

In elderly individuals with ASCVD, statin therapy is recommended in the same manner as in younger patients [106].

ESC/EAS IA (GGR A, LE 1)

In elderly individuals at high and very high risk, statin therapy is recommended for primary prevention [106].

ESC/EAS IA (GGR A, LE 1)

In patients over 75 years of age at high and very high risk, statin therapy is recommended for primary prevention [106].

ESC/EAS IIbB (GGR A, LE 1)

In elderly patients with a potential risk of drug-drug interactions, it is recommended to prescribe a low-dose statin followed by titration until the target LDL-C level is achieved [107, 108, 109]. If a lower target LDL-C level needs to be achieved in very high- and extreme-risk patients, combination therapy with low-dose statin and ezetimibe should be considered [50].

ESC/EAS IC (Reliability of Evidence Level C, Reliability of Evidence Grade 5)

3.5.6 Dyslipidemia in Women, during Pregnancy and Lactation

Lipid-lowering therapy is not recommended when planning pregnancy, during pregnancy, and during breastfeeding. In female patients with severe HeFH, the use of bile acid sequestrants (non-absorbable) and/or plasmapheresis, plasmasorption may be considered [50].

ESC/EAS not available (LoE C, LoR 5)

In high-risk women outside of pregnancy and breastfeeding, statins are recommended for the primary prevention of CHD [39, 42].

ESC/EAS not available (LoE C, LoR 1)

For secondary prevention outside of pregnancy and breastfeeding, women are recommended to receive statins according to the same indications and with the same LDL-C target levels as men [39, 42].

ESC/EAS not available (LoE C, LoR 1)

Comments: the use of modern low-dose combined oral hormonal contraceptives in women of reproductive age does not increase the risk of acute coronary events [110]. They can be used in women after lipid profile evaluation and with normal cholesterol levels. In the presence of hypercholesterolemia (LDL-C levels above 4 mmol/L) and/or multiple cardiovascular risk factors and/or a high risk of thromboembolic complications, alternative oral hormonal contraceptives should be considered [111]. Estrogen replacement therapy, despite its positive effect on lipid profile parameters, has not demonstrated the ability to reduce cardiovascular risk and cannot be recommended for cardiovascular prevention in women [112].

The use of lipid-lowering drugs during pregnancy planning, pregnancy, and lactation is contraindicated. In female patients with severe HeFH during pregnancy/lactation, plasmapheresis and plasmasorption should be used.

Women of reproductive age:

- must use adequate methods of contraception during treatment;

- women with HeFH must receive preconception counseling and instructions on discontinuing lipid-lowering drugs no later than 4 weeks before stopping contraception and must not take these drugs until breastfeeding is completed;

- in case of an unplanned pregnancy, a woman with HeFH must immediately stop taking any lipid-lowering drugs and urgently consult her attending physician;

- due to the results of several pilot clinical studies on the negative impact of statins on male fertility, a patient with HeFH can be advised to abstain from taking statins during the planned conception period.

3.5.7 Dyslipidemia and Cerebrovascular Disease

Patients with a history of ischemic stroke are recommended intensive lipid-lowering therapy to achieve a target LDL-C level of less than 1.4 mmol/L [38, 50, 113, 114, 203, 204, 205].

ESC/EAS I A (LoE B, GoR 1)

Comment: additional benefits from lowering LDL-C levels below 1.8 mmol/L were demonstrated in the TST (Treat Stroke to Target) trial: in patients with a prior ischemic stroke, this treatment strategy reduced the risk of recurrent cardiovascular events by 22%. The results of the IMPROVE-IT trial and two meta-analyses showed an additional reduction in the risk of cardiovascular events with LDL-C reduction <1.4%, supporting the principle "the lower the LDL-C, the lower the risk of CV events".

Most patients with ischemic stroke or TIA are recommended high-intensity statin therapy at maximally tolerated doses to achieve the target LDL-C level [76, 204, 207].

ESC/EAS I A (LoE B, LoR 1)

Comment: high-intensity statin therapy refers to the administration of atorvastatin** at 40–80 mg/day or rosuvastatin at 20–40 mg/day. If triglyceride levels rise above the target value (2.3 mmol/L), statin therapy is also the first-line treatment.

Patients older than 75 years with a history of ischemic stroke or TIA are recommended to start moderate-intensity statin therapy [207, 208, 209].

ESC/EAS I A (LoE A, LoR 1)

Comment: moderate-intensity statin therapy refers to the administration of atorvastatin** 10–20 mg/day, rosuvastatin 5–10 mg/day, pitavastatin 4 mg.

Patients older than 75 years with ischemic stroke or TIA who were previously receiving high-intensity statin therapy are recommended to continue it without changing the intensity regimen [210, 211].

ESC/EAS not available (LoE C, LoR 4)

Patients with ischemic stroke or TIA who have not reached LDL-C target values on therapy with maximally tolerated statin doses for 4–12 weeks are recommended to add ezetimibe to their therapy [203, 212].

ESC/EAS I A (LoE B, LoR 4)

Patients with ischemic stroke or TIA and statin intolerance are recommended to receive ezetimibe to achieve the target LDL-C value [72, 73].

ESC/EAS I B (LoE C, LoR 5)

Comment: statin intolerance is defined as the development of adverse effects following discontinuation and rechallenge of therapy, including with a different statin and/or at a reduced dose.

Patients with ischemic stroke or TIA are recommended to add alirocumab**, inclisiran**, or evolocumab** to ongoing statin and ezetimibe therapy to achieve the target LDL-C value [40, 206, 250-252].

ESC/EAS I A (LoE A, LoR 1)

Patients with ischemic stroke and TIA are recommended an evaluation of the efficacy, safety, and patient adherence to ongoing lipid-including lifestyle modifications lowering therapy [213, 214].

ESC/EAS not available (LoE C, LoR 4)

Comment: it is advisable to evaluate laboratory parameters (fasting lipid profile, ALT, AST) 4–12 weeks after initiating statin therapy or increasing the dose. After achieving target LDL-C and triglyceride levels (target triglyceride level is less than 2.3 mmol/L), annual laboratory monitoring is recommended (in the absence of adherence issues or other specific reasons for more frequent monitoring). Routine monitoring of liver enzymes during statin treatment is not recommended unless symptoms indicative of liver pathology are present.

3.5.8 Dyslipidemia and Valvular Heart Disease

Patients with aortic stenosis without concomitant coronary heart disease are not recommended to initiate lipid-lowering therapy to slow the progression of aortic stenosis in the absence of other indications for such treatment [115, 116, 117, 118].

ESC/EAS IIIA (LoE A, LoR 2)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

All patients with lipid metabolism disorders are recommended to have an individual rehabilitation plan developed, including recommendations for achieving LDL-C targets, improving treatment adherence, diet, physical activity, and weight control [108].

ESC/EAS not available (LoE B, LoR 2)

To reduce the risk of cardiovascular events, all patients with dyslipidemia are recommended at least 3.5–7 hours of moderate physical activity per week or 30–60 minutes most days of the week [119, 120, 121].

ESC/EAS not available (LoE A, LoR 1)

5. Prevention and Dispensary Observation

Smoking

Smoking cessation in any form is recommended [173]

ESC/EAS I A (LoE B, LoR 2)

Smokers are recommended nicotine replacement therapy or varenicline [174, 175]

ESC/EAS IIa A (LoE A, LoR 1)

Smoking cessation is recommended regardless of weight gain, as weight gain does not diminish the cardiovascular benefits of smoking cessation [176].

ESC/EAS I B (LoE B, LoR 3)

Comments: although heat-not-burn cigarettes contain fewer toxic substances than conventional cigarettes, they contain tobacco and therefore their use is not recommended. The long-term impact of electronic cigarettes on the cardiovascular and respiratory systems requires further research [177].

Physical activity

Adults of any age are recommended to aim for at least 150–300 minutes of moderate-intensity aerobic physical activity per week, or 75–150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination thereof, to reduce all-cause mortality, cardiovascular morbidity, and mortality [178]

ESC/EAS I A (LoE C, LoR 5)

Adults who cannot perform 150 minutes of moderate-intensity physical activity per week are recommended to be as physically active as their abilities and health condition allow [179]

ESC/EAS I A (LoE B, LoR 2)

Nutrition

To reduce cardiovascular disease risk, the use of the Mediterranean diet and its analogs [46], replacement of saturated fats with unsaturated fats [180], and salt restriction [181] are recommended.

ESC/EAS I A (LoE B, LoR 1)

It is recommended to consume more fiber-rich plant foods, including whole grains, fruits, vegetables, legumes, and nuts [182], fish, preferably oily varieties, at least once a week, and to limit processed meat [183]. It is recommended to limit the intake of simple carbohydrates, specifically sugar-sweetened beverages, to a maximum of 10% of total energy intake [184].

ESC/EAS I B (LoE C, GoR 5)

It is recommended to limit alcohol consumption to 100 g (pure alcohol) per week [185].

ESC/EAS I B (LoE B, GoR 2)

Obesity

Weight loss is recommended for overweight and obese individuals to reduce blood pressure, dyslipidemia, and the risk of type 2 diabetes, thereby improving the cardiovascular risk profile [186].

ESC/EAS I A (LoE A, GoR 1)

Bariatric surgery should be considered in cases of morbid obesity when non-pharmacological measures fail [187].

ESC/EAS IIa B (LoE A, GoR 1)

Diabetes mellitus

To screen for diabetes mellitus in individuals with or without ASCVD, it is recommended to evaluate HbA1c (which can be drawn non-fasting) or fasting blood glucose levels [188].

ESC/EAS IIa A (LoE C, GoR 5)

The recommended HbA1c level to reduce cardiovascular risk and microvascular complications of diabetes in most patients with type 1 and type 2 diabetes is <7.0% [189].

ESC/EAS I A (LoE A, GoR 2)

Blood pressure

Achieving a blood pressure level of <140/90 mm Hg is recommended for all patients; individual target levels depend on age and comorbidities [190].

ESC/EAS I A (LoE A, GoR 1)

It is recommended for patients aged 18–69 years to maintain SBP within the range of 120–130 mm Hg [191]. In patients ≥70 years receiving therapy, the target SBP value is recommended to be <140 mm Hg, with a reduction to 130 mm Hg if well tolerated [192]. In all patients receiving therapy, a reduction in DBP to <80 mm Hg is recommended [193].

ESC/EAS I A (LoE A, GoR 1)

Antithrombotic therapy

Antithrombotic therapy is recommended for secondary prevention of CVD [194].

ESC/EAS I A (LoE A, GoR 1)

Prevention in various clinical conditions

Patients with oncological diseases are recommended to undergo screening and control of ASCVD risk factors [196].

ESC/EAS I C (LoE C, GoR 4)

All patients with COPD are recommended to be screened for ASCVD and ASCVD risk factors [197].

ESC/EAS I C (LoE B, GoR 2)

In adults with rheumatoid arthritis, it is recommended to multiply the existing cardiovascular risk score by 1.5 [198].

ESC/EAS IIa B (LoE B, GoR 3)

Patients with ASCVD, obesity, and hypertension should be regularly screened for sleep quality (e.g., using the question: "How often have you been troubled by problems with falling asleep, daytime drowsiness, or sleeping too long?") [199].

ESC/EAS I C (LoE C, GoR 5)

Men with erectile dysfunction should be evaluated for cardiovascular risk [200, 201].

ESC/EAS IIa C (LoE B, GoR 3)

Dynamic follow-up is an extremely important component of medical care for patients with dyslipidemia, the objectives of which are: maintaining target LDL-C and TG levels, monitoring compliance with medical recommendations for risk factor modification, and monitoring adherence to pharmacotherapy. All recommendations given to the patient must be clear, concise, and appropriate for their intellectual level. To ensure the patient's informed participation in the treatment and prevention process and to increase treatment efficacy, it is advisable for certain patients, for whom verbal recommendations are insufficient, to provide them in written form.

Following the initiation or dosage adjustment of lipid-lowering therapy, serum lipid levels must be checked after 8 (±4) weeks until target lipid levels are achieved, and annually thereafter (unless there are adherence issues or other reasons for more frequent monitoring). ALT, AST, bilirubin, and CK levels are checked 4–6 weeks after changing lipid-lowering therapy; routine monitoring is not required once target lipid levels are achieved, and should only be performed if there are symptoms suggestive of liver or muscle injury.

According to the guidelines for dispensary follow-up of patients with hypertension, stable CAD, and a history of stroke, monitoring of LDL-C and blood pressure is required twice a year. In cases of hypercholesterolemia exceeding 8.0 mmol/L, monitoring of LDL-C is recommended at least once a year. In patients with carotid artery stenosis greater than 50%, monitoring of LDL-C is required twice a year [202].

Regular monitoring of HbA1c and/or plasma glucose levels should be performed in patients at high risk for diabetes and those receiving high-dose statin therapy.

To ensure timely modification of cardiovascular risk in patients with dyslipidemia, dynamic monitoring of the progression of the atherosclerotic process is recommended. According to the consensus of Russian experts [256], in the absence of atherosclerotic plaques in the carotid and femoral arteries, the patient should be recommended a repeat ultrasound after 3 years. In the presence of atherosclerotic plaques with a height of <1.5 mm and maximum stenosis of <25% in the carotid arteries, as well as maximum stenosis of <25% in the femoral arteries, a repeat arterial ultrasound should be performed after 2 years. When atherosclerotic plaques have a height of ≥1.5 mm and maximum stenosis of <50% in the carotid arteries, as well as maximum stenosis of 25–49% in the femoral arteries, repeat ultrasound is recommended after 1 year; in the absence of progression of the atherosclerotic process, the frequency of examinations can be reduced to once every 2–3 years. When maximum stenosis of ≥50% is detected in the carotid arteries, standard duplex scanning of the extracranial brachiocephalic arteries should be performed annually; this frequency can be reduced to once every 2 years in the absence of progression of the atherosclerotic process.

6. Organization of Medical Care

Indications for planned hospitalization: not applicable

Indications for emergency hospitalization: not applicable

Indications for patient discharge from the hospital: not applicable

Other organizational technologies

When analyzing the performance of a medical organization regarding patients with lipid metabolism disorders, it is advisable to analyze the following indicators:

percentage of high-risk patients who achieved the LDL-C target level of less than 1.8 mmol/L at 8 and 52 weeks of follow-up;
percentage of patients receiving combination lipid-lowering therapy.

7. Additional Information

Achieving and maintaining target LDL-C and TG levels is a key factor influencing prognosis and improving cardiovascular outcomes in patients with both CVD and diabetes.

Important goals in the treatment of dyslipidemia include:

- maximum reduction of the risk of cardiovascular events and fatal outcomes;

- correction of all modifiable risk factors (smoking, overweight, obesity, hyperglycemia, hypertension).

Criteria for Evaluating the Quality of Medical Care

№	Quality criterion	ESC Class and Level	GoR	LoE	Yes/ none
1	Laboratory testing of cholesterol and LDL-C levels performed in individuals over 40 years of age	IC	C	1	Yes/No
2	Laboratory assessment of non-HDL-C performed in patients with high triglycerides, diabetes, obesity, metabolic syndrome, or very low LDL-C	IC	C	1	Yes/No
3	Total risk assessment using the SCORE2 scale performed in all asymptomatic adults older than 40 years without CVD, diabetes, CKD, or HoFH, with LDL-C < 4.9 mmol/L	IC	C	5	Yes/No
4	Anamnesis collected regarding the patient's history of CAD, hypertension, diabetes, peripheral arterial disease, HoFH, metabolic syndrome, obesity, or chronic kidney disease	IC	C	5	Yes/No
5	Physical examination performed to detect cutaneous and tendon xanthomas, xanthelasma, and corneal arcus	IC	C	5	Yes/No
6	Ultrasound examination of the carotid and femoral arteries performed to detect atherosclerotic plaques	IIaB	A	2	Yes/No
7	As initial therapy, a patient with a diagnosed lipid metabolism disorder was prescribed a statin regimen at a dose sufficient to achieve the target LDL-C level	IA	A	1	Yes/No
8	If the target LDL-C level was not achieved on maximally tolerated statin doses after 8±4 weeks, ezetimibe or alirocumab/evolocumab/ inclisiran** was added to the therapy (in very high-risk patients)	IB	B	2	Yes/No
9	If the target LDL-C level was not achieved on maximally tolerated doses of statins and ezetimibe after 8±4 weeks, alirocumab/evolocumab/inclisiran** was added to the therapy	IA	A	1	Yes/No
10	Target LDL-C level of < 1.8 mmol/L (or a reduction of at least 50% from baseline) achieved in high-risk patients after 8±4 weeks of therapy	IA	A	1	Yes/No
11	Target LDL-C level of < 1.4 mmol/L (or a reduction of at least 50% from baseline) achieved in very high-risk patients (excluding those with HoFH) after 8±4 weeks of therapy	IC	C	1	Yes/No

References

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Appendix A1. Working Group Composition

Steering Committee of the Working Group:

Ezhov M. V.

Kukharchuk V. V.

Sergienko I. V.

Other working group members:

Alieva A. S.

Antsiferov M. B.

Ansheles A. A.

Arabidze G. G.

Aronov D. M.

Arutyunov G. P.

Akhmedzhanov N. M.

Balakhonova T. V.

Barbarash O. L.

Boytsov S. A.

Bubnova M. G.

Voevoda M. I.

Galstyan G. R.

Galyavich A. S.

Gornyakova N. B.

Gurevich V. S.

Dedov I. I.

Drapkina O. M.

Duplyakov D. V.

Eregin S. Ya.

Ershova A. I.

Irtyuga O. B.

Karpov R. S.

Karpov Yu. A.

Kachkovsky M. A.

Kobalava Zh. D.

Koziolova N. A.

Konovalov G. A.

Konstantinov V. O.

Kosmacheva E. D.

Kotovskaya Yu. V.

Martynov A. I.

Meshkov A. N.

Nebieridze D. V.

Nedogoda S. V.

Obrezan A. G.

Oleynikov V. E.

Pokrovsky S. N.

Ragino Yu. I.

Rotar O. P.

Skibitsky V. V.

Smolenskaya O. G.

Sokolov A. A.

Sumarokov A. B.

Tkacheva O. N.

Filippov A. E.

Khalimov Yu. Sh.

Chazova I. E.

Shaposhnik I. I.

Shestakova M. V.

Shlyakhto E. V.

The members of the Working Group confirmed the absence of financial support/conflict of interest. If a conflict of interest was reported, the working group member(s) were excluded from the discussion of sections related to the conflict of interest area.

Appendix A2. Methodology for Developing Clinical Guidelines

These Guidelines have been developed on the basis of the 2019 Guidelines for the management of dyslipidaemias of the European Society of Cardiology and the European Atherosclerosis Society [50].

Based on the results of major epidemiological and randomized clinical trials and meta-analyses, the Guidelines summarize and outline the fundamental principles of treating patients with lipid metabolism disorders in general and in specific clinical situations. The primary objective of the Guidelines is to facilitate decision-making when selecting the optimal treatment strategy for a particular patient with dyslipidemia. Nevertheless, the final treatment decision must be made taking into account the individual features of the development mechanisms and clinical course of the disease.

Target audience for these clinical guidelines:

1. Cardiologist.

2. General practitioner / Physician.

3. General practitioner.

4. Endocrinologist.

5. Neurologist.

Since members of the Russian Society of Cardiology are also members of the European Society of Cardiology (ESC), all ESC guidelines are formulated with the participation of Russian experts who co-author the European guidelines. Thus, the existing ESC guidelines reflect the consensus of leading Russian and European cardiologists. Accordingly, these National Guidelines were developed on the basis of the ESC guidelines, taking into account national specifics, examination and treatment modalities, and the availability of medical care. For this reason, the text of these clinical guidelines simultaneously uses two grading scales for the reliability of guideline evidence: the ESC levels of evidence combined with levels of recommendation reliability (LORR) and levels of evidence (LOE). ESC recommendation classes have also been added to assess the necessity of performing a given recommendation statement (Tables 1, 2, 3, 4, 5).

Table 1. European Society of Cardiology (ESC) recommendation classes

ESC Class of Recommendation	Definition	Suggested Wording
I	Evidence and/or general agreement that a given diagnostic procedure or treatment is beneficial, useful and effective.	Recommended/ indicated
II	Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given procedure, intervention, treatment	Should be considered apply
IIa	Weight of evidence/opinion is in favor of usefulness/efficacy	Should be considered apply
IIb	Usefulness/efficacy is less well established by evidence/opinion	May be considered apply
III	Data or unified consensus that the diagnostic procedure, intervention, or treatment is useless/ineffective, and in some cases may be harmful	Not recommended apply

Table 2. European Society of Cardiology (ESC) levels of evidence

	ESC Level of Evidence
A	Data derived from multiple randomized clinical trials or meta-analyses
B	Data derived from a single randomized clinical trial or large non-randomized studies
C	Consensus of expert opinion and/or small studies, retrospective studies, registries

Table 3. Levels of Evidence (LOE) for preventive, therapeutic, and rehabilitative methods (interventions)

Levels of Evidence (LOE) Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development and revision of clinical guidelines, their standard template, and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines" (Registered on May 8, 2019, No. 54588)
1	Systematic review of randomized controlled trials with meta-analysis
2	Individual randomized clinical trials and systematic reviews of studies of any design, excluding randomized clinical trials, with meta-analysis
3	Non-randomized comparative studies, including cohort studies
4	Non-comparative studies, case reports or case series, case-control studies
5	Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available

Table 4. Levels of Evidence (LOE) for diagnostic methods (interventions)

LoE	Definition
1.	Systematic reviews of studies with reference standard control or systematic reviews of randomized clinical trials with meta-analysis
2.	Individual studies with reference method control or individual randomized clinical trials and systematic reviews of studies of any design, excluding randomized clinical trials with meta-analysis
3.	Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies
4.	Non-comparative studies, case report
5.	Only justification of mechanism of action or expert opinion is available

Table 5. Levels of Recommendation Reliability (LORR) for preventive, diagnostic, therapeutic, and rehabilitative methods (interventions)

Level of Recommendation Reliability (LORR), Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development and revision of clinical guidelines, their standard template, and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines" (Registered on May 8, 2019, No. 54588)
A	Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent)
C	Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent)
C	Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent)

Level of Recommendation Reliability (LORR), Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development and revision of clinical guidelines, their standard template, and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines"

(Registered on May 8, 2019, No. 54588)

Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent)

Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent)

Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic updating—at least once every three years or upon the emergence of new information on the management tactics of patients with this condition. The decision to update is made by the Russian Ministry of Health based on proposals submitted by medical non-profit professional organizations. The formulated proposals must take into account the results of comprehensive assessments of medicinal products, medical devices, and the results of clinical probation.

Appendix A3. Reference Materials

1. Order of the Ministry of Health of the Russian Federation No. 918n dated November 15, 2012, "On approval of the Procedure for providing medical care to patients with cardiovascular diseases".

2. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On approval of criteria for assessing the quality of medical care".

3. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development and revision of clinical guidelines, their standard template, and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines" (Registered on May 8, 2019, No. 54588)

Table A3.1. Classification of dyslipidemias (WHO, adapted from the Fredrickson classification)

Phenotype		Synonym	Elevated plasma lipoprotein levels	Elevated plasma lipid levels	Atherogenicity	Frequency (%) in the structure of DLP
I	a	Familial chylomicronemia syndrome, lipoprotein lipase deficiency	CM	TG	?	<1
	b	Familial apolipoprotein CII deficiency
	c	Hyperchylomicronemia due to circulating inhibitor Lipoprotein lipase
II	a	Familial hypercholesterolemia, polygenic familial hypercholesterolemia	LDL	Cholesterol	+++	10
II	b	Combined hyperlipidemia	LDL, VLDL	TC and TG	+++	40
III		Familial dysbetalipoproteinemia	IDL	TG and TC	+++	<1
IV		Familial hypertriglyceridemia	VLDL	TG	+	45
V		Mixed hyperlipidemia	CM, VLDL	TG and TC	+	5

DLP — dyslipidemia, TC — total cholesterol, HDL — high-density lipoproteins, LDL — low-density lipoproteins, TG — triglycerides, VLDL — very low-density lipoproteins, CM — chylomicrons.

Table A3.2. Optimal values of lipid parameters depending on risk category

Appendix A3. Reference Materials — Lipid Metabolism Disorders

* And a reduction in LDL-C >50% from baseline.

HDL — high-density lipoproteins, LDL — low-density lipoproteins, TG — triglycerides, Lp(a) — lipoprotein(a).

Table A3.3. Risk factors for the development and progression of atherosclerosis

Risk factors
Age	Men >40 years old, women >55 years old or with early menopause
Smoking	Regardless of the number
Arterial hypertension	BP ≥ 140/90 mmHg or regular intake of antihypertensive drugs
Type 2 diabetes mellitus	Fasting glucose >6.1 and 7.0 mmol/L (capillary and venous blood, respectively)
Early onset of coronary artery disease in close relatives (family history of premature CVD)	Myocardial infarction or unstable angina in men aged <55 years, in women <60 years
Familial hyperlipidemia, according to medical history	Type IIa, IIb, and III
Abdominal obesity	Waist circumference: in men ≥94 cm, in women ≥80 cm
Chronic kidney disease	Decreased glomerular filtration rate <60 mL/min
Obesity	Elevated BMI > 25 kg/m2

Appendix A3.1. Principles of diagnosis and cardiovascular risk assessment

Table A3.4. Quantitative assessment of the coronary artery calcium score

Coronary artery calcium score	Coronary artery changes	Risk
0	No evidence of lesions	low
1–10	Minimal calcification	moderate
11–100	Mild calcification. Atherosclerotic plaques up to 50% are usually present	high
101–400	Moderate calcification. Usually 2–4 atherosclerotic plaques with coronary artery stenosis greater than 50%	high or very high
> 400	Severe calcification	very high

Table A3.5. Main hereditary (genetic) dyslipidemias [9]

Dyslipidemia	Gene defect	Elevation of lipids or lipoproteins	Clinical features	Occurrence
Familial hypercholesterolemia	LDLR, PCSK9, APOB	LDL-C	Tendon xanthomas, early atherosclerosis	1/250 — heterozygous, 1/300 000 — homozygous
Familial chylomicronemia syndrome	LPL, APOC2	Chylomicrons	Eruptive xanthomas, hepatosplenomegaly, pancreatitis	1/1 000 000
Hereditary hepatic lipase deficiency	Hepatic lipase	VLDL remnants (IDL)	Early atherosclerosis, pancreatitis	1/10 000
Beta-sitosterolemia	APOE	Chylomicrons, VLDL remnants	Palmar and tuberoeruptive xanthomas, peripheral atherosclerosis	1/1 000 000
Familial dysbetalipoproteinemia	APOE	Chylomicrons, VLDL remnants	Palmar and tuberoeruptive xanthomas, peripheral atherosclerosis	1/10 000
Familial combined hyperlipidemia	Modifier genes	LDL-C, VLDL-C	–	1/200
Tangier disease, familial hypo-alpha-lipoproteinemia	ABCA1	Decreased HDL-C	Hepatosplenomegaly, tonsillar enlargement, coronary artery disease	1/1 000 000

LDL-C — low-density lipoprotein cholesterol; VLDL-C — very-low-density lipoprotein cholesterol; IDL-C — intermediate-density lipoprotein cholesterol; HDL-C — high-density lipoprotein cholesterol; CAD — coronary artery disease.

Table A3.6 Population-based LDL-C indicators by sex and age for the Russian Federation.

Gender	Age	LDL-C (mmol/L) 95th percentile
Masculine	25–34	4,56
	35–44	5,04
	45–54	5,31
	55–64	5,16
Feminine	25–34	4,24
	35–44	4,68
	45–54	5,29
	55–64	5,56

Table A3.7. Simon Broome Register diagnostic criteria

Table A3.8. Diagnostic criteria for HoFH

Table A3.9. Drugs with potential interactions with statins

Systemic anti-infective drugs	Calcium channel blockers	Other
Itraconazole	Verapamil**	Cyclosporine**
Ketoconazole	Diltiazem	Danazol
Posaconazole**	Amlodipine**	Amiodarone**
Erythromycin		Ranolazine
Clarithromycin**		Grapefruit juice

Table A3.10. Comparison of the efficacy of fenofibrate**, statins and ezetimibe [38, 62, 63, 148, 8]

Mechanism of action	Statins	Ezetimibe	Fenofibrate**
inhibit the enzyme HMG-CoA reductase, which is involved in cholesterol synthesis	selectively inhibits the absorption of cholesterol and certain plant sterols in the intestine	activates cellular PPARa receptors, which normalize lipid metabolism
Reduction of LDL-C concentration	18–55%	15–30%	5–20%
Reduction of triglyceride levels	7–20%	3–5%	20–50%
Increase in HDL-C levels	5–15%	3–5%	10–20%
Increase in LDL particle size	none	none	50%

Table A3.11. Calculation of the degree of LDL-C reduction with various lipid-lowering therapy regimens

Therapy	LDL-C reduction in %
Moderate-intensity statin therapy	≈ 30
High-intensity statin therapy	≈ 50
High-intensity statin therapy + ezetimibe	≈ 65
Alirocumab/evolocumab/inclisiran**	≈ 60
Alirocumab/evolocumab/inclisiran** + high-intensity statin therapy	≈ 75
Alirocumab/evolocumab/inclisiran** + high-intensity statin therapy + ezetimibe	≈ 85

Table A3.12. Indications for plasmapheresis, plasmasorption

Indications
Homozygous familial hypercholesterolemia — absolute indication
Heterozygous familial hypercholesterolemia — severe course. Insufficient response to pharmacotherapy; drug intolerance
Other forms of hypercholesterolemia refractory to maximum pharmacotherapy in patients with coronary artery disease
Hyperlipoproteinemia (a) (>60 mg/dL) in patients with coronary artery disease, especially in combination with hypercholesterolemia refractory to therapy
Therapy-refractory hypercholesterolemia in patients undergoing revascularization, to prevent restenosis and graft and stent occlusion
Refractory dyslipidemia in pregnant women at high risk for complications, particularly with hereditary dyslipidemia, hyperlipoproteinemia (a), and marked blood hyperviscosity

FH — familial hypercholesterolemia.

Table A3.13. Summary data on the effects of lipid-lowering drugs [149]

ATC code	Drugs and daily doses	Lipid effects	Side effects	Note
C10AA HMG-CoA reductase inhibitors (statins)	Simvastatin (20–40 mg) Atorvastatin (10–80 mg) Rosuvastatin 5–40 mg Pitavastatin 1–4 mg	LDL-C ↓ 20–60% HDL-C ↑ 5–15% TG ↓ 7–30% Non-HDL-C ↓ 15–50%	Myalgia Myositis Elevated serum transaminases	Rare complications: rhabdomyolysis, cognitive decline, development of DM
C10AX Other lipid-lowering agents	Ezetimibe 10 mg	LDL-C ↓ 15–22% HDL-C ↑ 1–2% TG ↓ 5–10% Non-HDL-C ↓ 14–19%	Headache Muscle pain	Effective in combination with statins
C10AX Other lipid-lowering agents	Evolocumab () (140 mg (1 ml), subcutaneously, every 2 weeks / 420 mg (3 x 1 ml), subcutaneously, once a month) Alirocumab () (75 mg, subcutaneously, every 2 weeks); 150 mg (1 ml) every 2 weeks / 300 mg (2 x 1 ml or 2 ml) once a month Inclisiran** (284 mg, subcutaneously, 1st year — 3 injections, then 2 injections per year)	LDL-C ↓ 50–70% HDL-C ↑ 4–7% TG ↓ 6–19% Non-HDL-C ↓ 20–50%	Injection site reaction (5%)	Does not affect transaminase levels Subcutaneous injection required
C10AB Fibrates	Fenofibrate**, 145 mg daily	LDL-C ↓ 10–15% HDL-C ↑ 10-20% TG ↓ 20–50% Non-HDL-C ↓ 5-19%	Dyspepsia Myopathy Possible ↑ creatinine and bile acids	Concomitant use in combination with statins and ezetimibe is possible
C10AX Other lipid-lowering agents	Omega-3 acid ethyl esters 2–4 g daily	LDL-C ↓ 6% — ↑ 25% HDL-C ↓ 5% — ↑ 7% TG ↓ 20–45% Non-HDL-C ↓ 5–14%	Fishy odor Eczema	Combination with statins improves postprandial TG levels

ATC code

Drugs and daily doses

Lipid

effects

Side effects

Note

C10AA HMG-CoA reductase inhibitors

(statins)

Simvastatin** (20–40 mg)

Atorvastatin** (10–80 mg)

Rosuvastatin 5–40 mg

Pitavastatin 1–4 mg

LDL-C ↓ 20–60%

HDL-C ↑ 5–15%

TG ↓ 7–30%

Non-HDL-C ↓ 15–50%

Myalgia

Myositis

Elevated serum transaminases

Rare complications: rhabdomyolysis, cognitive decline, development of DM

C10AX

Other lipid-lowering agents

Ezetimibe 10 mg

LDL-C ↓ 15–22%

HDL-C ↑ 1–2%

TG ↓ 5–10%

Non-HDL-C ↓ 14–19%

Headache

Muscle pain

Effective in combination with statins

C10AX

Other lipid-lowering agents

Evolocumab (**) (140 mg (1 ml), subcutaneously, every 2 weeks / 420 mg (3 x 1 ml), subcutaneously, once a month)

Alirocumab (**) (75 mg, subcutaneously, every 2 weeks); 150 mg (1 ml) every 2 weeks / 300 mg (2 x 1 ml or 2 ml) once a month

Inclisiran** (284 mg, subcutaneously, 1st year — 3 injections, then 2 injections per year)

LDL-C ↓ 50–70%

HDL-C ↑ 4–7%

TG ↓ 6–19%

Non-HDL-C ↓ 20–50%

Injection site reaction (5%)

Does not affect transaminase levels

Subcutaneous injection required

C10AB

Fibrates

Fenofibrate**, 145 mg daily

LDL-C ↓ 10–15%

HDL-C ↑ 10-20%

TG ↓ 20–50%

Non-HDL-C ↓ 5-19%

Dyspepsia

Myopathy Possible ↑ creatinine and bile acids

Concomitant use in combination with statins and ezetimibe is possible

C10AX

Other lipid-lowering agents

Omega-3 acid ethyl esters 2–4 g daily

LDL-C ↓ 6% — ↑ 25%

HDL-C ↓ 5% — ↑ 7%

TG ↓ 20–45%

Non-HDL-C ↓ 5–14%

Fishy odor

Eczema

Combination with statins improves postprandial TG levels

Appendix B. Physician Action Algorithms

Appendix B1. Algorithm for the Treatment of Hypertriglyceridemia

Note. Omega-3 PUFAs — Omega-3 acid ethyl esters, including other esters and acids, at a dose of 2–4 g/day. In severe hypertriglyceridemia, consider the use of plasmapheresis or plasmasorption.

Appendix B2. Algorithm of pharmacotherapy to achieve target LDL-C levels

Table B1. Laboratory safety and efficacy monitoring (parameters, frequency) before and during lipid-lowering therapy

Serum lipid determination
Before prescribing lipid-lowering therapy	at least 2 measurements at an interval of 1–12 weeks are required, except for patients with ACS and those at very high risk
After initiation of lipid-lowering therapy	at 8 (±4) weeks until target level is reached
Once the patient reaches the target lipid level	annually (unless there are adherence issues or other reasons for more frequent monitoring)
ALT and muscle enzymes
Frequency of laboratory monitoring of ALT, AST	· before starting lipid-lowering therapy · once at 8–12 weeks after initiating lipid-lowering therapy · routine monitoring thereafter is not recommended (except when symptoms of potential liver injury appear) · during fibrate therapy
Physician actions upon detection of elevated ALT levels during lipid-lowering therapy:	*ALT elevation ˂ 3 ULN* · continue lipid-lowering therapy · recheck ALT in 4–6 weeks *ALT elevation ≥ 3 ULN* · discontinue lipid-lowering therapy, · check ALT 4–6 weeks after discontinuation · resume lipid-lowering therapy after ALT normalization · if ALT elevation persists, investigate other potential causes of elevated ALT
CK (creatine phosphokinase) monitoring	· before starting therapy · if baseline CK level > 4 ULN, do not initiate lipid-lowering therapy *monitoring during lipid-lowering therapy: · routinely not recommended · performed when myalgia/muscle weakness appears risk factors for myopathy/CK elevation during lipid-lowering therapy:* · older age, concomitant therapy (with potential adverse interactions with lipid-lowering drugs) · athletes · liver or kidney disease *CK elevation ˂ 4 ULN:* · in the absence of myopathy symptoms, continue statin therapy (if symptoms appear, the patient should consult a physician for laboratory CK testing) · in the presence of myopathy symptoms, regular CK monitoring is required · if myopathy symptoms persist, discontinue statin therapy, re-evaluate symptoms and CK levels 6 weeks after discontinuation · after symptom resolution and CK normalization, resume statin therapy at a lower dose, with an alternate-day or twice-weekly dosing schedule · combination lipid-lowering therapy is possible *CK elevation ≥ 4 ULN:* evaluate indications for statin therapy *CK elevation > 10 ULN:* · discontinue statin · monitor renal function · CPK monitoring every 2 weeks *CPK elevation < 10 ULN, no myopathy symptoms: · continue statin therapy, · monitor CPK in 2–6 weeks CPK elevation < 10 ULN, myopathy symptoms present:* · discontinue statin · monitor CPK levels until normalization · after CPK normalization, restart statin therapy at a lower dose · rule out other potential causes of CPK elevation (physical exertion) · if CPK levels remain elevated during monitoring — confirm the development of myopathy
Monitoring of HbA1c and/or fasting plasma glucose	· regular monitoring of HbA1c and/or plasma glucose should be performed in patients at high risk of diabetes mellitus and receiving high-intensity statin therapy · plasma glucose monitoring is indicated for elderly patients with metabolic syndrome, obesity, and signs of insulin resistance

Table B3/4. Statin therapy intensity

High-intensity statin daily dose for ↓ LDL-C ≥ 50%	Moderate-intensity statin daily dose for ↓ LDL-C from 30% to <50%
Atorvastatin (**), 40–80 mg	Atorvastatin (**), 10–20 mg
Rosuvastatin, 20–40 mg	Pitavastatin, 2–4 mg
	Rosuvastatin, 5–10 mg
	Simvastatin (**), 20–40 mg

Appendix B4: principles of lipid-lowering therapy and follow-up monitoring of patients with dyslipidemia

Table B4/1. Management tactics depending on cardiovascular risk and cholesterol level [50]

Note: LDL-C — low-density lipoprotein cholesterol. In patients with CVD, statin therapy is prescribed regardless of cholesterol levels.

1 LS: treatment is not required; maintaining a healthy lifestyle and risk factor control are recommended.

2 LS±MT: maintaining a healthy lifestyle and, potentially (at the physician's discretion), prescribing lipid-lowering therapy are recommended if the target LDL-C level is not achieved.

3 LS+MT: maintaining a healthy lifestyle and simultaneous initiation of lipid-lowering therapy are recommended.

Table B4/2 Impact of lifestyle modification on lipid levels [50]

Lifestyle changes to reduce TC and LDL-C levels		Literature source
Elimination of trans fats	++	[122, 123]
Reduction of saturated fat intake	++	[122, 124]
Increase dietary fiber intake	++	[125, 126]
Consumption of phytosterol-enriched foods	++	[127, 128]
Red yeast rice	++	[129, 130]
Reduction of excess body weight	++	[131, 132]
Reduction of dietary cholesterol	+	[133, 134]
Increase in regular physical activity levels	+	[135]
Lifestyle changes to reduce TG levels
Reduction of excess body weight	+	[131, 132]
Elimination of alcohol	+++	[136, 137]
Increase in regular physical activity levels	++	[135, 138]
Reduction of total dietary carbohydrate intake	++	[131, 139]
Use of omega-3 PUFAs as a dietary supplement	++	[140, 141]
Reduction of mono- and disaccharide intake	++	[142, 143]
Replacement of saturated fats with mono- and polyunsaturated fats	+	[122, 46]
Lifestyle changes to increase HDL-C levels
Reduction of trans fat intake	++	[122, 144]
Increase in regular physical activity levels	+++	[135, 145]
Reduction of excess body weight	++	[131, 132]
Reduction of dietary carbohydrate intake and replacement with unsaturated fats	++	[131, 146]
Moderate alcohol consumption	++	[137]
Smoking cessation	+	[147]

Note: +++ General consensus on the effectiveness of influencing lipid levels. ++ Less pronounced effect on lipid levels; available evidence/expert opinion indicates the effectiveness of the interventions. + Conflicting data.

Appendix C. Patient Information

Table B1. Dietary recommendations for improving the overall lipoprotein profile

	Preferable	Consume in moderation	Consume rarely and in limited quantities
Grains	Whole grains	Refined bread, rice and pasta, cookies, cornflakes	Pastries, muffins, pies, croissants
Vegetables	Raw and processed vegetables	Potatoes	Vegetables prepared with butter or cream
Legumes	Lentils, beans, broad beans, peas, chickpeas, soybeans
Fruits	Fresh and frozen fruits	Dried fruit, jelly, jam, canned fruit, sherbet, fruit ice cream, fruit juice
Sweets and sweeteners	Non-caloric sweeteners	Sucrose, honey, chocolate, candies	Ice cream, fructose, soft drinks
Meat and fish	Lean and fatty fish, skinless poultry	Lean cuts of beef, lamb, pork, or veal, seafood, mollusks, and crustaceans	Sausages, salami, bacon, pork ribs, hot dogs, organ meats
Dairy and eggs	Skim milk and yogurt	Milk, reduced-fat cheeses, other dairy products, eggs	Regular cheese, cream, whole milk, and yogurt
Condiments	Vinegar, mustard, fat-free condiments	Olive oil, non-tropical vegetable oils, soft margarines, mayonnaise, ketchup	Trans fats and hard margarines, palm, coconut, and butter, lard
Nuts		All unsalted (except coconut)	Coconut
Food preparation	Grilling, steaming	Frying	Frying

Note: moderate alcohol consumption (no more than 50 mg per day of spirits, 200 mg of red or white wine, and no more than 350 ml of beer with a meal) is acceptable, provided that triglyceride levels are not elevated, and there is no hypertension and/or liver failure.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Dutch Lipid Clinic Network criteria for heterozygous familial hypercholesterolemia

Russian title: Dutch diagnostic criteria for heterozygous familial hypercholesterolemia

Original title (if available): Dutch Lipid Clinic Network criteria

Source (official website of developers, validation publication): [9]

Type (underline): rating scale

Purpose: establishing a clinical diagnosis of heterozygous familial hypercholesterolemia

Content (template):

Criterion	Points
1. Family history
Premature CVD (in men <55 years; in women <60 years) or LDL-C level above the 95th percentile in a first-degree relative	1
Presence of tendon xanthomas in a first-degree relative or LDL-C level above the 95th percentile in children under 18 years of age	2
2. Personal history
Premature CVD (in men <55 years; in women <60 years)	2
Premature atherosclerotic disease of cerebral/peripheral arteries (in men <55 years; in women <60 years)	1
3. Physical examination*
Tendon xanthomas	6
Arcus corneae in individuals <45 years	4
4. LDL-C level
> 8.5 mmol/L	8
6.5–8.4 mmol/L	5
4.9–6.4 mmol/L	3
4.0–4.8 mmol/L	1
5. DNA analysis
Functional mutation of LDLR, APOB or PCSK9 genes	8

* mutually exclusive (i.e. maximum 6 points). CVD — cardiovascular disease, LDL-C — low-density lipoprotein cholesterol, FH — familial hypercholesterolemia.

Key (interpretation): The diagnosis is made based on the total score: "definite" FH — >8 points, "probable" OR "likely" FH — 6–8 points, "possible" FH — 3–5 points, "unlikely" FH — 0–2 points.

Table G2. SCORE2 scale for calculating non-fatal cardiovascular events for very high-risk countries.

Russian title: SCORE2 scale

Original title (if available): Systematic COronary Risk Evaluation model

Source (official website of developers, validation publication): escardio.org. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe // European heart journal. 2021. Vol. 42. №. 25. P. 2439–2454.

Type (underline): rating scale

Purpose: calculation of the risk of non-fatal cardiovascular events

Content (template) and interpretation:

SCORE2 for older adults aged 70–89 in very high-risk populations

Appendix G1 - G... Assessment Scales, Questionnaires — Lipid Metabolism Disorders

SCORE2 for individuals aged 40–69 in very high-risk populations

Notes: non-HDL-C = TC - HDL-C

Table G3. Global 10-year cardiovascular risk assessment scale

Russian name: 10-year global cardiovascular risk assessment scale

Original name (if applicable): none

Type (underline): rating scale

Purpose: assessment of 10-year cardiovascular risk

Content (template) and interpretation:

AH – arterial hypertension, CKD – chronic kidney disease, GFR – glomerular filtration rate, TIA – transient ischemic attack, CVD – cardiovascular disease, ASB – atherosclerotic plaque, FH – familial hypercholesterolemia, RF – risk factor.

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