1. Preamble. Why do we need new guidelines in 2021? Despite 30 years (simvastatin was approved for clinical use by the FDA in 1991 [1]) of experts’, societies’, and patient organisations’ efforts, lipid disorders still comprise a diagnostic and, before all, therapeutic challenge. This applies to adequate risk assessment in patients, introduction of appropriate treatment, problems with patient compliance, as well as to problems with so important non-pharmacological treatment – diet, body mass reduction, or regular exercise [2]. The significance of therapeutic inertia, either in the form of inadequate therapy (usually the lack of intensive statin treatment or, even less likely, combination therapy) or evident errors such as dose reduction or cessation of treatment following achievement of the therapeutic target, also cannot be diminished. That is why in Poland there are still nearly 20 million individuals with hypercholesterolaemia, most of them unaware of their condition [3]; that is why only ca. 5% of patients with familial hypercholesterolaemia out of predicted as much as 140,000 have been diagnosed; that is why other rare cholesterol metabolism disorders are so rarely diagnosed in Poland [4, 5]. Let us hope that these guidelines, for the first time being an effect of work of experts representing 6 scientific societies, as well as the network of Polish Lipid Association (PoLA) lipid centers (currently under development, https://ptlipid.pl/siec-centrow-lipidowych) (the list of centers is presented in Appendix), being a part of the European Atherosclerosis Society (EAS) European lipid centers, certification of lipidologists by PTL, or the growing number of centers for rare diseases, with a network planned by the Ministry of Health, improvements in coordinated care for patients after myocardial infarction (KOS-Zawał) associated with the need of lipid profile assessment at specific time points, reimbursement of innovative agents (after PCSK9 inhibitors, hopefully also inclisiran, bempedoic acid, evinacumab, and pelacarsen), as well as introduction in Poland of an effective (at least) primary prevention program, will make improvement in relation to these unmet needs in diagnostics and treatment of lipid disorders possible. Moreover, over the last few years the approach to treatment of patients with a high cardiovascular risk has totally changed from treatment aimed at a specific risk factor (i.e., glucocentricity or lipo-centricity) to effective diagnostics, monitoring, and treatment of all risk factors and general cardiovascular risk as well as concomitant diseases, stressing the role of residual risk, and the intensity of the applied therapy. In the case of lipid disorders, intensive lipid-lowering treatment is currently recommended (and not just intensive statin treatment, as it has been for years) in order to achieve in our patients as low concentrations of low density lipoprotein (LDL) cholesterol as possible, according to the rule of “the lower the better”, but also to do it as soon as possible (“the earlier the better”) and maintain it as long as possible (“the longer the better”), as this gives us a chance to reduce the risk of cardiovascular events even in every other patient (50–55%) [6, 7]. Taking into consideration immense challenges still present in diagnostics and therapy of lipid disorders, changes in the approach to treatment, including innovative molecules, as well as the most recent results of numerous studies (lipidology and atherosclerosis research are currently the most rapidly developing specialty in medicine), Polish Lipid Association (PoLA), along with College of Family Physicians in Poland (CFPiP), Polish Cardiac Society (PCS), Polish Society of Diabetology (PSD), Polish Society of Laboratory Diagnostics (PSLD), and Polish Society of Hypertension (PSH), decided to prepare comprehensive guidelines concerning management of lipid disorders, with special attention paid to the practical aspect of these guidelines, as we would like to make them an actual tool for everyday work with patients suffering from lipid disorders. 2. Introduction Although 5 years elapsed since the time of publication of the previous guidelines, lipid metabolism disorders remain the most common and the worst controlled cardiovascular risk factor in Poland [8]. Along with tobacco smoking, type 2 diabetes mellitus, arterial hypertension, improper dietary habits, and insufficient physical activity leading to overweight and obesity, they are the primary modifiable risk factors of atherosclerosis and its most important complications, such as ischaemic heart disease, cerebral stroke, and peripheral artery disease [9]. The results of epidemiological studies performed in our country indicate that their prevalence grows constantly due to spreading of unhealthy dietary habits and sedentary lifestyle resulting in an epidemic of overweight and obesity [10], in which the coronavirus pandemic also played a very detrimental role in the last 2 years. Recent results of large observational studies by Non-Communicable Disease Risk Factor Collaboration (NCD-RisC) indicate that Poland belongs to countries in which the least changes in mean total cholesterol or non-high density lipoprotein (non-HDL) cholesterol concentration may be observed, even with trends indicating their growth in men in subsequent years, which, unfortunately, has translated into a slight decrease or the lack of reduction of mortality due to ischaemic heart disease and ischaemic stroke dependent on this risk factor in the years 1990–2017 [11, 12]. Therefore, their control, with particular emphasis on lipid disorders, remains one of the main public health challenges, also in the present context of struggle to improve the health of Poles in the post-pandemic era. To face these challenges, comprehensive preventive activities at the population level are needed, especially those concerning primary prophylaxis, which should be concentrated on selection of high-risk patients, adequate widespread health education, and optimum treatment (including non-pharmacological interventions), to avoid or delay development of ischaemic heart disease, stroke, or peripheral artery disease. Family physicians, as well as other healthcare professionals (cardiologists, diabetologists, internists, nurses), bear a special responsibility with respect to high-risk patients, i.e., the group to which numerous patients with dyslipidaemia belong. This common, well-organised struggle, with good communication between family physicians and specialists (which is still often missing), should be an element of a wider strategy aimed at reduction of the total cardiovascular risk, and ultimately at reduction of mortality, morbidity, and disability due to cardiovascular disease. 3. Development of the Guidelines Members of the Steering Committee who prepared these guidelines were selected and indicated by Polish Lipid Association (PoLA), College of Family Physicians in Poland (CFPiP), Polish Cardiac Society (PCS), Polish Society of Diabetology (PSD), Polish Society of Laboratory Diagnostics (PSDL), and Polish Society of Hypertension (PSH) as experts in treatment of patients with lipid disorders. The Steering Committee has carefully reviewed published evidence on the management of dyslipidaemia, including its diagnosis, treatment, and prevention, as well as critical evaluation of diagnostic and therapeutic procedures, including benefit-risk assessment and cost-effectiveness indicators. The level of evidence and the strength of recommendations for each intervention were weighed and categorised using widely recognised defined classifications presented in Tables I and II. As these guidelines are intended to be a practical tool, apart from application of the appropriate class and strength of recommendation, each chapter is additionally independently summarised, pointing to the information necessary to remember by physicians and key points of recommendation, in terms of their application in everyday clinical practice. Table I Classification of recommendations in the guidelines Class of recommendation Definition Suggestion of use Class I There is scientific evidence and/or general agreement that a specific treatment/procedure is beneficial, useful, and effective It is recommended/It is indicated Class II Scientific evidence is ambiguous and/or there are conflicting opinions as to the usefulness/efficacy of a specific treatment/procedure Class IIa Prevailing evidence/opinions confirm the usefulness/efficacy of a specific treatment/procedure It should be considered Class IIb Evidence/opinions do not sufficiently confirm the usefulness/efficacy of a specific treatment/procedure It may be considered Class III There is scientific evidence and/or general agreement that a specific treatment/procedure is useless/ineffective, and in certain cases it may be harmful It is not recommended Table II Level of evidence Level A Data obtained from multiple randomised clinical trials or meta-analyses Level B Data obtained from a single randomised clinical trial or large non-randomised trials Level C A consensus expert opinion and/or data from small trials; retrospective studies, and registries Experts being members of the Writing Committee submitted the declaration of interest forms regarding all associations that could be perceived as actual or potential sources of conflict of interest (see details at the end of this document). After final approval of their content, the final pre-print version of the guidelines will be published immediately on the webpages of the relevant societies and then, if possible, simultaneously published in the Archives of Medical Science (indicated by PoLA), Lekarz Rodzinny (official journal of CFPiP), Kardiologia Polska (Polish Heart Journal, PCS), Diagnostyka Laboratoryjna (Laboratory Diagnostics, PSDL), Current Topics in Diabetes (PSD), Nadciśnienie Tętnicze w Praktyce (PSH) and additionally Lekarz POZ to reach as many interested parties as possible. Family physicians and physicians of other specialities involved in the care of patients with lipid disorders are encouraged to take these guidelines into full consideration in clinical evaluation as well as in development and implementation of medical strategies for prevention, diagnostics, or treatment. However, these guidelines do not in any way disclaim the individual responsibility of physicians for making appropriate and accurate decisions, taking into account the condition of a specific patient, and following consultation with the patient and, if necessary, with the patient’s caregiver. Healthcare professionals are also responsible for verification of the rules and regulations concerning medicines and devices at the time of their prescription/application. 4. Epidemiology of lipid disorders in Poland Disorders of lipid metabolism are the most common cardiovascular risk factor; this has also been confirmed in Polish screening studies [4, 10]. Despite continuous education of physicians and patients and availability of different lipid-lowering therapies, the effectiveness of detection and treatment of dyslipidaemia in Poland remains unsatisfactory. Over the last nearly 40 years, numerous, extensive studies have been conducted in Poland to evaluate the prevalence of dyslipidaemia. A summary of the most important studies concerning lipid disorders, including the method of patient sample selection and the years of their conduction, is presented in Table III. Table III Summary of Polish epidemiological studies on dyslipidaemia according to the method of patient sample selection Studies with random sampling in the overall population Studies in active primary care patients Study acronym Years of conduction Study acronym Years of conduction Pol-MONICA 1984–1993 SPES 1997 NATPOL III PLUS 2002 POLSCREEN 2002 WOBASZ 2003–2005 LIPIDOGRAM2003 2003 NATPOL 2011 2011 LIPIDOGRAM2004 2004 WOBASZ II 2013–2014 LIPIDOGRAM2006 2006 LIPIDOGRAM 5 LAT 2004–2010 LIPIDOGRAM2015 2015–2016 Depending on the sample selection method, the prevalence of dyslipidaemia in Poland is estimated at 60–80% of people in the population over 18 years of age [13]. The first data on the prevalence of hyperlipidaemia (the Pol-MONICA study) indicated hypercholesterolaemia in just over 70% of women and nearly 73% of men [14]. In that study, the percentage of individuals with the low-density lipoprotein-cholesterol (LDL-C) concentration above the normal range was higher in men (60%) than in women (53%) [14]. Decreased HDL-C concentration was observed in nearly 2% of women and 10% of men, while elevated triglyceride (TG) concentration was observed in 6% of women and 21% of men [14]. In another study (SPES – Southern Poland Epidemiological Survey) hypercholesterolaemia was reported in nearly 56% of the subjects (58% of women and 52% of men, respectively) [15]. The cited results, however, were not nationwide but restricted to the ex-voivodeships of Warsaw and Tarnobrzeg (the Pol-MONICA study), and Katowice and Bielsko-Biala (the SPES study). Further data on the prevalence of dyslipidaemia in Poland came from two nationwide studies with random sampling: the NATPOL III PLUS study and the WOBASZ study. The prevalence of hypercholesterolaemia was estimated in the NATPOL study at 59.5% in men and 62% in women, while in the WOBASZ study it was 67% and 64%, respectively [16, 17]. In the NATPOL study, the observed percentage of patients with the LDL-C concentration above the normal range was almost the same in men and women (55%) [16]. In the WOBASZ study, elevated LDL-C concentration was observed in 60% of men and 55% of women [17]. The proportion of patients with decreased HDL-C concentration in the NATPOL study was 17% and 6% in men and women, respectively, and in the WOBASZ study, 15% and 17%, respectively [16, 17]. The NATPOL study results showed that in Poland hypertriglyceridaemia occurred in 30% of the subjects, more often in men than women (38% vs. 23%) [16]. In the WOBASZ study, elevated TG concentration was observed in 31% of men and 20% of women [17]. Significant prevalence of lipid disorders, estimated according to the US NCEP-ATP III (National Cholesterol Education Program – Adult Treatment Panel III) guidelines, was also observed in the nationwide studies LIPIDOGRAM2003, LIPIDOGRAM2004 and LIPIDOGRAM2006, in which a total number of nearly 49,000 primary health care (PHC) patients were eventually included in the databases (including LIPIDOGRAM 2015) [18–20]. In the LIPIDOGRAM2003 study, the mean values of lipid profile parameters were: total cholesterol (TC) – 228 mg/dl (5.9 mmol/l), LDL-C – 140 mg/dl (3.6 mmol/l), HDL-C – 57 mg/dl (1.5 mmol/l), and TG – 156 mg/dl (1.8 mmol/l) [18]. Hypercholesterolaemia > 200 mg/dl (> 5.2 mmol/l) was reported in 72% of the subjects, more often in women than in men (76% vs. 67%). Elevated LDL-C concentration (according to the normal values accepted at the time) of > 160 mg/dl (4.1 mmol/l) occurred in 28% of the enrolled subjects, more often in women than in men (30% vs. 24%). Decreased HDL-C concentration 200 mg/dl (2.3 mmol/l) were observed in 22% of the subjects, more often in men than in women (26% vs. 19%) [18]. Mean values of specific lipid profile parameters and the percentage of abnormal values in subsequent studies – LIPIDOGRAM2004 [19] and LIPIDOGRAM2006 [20] – are presented in Figure 1. Figure 1 Mean values of lipid profile parameters in the LIPIDOGRAM2004 and LIPIDOGRAM2006 studies In another study, i.e. NATPOL 2011, mean values of lipid profile parameters in men and women, respectively, were: TC – 197.1 mg/dl (5.1 mmol/l) and 198.6 mg/dl (5.1 mmol/l), LDL-C – 123.6 mg/dl (3.2 mmol/l) and 123.7 mg/dl (3.2 mmol/l), HDL-C – 45.8 mg/dl (1.2 mmol/l) and 54.1 mg/dl (1.4 mmol/l), and TG – 140.9 mg/dl (1.6 mmol/l) and 104.0 mg/dl (1.2 mmol/l). The percentages of subjects with abnormal values were: TC > 190 mg/dl (4.9 mmol/l) – 54.3% (54.3% of men and 54.4% of women), LDL-C > 115 mg/dl (3.0 mmol/l) – 57.8% (58.3% of men and 57.3 of women), HDL-C 150 mg/dl (1.7 mmol/l) – 21.1% (28.4% of men and 14.0% of women) [4]. In the WOBASZ II study conducted 2 years later, hypercholesterolaemia was reported in 70.3% of men and 64.3% of women aged > 20 years (67.1% of the overall study population), while hypertriglyceridaemia with normal cholesterol concentration was observed in 5.6% of men and 2.4% of women [21]. Decreased HDL-C with normal TC and TG concentration was observed in 5.1% of men and 7.3% of women. Overall, at least one type of dyslipidaemia was reported in as much as 81.0% of women and 74.0% of women. As much as 60.6% of subjects with hypercholesterolaemia were not aware of this fact, and only 6% of patients were effectively treated and achieved reference values of lipid profile parameters [21]. In a 5-year nationwide prospective cohort study of LIPIDOGRAM 5-YEARS, conducted in the years 2004–2010 in a population of PHC patients treated for dyslipidaemia (n = 1841), the reduction of lipid profile parameter values was ineffective in nearly 50% of individuals with TC and LDL-C concentration above the normal range and in more than 30% of individuals with elevated TG levels [22–24]; this de facto confirmed the lack of improvement of effectiveness of treatment of lipid disorders observed also in the earlier screening studies of LIPIDOGRAM2004 and LIPIDOGRAM2006 [22–24]. Insufficient control of hypercholesterolaemia was also observed in subsequent studies, including a study in patients hospitalised for ischaemic heart disease followed up in the Krakow Ischaemic Heart Disease Secondary Prevention Programme [25]. The target LDL-C concentration of 190 mg/dl (4.9 mmol/l) in 58% of active PHC patients > 18 years of age; LDL-C concentration > 115 mg/dl (3.0 mmol/l) was observed in 61% of the subjects, while decreased HDL-C concentration 150 mg/dl (1.7 mmol/l) was observed in 33% of patients. Mean values of lipid profile parameters in the overall population as well as in patients treated and not treated due to lipid disorders, depending on the prevalence of cardiovascular disease (CVD), are presented in detail in Table IV [10]. Table IV Mean values of lipid profile parameters in patients with cardiovascular disease (CVD) and without CVD in the LIPIDOGRAM2015 study population Parameter Overall population CVD (+) CVD (–) Men CVD (+) CVD (–) Women CVD (+) CVD (–) Overall population N 13724 1965 11759 5034 956 4078 8690 1009 7681 TC [mg/dl] 202 ±44 184 ±45 206 ±43 198 ±45 175 ±41 203 ±44 205 ±44 192 ±47 207 ±43 HDL-C [mg/dl] 55 ±15 50 ±14 56 ±15 48 ±13 45 ±12 49 ±13 59 ±15 55 ±14 59 ±15 LDL-C [mg/dl] 129 ±41 114 ±41 131 ±40 127 ±40 109 ±38 132 ±39 129 ±41 118 ±43 131 ±40 Non-HDL-C [mg/dl] 148 ±42 134 ±42 150 ±42 150 ±44 130 ±39 154 ±43 146 ±41 137 ±44 147 ±41 TG [mg/dl] 148 ±118 153 ±104 147 ±121 172 ±153 160 ±127 174 ±158 135 ±90 146 ±76 133 ±92 Treated for dyslipidaemia N 4703 1296 3407 1899 651 1248 2804 645 2159 TC [mg/dl] 192 ±47 178 ±45 197 ±46 186 ±46 171 ±40 194 ±47 196 ±47 185 ±48 199 ±46 HDL-C [mg/dl] 52 ±15 49 ±14 54 ±15 47 ±13 44 ±12 48 ±14 56 ±15 54 ±14 57 ±15 LDL-C [mg/dl] 118 ±42 108 ±40 121 ±42 115 ±39 105 ±36 120 ±40 120 ±44 110 ±43 122 ±43 Non-HDL-C [mg/dl] 139 ±44 129 ±42 143 ±45 139 ±45 127 ±38 146 ±47 140 ±44 131 ±45 142 ±44 TG [mg/dl] 164 ±142 158 ±115 167 ±150 183 ±174 166 ±140 192 ±189 151 ±112 150 ±81 152 ±120 Not treated for dyslipidaemia N 9021 669 8352 3135 305 2830 5886 364 5522 TC [mg/dl] 208 ±42 195 ±44 209 ±42 205 ±43 183 ±43 207 ±42 210 ±41 205 ±42 210 ±41 HDL-C [mg/dl] 56 ±15 52 ±13 57 ±15 49 ±13 46 ±11 49 ±13 60 ±15 57 ±13 60 ±15 LDL-C [mg/dl] 134 ±39 125 ±40 135 ±38 135 ±38 119 ±40 137 ±38 134 ±39 131 ±39 134 ±39 Non-HDL-C [mg/dl] 152 ±40 144 ±40 152 ±40 156 ±42 138 ±40 158 ±41 150 ±40 148 ±40 150 ±40 TG [mg/dl] 140 ±103 144 ±80 140 ±105 165 ±137 151 ±92 166 ±141 127 ±77 139 ±68 126 ±77 Despite changes in the prevalence of cardiovascular diseases and their risk factors (including lipid disorders) observed in Poland between the year 1990 and 2017, differences between Poland and Western Europe remain very high [29]. In Poland, as in other European countries, there are still discrepancies between the current clinical guidelines (2020) and clinical practice with respect to diagnostics and treatment of lipid disorders – only one in 3 patients in Europe and one in 4 in Poland achieves therapeutic goal; only 18% of patients in Europe, 17% in Poland, and only 13% in Central and Eastern European countries achieve the therapeutic goal for very high-risk patients ( 20% 1,2 ; status post-acute coronary syndrome (ACS) with another vascular incident within the past 2 years; status post-ACS and peripheral vascular disease or polyvascular disease 3 (multilevel atherosclerosis); status post-ACS and concomitant multivessel coronary artery disease; status post-ACS and familial hypercholesterolaemia; status post-ACS in a patient with diabetes mellitus and at least one additional risk factor (elevated Lp(a) > 50 mg/dl or hsCRP > 3 mg/lor chronic kidney disease (eGFR 20 years; chronic kidney disease with eGFR 8 mmol/l (> 310 mg/dl), LDL-C > 4.9 mmol/l (> 190 mg/dl), or arterial blood pressure ≥ 180/110 mm Hg; familial hypercholesterolaemia without other risk factors; diabetes without organ damage (regardless of duration) 7 ; chronic kidney disease with eGFR 30–59 ml/min/1.73 m2; Pol-SCORE risk ≥ 5% and 190 mg/dl); 2 The same risk is recommended based on the SCORE2 or SCORE-OP based on the recent 2021 ESC Prevention Guidelines; 3 polyvascular disease (= multilevel atherosclerosis) – the presence of significant atherosclerotic lesions in at least two of three vascular beds, i.e. coronary vessels, cerebral arteries, and/or peripheral arteries; 4 target organ damage is defined as the presence of microalbuminuria, retinopathy, neuropathy, and/or left ventricular myocardial damage; 5 ”other” means 2 or more; 6 major risk factors include: age ≥ 65 years, hypertension, dyslipidaemia, smoking, obesity; 7 not applicable to young adults ( 1.7 mmol/l (150 mg/dl)), being a chronic condition in many individuals with obesity, metabolic syndrome, or diabetes mellitus, intravascular remodelling of LDL particles with formation of small dense LDL (sdLDL) occurs, which may not be reflected by plasma/serum LDL-C concentration. SdLDL particles, readily oxidised and/or glycated, have potent atherogenic activity. Hypertriglyceridaemia accompanied by increased sdLDL fraction and decreased HDL-C plasma/serum concentration is referred to as atherogenic dyslipidaemia [43, 44]. Since blood sdLDL concentration is not routinely determined, hypertriglyceridaemia remains its main indicator. Lipoprotein (a) is a recognised independent cardiovascular risk factor, mainly of ischaemic heart disease/myocardial infarction and aortic valve stenosis [45]. Lp(a) has interindividual structural variability, and isoforms occurring in specific individuals are genetically determined and have an indirect effect on plasma/serum concentration of this lipoprotein (Section 6.8). Its elevated concentration associated with a high cardiovascular risk occurs in up to 20% of the population, up to 30–40% of patients with atherosclerotic cardiovascular disease, and 30–40% of individuals with familial hypercholesterolaemia. Elevated values are also observed in pregnant women, which may affect prognosis associated with the risk of preeclampsia, pre-term labour, or low birth weight [45–47]. Atherosclerosis is a polyaetiological condition and, similarly to cardiovascular diseases being its result (ASCVD), depends on many risk factors. In addition to “classical” risk factors of atherosclerosis, known since the time of the Framingham Heart Study (FHS), i.e., dyslipidaemia, tobacco smoking, and arterial hypertension, these include obesity, prediabetes and diabetes mellitus, chronic kidney disease, persistent inflammation, sedentary lifestyle, and many others. According to the principle of primary and secondary prevention of cardiovascular events, i.e., detect and eliminate or control all possible risk factors, these should be identified, and the patient should be classified in the appropriate total cardiovascular risk category (Table V). The overall risk determines the management to control its factors, and in dyslipidaemia sets the goals of treatment (Section 7). A cardiovascular risk assessment tool widely used in primary prevention, especially in the primary care setting, is the Pol-SCORE scale (Figure 2) [48], a modification of the SCORE (systemic coronary risk evaluation) scale developed by the European Society of Cardiology (ESC) experts. It is used to estimate the 10-year risk of cardiovascular death based on the patient’s sex, age, systolic blood pressure, smoking status, and plasma/serum total cholesterol concentration. The scale has been developed for people over 40 years of age and should not be used in patients with diabetes and/or chronic kidney disease. Figure 2 SCORE tables calibrated for the Polish population (Pol-SCORE 2015) [48]. Numbers in the table represent 10-year risk of cardiovascular death Evaluation of the total cardiovascular risk beyond the SCORE scale (Table V) requires extended diagnostics, including detailed clinical assessment, especially of the cardiovascular system, as well as tests concerning the carbohydrate metabolism/diabetes complications, renal function, etc. In the latest ESC/EAS 2019 guidelines [9] on the management of lipid disorders, the concept of extreme risk has been introduced to differentiate the risk among very high-risk patients (being a very heterogeneous group). Based on the results of available studies [48, 49], the definition of extreme risk was then extended in the PSDL/PoLA 2020 guidelines [50], and the current guidelines provide the optimum definition according to evidence-based medicine (EBM). Although achievement of therapeutic goals for this group ( 5 mmol/l (440 mg/dl) [35, 55]. The determined lipid concentrations are characterised by intra-subject variability of 5–10% for TC and > 20% for TG. In addition to genetic predispositions, variability in TC and TG concentration results from physical activity, diet, including carbohydrate and alcohol content, and smoking. Changes in lipid profile occur during pregnancy, particularly in the third trimester, mainly as an increase in TG (up to 3 times), TC and Lp(a) concentration, to a lesser extent, LDL-C (usually up to 50%) and HDL-C [8]. Higher TC and TG concentrations are observed in winter [51, 53, 55]. TC and LDL-C concentration is reduced for several weeks after a cardiovascular event and in chronic inflammation, e.g., in rheumatic diseases (lipid paradox), as well as in the elderly, especially those over 75 years of age [4, 56, 57]. Cholesterol and triglycerides are components of large molecule lipoproteins; therefore, maintenance of a compression band > 3 min or standing up for > 30 min before blood sampling may increase their concentration by 10–12% due to increased blood density, which should be avoided. Serum TC, HDL-C, LDL-C, and TG concentrations are approximately 3% higher than in plasma. Plasma/serum samples can be stored at a temperature of ~+4°C up to 4 days, while longer storage requires freezing at a temperature of –70°C [35]. 6.2. Triglycerides Triglycerides or triacylglycerols (TG) are esters of glycerol (an alcohol) and 3 molecules of fatty acids. TG are largely used as an energy source for the body and constitute the main component of fat cells [58]. They are synthesised endogenously and constitute most of the fat mass of food (exogenous origin – as chylomicron triglycerides) [58, 59]. Hypertriglyceridaemia reflects increased concentration of TG-rich lipoproteins, including atherogenic molecules (VLDL, CM remnants and VLDL remnants) leading to cardiovascular diseases, chronic inflammation, and increased overall mortality [60]. Increased TG concentration coexisting with low HDL-C concentration and high levels of small dense LDL particles is called atherogenic dyslipidaemia. Therefore, TG concentration is essential in the assessment of residual risk, as a high TG concentration even with the target LDL-C concentration significantly and independently increases cardiovascular risk [61–63]. In addition, very high hypertriglyceridaemia is associated with an increased risk of acute pancreatitis. Plasma/serum TG concentration is measured using enzymatic assays and automated analysers [64]. The acceptable total error of TG measurement, as recommended by the US National Cholesterol Education Program (NCEP), is ±15%, and according to the Centre for Quality Assessment in Laboratory Diagnostics (COBJwDL), ±10% [50]. 6.3. Total cholesterol Cholesterol is obtained from food (~30%) or synthesised de novo, mainly in the liver and intestines (~70%). The amount of synthesised cholesterol depends on its level in the cells. Cholesterol affects the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase by inhibiting its gene expression. The enzyme, HMG-CoA reductase, catalyses the key reaction in this pathway and is the site of action for statins. As the only de novo synthesised steroid, cholesterol is a substrate for the synthesis of steroid hormones, bile acids, and cardiotonic steroids (CTS). Cholesterol also plays an important role as a component of biological membranes, i.e., cytoplasmic and cell organelle membranes. Ca. 70% of blood cholesterol is transported by LDL; therefore, total cholesterol concentration indirectly and approximately reflects the amount of cholesterol in these plasma lipoproteins [50]. In clinical practice, TC concentration is used to stratify cardiovascular risk using the SCORE scale and to assess the severity of hypercholesterolaemia (suspected familial hypercholesterolaemia) and as the basis for therapeutic decisions in the absence of LDL-C calculation/test results (very rarely at present) [9, 65, 66]. Furthermore, the TC concentration must be known in order to calculate the LDL-C and non-HDL-C concentration. In medical laboratory practice, serum/plasma TC concentration is measured using enzymatic assays and automated analysers [67]. The acceptable total error of TC measurement, as recommended by the NCEP, is ±9%, and according to the COBJwDL – ±8% [50]. 6.4. High density lipoprotein cholesterol High density lipoproteins (HDL) are a heterogeneous group consisting of essentially two lipoprotein fractions of different particle size and density. In physiological conditions, HDL inhibit development of atherosclerosis mainly by their participation in reverse cholesterol transport from tissues, including macrophages in arterial walls, to the liver [68]. In addition, HDL have anti-oxidative activity and inhibit LDL oxidation [69], restore vascular endothelial function, and demonstrate anti-inflammatory and anti-apoptotic effects [70]. Inflammation and oxidative stress as well as glycation lead to changes in particle composition and dysfunctional HDL formation, with the loss of their anti-oxidative and anti-inflammatory properties and limitation of their activity in reverse cholesterol transport [71]. As a result, pro-atherogenic activity is attributed to dysfunctional HDL [71–73]. Laboratory tests used routinely to determine the HDL-C concentration in the blood do not make it possible to differentiate fractions (subfractions/subpopulations) or to assess functionality of these lipoproteins and therefore their role in atherogenesis in the examined patient. Methods of assessment of both heterogeneity and functionality of HDL are not available for routine laboratory diagnostics [35, 74–76]. Although an inverse relationship between blood HDL-C concentration and the risk of cardiovascular events has been demonstrated repeatedly, studies concerning agents increasing its concentration (i.e., niacin or cholesterol ester transfer protein (CETP) inhibitors) have not yet demonstrated their beneficial effects in terms of cardiovascular risk reduction [77, 78]. At present, HDL-C concentration is not recommended as a target in treatment of dyslipidaemia, a predictor of cardiovascular risk, or in monitoring of lipid disorders. However, HDL-C may be considered as an additional parameter in cardiovascular risk stratification using the SCORE scale. Nevertheless, HDL-C concentration remains an important element of the lipid profile as it is used to calculate LDL-C and non-HDL-C concentration [50]. Although plasma/serum HDL-C concentration brings only indirect information on the HDL blood content, it is still the main parameter in assessment of the number of HDL particles. Direct methods of measurement of the number of HDL particles (HDL-P) and their individual fractions (nuclear magnetic resonance spectrometry, ion mobility analysis, electrophoretic techniques) are not available for routine laboratory diagnostics. In addition, they do not provide sufficient new data to recommend them [50]. In diagnostic laboratories, enzymatic direct (homogenous) methods and automated analysers are commonly used for determination of plasma/serum HDL-C concentration. In these methods, detergents dissolving HDL and adsorptively blocking the access of enzymes to cholesterol in VLDL and LDL particles are used as reagents [35]. They are standardised and lower accuracy of measurements may be due to the matrix effect (media), e.g., in dyslipidaemias. According to the NCEP recommendations, the acceptable total error for direct HDL-C measurement methods is ±13% for normolipaemic samples and –20% to +36% for dyslipidaemic samples. Inaccurate results are mostly observed at HDL-C concentrations 4.5 mmol/l (400 mg/dl) – in such conditions, the TG/VLDL-C ratio is different from the assumed. The results of calculations using the Friedewald formula are also less accurate if intermediate density lipoproteins (IDL) are present in the plasma as well as in conditions in which the composition of lipoprotein particles is changed (obesity, type 2 diabetes mellitus, metabolic syndrome, kidney, and liver diseases). The Friedewald formula also tends to decrease the results at low LDL-C concentrations 1.7 mmol/l (150 mg/dl) [80]. The calculated LDL-C concentration is also affected by the sum of errors of measurements used in the formula. A modification of the Friedewald formula is the Martin and Hopkins formula (2013) [79]: LDL-C = TC – HDL-C – TG/x (in mg/dl) where x is the TG/VLDL-C ratio based on the concentration of TG and non-HDL-C; these values are available in special tables or online calculators, e.g., www.ldlcalculator.com. It has been demonstrated that this formula is more accurate than the Friedewald formula for calculation of LDL-C at low concentrations and TG concentration in the range of 2.0–4.5 mmol/l (175–400 mg/dl), also in non-fasting samples [80–82]. The use of the Martin and Hopkins formula is limited by the need to purchase the license. Recently, a new formula for LDL-C calculation has been proposed, which provides more accurate results than both the above. The formula is more complex but compatible with modern laboratory IT systems. The new formula may be used in patients with low LDL-C concentration and those with significant hypertriglyceridaemia, up to 8.8 mmol/l (800 mg/dl) [83]. However, assessment of its practical use in laboratories will require time and further studies. LDL-C concentration may be measured by enzyme-based direct (homogenous) methods using reagents containing detergents, surfactants, and other blocking components, or dissolving individual lipoprotein fractions, making LDL-C selectively available to the enzymes. The measurements are performed using automated analysers. The acceptable total error of measurement/calculation of LDL-C concentration, as recommended by the NCEP, is ±12 [50]. Currently, due to the limitations of the LDL-C concentration calculation described above, it is also recommended to calculate the non-HDL-C concentration or measurement of apoB concentration as an alternative to LDL-C concentration, and not its direct measurement [9, 35]. The calculated/measured LDL-C concentration is the sum of LDL-C and Lp(a) cholesterol concentration, which may result in elevated LDL-C concentration. The LDL-C concentration calculated using the Friedewald formula may be corrected for Lp(a) cholesterol using the Dahlen’s modification based on the assumption that cholesterol accounts for 30% of weight of Lp(a) particles [50, 84]: LDL-Ccorr = TC – HDL-C – TG/5 – [Lp(a) × 0.3] (in mg/dl) This adjustment can be made for LDL-C concentrations determined in any other way. 6.6. Non-HDL cholesterol Non-HDL cholesterol (non-HDL-C) concentration reflects the plasma content of all apoB-containing lipoproteins: LDL, VLDL, IDL, CM, CM remnants, VLDL remnants, and Lp(a), involved in the initiation of atherogenesis, and development and destabilisation of atherosclerotic plaques [85, 86]. As an indicator of atherogenic lipoprotein concentration, non-HDL-C concentration is very important for the assessment of cardiovascular risk and should be a permanent component of the lipid profile. This is of particular diagnostic importance if the accuracy of the LDL-C concentration calculation is limited. According to numerous studies, non-HDL-C concentration is more predictive for cardiovascular risk than LDL-C concentration [87, 88]. Non-HDL-C concentration is calculated using the following formula: Non-HDL-C = TC – HDL-C (in mmol/l or mg/dl) The calculated non-HDL-C concentrations are based on TC concentration calculated or determined using standardised methods and HDL-C concentration also determined by standardised direct methods. Nevertheless, the result of non-HDL-C concentration calculation is affected by the sum of errors of both measurements. 6.7. Apolipoprotein B Apolipoprotein B (apoB), a component of all lipoproteins except HDL, occurs in two isoforms: apoB 100 present in VLDL, IDL and LDL, and apoB 48 (a fragment of apoB 100) present in CM and their remnants [9, 89]. Each LDL particle contains one apoB 100 molecule; therefore, the concentration of this apolipoprotein is a measure of the content of LDL particles in plasma/serum and a cardiovascular risk factor equivalent to the LDL-C concentration [90]. Measurement of the apoB concentration should be, in addition to calculation of the non-HDL-C concentration, an alternative to LDL-C calculation when its accuracy is reduced [9, 50]. Unfortunately, in Poland, apoB is still very rarely measured, which is due to the ongoing debate on the actual added value of this parameter in relation to LDL-C and non-HDL-C, as well as to additional costs of the test. In laboratory practice, plasma/serum apoB concentration is determined using standardised immunoturbidimetric or immunonephelometric methods and automated analysers. The antibodies used in these methods are directed against apoB 100, although apoB 48 may also be measured using some of them. Possible interference with apoB 48 is marginal, as in the analysed material apoB 100 molecules, almost entirely LDL components, constitute of > 90% of apoB. The limit of acceptable error for apoB concentration measurement recommended by the NCEP is ±6% [50]. 6.8. Lipoprotein (a) Lipoprotein (a) (Lp(a)) particles are a subpopulation of LDL of similar structure, containing one apoB 100 molecule combined with apolipoprotein (a) [apo(a)]. There is significant inter-individual variability as to molecular weight of Lp(a), depending on the number of repetitions of the kringle IV type 2 (KIV-2) domain, ranging from 3 to 40, genetically determined. This genetically determined Lp(a) particle size is inversely proportional to the rate of its synthesis, mainly in the liver, and its plasma/serum concentration [9, 91]. In Poland, the concentration of Lp(a) is measured definitely too rarely, and the knowledge about it is still very limited. Therefore, every effort should be made to change it as soon as possible. This is necessary due to a great scientific progress in this field. Today we know that Lp(a) is an independent cardiovascular risk factor and that up to > 30% of patients with familial hypercholesterolaemia and/or acute coronary syndrome may have an elevated Lp(a) concentration, often with the desired LDL-C concentration, and there are options for pharmacological reduction of Lp(a) concentration [45, 92–95]. Therefore, we recommend that plasma/serum Lp(a) concentration should be measured once in every adult individual’s life to detect patients with its elevated concentration in whom the cardiovascular risk is high. Specific indications for Lp(a) measurement are: premature onset of cardiovascular disease, the lack of expected effect of statin therapy, and the need for better risk stratification in moderate- to high-risk individuals [50]. In diagnostic laboratories, plasma/serum Lp(a) concentration is determined mainly by immunochemical methods, i.e., immunoturbidimetric or immunonephelometric, or various immuno-enzyme methods, including ELISA. These tests may be performed routinely and readily available. Although the methods are standardised, sufficient harmonisation of results has not been achieved; this is considered a consequence of the impact of apo(a) particle size variation on the results of Lp(a) immunochemical assays [84, 96–98]. Therefore, for repeated Lp(a) concentration measurements the same method should be applied. 6.9. Laboratory report of the lipid profile The lipid profile includes a set of blood plasma/serum tests discussed above performed for the diagnosis and monitoring of treatment of dyslipidaemia and to obtain a general picture of cardiovascular risk: total cholesterol concentration (TC), HDL cholesterol concentration (HDL-C), LDL cholesterol concentration (LDL-C), non-HDL cholesterol concentration (non-HDL-C), triglycerides concentration and ordered as indicated: apolipoprotein B concentration (apoB), lipoprotein (a) concentration (Lp(a)). In addition to the measured/calculated results, the laboratory lipid profile report (Table VIII) should include information on how the LDL-C concentration was determined, as well as the target (desired) and alarm concentrations of individual analytes [100]. If severe dyslipidaemia is suspected, it should also contain information on the need for an urgent medical consultation in case of LDL-C concentration indicating a possible diagnosis of heterozygous (> 5.0 mmol/l, 190 mg/dl) or homozygous (> 13.0 mmol/l, 500 mg/dl) familial hypercholesterolaemia (FH), Lp(a) concentration > 180 mg/dl (450 nmol/l) indicating a very high risk of cardiovascular events, or TG concentration > 10.0 mmol/l (880 mg/dl) indicating a high risk of acute pancreatitis or suspected familial chylomicronaemia syndrome (FCS) [99]. It is helpful for interpretation and authorisation of the results by laboratory technicians to provide information on the referral form whether the patient is overweight/obese and/or suffers from diabetes, and whether they receive lipid-lowering therapy (Table IX). Table VIII Lipid profile – recommended contents of the laboratory report Parameter Result [mg/dl] [mmol/l] Target values Alarm values Total cholesterol (TC) Fasting and non-fasting: 290 mg/dl (7.5 mmol/l) 1 – suspected heterozygous FH HDL cholesterol (HDL-C) Fasting and non-fasting: > 40 mg/dl (1.0 mmol/l) for men and > 45 mg/dl (1.2 mmol/l) for women Triglycerides (TG) Fasting: 880 mg/dl (10.0 mmol/l) – suspected familial chylomicronaemia syndrome (FCS) LDL cholesterol (LDL-C) 2 Fasting and non-fasting; cardiovascular risk: extreme 500 mg/dl (13 mmol/l) – suspected homozygous FH (> 300 mg/dl [8 mmol/l] in patients on treatment); > 190 mg/dl (5.0 mmol/l) – suspected heterozygous FH Non-HDL cholesterol (non-HDL-C) Fasting and non-fasting; cardiovascular risk: extreme 50 mg/dl (125 nmol/l) high risk; > 180 mg/dl (450 nmol/l) very high cardiovascular risk 1 FH – familial hypercholesterolaemia; in relation to the Simon Broome (UK) and MEDPED (US) FH diagnosis criteria [100]; 2 at TG > 400 mg/dl (4.5 mmol/l), the LDL-C concentration is not calculated. An equivalent cardiovascular risk indicator is non-HDL-C or apoB concentration. URGENT MEDICAL CONSULTATION REQUIRED* *To be added to alarm findings indicating suspicion of severe dyslipidaemia. Table IX Recommendations concerning the lipid profile measurement Recommendations Class Level LDL-C concentration is a key lipid parameter determining the cardiovascular risk and defining the goals of lipid-lowering therapy. I A TG is a permanent component of the lipid profile. A high TG concentration, as a part of atherogenic dyslipidaemia, increases cardiovascular risk regardless of the achieved target LDL-C. I B Non-HDL-C is a permanent component of the lipid profile. I C ApoB is a predictor of cardiovascular risk equivalent to LDL-C concentration and it is recommended to be measured primarily in individuals with TG concentration > 4.5 mmol/l (400 mg/dl), obesity, diabetes mellitus, metabolic syndrome, and low TC and LDL-C concentration. I C Lp(a) concentration should be measured at least once in every adult individual’s life. IIa C Measurement of Lp(a) should be considered in all patients with premature onset of cardiovascular disease, the lack of expected statin therapy effect, and in those with a borderline risk between moderate and high, for better risk stratification. IIa C Measurement of Lp(a) may be considered in patients with very high cardiovascular risk and atherosclerotic cardiovascular disease, in patients with familial hypercholesterolaemia, and in pregnant women as a prevention of pre-eclampsia or miscarriage, in recurrent pregnancy loss, or intrauterine growth restriction. IIb C KEY POINTS TO REMEMBER The lipid profile includes measurement of serum/plasma concentrations of TG, TC, HDL-C, LDL-C, non-HDL-C, and, as indicated, apoB and Lp(a). In is not necessary to obtain blood samples for lipid profile testing in fasting conditions; repetition of the tests in fasting conditions should be considered at TG concentration > 5 mmol/l (440 mg/dl) in non-fasting conditions. A high TG concentration even with the target LDL-C concentration attainment significantly increases cardiovascular risk (residual cardiovascular risk). HDL-C concentration is not a predictor of cardiovascular risk or a target of lipid-lowering therapy. LDL-C concentration is a key lipid parameter determining cardiovascular risk and a target of lipid-lowering therapy. LDL-C concentration may be calculated using the Friedewald formula or Martin and Hopkins formula with TG ≤ 4.5 mmol/l (400 mg/dl); at low LDL-C concentration 2.0 mmol/l (175 mg/dl), Martin and Hopkins formula is recommended. In individuals with TG concentration > 4.5 mmol/l (400 mg/dl), obesity, diabetes mellitus, metabolic syndrome, or low TC and LDL-C concentration, calculation of non-HDL-C or measurement of apoB concentration is recommended. It is recommended to calculate non-HDL-C concentration along with calculation/measurement of LDL-C. It is a very important parameter in evaluation of cardiovascular risk; more predictive than LDL-C concentration. Plasma/serum Lp(a) concentration should be measured once in every adult individual’s life to detect patients with elevated concentration increasing cardiovascular risk, especially those with extremely high Lp(a) levels ≥ 180 mg/dl (≥ 430 nmol/l) and therefore with a very high lifetime risk of ASCVD, approximately equivalent to the risk associated with HeFH. The laboratory lipid profile report should include the results of measurements as well as the target (desired) and alarm concentrations of the analytes, and information on the need for urgent medical consultation. 7. Therapy goals of lipid disorders – target values depending on the risk The most important parameter of the lipid profile is LDL cholesterol. This is due to several facts, well-known for a long time. Firstly, epidemiological studies have demonstrated a close relationship between cholesterol concentration and the risk of cardiovascular events, mainly coronary events [8, 9]. Secondly, experimental studies indicate the central role of cholesterol in the pathogenesis of atherosclerosis and its complications [8, 9]. Thirdly, it has been demonstrated that cholesterol present in atherosclerotic plaques is derived from LDL particles [8, 9]. Fourthly, intensive pharmacological reduction of LDL-C concentration results in regression of atherosclerosis [101–103]. Fifthly, reduction of cholesterol concentration is associated with a proportional reduction of the risk of cardiovascular events [104, 105]. For these reasons, reduction of LDL-C concentration is the main (primary) target of lipid-lowering therapy. However, in recent years it has also been unequivocally demonstrated that not only effective reduction of cholesterol concentration according to the rule of “the lower the better” is important, but that achievement of the therapeutic goal for LDL-C as soon as possible, according to the rule of “the earlier the better”, and maintaining it as long as possible (= “the longer the better”), is also of critical importance [2, 6, 7, 106]. No LDL cholesterol concentration has been identified below which no further benefits of lipid-lowering therapy can be observed (even for 20% (Tables V and X). However, it seems, particularly in the context of the latest analysis of the TERCET registry, in which we attempted to validate all available definitions and select those risk factors that significantly increase the risk of another myocardial infarction in a 12- to 36-month follow-up period, that this definition may still be changed [114]. Table X Recommended LDL-C concentrations as lipid-lowering treatment goals Recommendations Class Level In secondary prevention patients with a very high cardiovascular risk, it is recommended to reduce LDL-C concentration to 20% OR after an acute coronary syndrome (ACS) and another vascular incident within the previous 2 years OR after an acute coronary syndrome with peripheral vascular disease or polyvascular disease OR after an acute coronary syndrome with multivessel coronary artery disease OR after an acute coronary syndrome with familial hypercholesterolaemia OR after an acute coronary syndrome with diabetes mellitus and at least one additional risk factor (elevated Lp(a) > 50 mg/dl or hsCRP > 3 mg/l or chronic kidney disease (eGFR 10% of food energy), significantly translates into increased TG concentration [120]. Fructose intake equivalent to 15–20% of food energy increases plasma TG concentration by up to 30–40% [124]. The best results in terms of reduction of plasma TG concentration are achieved with food products with a low glycaemic index (e.g., raw fruit, vegetables, thick groats, oat bran, cottage cheese, fish). Glycaemic index makes it possible to identify foods with a rapid glucose absorption profile and differentiate them from products from which carbohydrates are slowly absorbed to plasma. Fibre contained in plant products decreases the glycaemic index of food products by means of glucose absorption followed by its gradual release during intestinal transit [125]. 8.3. Effect on HDL-C High density lipoproteins with normal functionality have anti-atherosclerotic properties. Anti-atherosclerotic activity of HDL is mainly related to their participation in reverse cholesterol transport, but also with their anti-inflammatory, anti-oxidative, anti-apoptotic, anticoagulation, cytoprotective, vasodilatory, or even antitumour activity [126, 127]. HDL-C concentration provides no information on HDL functionality. Unfortunately, pharmacological attempts to increase concentration of these lipoproteins have not produced satisfactory effects in terms of cardiovascular risk reduction; therefore, only methods of behavioural medicine remain at present at our disposal. Lifestyle modification leading to weight reduction contributes to an increase in HDL-C plasma concentration by 0.01 mmol/l (0.4 mg/dl) for every kg lost. Systematic exercise of moderate intensity ca. 300 min per week may increase HDL-C concentration by 0.15 mmol/l (6 mg/dl) [128]. Each 1000 kcal used translates into an increase of HDL-C concentration by ca. 3 mg/dl. Smoking cessation is also beneficial, provided that it does not result in body weight increase [129]. The most significant HDL-C increase may be observed as a result of trans-fats intake reduction; moreover, unsaturated trans fats increase LDL-C concentration. An increase in HDL-C is observed when SFA intake is increased. Unfortunately, this increase is associated with an increase in LDL-C, which in turn does not produce a beneficial effect in terms of cardiovascular risk reduction and cannot be recommended. It should be emphasised that conversion from fat to monosaccharides as a food energy source results in reduction of HDL-C concentration. However, this effect was not observed with conversion to complex carbohydrates and fibre-rich foods (with a low glycaemic index) [116]. Alcohol consumption is a dietary habit inducing an increase of HDL-C concentration. However, it should be remembered that this applies only to moderate alcohol consumption (up to 30 g/day in men and up to 20 g/day in women), and its abuse is a risk factor of numerous diseases. Due to the risk of dependence and alcohol-related harm, its consumption should not be recommended to patients; moreover, recent analyses of the Global Burden of Disease (GBD) expert group clearly indicate that any amount of alcohol is harmful, and such a recommendation should be given to patients [130]. 8.4. Significance of nutraceuticals and modified foods Functional foods/nutraceuticals have potentially significant functional effect that helps to achieve therapeutic goals in terms of concentration of TC and individual fractions. Interestingly, most natural products have pleiotropic effects (although it is an incorrect name), affecting not only the lipid profile but also glucose concentration, insulin resistance, vascular stiffness, blood pressure, inflammation, or oxidative stress [131]. Moreover, as natural products, they are very safe, provided that production quality is maintained, and no impurities or additional substances are present (e.g., citrinin in red rice). Therefore, for several years, apart from their focus on the properties of nutraceuticals, manufacturers and experts have also very seriously treated safety, its monitoring and reporting the occurrence of all adverse reactions (nutrivigilance) [132, 133]. Below we present only a few examples of nutraceuticals with documented lipid-lowering properties; see Table XIII for a complete list. The experts of these guidelines have adapted with minor modifications the recommendations of the International Lipid Expert Panel (ILEP) on the use of nutraceuticals in treatment of lipid disorders [134–136]. Table XIII Recommendations for the use of nutraceuticals in treatment of lipid disorders (adapted International Lipid Expert Panel 2017 guidelines with modifications [134, 135]) Name Recommended dosage Expected LDL-C reduction Class of recommendation Level of recommendation Inhibitors of cholesterol absorption from the intestine Plant sterols and stanols 400–3000 mg –8% to –12% IIa A Soluble fibre (beta-glucan, psyllium, glucomannan) 5–15 g –5% to –15% IIa A Chitosan 1–6 g –5% IIb A Probiotics Depending on bacterial strain –5% IIb B Inhibitors of hepatic cholesterol synthesis Red yeast rice extract 3 years), not only confirmed their high efficacy [178], but also provided the basis for identification of patients with extreme cardiovascular risk and creation of a reimbursement programme which since November 1st, 2018, has been available for patients with familial hypercholesterolaemia, and since November 1st, 2020, for patients post myocardial infarction. Unfortunately, the adopted reimbursement criteria make it possible to include only about 5–7% of patients with FH (due to the required high LDL-C concentration despite treatment) and a relatively small group of post-MI patients (mainly due to the need to include them within 12 months of MI onset). Due to all the above, at the time of preparation of these guidelines approximately 200 patients in total, mostly those with FH (a little more than 150) in nearly 30 centres in Poland (the list is available on PoLA website: https://ptlipid.pl/2020/09/28/osrodki-w-osrodki-w-polsce-w-polsce-w-ktorych-jest-realizowany-program-lekowy-ktorych-jest-realizowany-program-lekowy-leczenie-hipercholesterolemii-rodzinnej-icd-10-e78-01/) have been included into the therapeutic programme. As a result of intensive activity of the Societies (PoLA, PSC), experts, and patient organisations, the criteria have been changed since September 1st 2021, currently enabling treatment of patients with FH as early as at LDL-C > 100 mg/dl (2.5 mmol/l) and after not 6 but 3 months of prior statin and ezetimibe therapy (Table XVI). Table XVI Therapeutic programme: treatment with PCSK9 inhibitors in patients with lipid disorders (ICD-10 E78.01, I21, I22, I25) Scope of guaranteed benefit Beneficiaries Dosing regimen In the programme Diagnostic tests performed As a part of the programme 1. Eligibility criteria 1.1. Treatment of patients with familial hypercholesterolaemia Meeting of the following cumulative conditions: age 18 years and over definite diagnosis of heterozygous familial hypercholesterolaemia, i.e., the Dutch Lipid Clinic Network score > 8 LDL-C > 100 mg/dl (2.5 mmol/dl) despite dietary intake, and: intensive statin treatment at maximum doses, i.e., atorvastatin 80 mg or rosuvastatin 40 mg, followed by atorvastatin 40–80 mg or rosuvastatin 20–40 mg in combination with ezetimibe 10 mg; used for a total of 3 months, including combination therapy with ezetimibe for at least 1 month or intensive statin treatment at maximum tolerated doses followed by a statin in combination with ezetimibe 10 mg; used for a total of 3 months, including combination therapy for at least 1 month 1.2. Treatment of patients at very high cardiovascular risk Meeting of the following cumulative conditions: age 18 years and over LDL-C > 100 mg/dl (2.5 mmol/l) despite diet and intensive statin treatment at maximum tolerated doses followed by statins at maximum tolerated doses with ezetimibe. A total treatment period of at least 3 months is required, including at least 1 month of combination therapy (a statin at maximum tolerated doses + ezetimibe). In patients with suspected statin-related rhabdomyolysis, treatment duration is determined by the treating physician according to ESC/EAS guidelines A history of myocardial infarction diagnosed using invasive methods within 12 months prior to inclusion in the therapeutic programme and: additional history of myocardial infarction and multivessel coronary disease, defined by at least 50% stenosis in at least 2 vessels or with atherosclerotic disease of non-coronary arteries, defined as: peripheral arterial disease (PAD), i.e., intermittent claudication with an ankle-arm index (ABI) 204 mg/dl and HDL-C 2.3 mmol/l). Adverse effects of fibrates are generally moderate and rarely observed. Myalgia and myopathy (in combination with high-dose statins) as well as increased aminotransferase activity have been reported. These agents increase creatinine concentration. It should be known that fibrates are in 60–90% excreted renally, which limits their use in chronic kidney disease. Increased homocysteine concentration, cases of acute pancreatitis, and thromboembolism were also observed [8, 115]. KEY POINTS TO REMEMBER The main indication for the fibrate therapy is severe hypertriglyceridaemia. In this case, fibrates are the first-line agents. In patients with hypertriglyceridaemia statins are the first-line agents. Addition of a fibrate to a statin should be considered in patients with persistent hypertriglyceridaemia (TG > 200 mg/dl or 2.3 mmol/l) despite statin therapy. 9.5. Omega-3 acids The importance of omega-3 has been discussed in detail in Section 8.4. It should be emphasised that their role in treatment of hypertriglyceridaemia has changed significantly over the last few years, especially after the REDUCE-IT (the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) study was published; it concerned highly purified eicosapentaenoic acid (EPA) (icosapent ethyl) which in a dose of 4 g/day demonstrated high efficacy in both primary prevention (in patients with diabetes and other risk factors) and secondary prevention in patients with ASCVD, reducing the primary endpoint of the study by 25% (HR = 0.75; 95% CI: 0.68–0.83; p 50 years for men and > 55 years for women) who were treated with vitamin D3 (2000 IU daily) and n-3 fatty acids of marine origin (1 g/day). The use of omega-3 acids did not significantly affect the study endpoints; only significant reduction in the risk of myocardial infarction was observed (HR = 0.72; 95% CI: 0.59–0.90) [193]. As noted in the comments, negative results of the study could be associated with a low-risk patient population (primary prevention), the form of omega-3 acids used (mixture), or a low dose used in the study. Therefore, in a subsequent STRENGTH (A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction with EpaNova in HiGh Cardiovascular Risk PatienTs with Hypertriglyceridemia) study the effect of a preparation containing EPA and DHA carboxylic acids in a dose of 4 g/day was investigated in over 13,000 patients with high cardiovascular risk and atherogenic dyslipidaemia treated with statins. Interestingly, in the study corn oil was used as placebo, which might have had an impact on the results of the study. The primary composite endpoint comprised cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. When 1384 patients experienced the primary endpoint (of the planned 1600 events), the study was prematurely terminated based on an interim analysis that demonstrated low probability of clinical benefit from the use of omega-3 CA vs. the comparator applied. The primary endpoint occurred in 785 (12.0%) omega-3-treated patients compared with 795 (12.2%) corn oil-treated patients (HR = 0.99; 95% CI: 0.90–1.09; p = 0.84) [194]. In the omega-3 group, a significant reduction in TG concentration by 19% and hsCRP by 20% in comparison with the control group was observed [194]. A meta-analysis summarising studies concerning omega-3 acids published in recent years, which finally included 13 studies covering 127,447 individuals, demonstrated significant reduction of the risk of death due to ischaemic heart disease (risk ratio (RR) = 0.91, 95% CI: 0.85–0.97, p = 0.010), major vascular events (RR = 0.95, 95% CI: 0.93–0.98, p = 0.001), nonfatal myocardial infarction (RR = 0.89, 95% CI: 0.83–0.95, p = 0.001) and all-cause mortality (RR = 0.95, 95% CI: 0.92–0.99, p = 0.025) [195]. The REDUCE-IT study significantly changed the view on omega-3 fatty acids and their use in treatment of hypertriglyceridaemia. In December 2019, the FDA approved an icosapent ethyl formulation (Vazkepa) for treatment of hypertriglyceridaemia in order to reduce cardiovascular risk in high-risk patients [196]. In January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending marketing authorisation of Vazkepa to reduce the risk of cardiovascular events in patients at high cardiovascular risk [196]. Therefore, currently we recommend the use of omega-3 acids (in Poland Vazkepa is still unavailable, and combined formulations of omega-3 acids in a dose of less than 1 g are dominant) in treatment of hypertriglyceridaemia in a dose of at least 2 g daily, as adjunct treatment to statins and fibrates, except in patients already using omega-3 acids in combination with statins, in whom fibrates can be used as a 3rd line treatment. KEY POINTS TO REMEMBER Omega-3 polyunsaturated acids significantly reduce triglyceride concentration (by 20–30%) and hsCRP (by 12–20%). In patients with hypertriglyceridaemia statins are the first-line agents. Addition of omega-3 acids in a dose of at least 2 g to a statin and a fibrate may be considered in patients with persistent hypertriglyceridaemia (TG > 200 mg/dl or 2.3 mmol/l) despite combination therapy. If available, icosapent ethyl should be considered in a dose of 2 × 2 g in addition to a statin in very high-risk patients with ASCVD with persistent TG concentration > 150 mg/dl. 9.6. Bile acids sequestrants (resins) Resins bind bile acids in the intestine, reducing their enterohepatic circulation. In this way, by feedback, conversion of cholesterol into bile acids in the liver is activated. Reduced cholesterol content in hepatocytes increases expression of the LDL receptor, which in turn reduces serum LDL-C concentration [197]. In some patients resins may increase hepatic VLDL formation, resulting in increased serum TG concentration. In addition, they reduce glucose concentration in patients with diabetes mellitus. Addition of colesevelam to antidiabetic agents significantly improves glycaemic control, although no data on the effect of such treatment on cardiovascular risk reduction are available [197]. Bile acids sequestrants in maximum doses, i.e., cholestyramine 24 g/day, colestipol 20 g/day, or colesevelam 4.5 g/day reduce LDL-C concentration by 18–25%. No significant effect on HDL-C levels has been observed. Treatment with cholestyramine in primary prevention in patients with hypercholesterolaemia resulted in significant reduction in cardiovascular episodes by 19% [198, 199]. A colesevelam preparation (Cholestagel) is available on the Polish market, and the use of ion exchange resins is currently limited to treatment of severe hypercholesterolaemia during pregnancy. Resins are not absorbed from the gastrointestinal tract and demonstrate no systemic toxicity. However, they often cause gastrointestinal adverse effects (constipation, flatulence, nausea). They reduce absorption of fat-soluble vitamins. To avoid reduced absorption of other medicines, ion exchange resins should be taken 4 h before or 1 h after other medicines. Colesevelam is the best tolerated resin [200]. KEY POINTS TO REMEMBER Bile acids sequestrants in monotherapy should be considered in statin-intolerant patients and may be considered in combination therapy if the treatment goal has not been achieved with the maximum tolerated statin doses. Bile acids sequestrants are safe in pregnant and breast-feeding women. 9.7. Nicotinic acid Nicotinic acid (niacin) inhibits lipolysis in adipose tissue, thus reducing synthesis of free fatty acids (FFA) and their inflow into the liver [8, 201]. This leads to reduction of the amount of FFA supplied to the liver and therefore VLDL production. Reduced VLDL synthesis in turn leads to reduced production of intermediate-density lipoprotein (IDL) and LDL [8, 201]. In addition, niacin directly inhibits hepatic diacylglycerol O-acyltransferase 2 (DGAT2) – the key enzyme in triglyceride synthesis [8], and increases synthesis of apoA1 in the liver, leading to increase in HDL-C concentration [8, 201]. Nicotinic acid in a dose of 2 g/day reduces LDL-C concentration by ca. 15–18%, TG by ca. 20–40%, and Lp(a) by 30%, as well as increases HDL-C concentration by 25% [8, 201, 202]. Niacin is rarely used (in most countries it is unavailable or available in targeted import only) due to negative study results as well as adverse effects [8]. Results of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) [203] and HPS2-THRIVE (The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) [204] studies contributed to a virtual lack of use of niacin in lipid-lowering therapy. In the AIM-HIGH trial, in high-risk patients with cardiovascular disease, addition of prolonged-release niacin (1500–2000 mg/dl) to standard statin therapy did not result in additional reduction of cardiovascular events (HR = 1.02; 95 CI: 0.87–1.21; p = 0.79), despite an increase of HDL-C concentration from 35 mg/dl (0.91 mmol/l) to 42 mg/dl (1.08 mmol/l), and a TG reduction from 164 mg/dl (1.85 mmol/l) to 122 mg/dl (1.38 mmol/l), Lp(a) from 36 to 27 nmol/l, and LDL-C from 74 mg/dl (1.91 mmol/l) to 62 mg/dl (1.60 mmol/l) [203]. Explanation of these results includes optimum treatment of ASCVD patients (during the study); what is interesting, despite the fact that in the niacin group almost twice as many patients had to reduce the dose because of adverse reactions (6.3%) and more patients discontinued treatment, the adherence was still above 75% in 90% of patients [203]. In the HPS2-THRIVE study, also no additional clinical benefit was observed from treatment with prolonged-release niacin and laropiprant (a compound that inhibits prostaglandin D2 synthesis responsible for skin flushing and hot flashes) in combination with a statin [204]. However, in the analysis of all components of the endpoints, significant reduction in coronary revascularisation and all revascularisation (10% reduction, p = 0.03) was observed in the niacin/laropiprant group. In this study, in comparison with statin monotherapy, significantly more cases of infection, hyperglycaemia, new cases of diabetes mellitus, gastrointestinal or musculoskeletal symptoms, gastrointestinal bleeding, and skin symptoms were noted. Those findings were surprising, given the earlier safety data for niacin; therefore, in comments following publication of the study, there was a suggestion that these adverse reactions could be largely due to the use of laropiprant [8, 9]. KEY POINTS TO REMEMBER Currently, there are no indications for the use of nicotinic acid and no formulation of this agent is available in Poland. In 2013, the EMA restricted the use of a slow-release formulation of nicotinic acid to the lipid disorders therapy with elevated triglyceride concentration, and only as an alternative therapy. At the same time, niacin in combination with laropiprant was withdrawn from the market. In justified circumstances (in which the benefits outweigh the risks), nicotinic acid may be considered in order to reduce residual risk in patients with high Lp(a) concentration if other agents (i.e., PCSK9 inhibitors or inclisiran) are not available. 9.8. Combination therapy and guidelines concerning treatment of lipid disorders In the context of potential combination therapy, we usually refer to high-risk and very high-risk patients. Unfortunately, more and more often we have problems with adequately effective treatment of low-risk patients, relatively young (40+, 50+), with one isolated risk factor, for example, elevated LDL-C concentration [2, 9]. In the European guidelines [8, 9], the management of this group has never been properly described from a practical point of view, i.e. what the non-pharmacological management should be, when to initiate pharmacological treatment, how to achieve the treatment goal effectively. Therefore, in reference to the ILEP recommendations [2], the authors of these guidelines point to the need of possibly optimum non-pharmacological management (lifestyle modification), and in case of failure (unfortunately, this may apply to up to 80% of individuals) [152], after not more than 6 months, to consider initiation of pharmacological treatment, i.e. nutraceuticals (preferably, in the form of polypills containing several natural substances with proven effect on LDL-C [135]), low-dose statin (with LDL-C reduction up to 30%), or ezetimibe (in case of statin intolerance), and if this is not effective, a combination of these therapies; the efficacy of this approach has been demonstrated in available studies (low-dose statin + nutraceutical, nutraceutical + ezetimibe) [135] (Figure 5). Figure 5 Recommendations for low-risk patients with persistently elevated LDL cholesterol concentration (modified according to the ILEP 2020 recommendations [2]) Although many patients achieve their LDL cholesterol target concentration with monotherapy using appropriate doses, a large proportion of high-risk and very high-risk patients, or those with markedly elevated LDL-C concentration, require additional treatment. In the EUROASPIRE-V study, as much as 71% of high-risk patients did not achieve the treatment goal, and in the Da Vinci study, it was true for 2/3 of all patients, regardless of risk, and as much as 82% of very high-risk patients; it is also estimated that only ca. 8% of extreme risk patients achieve the treatment goal [30, 31, 205]. In such cases, combination therapy is justified and should be initiated as soon as possible, and in justified cases immediately after a diagnosis of lipid disorders was established. According to the ESC/EAS 2019 guidelines, addition of ezetimibe (as early as after 4–6 weeks) is recommended in very high-risk individuals and those at high risk despite statin therapy with maximum tolerable doses; if this is not sufficient to achieve treatment goals, addition of a PCSK9 inhibitor is recommended (after another 4–6 weeks). Therefore, the guidelines have definitely shortened the time in which our patient should receive combination therapy – to as little as 8 weeks. At the same time, for the first time (in line with the results of the EVOPACS, EVACS and VCU-alirocRT trials [179–181], the possibility of combination therapy with PCSK9 inhibitors during hospitalization was recommended. In most very high-risk patients this is the only chance to achieve the therapeutic goal, in accordance with the rules: “the lower the better”, but also “the earlier the better”. Therefore, the authors of these guidelines also recommend that in very high-risk patients (1) with baseline LDL-C concentration that prevents achievement of the therapeutic goal with statin monotherapy (e.g. in patients with LDL-C > 120 mg/dl (3.1 mmol/l), assuming that intensive treatment reduces LDL-C concentration by ca. 50%), (2) in those with extreme cardiovascular risk, (3) those with statin intolerance (complete or partial), and (4) in patients already receiving intensive statin treatment prior to hospitalisation, combination therapy with ezetimibe should be initiated immediately. Each patient group listed above should achieve the treatment goal as soon as possible, and LDL-C concentration should be as low as possible, even 10 mmol/l (885 mg/dl); the latter is associated with a high risk of pancreatitis [211]. Mild to moderate HTG is related to elevated concentration of VLDL triglycerides (VLDL-TG) or triglyceride-rich lipoprotein (TRL) remnants, while in severe HTG, occurring much less often, chylomicrons in fasting plasma are present. HTG is classified as primary (Table XIX) or secondary (Table XX). Before treatment initiation, it should be diagnosed whether HTG is a primary disorder (occurring in only a few percent of patients) or is associated with another disease or medication. Primary hypertriglyceridaemia is a monogenic (rare) or polygenic (common) disorder [211]. Large population-based studies, clinical trials in secondary prevention, and genetic studies (variants of genes affecting TG concentration) have demonstrated an association between TG concentration and the risk of cardiovascular diseases [212]. Apparently, atherogenic properties are associated not as much with triglycerides themselves as with TG-containing lipoproteins, primarily smaller VLDL and so-called remnants, i.e., partially catabolised VLDL (largely free of triglycerides) and chylomicrons. Therefore, complex hyperlipidaemia (small VLDL + elevated LDL-C concentration) and dysbetalipoproteinaemia (remnants) are associated with a high risk of cardiovascular disease. The mechanism of atherogenic action of smaller VLDL and remnants is similar to that of LDL molecules. Newly formed chylomicrons themselves are not atherogenic because they are too large to enter the vascular wall. Thus, the main threat associated with severe HTG with fasting chylomicronaemia is acute pancreatitis (AP) [99, 213]. Up to 10% of AP cases develop as a consequence of severe HTG. Table XIX Classification of primary hypertriglyceridaemia Types of HTG Risk Diagnostic evaluation Clinical Laboratory Monogenic chylomicronaemia (familial chylomicronaemia syndrome, FCS) mutation of one of the 5 genes: most frequently lipoprotein lipase, apolipoprotein CII, apolipoprotein CV, LIMF1, or GPIHBP1 Risk of recurrent acute pancreatitis Xanthomata or yellow papules (xanthomas) on the skin, retinal lipaemia in homozygotes Paroxysmal abdominal pains may occur High TG and total cholesterol (TC) concentration – it is chylomicron cholesterol LDL-C and apolipoprotein B not elevated Milky fasting serum Positive cold flotation test (chylomicron layer at the serum surface) Multifactorial or polygenic chylomicronaemia (multifactorial chylomicronaemia syndrome, MCS) accumulation of genes associated with increased TG concentration Risk of acute pancreatitis Risk of CVD may be increased Paroxysmal abdominal pains may occur High TG and TC concentrations – this is chylomicron cholesterol and VLDL cholesterol LDL-C, usually not elevated Milky fasting serum Positive cold flotation test (chylomicron layer at the surface, cloudy serum under chylomicron layer due to increased VLDL-TG Dysbetalipoproteinaemia (formerly type III HLP or dysbetalipoproteinaemia or remnant disease) – apo E2/apo E2 homozygosity Very high risk of CVD Characteristic palmar tendon xanthomas ↑ TG and ↑ TC (from remnants) ↓ HDL-C Apo B not elevated DNA testing (genotype apo E2/apo E2) Multifactorial or polygenic hypertriglyceridaemia (formerly type IV HLP or familial HTG) Increased risk of CVD. May be a risk factor of AP with high VLDL-TG concentration – Significantly elevated TG concentration (VLDL-TG) LDL-C normal or slightly increased Cold flotation test negative – cloudy to milky serum without a chylomicron layer on the surface after 10–12 h of refrigerated storage Combined hyperlipoproteinaemia (formerly type IIb HLP or familial combined hyperlipoproteinaemia). This is a polygenic disorder High risk of CVD Premature CVD and/or combined hyperlipidaemia in first-degree relatives Intraindividual and interindividual (relatives, phenotypic variation), i.e. periodically elevated TG and LDL-C, or elevated TG alone or LDL-C alone Typically elevated concentration of TG, LDL-C and apo B Table XX Secondary causes of hypertriglyceridaemia Obesity Diabetes mellitus Excessive alcohol consumption Hypothyroidism Renal diseases (proteinuria, uraemia, glomerulonephritis) Paraproteinaemia, systemic lupus erythematosus Pregnancy (especially third trimester) Diet rich in monosaccharides Medicines: glucocorticosteroids, oral oestrogens, non-cardioselective β-adrenolytic drugs, thiazides, retinols, agents disrupting bile acid circulation, protease inhibitors used in HIV treatment, tamoxifen, cyclophosphamide, cyclosporine, L-asparaginase, second-generation antipsychotics (clozapine, olanzapine) In patients diagnosed with hypertriglyceridaemia, secondary causes should be first ruled out, as appropriate management of a concomitant condition or modification of medications used may improve lipid profile. It should be noted that in secondary HTG indeterminated multigene genetic basis may also be present. In case of severe HTG, fasting serum is equally lipaemic (milky), and when stored in a refrigerator (temperature +4°C) for over 12 h, a layer of fat (chylomicrons) separates on the serum surface [99, 214]; this is a positive result of the cold flotation test (fridge test). Severe HTG with the presence of chylomicrons in fasting serum may be monogenic (very rarely) or polygenic (much more often) (Table XIX). Monogenic chylomicronaemia (formerly called familial chylomicronaemia syndrome, FCS or historically, according to the Fredrickson classification, type 1 hyperlipoproteinaemia) occurs with a prevalence of 1 case/100,000 population. Clinical signs, especially in homozygous individuals, include nodular xanthomatosis, yellow papules on the trunk, arms and lower extremities, and retinal lipaemia. In multifactorial or polygenic chylomicronaemia syndrome (MCS, or Fredrickson type 5 hyperlipoproteinaemia), in addition to chylomicrons, VLDL-TG concentration is also elevated. This lipid disorder is usually associated with factors increasing hypertriglyceridaemia, such as alcohol, carbohydrate-rich diet (fructose), uncontrolled diabetes mellitus, obesity, hypothyroidism, pregnancy, or certain medications [99]. In Table XIX, in addition to primary severe hypertriglyceridaemia, classification of mild to moderate hypertriglyceridaemia is presented. It includes multifactorial or polygenic HTG (formerly familial HTG or type 4 hyperlipoproteinaemia with increased VLDL-TG concentration), dysbetalipoproteinaemia (formerly type 3 hyperlipoproteinaemia or dysbetalipoproteinaemia or remnant disease) with elevated concentration of VLDL remnants and chylomicron remnants as a result of their impaired catabolism, and combined hyperlipoproteinaemia (formerly type 2b hyperlipoproteinaemia or familial combined hyperlipoproteinaemia) with elevated VLDL-TG and LDL-C concentration [212]. Although the target triglyceride concentrations have not been established, lower concentrations indicate lower cardiovascular risk and values > 2.3 mmol/l (200 mg/dl) have been considered an indication for pharmacological reduction [8, 9]. Failure to set the TG target results from the lack of evidence from randomised clinical trials that would make its determination possible. The most important treatment goal in prevention of cardiovascular diseases remains low LDL-C concentration, and in patients with TG concentration > 4.5 mmol/l (400 mg/dl), non-HDL-C concentration. 9.9.1. Dietary management Dietary management is of significant importance in treatment of hypertriglyceridaemia [8, 9]. It may vary depending on whether the condition is a result of elevated concentration of VLDL triglycerides or chylomicron triglycerides and VLDL-TG. In patients with elevated VLDL-TG concentration, reduction and preferably avoidance of alcohol consumption is considered important. Obese patients should reduce body weight (improved sensitivity to insulin). Hyperinsulinaemia associated with abdominal obesity stimulates TG synthesis in the liver; lipolysis in adipose tissue is increased, and released fatty acids transported to the liver are a substrate for TG synthesis. Hypertriglyceridaemia may be a symptom of metabolic syndrome, in which abdominal obesity is usually the main feature. It may be said that obesity removes the mask of a patient with HTG. This also applies to alcohol and carbohydrate consumption [8, 9]. Important nutritional recommendations with high efficacy in reducing VLDL-TG include reduction of total carbohydrate intake, in particular mono- and disaccharides (fructose and sucrose). Carbohydrates are substrates for hepatic TG production. The effect of carbohydrate-rich products on triglycerides is much weaker if diet is based on high-fibre foods with low glycaemic index. In reduction of TG concentration, physical activity is also very important as working muscles use fatty acids contained in them as a source of energy [8, 9]. It must not be forgotten to replace saturated fats with mono-, and above all polyunsaturated fats [139, 143], or generally speaking animal fats with vegetable fats, with the exception of two tropical oils, i.e., coconut and palm oil. In patients with elevated concentration of chylomicron triglycerides and VLDL triglycerides (polygenic chylomicronaemia), diet is very important, although more difficult to implement, as it should be targeted at reduction of chylomicron synthesis in the intestinal epithelium, so fat intake must be very limited ( 2.3 mmol/l (200 mg/dl), treatment is always initiated with a statin (atorvastatin or rosuvastatin). This is a class I recommendation. Following publication of the REDUCE IT study results, in which the use of EPA (icosapent ethyl 2 × 2 g/day) for 4.9 years in patients optimally treated with statins with fasting TG concentration 1.5 to 5.6 mmol/l (135–499 mg/dl) and high cardiovascular risk resulted in a reduction of incidence of cardiovascular events by 25% [147], European experts recommended adding EPA to a statin in such cases (IIaB) [9]. A fibrate may also be added to a statin in primary prevention (IIbB) as well as in high-risk patients in whom LDL-C concentration corresponds to the target and TG concentration exceeds 2.3 mmol/l (IIbC) [9]. The authors of these guidelines generally accept European recommendations, however, pointing out a much greater role of fibrates in high-risk patients, which may be very effective in reduction of the risk of micro- and macrovascular complications (recommendation level IIaB), and the fact that icosapent ethyl is still unavailable on Polish market; therefore, the recommendations include for the first time omega-3 acids in high doses (at least 2 g/day – recommendation level IIbC) (see sections on omega-3 acids and fibrates; Table XXI and Figure 11). Table XXI Recommendations on treatment of hypertriglyceridaemia Recommendation Class Level Statins are recommended as first-line therapy to reduce the risk of CVD in high-risk individuals with hypertriglyceridaemia (TG > 2.3 mmol/l/> 200 mg/dl). I B In at least high-risk patients with TG ≥ 1.7 mmol/l (≥ 150 mg/dl) despite statin treatment, icosapent ethyl (2 × 2 g/day) in combination with a statin should be considered.* IIa C In at least high-risk patients with TG ≥ 2.3 mmol/l (≥ 200 mg/dl) despite statin therapy, omega-3 acids (PUFA in a dose of 2 to 4 g/day) in combination with a statin may be considered. IIb C In patients in primary prevention who achieved their LDL-C goals with persistent TG concentration > 2.3 mmol/l (> 200 mg/dl), fenofibrate in combination with a statin may be considered. IIb B In high-risk patients who achieved their LDL-C goals with persistent TG concentration > 2.3 mmol/l (> 200 mg/dl), fenofibrate in combination with a statin should be considered. IIa B * Increased risk of atrial fibrillation should be kept in mind. Figure 11 Recommendations on treatment of hypertriglyceridaemia (adapted and modified, based on the EAS Expert Opinion 2021 [140]) If TG concentration is ≥ 5.6 mmol/l (500 mg/dl), treatment is initiated with fibrate to quickly decrease its concentration and reduce the risk of AP. If chylomicrons are present in the fasting state and VLDL-TG concentration is increased (multifactorial or polygenic chylomicronaemia), combination pharmacotherapy with a fibrate and n-3 PUFA (2 × 2 g/day) is used together with diet. In monogenic chylomicronaemia, the efficacy of treatment with a fibrate and PUFA n-3 is low, and as mentioned above, effective pharmacotherapy has become possible only recently [215]. It is also worth noting that recently (May 2019) the EMA has granted conditional approval for the use of a novel agent effectively lowering TG concentration in monogenic chylomicronaemia [215]. Volanesorsen is an antisense oligonucleotide that inhibits translation of apolipoprotein CIII (Apo CIII) mRNA. Apo CIII, present in lipoproteins transporting TG, inhibits lipoprotein lipase (LPL) activity. Volanesorsen is administered subcutaneously once a week for 3 months, then once every 2 weeks. It still has not been approved by the FDA. Thrombocytopenia is a common adverse reaction associated with volanesorsen (see section on new agents in treatment of lipid disorders) [215]. A practical summary of management of hypertriglyceridaemia is presented in Table XXII. Table XXII Summary of hypertriglyceridaemia management recommendations Variable Mild to moderate – Elevated VLDL-TG Severe – Chylomicrons and ↑VLDL-TG present TG concentration 150–885 mg/dl (1.7–10 mmol/l) > 885 mg/dl (> 10 mmol/l) Primary treatment goal Target LDL-C concentration TG reduction Secondary treatment goal Target non-HDL-C concentration Target LDL-C and non-HDL-C, if the risk of AP is reduced Non-pharmacological treatment Limited consumption of alcohol or abstinence Weight reduction in case of obesity Reduction of carbohydrate intake, in particular fructose and sucrose Increased physical activity Substitution of saturated fats with unsaturated fats (especially polyunsaturated) Alcohol abstinence Restrictive low-fat diet (10–15% of total energy) Weight reduction in case of obesity Reduction of total carbohydrate intake, particularly fructose and sucrose Increased physical activity Pharmacological treatment Statin (atorvastatin, rosuvastatin, pitavastatin) Start with fibrate alone if TG > 500 mg/dl (5.6 mmol/l) to reduce the risk of ACS Consider adding PUFA n-3 in case of high cardiovascular risk and TG > 150 mg/dl (1.7 mmol/l) Consider adding a fibrate if the target LDL-C has been achieved and TG > 200 mg/dl (> 2.3 mmol/l) in primary prevention and in high-risk patients Fibrate (fenofibrate) + PUFA n-3 Volanesorsen in monogenic chylomicronaemia (family chylomicronaemia syndrome, FCS) (still unavailable in Poland) Genetic testing HTG mainly polygenic. No indications for genetic testing HTG very likely to be monogenic. Genetic tests indicated in children and adolescents. Recommended cold flotation test 9.10. New agents in lipid disorders therapy 9.10.1. Bempedoic acid Bempedoic acid is an ATP-citrate lyase (ACL) inhibitor that decreases LDL-C concentration by means of inhibition of cholesterol synthesis in the liver. ACL is an enzyme preceding 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway [216]. Importantly, bempedoic acid is an inactive prodrug and requires activation by coenzyme A (CoA) with long-chain acyl-CoA 1 synthetase (ACSVL1), and the entire process takes place in the liver rather than in skeletal muscles, which from the very beginning indicated that it may be a very effective agent for statin-intolerant patients [216]. Inhibition of ACL by bempedoic acid decreases hepatic cholesterol synthesis and reduces blood LDL-C concentration by increasing the activity of LDL receptors; it also affects simultaneous inhibition of hepatic biosynthesis of fatty acids [216]. The efficacy of bempedoic acid has been investigated in numerous phase II studies and 4 pivotal phase III studies in the CLEAR programme (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen). In the CLEAR Tranquility study [217], patients with a history of statin intolerance and LDL-C concentration ≥ 100 mg/dl were enrolled. After a 4-week lead-in period of treatment with ezetimibe, 269 patients were randomised 2 : 1 to bempedoic acid 180 mg or placebo once daily added to ezetimibe for 12 weeks. Bempedoic acid reduced LDL-C cholesterol by 28.5% in comparison with placebo (p 50 mg/dl [9, 45]. The assumed desired Lp(a) concentration is 180 mg (> 450 nmol/l) indicated a very high risk of myocardial infarction and aortic valve stenosis [9, 50, 249]. Detailed recommendations on when and in whom Lp(a) concentration should be measured have been discussed above in Sections 6.8 and 6.9, and Tables VIII and IX. Experts agree that at least once in every adult individual’s life Lp(a) concentration should be measured to detect patients at the highest risk, i.e., those with Lp(a) > 180 mg/dl. Furthermore, Lp(a) measurement should be considered in all patients with premature onset of cardiovascular disease, lack of effect of statin treatment, and in those at moderate to high risk. The authors of these guidelines also recommend consideration of Lp(a) measurement in individuals with ASCVD or FH, and in pregnant women. LP(a) has also been added to the definition of extreme risk patients as an additional risk-modifying factor in patients with ACS and diabetes (Table X). Clinical trial results have demonstrated that lipid-lowering agents reduce Lp(a) concentration, although their effects are very variable (Table XXV). The most controversial results were obtained in patients treated with statins as both reduced and increased Lp(a) concentrations (particularly with pitavastatin) were observed [92]. Of currently available agents, the most promising clinical significance in Lp(a) reduction and incident reduction is attributed to PCSK9 inhibitors [251–253]. In the FOURIER study, in a group of patients with stable coronary artery disease treated with evolocumab, a 26.9% (6.2–46.7%) reduction of Lp(a) concentration was achieved, and a 23% incident reduction (HR = 0.77; 95% CI: 0.67–0.88) in those with baseline Lp(a) above the median (37 nmol/l ~15 mg/dl), while in the group with Lp(a) below the median by only 7% (HR = 0.93; 95% CI: 0.80–1.08) [252]. The number needed-to-treat (NNT) was 41 and 105, respectively. A significant relationship between a 15% reduction in the risk of major coronary events (95% CI: 2–25%; p = 0.0199) and a reduction of Lp(a) by 25 nmol/l was demonstrated after adjustment for LDL [252]. Table XXV Effects of lipid-lowering drugs on Lp(a) Treated Estimated % Lp(a) change Antisense oligonucleotides against apo(a) ↓ by 70–90% Lipoprotein apheresis ↓ by 20–30% Niacin ↓ by 30% PCSK9 inhibitors ↓ by 20–30% CETP inhibitors ↓ by 25% Mipomersen ↓ by 25% Inclisiran ↓ 15–26% Ezetimibe ↓ up to 7% Statins Possible ↑ by 6–10% Similar results have been obtained in a subanalysis of the ODYSSEY OUTCOMES study in post-ACS patients treated with alirocumab. Risk reduction after 4 months of treatment analysed in patient groups with baseline Lp(a) concentration 180 mg/dl (> 450 nmol/l). Measurement of Lp(a) should be considered in patients with premature onset of cardiovascular disease, lack of statin effect, and in those with a borderline risk level between moderate and high to improve risk assessment. Measurement of Lp(a) may be considered in patients with very high cardiovascular risk and atherosclerotic cardiovascular disease, in patients with familial hypercholesterolaemia, and in pregnant women in prevention of pre-eclampsia or miscarriage, in recurrent pregnancy loss, or intrauterine growth restriction. High Lp(a) concentration may cause an artifactual increase in LDL-C concentration. 9.12. The importance of antihyperglycaemic agents in treatment of lipid disorders and cardiovascular risk reduction Pharmacological reduction of hyperglycaemia in multifactorial treatment of type 2 diabetes mellitus (in addition to treatment of hypertension and dyslipidaemia, lifestyle modification, antiplatelet therapy, etc.) is essential in prevention and inhibition of the progress of chronic diabetes-related complications (macro- and microvascular) and thus affects life expectancy [125, 256, 257]. In selection of therapy and combination of antihyperglycaemic medications, their effects on non-glycaemic parameters (mortality, cardiovascular or renal risk, body weight, risk of hypoglycaemia, lipid profile, etc.) should be taken into consideration while following the principle of personalisation of treatment. In patients with atherosclerotic cardiovascular disease, systolic heart failure, chronic kidney disease, or multiple cardiovascular risk factors, agents with proven beneficial effects on the risk of progression of these conditions as well as on overall and cardiovascular mortality should be used first (Table XXVI). This effect has been demonstrated for certain inhibitors of sodium-glucose cotransporter-2 (SGLT2) (flozins) and certain glucagon-like peptide-1 (GLP-1) receptor agonists [125, 256, 257]. In patients with chronic kidney disease and systolic heart failure, the choice of a flozin should be preferred, and if they are contraindicated, a GLP-1 analogue [125, 256, 257]. In patients diagnosed with ASCVD, both classes should be considered, and in the case of multiple risk factors, GLP-1 receptor agonists should be considered first. Early combination therapy with metformin and certain flozins and/or GLP-1 receptor agonists should be considered in the cases listed above in each patient, regardless of the achievement of the treatment goal [125, 256, 257]. Also in concomitant obesity, it is recommended to prefer GLP-1 receptor agonists or SGLT2 inhibitors. If the risk of hypoglycaemia is high, the same classes of agents and a dipeptidyl peptidase 4 (DPP-4) inhibitor or a peroxisome proliferator-activated receptors (PPAR-γ) agonist should be considered. In Poland, with limited reimbursement of new antihyperglycaemic agents, the most readily available and affordable classes of agents are sulfonylurea derivatives, PPAR-γ agonists, and acarbose [125, 256, 257]. Table XXVI The effects of antihyperglycaemic agents on the lipid profile and cardiovascular risk Antihyperglycaemic agent LDL-C TG HDL-C Body weight Effect on atherosclerotic cardiovascular events Heart failure Metformin ↓ ↓ ↑ ↓ ↔ Favourable Neutral Sulfonylurea derivatives ↔ ↔ ↔ ↑ with the exception of gliclazide Neutral Neutral SGLT-2 inhibitors (flozins) ↔ or ↑ ↔ ↑ ↓ Favourable (empagliflozin, canagliflozin, dapagliflozin) Favourable (empagliflozin, canagliflozin, dapagliflozin) GLP-1 receptor agonists (incretins) ↓ ↓ ↑ ↓↓ Favourable (liraglutide, semaglutide, dulaglutide) Neutral DPP-4 inhibitors (gliptins) ↓ ↔ ↔ ↔ ↔ Neutral Neutral (unfavourable saxagliptin) Pioglitazone ↔ ↓ ↑ ↑ Potentially favourable Unfavourable Acarbose ↔ ↔ ↔ ↔ Neutral Neutral Insulin ↔ ↓ ↑ ↑ Neutral Neutral 9.13. Apheresis in lipid disorders 9.13.1. LDL apheresis LDL apheresis is a mechanical method of removal of LDL particles from serum. Blood collected from the patient is first divided in a separator into morphotic elements and plasma, which goes further into a set of LDL-C-separating filters. Once the plasma is filtered, it is transfused back to the patient together with cellular elements. The entire procedure lasts from 2 to 4 h. During this period, about 1.5–3 l of blood is filtered, and a reduction of LDL-C by 55–70% is achieved [258]. During apheresis, not only LDL-C, but also VLDL, fibrinogen, Lp(a), α2-macroglobulin, and coagulation factors are removed from the plasma [259]. Clinical observations suggest that long-term use of LDL-apheresis in patients with severe HoFH contributes to regression and stabilisation of atherosclerotic plaques, improves cardiovascular prognosis, and reduces xanthomata of the skin and tendons [260]. Despite high costs (the mean procedure cost amounts to PLN 5616) and the burden for the patient, LDL apheresis is still a very important complementary therapy for homozygous FH [259, 261–263]. The most recent ESC/EAS recommendations [9] and the position of the EAS experts [264] on HoFH did not significantly change the position on this issue, while recommending maintenance of pharmacological treatment at maximum tolerated doses [9, 264]. Importantly, LDL apheresis is a safe method for pregnant women [259, 261]. The results of key clinical trials which may significantly affect the position of LDL-apheresis in the next edition of recommendations are worth noting; even today, they are a real clinical alternative for the few patients undergoing these procedures in our country. The results of the TESLA [265] and TAUSSIG [266] studies concerning treatment of HoFH with evolocumab have demonstrated the efficacy of PCSK9 inhibitors in LDL-C reduction, comparable to LDL apheresis, with good treatment tolerance. Also in HeFH well-documented clinical trials have been performed and their results allow for replacement of apheresis with biological treatment. The ODYSSEY ESCAPE study met its primary endpoint showing that in patients in whom alirocumab was added to their previous regimen a significant 75% reduction in the frequency of apheresis in comparison with placebo was achieved. In 63% of patients receiving alirocumab apheresis was no longer required, compared with no such patients among those receiving placebo [267]. In view of lower costs and definitely better tolerability in comparison with LDL-apheresis, this creates a highly promising perspective for patients with HeFH. For patients with confirmed FH, such an alternative is already available in a therapeutic programme financed by the NHF (Table XVI). In the position of the Working Group for Apheresis of the Polish Society of Nephrology [268] which was widely discussed and criticised at many sites, other (in addition to HoFH and HeFH) indications for treatment with LDL-apheresis have also been listed: Primary prevention of cardiovascular disease: in patients with documented risk factors for coronary artery disease or its equivalent (e.g. peripheral atherosclerotic disease) who cannot be diagnosed with FH according to the Dutch criteria, although they have lipid disorders and do not achieve their LDL-C targets, according to the adopted guidelines (…), and in whom all other standard therapies have failed (for at least 3 months) or are poorly tolerated, and/or there are contraindications to pharmacological treatment (adverse effects, complications, e.g. rhabdomyolysis). Secondary prevention of cardiovascular disease in high-risk patients diagnosed with cardiovascular disease (status post myocardial infarction or stroke, peripheral arterial disease), type 2 diabetes, or moderate to severe chronic kidney disease (CKD 4-5): in patients who cannot be diagnosed with FH according to Dutch criteria, although they have lipid disorders and do not achieve their LDL-C targets, according to the adopted guidelines (…), and in whom all other standard therapies have failed (for at least 3 months) or are poorly tolerated, and/or there are contraindications to pharmacological treatment (adverse effects, complications, e.g. rhabdomyolysis). Isolated Lp(a) hyperlipoproteinaemia > 60 mg/dl with normal and/or high LDL-C concentration despite diet and maximum tolerated treatment for 3 months, with documented coronary artery disease. Severe mixed hyperlipidaemia (refractory nephrotic syndrome in the course of focal segmental glomerulosclerosis). Sudden sensory loss of hearing. Severe hypertriglyceridaemia (TG ≥ 11.3 mmol/l (1000 mg/dl)) with acute pancreatitis with the use of double filtration LDL apheresis with citrate anticoagulation. The most important adverse effects of LDL-apheresis include: hypotension, abdominal pain, nausea, vomiting, vertigo and headache, hypocalcaemia, iron deficiency anaemia, allergic reactions, haemolysis, and thrombocytopenia. Due to the risk of hypotension in patients treated for arterial hypertension, it is recommended to omit hypotensive medication on the day of the procedure. Complete blood count and iron concentration should be monitored and supplemented, if necessary [9]. Antiplatelet therapy should not be discontinued. 9.13.2. Apheresis in severe HTG The procedure may be used in prevention of acute pancreatitis [269]. It is estimated that ca. 7% of cases of acute pancreatitis are associated with hypertriglyceridaemia [269]. The apheresis procedure may be considered on an individual basis, in addition to other elements of standard therapy [270], i.e., reduction of food energy and fat content, alcohol abstinence, and pharmacotherapy: fibrates (fenofibrate) and omega-3 fatty acids (2–4 g/day) (Sections 9.4 and 9.9). Effective insulin therapy is required in patients with diabetes. The efficacy of apheresis in acute pancreatitis has not been confirmed yet. The results of the only study comparing the efficacy of intensive insulin therapy with that of plasmapheresis are still unknown at the time of publication of these recommendations [271]. 9.13.3. Lp(a) apheresis The effects of reduction of Lp(a) concentration by means of apheresis have been documented not only in terms of anti-atherosclerotic, but also anti-inflammatory and anticoagulant activity; therefore, it is considered the intervention of choice in patients with high Lp(a) levels and signs of rapid progression of atherosclerosis [272]. German findings based on the German Lipoprotein Apheresis Registry (GLAR) demonstrated a 71% decrease in Lp(a) concentration with an associated decrease in MACE by 78% as early as after 2 years of follow-up [273]. As high efficacy of LDL-apheresis in reduction of Lp(a) concentration (> 60%) has been demonstrated, even in comparison with new treatment options (mipomersen ~25%, CETP inhibitors ~25%, PCSK9 inhibitors ~30%; Table XXV) it seems an interesting option for patients with high Lp(a) concentration and rapidly progressive atherosclerosis [274]. KEY POINTS TO REMEMBER LDL-apheresis may be considered as adjunctive therapy in patients with HoFH. LDL-apheresis should be considered in patients not meeting the criteria for treatment with PCSK9 inhibitors in therapeutic programmes (currently in HeFH and secondary prevention), when further progression of clinically evident atherosclerosis is observed despite maximum tolerated lipid-lowering therapy. LDL apheresis should be considered in patients with high Lp(a) concentration and signs of rapid progression of atherosclerosis. 10. Treatment of lipid disorders in specific populations 10.1. Familial hypercholesterolaemia Familial hypercholesterolaemia is a single-gene, autosomal dominant dyslipidaemia that results in life-long elevated serum LDL-C concentration, leading to premature complications of atherosclerosis. Untreated, it usually leads to premature CAD (in women before 60 years of age, and in men before 55 years) which means an up to 10-fold increase in the risk of CAD [275]. Heterozygous FH (HeFH) is relatively common; according to the latest meta-analysis including over 11 million patients, the rate for the world population is 1 : 313, but in patients with ischaemic heart disease the incidence is 10 times higher (1 : 31), with premature ischaemic heart disease 20 times (1 : 15), and in those with severe hypercholesterolaemia, 23 times higher (1 : 14) [276]. The global number of people affected by FH is estimated at 14–34 million [277], with only a small proportion of them diagnosed and treated [278]. In Poland, according to a meta-analysis of six large observational studies, based on the Dutch Lipid Clinic Network (DLCN) criteria (Table XXVII), FH was diagnosed in approximately one in 250 individuals aged 20–79 years [279], which translates into approximately 122.5 thousand people with FH in our country (based on the 2014 GUS data on the population of Poland). Similar estimates were obtained in other studies, although according to the LIPIDOGRAM study, which enrolled nearly 34,000 patients, the estimated prevalence may be even higher [278, 280]. Table XXVII Diagnostic criteria for heterozygous familial hypercholesterolaemia (HeFH) according to the Dutch Lipid Clinic Network [8, 9] Parameter Criteria Score Family history A first-degree relative with premature cardiovascular disease and/or LDL-C > 95 centile (190 mg/dl, i.e. 5.0 mmol/l) 1 A first-degree relative with tendinous xanthomata and/or 95 centile (155 mg/dl, i.e. 4.0 mmol/l) 2 Clinical history Premature cardiovascular disease (before 55 years of age in men and before 60 years in women) 2 Premature cerebrovascular or peripheral arterial disease 1 Physical examination Tendinous xanthomata 6 Arcus cornealis before 45 years of age 4 LDL-C ≥ 330 mg/dl (≥ 8.5 mmol/l) 8 250–329 mg/dl (6.5–8.4 mmol/l) 5 190–249 mg/dl (5.0–6.4 mmol/l) 3 155–189 mg/dl (4.0–4.9 mmol/l) 1 DNA testing LDLR, ApoB or PCSK9 gene mutation 8 *Interpretation: > 8 points, certain HeFH; 6–8 points, probable HeFH; 3–5 points, possible HeFH. Genetic causes of FH are single-gene loss of function mutations in the LDLR or ApoB genes or gain of function mutations in the PCSK9 gene. LDLR mutations are definitely most common (> 1700 different mutations have been identified [281]), while gain of function mutations in the PSCK9 gene comprise only a few percent of all FH cases. In most cases, the diagnosis of FH is based on the clinical presentation, although significance of molecular testing is increasingly emphasised in the literature [282]. The superiority and importance of genetic testing consists primarily in the possibility of diagnosis at an early age by performing cascade diagnostics among first-degree relatives [9, 283, 284]. DLCN criteria, presented in the table above, are usually used in clinical diagnosis; alternatively, the Simone Broome registry or WHO criteria are used [8, 9]. It should be stressed that for proper assessment, one (the highest) criterion in each category (family history, clinical history, physical examination, LDL-C concentration, genetic testing) should be summed up. It is worth noting that LDL-C concentration should be measured without treatment; with statins, the values obtained may be multiplied by 1.43 [285] to estimate LDL-C concentration without a specific lipid-lowering therapy. In the management of FH patients, effective treatment reducing LDL-C concentration (to the target values compliant with the ESC recommendations) [9] which may significantly reduce the risk of CAD is the most important issue. According to the criteria adopted in these guidelines, subjects with FH and without other major risk factors are considered high-risk patients, while those with FH and ASCVD or other major risk factors are considered very high-risk patients, which implies a recommendation to achieve specific treatment goals ( 10 years, the target LDL-C concentration should be 500 mg/dl) and an increased rate of atherosclerosis development (tendon and skin xanthomata below 10 years of age) and significantly increased cardiovascular risk [9, 265]. The prognosis in untreated HoFH is poor, and the majority of patients die before the age of 30 years. Since effective LDL-C reduction is the most important method to improve the prognosis in HoFH, intensive treatment should be carried out, involving all available interventions, i.e., high doses of potent statins, ezetimibe, PCSK9 inhibitors, and LDL apheresis [265, 284]. The ESC recommendations, as well as these guidelines, emphasise the importance of LDL apheresis [9], with the frequency adjusted to the patient’s individual needs. In this patient group, the efficacy of LDL-C reduction using PCSK9 inhibitors, i.e., evolocumab [265] and alirocumab [288], is well documented. Early genetic testing (including cascade screening of the patient’s relatives) and early intensive lipid-lowering therapy remain essential for the survival of patients with HoFH. Highly promising results have been achieved using new agents dedicated to this group of patients, including lomitapide (Lojuxta) [289] available in doses from 5 to 60 mg, mipomersen (Kynamro, which was not authorised for use by the EMA in 2013), as well as new therapies, including, above all, evinacumab (Evkeeza) (Section 9.10), which since June 2021, following a positive decision of the EMA, have been authorised for use in patients with HoFH in the European Union. KEY POINTS TO REMEMBER Heterozygous familial hypercholesterolaemia is a relatively common condition in Polish population with a prevalence of 1 case per 250 adults or higher (even up to 120-140,000 adult Poles). In Poland, only ca. 5% of patients with FH have been diagnosed; most of them still remain undiagnosed and are not treated. Genetic testing is highly useful in confirming the diagnosis of FH, especially in young patients and in screening of the family members (cascade screening), but is not required to initiate therapy; Potent statins in the highest doses should be used in combination with ezetimibe; if therapeutic goals are not achieved, PCSK9 inhibitors should be added. In extreme-risk patients (FH and ACS) and in those with high baseline LDL-C concentration (> 120 and > 300 mg/dl, respectively), immediate combination therapy with a statin and ezetimibe (polypill combination therapy is preferred) or triple therapy should be considered; In primary prevention in very high-risk patients with FH and in patients with FH and ASCVD, the recommended treatment goal is reduction of LDL-C concentration by ≥ 50% from baseline and a target LDL-C concentration 50 mg/dl or hsCRP > 3 mg/l or chronic kidney disease (eGFR 20 years High Diabetes mellitus without organ damage (regardless of duration) 4 1 Organ damage is defined as the presence of microalbuminuria, retinopathy, neuropathy, and/or left ventricular muscle damage; 2 other means at least 2 or more; 3 major risk factors include: age ≥ 65 years, hypertension, dyslipidaemia, tobacco smoking, obesity; 4 not applicable to type 1 diabetes in young adults ( 200 mg/dl (2.3 mmol/l). Subjects with type 1 diabetes with coexisting microalbuminuria and chronic kidney disease should be treated with statins regardless of baseline LDL-C values. Their goal should be reduction of LDL-C concentration by at least 50% from baseline [9] (Table XXIX). Table XXIX Recommendations on treatment of lipid disorders in patients with diabetes Recommendation Class Level In patients with obesity and pre-diabetes or type 2 diabetes, weight reduction is recommended by changing dietary habits and increased exercise. I A Patients with type 2 diabetes at very high cardiovascular risk should be treated in order to reduce LDL-C concentration by ≥ 50% from baseline; the recommended target is 50 mg/dl or hsCRP > 3 mg/l or chronic kidney disease (eGFR 200 mg/dl (2.3 mmol/l). IIa B Statins are recommended for patients with type 1 diabetes at high or very high risk. I A 10.3. Arterial hypertension and lipid disorders Elevated arterial blood pressure and hypercholesterolaemia are, beside smoking, two main modifiable cardiovascular risk factors determining cardiovascular risk. An approach targeting both risk factors if they coexist is the basis for primary and secondary prevention of cardiovascular events. In the WOBASZ II study, performed in the years 2013–2014 in a randomly selected cross-sectional sample of over 6000 individuals aged 19–99 years, the coexistence of arterial hypertension and hypercholesterolaemia in Polish population was assessed. In 34.5% of men and 31% of women (32.2% of the overall population), coexistence of these two main cardiovascular risk factors was found [300]. The prevalence of coexistence of lipid disorders and arterial hypertension depends on age. In the population of individuals aged 50–59 years, arterial hypertension and hypercholesterolaemia coexist in nearly half of the patients (46.2%). After 60 years of age, in more than 50% of the population lipid disorders coexist with arterial hypertension [300]. The WOBASZ study also made it possible to assess the frequency of control of arterial hypertension and lipid disorders [300]. The control rate of both arterial hypertension and lipid disorders in the overall population was 5.4% and in no age group, except for those aged 80 years and older, exceeded 10%. It should be noted that the low control rate could result from an unsatisfactory percentage of patients receiving pharmacological treatment – of patients with concomitant arterial hypertension and lipid disorders, only 59% received hypotensive treatment and only 31% lipid-lowering therapy. Factors associated with control of arterial hypertension and lipid disorders have also been identified. Multivariate analysis demonstrated that higher education and diagnosed cardiovascular disease were associated with achievement of therapeutic goals, whereas smoking was associated with worse control of arterial blood pressure and LDL-C concentration [300] (Section 13). Treatment of arterial hypertension should be carried out in accordance with the Polish Society of Hypertension (PSH) 2019 guidelines, in which the 2018 ESC/ESH guidelines have been adapted. The need to use combination therapy, based on fixed-dose combinations (a two-component product in the 1st step of the therapy and a three-component product in the 2nd step), and to achieve lower arterial blood pressure values than previously accepted (i.e., 120–129/70–79 mm Hg) in patients below 65 years of age, should be emphasised [301, 302]. It has been demonstrated that simplified therapy with the use of fixed-dose combination products is associated with improved compliance [303]. Therefore, combination products containing antihypertensive agent(s) and a statin are a valuable supplement to the therapy. Combination products available in Poland containing two antihypertensive agents and a statin are based on optimum and consistent with the guidelines combinations of long-acting antihypertensive agents and a potent, long-acting statin; therefore, they can be used once daily in the morning [301]. Special populations should also be taken into consideration, which should be more often and more closely than individuals in the general population controlled for risk factors, including arterial blood pressure and lipid profile parameters: patients with arterial hypertension and target organ damage (left ventricular hypertrophy, moderate albuminuria) [301, 302, 304], women with a history of pre-eclampsia or gestational hypertension [305], young people with isolated systolic hypertension [306], patients with obstructive sleep apnoea [306], patients with primary hyperaldosteronism [306], patients with atherosclerotic renal artery stenosis [306]. The patient groups listed above are at increased cardiovascular risk; therefore, therapeutic interventions should be earlier and more intensive in these groups. KEY POINTS TO REMEMBER Coexistence of arterial hypertension and hypercholesterolaemia is very common. The level of control of arterial hypertension and hypercholesterolaemia is definitely too low. Treatment of arterial hypertension is based on combination therapy with fixed-dose combination products. Combination products containing an anti-hypertensive agent (or agents) and a statin are available; their use may lead to improved control of arterial hypertension and hypercholesterolaemia by simplifying therapy and increasing compliance (adherence). Several groups of patients have been identified which, due to their cardiovascular risk being higher than that assessed using classic risk scores, require careful control of arterial blood pressure and cholesterol concentration, as well as earlier and more intensive therapeutic decisions, e.g. patients with arterial hypertension and target organ damage, women with a history of gestation-related hypertensive states, young individuals with isolated systolic hypertension, and patients with secondary forms of arterial hypertension. 10.4. Ischaemic heart disease 10.4.1. Stable coronary syndromes All patients with documented coronary atherosclerosis are at very high cardiovascular risk or extreme cardiovascular risk as defined previously. The rules for management of lipid disorders in this group of patients remain the same as in other patients at very high and/or extreme risk. In patients at very high cardiovascular risk, the treatment goal is to reduce LDL-C concentration by ≥ 50% from baseline and achieve a target LDL-C concentration of 50 mg/dl or hsCRP > 3 mg/l or chronic kidney disease (eGFR 100 mg/dl), (3) in untreated patients with baseline LDL-C concentration too high to achieve their target LDL-C concentration after 4–6 weeks of statin treatment (> 120 mg/dl), (4) in extreme-risk patients, and (5) in patients with partial or complete statin intolerance (Table XXXI, Section 9.8, Figures 6–9). Table XXXI Recommendations for lipid-lowering therapy in patients with acute coronary syndromes (ACS) Recommendation Class Level In all ACS patients without contraindications or a history of confirmed intolerance, it is recommended to initiate or continue high-dose statin therapy as early as possible, regardless of baseline LDL-C concentration. I A Lipid concentration should be re-evaluated 4–6 weeks after ACS to determine if reduction of LDL-C concentration ≥ 50% from baseline and the target LDL-C concentration of 100 mg/dl), (3) in untreated patients with baseline LDL-C concentration too high to achieve their target LDL-C concentration after 4–6 weeks of statin treatment (> 120 mg/dl), including patients with familial hypercholesterolaemia, (4) in patients at extreme cardiovascular risk, and (5) with partial or complete statin intolerance, initiation of combination therapy with a statin and ezetimibe may be considered during hospitalisation. IIb C If the target LDL-C values have not been achieved after 4–6 weeks of treatment with the maximum tolerated statin dose in combination with ezetimibe, it is recommended to add a PCSK9 inhibitor. I A In patients with confirmed statin intolerance or in whom statins are contraindicated, the use of ezetimibe should be considered. IIa C In patients who develop ACS and have not achieved their target LDL-C concentration despite the use of a statin in the highest tolerated dose in combination with ezetimibe, addition of a PCSK9 inhibitor immediately after the event (during hospitalisation due to ACS, if possible) should be considered. IIa C LDL-C – low density lipoprotein cholesterol, ACS – acute coronary syndrome, PCSK9 – subtilisin/kexin type 9 proprotein convertase. As in patients with stable coronary syndrome, in those undergoing percutaneous coronary intervention for ACS, routine initial treatment or loading (in patients receiving chronic statins) with a high dose of statin should be considered. Such treatment in ACS reduces infarction size [311]. Initial treatment with a statin also reduces the risk of contrast-induced acute kidney injury after coronary angiography or PCI. If a statin-based regimen is not tolerated at any dose (even after rechallenge), the use of ezetimibe in monotherapy or in combination with PCSK9 inhibitors should be considered [312]. The algorithms for management of patients with myocardial infarction, including those with extreme cardiovascular risk, are presented in Figures 6–9. KEY POINTS TO REMEMBER In each patient with acute coronary syndrome, the maximum tolerated statin dose should be initiated as soon as possible, regardless of the lipid profile. In each patient with acute coronary syndrome, administration of a loading dose of a potent statin before PCI should be considered. In each patient post-acute coronary syndrome, one should aim to achieve LDL-C concentration 95%) of chronic lower limb ischaemia and amputation. Symptoms of lower limb ischaemia in the form of intermittent claudication may sometimes be the first clinical manifestation of systemic atherosclerosis [9]. Peripheral arterial atherosclerotic lesions are an independent risk factor for cardiovascular events, including ACS and stroke. To improve prognosis, in a patient with peripheral arterial atherosclerosis active pharmacological and non-pharmacological management should be urgently initiated [10]. In this group of patients, lipid-lowering therapy not only contributes to inhibition of atherosclerosis progression in the peripheral arterial bed, but reduces the risk of serious events in other vascular beds (i.e., coronary, cerebral) [9]. That is why not only peripheral vascular disease, but multibed disease, defined as the involvement of at least two out of three vascular beds, has been recently discussed. Especially now, in the era of innovative therapies, analyses are available indicating that intensive lipid-lowering therapy, especially combination therapy with the use of PCSK9 inhibitors, may translate into a highly significant reduction in the risk of patients with multibed disease, and the more advanced the disease (more beds involved), the greater the benefits. Data concerning alirocumab indicate that such treatment may translate into an absolute risk reduction by up to 13%, with the benefit seen in every 7–8 patient (NNT = 8) [113]. A meta-analysis of 18 clinical trials involving more than 10,000 patients with lower limb atherosclerosis has demonstrated that lipid-lowering therapy decreases the risk of cardiovascular events by nearly 20% and reduces all-cause mortality by 14% [314]. Patients with peripheral atherosclerotic disease (multibed disease) should be treated as patients with very high or extreme cardiovascular risk, and the treatment goal should be reduction of LDL-C concentration by ≥ 50% from baseline and achievement of the target LDL-C concentration of 100 mg/dl (2.6 mmol/l) and/or elevated TG concentration (children 2 years and adolescents with lipid disorders, early lifestyle modification is recommended as first-line treatment. I A An appropriate diet, increased physical activity, normalisation of body weight, and cessation of alcohol consumption and smoking are recommended. I A Adequate (well-balanced) intake of nutrients and calories to ensure normal development and regular monitoring of the efficacy and safety of dietary interventions are recommended. I B In primary cardiovascular prevention, initiation of pharmacotherapy is recommended after 6 months if lifestyle modification is not sufficient. I A Statin therapy should be considered in children ≥ 10 years of age without risk factors with persistent LDL-C > 190 mg/dl, and in those with risk factors at LDL-C > 160 mg/dl, beginning with a low statin dose and gradually increasing it. IIa B In children with FH, the initiation of pharmacotherapy may be considered at an earlier age, i.e., over the age of 8 years. IIb C Dietary management should be initiated in every child with dyslipidaemia above 2 years of age. Dietary interventions at an earlier age should be introduced by an experienced physician at a specialist clinic, with the assistance of a dietician. If possible, a dietician should be involved in the entire treatment process, especially as all dietary changes require careful monitoring of the child’s development [347]. If the effect of dietary treatment supervised by the family physician is insufficient, the patient and the family should be referred for dietary consultation (which extends beyond the care guaranteed by the NHF) or to a specialist clinic (cardiology, metabolic diseases) that provides such services. Elevated LDL-C concentration is an indication for: reduction of the energy supply from fats to 30%, including 97 percentile. 2 Intermediate risk factors: arterial hypertension without pharmacotherapy, HDL 8 years of age (accumulating data support lowering of this age even to 6 years), and in children with homozygous FH 500 mg/dl (12.9 mmol/l)) [344]. Results of two measurements (performed 2 weeks to 3 months apart) in the fasting state and assessment of cardiovascular risk factors should be taken into account. Treatment starts with the lowest available dose, administered once daily in the evening [344]. The dose should be increased slowly, depending on the therapeutic effect, and the occurrence of possible adverse reactions should be monitored. The activity of aminotransferases and creatine kinase should be assessed prior to treatment [8, 344, 354]. Treatment with ezetimibe should be initiated under the supervision of a physician at a specialist clinic. The safety and efficacy of this agent in patients under the age of 17 have not been established, although there is also no evidence of any risk associated with such treatment. No precise dosing recommendations are available; in this case, based on data for the adult population, a dose of 10 mg/day should be suggested. Principles of the use of new therapeutic options, i.e., mipomersen [355] or PCSK9 inhibitors, have not yet been established in children, although in treatment of familial hypercholesterolaemia, these agents provide some hope for the future, especially when studies with alirocumab and evolocumab have been completed in children with both homo- and heterozygous FH. Available results from the Odyssey KIDS and HAUSER-RCT studies indicate the safety of PCSK9 inhibitors in the paediatric population and high efficacy (LDL-C reduction from 44.5 to 46%) [356, 357]. In addition, studies with inclisiran in children with FH (ORION 13 and 16) were also initiated. Dosage of lipid-lowering agents in children as well as adverse effects and contraindications are presented in Table XXXV. If the target LDL-C concentration has not been achieved with lifestyle modification and maximum statin doses, combination of lipid-lowering agents may be considered [358]. Table XXXV Agents used in treatment of lipid disorders in children and adolescents available in Poland Agent name(s) Doses initial maximum Possible adverse effects Contraindications in children Statins:SimvastatinAtorvastatinRosuvastatinPravastatin 5–40 mg5–40 mg5–20 mg5–20 mg before 13 years of age40 mg before 18 years of age Elevated hepatic aminotransferases, myalgia, myopathy, rhabdomyolysis (very rare), gastrointestinal disorders, fatigue, insomnia, headache, skin lesions, peripheral neuropathy, lupus-like syndrome Drug hypersensitivity, myopathy due to statin administration, active liver disease, high activity of aminotransferases or 3 times the upper limit of normal range during statin administration, renal failure, severe infections, serious trauma and surgery, severe metabolic disorders, hormonal, uncontrolled epileptic seizures Inhibitor of cholesterol absorption:Ezetimibe 10 mg Myalgia, myopathy, fatigue, headache, abdominal pain, diarrhoea, flatulence, dyspepsia, gastroesophageal reflux disease, nausea, elevated aminotransferase activity Drug hypersensitivity, impaired hepatic function, high aminotransferase activity In case of hypertriglyceridaemia, pharmacotherapy is usually reserved for patients with a high TG concentration (> 500 mg/dl – risk of acute pancreatitis, urgent reduction required) and genetic diseases (Section 9.9). The child should be referred to a specialist clinic for detailed diagnostics of elevated triglyceride concentration, and the possibility of treatment with statins, fibrates and omega-3 fatty acids should be considered [359, 360]. KEY POINTS TO REMEMBER Treatment of lipid disorders should be initiated in childhood, since delaying therapy to adulthood may lead to development of cardiovascular diseases as early at a young age. The aim of treatment of dyslipidaemia in children and adolescents is to achieve an LDL-C concentration 8 years in children with heterozygous familial hypercholesterolaemia). 10.10. Elderly individuals Cholesterol is a significant risk factor for coronary artery disease, regardless of age, although this relationship is somewhat less pronounced in the elderly. A reduction in TG concentration by 1 mmol/l (38.7 mg/dl) is associated with a reduction in cardiovascular mortality in patients aged 40–49 by about 50%, and in patients aged 80–89 by only 15% (HR = 0.85) [361, 362]. The most important way to prevent cardiovascular diseases in the elderly is to promote a healthy lifestyle. A meta-analysis of 28 randomised clinical trials in patients over 75 years of age demonstrated that statin therapy reduced the relative risk of major cardiovascular events by 21% (RR = 0.79, 95% CI: 0.77–0.81) for each 1.0 mmol/l of reduction in LDL-C concentration [363]. These benefits were independent of age for individuals diagnosed with cardiovascular disease (also in the oldest population) but decreased with age in those receiving statins in primary prevention and no significance for individuals older than 70 years of age was shown. In the same study, a 12% (RR = 0.88, 95% CI: 0.85–0.91) reduction in the risk of cardiovascular death for every 1 mmol/l of reduction in LDL-C concentration was also observed [363]. Another meta-analysis confirmed these results not only for statins, but also for non-statin agents, showing a significant reduction in the risk of major vascular events for all assessed endpoints, regardless of age. However, it should be noted that also in this analysis, individuals in secondary prevention comprised a majority [364]. A valuable supplement to the results discussed above is the latest meta-analysis of 10 observational studies which included over 815,000 patients aged over 65 years in primary prevention [365]. This analysis is the more valuable because in randomised trials primarily composite endpoints are assessed rather than the effect of a specific therapy on the components of these endpoints; usually, the number of elderly patients is very limited, not to mention the follow-up duration, usually up to 5 years (in this analysis, the follow-up ranged from 5 to 24 years) [365]. The authors demonstrated that statin therapy in the elderly was associated with a significant 14% reduction in all-cause mortality, a 20% reduction in cardiovascular mortality, a 15% reduction in stroke, and a 26% numerical reduction (not statistically significant) in the risk of myocardial infarction. Importantly, this significant effect (reduction of all-cause mortality) was maintained regardless of age, also in patients > 75, > 80, and > 85 years of age (risk reduction of 12, 16, and 12%, respectively), in both women and men, but mainly in individuals with diabetes (18% risk reduction) [365]. The most recent ESC/EAS guidelines (2019) on the management of lipid disorders recommend that treatment with statins in primary prevention in individuals ≤ 75 years of age be used according to the estimated level of cardiovascular risk (IA). After 75 years of age, statin treatment in primary prevention may be considered in high- or very high-risk individuals (IIb B) [9]. In secondary prevention, statin treatment is recommended in elderly patients diagnosed with cardiovascular disease, according to the same rules as in younger patients (IA) [9]. Old age is a factor causing significant changes in pharmacokinetics, mainly at the stage of distribution (increased content of adipose tissue and α1 acid glycoprotein, reduced water content and albumin concentration) and elimination (impaired renal function, slower hepatic metabolism) [153, 366]. In addition, treatment in this group of patients is complicated by multimorbidity, the need of polypharmacotherapy, and patient non-compliance. Old age is an independent factor of increased risk of statin intolerance, especially muscle complaints [153]. Therefore, the International Lipid Expert Panel recommends treatment of the elderly with hydrophilic statins (rosuvastatin, pravastatin), as it is associated with greater safety [153]. Statin therapy should be initiated with low doses, gradually increasing them to achieve the target LDL-C concentration [8, 9]. Temporary discontinuation of a statin should be considered in elderly patients in situations in which there is an increased risk of intolerance, e.g., hypothyroidism, acute severe infection, major surgery, or malnutrition, bearing in mind that discontinuation of therapy increases both general and cardiovascular mortality [153] (Table XXXVI). Table XXXVI Recommendations on treatment of lipid disorders in the elderly Recommendations Class Level Statin therapy is recommended in elderly patients diagnosed with cardiovascular disease in the same way as in younger patients. I A Statin treatment is recommended for primary prevention in elderly patients ≤ 75 years of age depending on the level of cardiovascular risk. I A Statin therapy in primary prevention > 75 years of age may be considered in high- or very high-risk individuals. IIb B In case of significant renal impairment and/or potential for drug interactions, it is recommended to start with a low-dose statin and then increase the dose to achieve the LDL-C treatment goal. I C 10.11. Autoimmune, rheumatic, and inflammatory diseases In the course of autoimmune, rheumatic and inflammatory diseases, an increased risk of cardiovascular diseases is observed [8, 367]. Increased cardiovascular risk in diseases such as systemic lupus erythematosus, psoriasis, psoriatic arthritis, antiphospholipid syndrome, rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease is associated with vasculitis and endothelial dysfunction, leading to aggravation of atherosclerosis [8, 368]. This results in higher rates of cardiovascular morbidity and mortality in individuals suffering from these diseases in comparison with general population [8, 369]. It should be emphasised that currently there are no indications for the preventive use of lipid-lowering agents solely on the basis of the presence of autoimmune diseases, rheumatic diseases, or diseases of inflammatory aetiology, and prevention and treatment of dyslipidaemia does not differ from general rules of management in this regard. However, it is worth remembering that in the case of autoimmune, rheumatic, or inflammatory diseases, the values of lipid parameters may increase as a result of anti-inflammatory treatment of these diseases [369]. It is also worth noting that in this patient population, lipid-lowering therapy may be difficult due to elevated creatine kinase (CK) activity; therefore, the therapy should be monitored, in close contact with the attending physician (rheumatologist or gastroenterologist). In such cases, a combination therapy (with low-dose statins) or even the use of non-statin lipid-lowering agents may be considered (depending on the risk and target LDL-C values). KEY POINTS TO REMEMBER Autoimmune, rheumatic, and inflammatory diseases are associated with aggravation of atherosclerosis resulting in increased cardiovascular morbidity and mortality. Before initiating treatment of dyslipidaemia in individuals with autoimmune and rheumatic diseases, it should be borne in mind that the classical use of the SCORE to assess cardiovascular risk in these patients may not be sufficient and the actual risk may be higher than estimated. Prevention and treatment of dyslipidaemia in patients with autoimmune, rheumatic, and inflammatory diseases does not differ from general rules of management in this regard. It should be remembered that lipid-lowering therapy may be difficult due to elevated CK activity and higher risk of statin intolerance; therefore, combination therapy may be considered in these patients, and therapy should be performed in cooperation with the attending physician. 10.12. Pregnancy and lactation During pregnancy, the greatest challenge associated with potential lipid disorders is significant up to 2.5× physiological increase in triglycerides in the second, and in particular the third trimester of pregnancy, which may be associated with a higher risk of pancreatitis. Total cholesterol and LDL-C concentration usually increase by not more than 50%, but a significant (30–40%) increase in lipoprotein(a) concentration may also be observed which may increase the risk of pre-eclampsia, premature delivery, or low birth weight [370]. Statins should be discontinued for at least 3 months before planned pregnancy, as well as during pregnancy and lactation [8]. Statins may have teratogenic properties and are classified as category X (the risk of using these agents considerably outweighs any benefits) according to the most recent ESC 2018 guidelines [371]. However, it should be strongly emphasised that teratogenicity or the occurrence of congenital defects following statin exposure were mainly observed in experimental studies. Recent data do not confirm these findings. A recent systematic review and a meta-analysis of nearly 2.5 million cases [372] demonstrated no significant increase in congenital malformations after statin therapy. The authors emphasised that there was no evidence of teratogenic effects of statins during pregnancy, and this issue required further investigation, especially as more and more pregnant women were at high cardiovascular risk (women with established cardiovascular disease, women with HoFH) and might benefit from statin therapy [372]. In this context, the available data from South Africa, where statins were used in pregnant women with homozygous FH, also did not reveal any risks for either the mother or the child [373]. Recent studies and data also indicated the possibility of using pravastatin in pregnant women during the last trimester of pregnancy to prevent pre-eclampsia [370]. Unfortunately, the latest results of a randomised study involving 1120 patients did not confirm this relationship; however, once again, the safety of statins in this group of women has been confirmed [374]. It should be emphasised that in women receiving chronic statin therapy, the risk of harm to the foetus is not high, and in the case of accidental pregnancy, the woman should be reassured, and the gynaecologist-obstetrician should be immediately informed of the fact [8, 9]. The only safe lipid-lowering agents in pregnancy are ion exchange resins (currently unavailable in Poland) [8]. The best tolerated resin is colesevelam. In women with HoFH, continuation of LDL-apheresis during pregnancy is safe and indicated [8, 9]. According to the latest guidelines, it is also possible to consider ezetimibe and fenofibrate (when potential benefits outweigh the risk) [371]. Recommended methods of contraception in women of childbearing potential with FH include low oestrogen oral contraceptives, intrauterine devices, and condoms. Oral contraceptives with high oestrogen content may increase triglyceride and LDL-C concentration and therefore it is important to monitor lipid profile in women with FH using these agents. Medical consultations are also necessary for all women of childbearing potential whose parents have been diagnosed with FH, as the risk of homozygous FH in their offspring is as high as 25% [8, 9]. KEY POINTS TO REMEMBER Lipid-lowering therapy should be discontinued in women at least 3 months before planned pregnancy, as well as during pregnancy and lactation. Statins are not recommended due to the risk of teratogenicity, despite the lack of clear evidence confirming such a relationship. More and more reports confirm the lack of risk of statins and the benefits of their use, especially in pregnant women with an underlying disease that threatens the life of the mother and the foetus (diagnosed cardiovascular disease or homozygous familial hypercholesterolaemia). 10.13. Cognitive disorders Cognitive disorders comprise a heterogeneous group of conditions with respect not only to aetiology but also the extent of impairment, including mild memory disorders, mild cognitive impairment (MCID), and, in the most advanced form, dementia. Many systems are used for classification of dementia, including those based on the location of the causative brain damage, the type of symptoms, or the aetiopathogenesis. The most common cause of dementia are neurodegenerative diseases of the central nervous system (CNS), including Alzheimer’s disease (resulting from deposition of β-amyloid in the extracellular space of the central nervous system), accounting for ca. 50–70% of cases [375]. Dementia due to vascular disease is the second most represented group of diseases and accounts for approximately 15% of cases. From the perspective of years and the available study results, it seems that lowering LDL-C concentration, and regardless of that the use of statins, reduces the amount of insoluble precursor protein for amyloid and has anti-inflammatory effects, which has a beneficial effect in terms of reduction of Alzheimer type neurodegenerative lesions. Reduction in LDL concentration is an established vascular protection factor. This has been confirmed in meta-analyses of tens of clinical trials concerning statins published in the last few years which demonstrated a significant reduction in Alzheimer’s dementia, vascular dementia, and generally mild cognitive impairment with statin use [376, 377], of which pleiotropic properties of this class of agents are supposed to be the cause. Data concerning the effect of the method and rate of achieving the LDL treatment goal on neurocognitive functions depending on the age of patients receiving a specific therapy are still scarce. Data are available that suggest that lipid-lowering treatment reducing LDL concentration prevents development of cognitive deficits in middle-aged and elderly individuals, but not after the age of 80. In these patients, high concentration of low-density lipoproteins is not considered a risk factor for dementia (this may also be associated with the lipid paradox observed in this group of patients) [378, 379]. Another important issue is neurological safety related to LDL reduction. With this respect, evidence is available from studies with PCSK9 inhibitors, including a subanalysis dedicated to neuropsychological evaluation (the EBBINGHAUS study) [176, 184, 380]. In those trials, patients achieving LDL concentration below 30 mg/dl did not show any deterioration of their cognitive processes in comparison with those with higher LDL concentration. These results confirm the few previous observations in individuals with loss of function PCSK9 gene mutations who, despite extremely low LDL concentration, often below 30 mg/dl, showed no neurocognitive disorders [381]. This also proves slightly different mechanisms of lipoprotein circulation in the CNS and the impermeability of both the blood-brain barrier and the blood-cerebrospinal fluid barrier to cholesterol and plasma lipoproteins (except for the precursor of small spherical HDL particles). There are also single reports that a disorder of local (rather than plasma) lipoprotein metabolism in the central nervous system and cerebrospinal fluid is most likely the cause of decreased supply of cholesterol necessary for the recovery of myelin sheaths, which is probably associated with neurodegenerative diseases [382]. For certain, the results of many studies with statins have proven no deterioration of cognitive function in people receiving this treatment. Therefore, the ESC position on the impact of these products on cognitive functions remains neutral [9]. KEY POINTS TO REMEMBER Treatment of lipid disorders in patients with neurocognitive disorders requires routine management based on the assessment of cardiovascular risk, determining the choice of therapy with adequate lipid-lowering potency. There is no convincing evidence of increased risk of cognitive disorders as a result of the use of statins or in individuals with low LDL-C concentration. On the contrary, scientific evidence supporting the protective effect of statins on the development of cognitive impairment, especially of vascular aetiology, is increasing. 10.14. Liver diseases For years, increased aminotransferase activity was considered by physicians a contraindication to statins; as a result, patients with high cardiovascular risk often received no lipid-lowering therapy at all. Unfortunately, this is still the most common cause of statin dose reduction or treatment discontinuation [8, 152]. However, further experimental, and clinical trials as well as cohort studies have shown that in fact direct mechanisms that could contribute to hepatocyte damage in the course of statin therapy are still not fully known, and the phenomenon of asymptomatic elevation of aminotransferase activity in the course of treatment is rare ( 3× the upper limit of normal (ULN), low-dose statins may be considered, with the need to monitor ALT monthly for 3 months and subsequently 4× per year [8, 9]. This has been confirmed by the results of the most recent meta-analysis of 9 studies evaluating the potential protective role of statins in patients with chronic viral liver disease [384]. The results demonstrated no significant difference in the risk of death from any cause between patients receiving and not receiving statins in the overall analysis. However, the risk of death was significantly reduced by 39% in patients receiving statins and followed-up for more than 3 years. In addition, the risk of HCC, fibrosis, and cirrhosis in statin users was reduced by 53%, 45%, and 41%, respectively. Interestingly, ALT and AST activity decreased slightly (and not increased!) after statin therapy; this reduction was not statistically significant [384]. KEY POINTS TO REMEMBER Liver enzyme (ALT) activity should be measured prior to initiation of therapy (it may be considered during dose titration) and no routine monitoring is necessary during treatment continuation (unless clinical symptoms develop). Due to the benefits related to the course of the disease itself and its complications, as well as reduced cardiovascular risk, statin therapy is recommended in patients with chronic hepatitis B and C. In patients with NAFLD/NASH, statin therapy is safe, contributes to improved disease course, and significantly reduces cardiovascular risk. The only contraindication to statin therapy is acute, active liver disease. In patients with liver diseases, lipid disorders should be treated in consultation with a hepatologist/gastroenterologist. 10.15. HIV/AIDS In terminal diseases and palliative conditions, careful assessment of the benefits and potential risk of adverse reactions in treatment of dyslipidaemia should be performed [385]. These groups of patients were typically excluded from large randomised clinical trials; therefore, the evidence is weak and leads to controversies and differences in the approach in guidelines published to date. Some studies also indicate that in palliative patients discontinuation of statin therapy was not associated with deterioration of cardiovascular parameters, including mortality, while significantly improving the quality of life of these patients [386, 387]. These data are still not sufficient to draw any conclusions; certainly, an individual approach to the patient should sometimes be considered, but one should always bear in mind that discontinuation of statin therapy may be associated with increased risk of cardiovascular events [153]. Patients with HIV/AIDS are such a difficult group of patients, with very scarce data from the studies. In this group, not only lipid-lowering therapy is important (in these patients, lipid disorders may occur as often as in general population), but particular attention should be paid to possible drug interactions, especially as these patients often receive multiple concomitant medications. Particular attention should be paid to interactions between statins and protease inhibitors in HIV patients due to metabolism via CYP3A4, leading to an increased risk of myopathy and rhabdomyolysis [9]. While in these patient groups TG and LDL-C concentrations are often decreased, treatment may negatively affect the lipid profile. Highly active antiretroviral therapy (HAART), primarily protease inhibitors, negatively affects the lipid profile, increasing in particular the risk of atherogenic dyslipidaemia [388]. If such lipid disorders are identified, the use of different agents in HAART may be considered; pravastatin may also be considered as it is recommended in patients with HIV due to its minimal metabolism by the cytochrome P450 isoenzyme system [8, 9]. The results of a recent study indicate that pitavastatin (available already in Poland), the metabolism of which practically does not involve cytochrome P450 isoenzymes (a few percent involvement of CYP 2C8 and 2C9), is more likely than pravastatin to contribute to a decrease in immune activation and arterial inflammation in HIV-infected individuals [389]. Furthermore, a subsequent study demonstrated that pitavastatin was more effective in reducing LDL cholesterol in this group of patients, with a safety profile comparable to that of pravastatin [390]. In addition to pravastatin and pitavastatin, other statins may be considered in treatment of dyslipidaemia in this group of patients, although dose adjustment may be necessary [391]. Detailed information on drug interactions in patients with HIV can be found at: www.hiv-druginteractions.org. It is also worth noting that cardiovascular risk in a HIV patient is higher than in a patient without HIV (by up to 60% and more), and antiretroviral agents, in particular protease inhibitors, increase the risk as much as two-fold [392, 393]. KEY POINTS TO REMEMBER In patients with HIV/AIDS, treatment should be selected depending on cardiovascular risk and the benefits the patient may obtain from long-term therapy. In most HIV patients receiving antiretroviral therapy, non-pharmacological management is insufficient, and the addition of a statin should be considered. Pitavastatin and pravastatin are the preferred statins in this group. In case of statin intolerance, ezetimibe (or combination therapy in partial intolerance) is a treatment option. 10.16. Terminal diseases and palliative conditions The aim of treatment of lipid disorders is to reduce cardiovascular events and mortality, as well as overall mortality. However, there is no evidence from clinical trials for the absolute benefit of statins in patients with terminal diseases and palliative conditions. For obvious reasons, such patients were excluded from randomised clinical trials. A randomised clinical trial was conducted several years ago comparing the 60-day mortality in patients with an estimated life expectancy from 1 month to 1 year who decided not to receive statins with those who continued treatment [394]. The duration of previous statin therapy, in primary or secondary prevention, was at least 3 months. There were 189 patients in the treatment discontinuation group and 192 in the continuation group. The mean age of patients was 74.1 ±11.6 years. Of these, 48.8% suffered from cancer, and 22% had cognitive impairment. Mortality did not differ significantly between the treatment continuation group and those who discontinued therapy (23.8% vs. 20.3%; p = 0.36). The quality of life (QoL) was also assessed using the McGill questionnaire, and the occurrence of various complaints using the Edmonton Symptoms Assessment scale. It turned out that the quality of life of patients who discontinued statin therapy was significantly higher that of those receiving a statin (McGill score: 7.11 vs. 6.85; p = 0.04). Based on those results, the authors concluded that discontinuation of therapy in this group of patients is safe and beneficial due to improved quality of life [394]. What is the real-life approach to statin therapy in patients with limited life expectancy? A study conducted in New Zealand may serve as an example [395]. The rate of statin discontinuation in the last 12 months of life was evaluated in 20,482 individuals over the age of 75, including 4832 people with cancer. The treatment was discontinued in 70.4% of patients with cancer diagnosis and in 55% without this disease (p 12 weeks after recovery), is increasing [402]. This is associated with the mechanisms of action of statins, not only their anti-inflammatory and anti-oxidative properties, stabilising atherosclerotic plaque (especially during the so-called cytokine storm), but also inhibition of the main coronavirus protease, reduction of the availability of lipid structural components of the virus envelope, degradation of so-called viral lipid rafts, or inhibition of its replication [403–405]. Some observations indicate potential benefits of statins (used prior to hospitalisation) on the course of COVID-19, manifested by reduced risk of severe course and death [406, 407]. One of the recent meta-analyses of 24 studies including over 32,000 patients has demonstrated that statin use significantly reduced the risk of admission to the intensive care unit in the course of COVID-19 (by 22%) and mortality (by 30%), with no significant effect on the risk of intubation. An additional analysis showed also that the risk of death was even lower if statins were used in hospital settings in patients with COVID-19 (60% risk reduction, 95% CI: 0.22–0.73) in comparison with prehospital use alone (23% reduction) [408]. In patients with COVID-19, due to possible use of antiviral, antiretroviral, or antirheumatic agents, consideration should be given to the possibility of drug interactions with statins and statin intolerance. In this case, the ILEP 2020 recommendations should be followed, in which possible interactions have been discussed in detail in the guidelines for patients with FH [157]. Regarding management of lipid disorders during the COVID-19 pandemic, the following recommendations should be proposed, presented in detail in Table XXXVII. Table XXXVII Recommendations on treatment of lipid disorders in patients with COVID-19 Recommendations Class Level In individuals with COVID-19, treatment of elevated LDL cholesterol concentration should be optimised as soon as possible, especially in those at high or very high cardiovascular risk, in whom the highest recommended statin doses should be used. IIa C Initiation or intensification of therapy and its monitoring is also possible by means of teleconsultations. I C Adequate control of cardiovascular risk factors, including in particular achievement of therapeutic goals for LDL cholesterol, becomes particularly important during the pandemic due to the need to reduce the risk of cardiovascular events and mortality in patients with COVID-19, in the circumstances of limited availability of healthcare resources. I C In individuals with COVID-19, optimum statin therapy should be continued, also during hospitalisation, as this may be associated with improved prognosis. IIa B 11. Adverse effects associated with treatment of dyslipidaemia/statin intolerance Statin intolerance is a phenomenon that has been observed for years, but the interest in it in recent years is associated with the introduction of new agents in combination therapy (PCSK9 inhibitors, inclisiran, and bempedoic acid) (Section 9.10). Non-adherence is associated with intolerance, as adverse reactions associated with statin use are the most common cause of non-adherence or treatment discontinuation. To this, reluctance to use statins and the effect of drucebo (the term introduced by Prof. Banach in the ILEP [409, 410]), i.e., adverse reactions observed in patients receiving a specific agent, but not being a result of its use, which may account for > 70% of all post-statin symptoms, should be added [152, 153, 410]. According to the results of the most recent meta-analysis, including data from more than 4 million patients, the global incidence of statin intolerance is 9.1%, and if intolerance is diagnosed using existing definitions, including the ILEP definition [153], the incidence ranges from 5.9% to 7% [411]. Statin intolerance should be defined as inability to receive statin therapy adequate (with respect to the product or the dose) to the existing cardiovascular risk [8]. In other words, statin intolerance is not only the lack of statin treatment due to clinical or biochemical symptoms (so-called complete intolerance, which affects only 3–5% of patients), but also the phenomenon of underdosage or the use of a statin too weak in relation to the cardiovascular risk [8]. In March 2015, the International Lipid Expert Panel (ILEP) proposed a new definition of statin intolerance [153] (Table XXXVIII). Table XXXVIII Definition of statin intolerance proposed in the ILEP recommendations (2015) Inability to tolerate at least 2 statins - one at the lowest initial daily dose and the other at any dose available. Intolerance associated with confirmed adverse effects associated with statin use and/or a significant increase in markers (creatine kinase). Reduction (improvement) of clinical symptoms and/or biochemical parameters after statin dose reduction or treatment discontinuation (the dechallenge phenomenon). Occurrence of clinical symptoms and/or change in biochemical parameters not associated with other factors or conditions that increase the risk of statin intolerance, including drug interactions. Therefore, one of the most difficult challenges is not only the right management, but above all the right, objective diagnosis of true statin intolerance. In this context, the authors of these guidelines recommend the use of the Statin-Associated Muscle Symptom Clinical Index (SAMS-CI) for objective assessment whether reported muscle pains are associated with statin treatment [412] (Table XXXIX). Table XXXIX Modified Statin-Associated Muscle Symptom Clinical Index (SAMS-CI) [412] SAMS-CI Score 1. Location and pattern of muscle symptoms (if more than one category applies, record the highest number) Symmetric, hip flexors or thighs 3 Symmetric, calves 2 Symmetrical, proximal upper extremity* 2 Asymmetric, intermittent, or not specific to any area. 1 2. Timing of muscle symptom onset in relation to starting statin regimen 12 weeks 1 3. Dechallenge – timing of muscle symptom improvement after withdrawal of statin 12 weeks or similar symptoms did not reoccur. 0 INTERPRETATION: (likelihood that the patient’s muscle symptoms are due to statin use): Probable 9–11 Possible 7–8 Unlikely 2–6 * The coracobrachialis muscle, the biceps brachii muscle, the brachialis muscle. It should be noted that there are many risk factors which may increase the chance for statin intolerance, including but not limited to: physical activity, especially after initiation or increase in intensity; liver and/or kidney disease, hypothyroidism, vitamin D deficiency [413], alcohol consumption, rheumatic diseases, major surgical procedures, low body weight, female gender, or elderly age [8, 153]. These risk factors were most cited as expert opinions and have never been confirmed with respect to potential causality or simply association with development of statin intolerance. In the meta-analysis mentioned above [411], the first attempt at such validation has been made. The most important risk factors for intolerance were: elderly age (OR = 1.33; as a continuous variable), female gender (1.48), Asian (1.25) or African origin (1.29), diabetes (1.27), obesity (1.31), hypothyroidism (1.38), chronic liver (1.24) or kidney disease (1.25), alcohol consumption (1.22), exercise (1.23), the use of antiarrhythmic agents (1.31), calcium channel blockers (1.36) or statins, primarily at high doses (1.38) [411]. Discussing the phenomenon of intolerance, attention should be paid to several key elements. Symptoms of intolerance in 90% occur within the first 6 months after initiation of statin therapy or dose increase, and in 75% within the first 12 weeks of this therapy [414]. Intolerance symptoms are unlikely to occur 1 year after treatment initiation or dose increase, unless a factor increasing this risk appears (disease exacerbation, a new medication interacting with statins) [414]. The most common reasons of statin intolerance are muscle symptoms manifested as pain (myalgia), muscle cramps or weakness, with or without elevated creatine kinase (CK) activity (myopathy), with or without inflammation (myositis) [415]. Myonecrosis and rhabdomyolysis are extremely rare ( 10× ULN: assess renal function and monitor CK every 2 weeks, CPK ≥ 4× ULN but 40 years, in women aged > 50 years, in postmenopausal women, in women with diabetes, in pregnant women, those with hypertension during pregnancy, in HIV-infected patients or those receiving HAART therapy, in men with erectile dysfunction, and in cases in which symptoms suggestive of cardiovascular diseases are present (Table XL). Table XL Recommendations on the assessment of lipid profile Regular lipid profile assessment should be performed in individuals: diagnosed with cardiovascular disease diagnosed with familial hypercholesterolaemia with a family history of premature cardiovascular disease diagnosed with diabetes mellitus with chronic kidney disease diagnosed with autoimmune, rheumatic, or inflammatory diseases chronic smokers with HIV infection or during HAART therapy In Table XLI the level of care at which a patient with dyslipidaemia should be treated is presented [433, 434]. Only good cooperation and continuous communication (e.g., organised as a part of coordinated care in primary prevention of cardiovascular diseases) between specific levels may guarantee appropriate and effective care for patients with lipid disorders. Table XLI Patient characteristics and levels of care in the healthcare system at which care is provided to patients with lipid disorders, including FH Level of care Primary healthcare (PCH) Combined care (PHC and OSC) Outpatient specialist care (OSC) Hospitalisation Patient: Without CVD Other risk factors are not present or are controlled Treatment goals (LDL-C) have been achieved Age over 18 years Patient: With stable CVD Certain risk factors are difficult to control Treatment goals slightly diverge from the desired values Mild symptoms of statin intolerance Heterozygous FH Age over 10 years Patient: Age less than 10 years Unstable CVD Several uncontrolled risk factors Recent myocardial infarction, stroke, or revascularisation, Treatment goal not achieved despite combination therapy (LDL-C) Severe symptoms of statin intolerance Homozygous FH Other: pre-conceptive period, pregnancy, apheresis, preparation for surgery Acute cardiovascular event Exacerbation of CVD Rhabdomyolysis End-stage renal disease Planned liver transplantation PHC – primary healthcare, OSC – outpatient specialist care, CVD – cardiovascular disease, FH – familial hypercholesterolaemia. While discussing the organisation of care for patients with lipid disorders in Poland, it seems necessary to mention the Prevention 40 PLUS programme, introduced by the Ministry of Health on July 1st, 2021, which constitutes a good beginning for coordinated care programmes in primary prevention. The programme has significant limitations in terms of the type and scope of tests, the lack of continuity of care (one-time package), and the lack of wide health-related education, which would be the best motivator to undergo such tests for young people, a majority of whom do not feel any disease; however, this is a step in the right direction (assuming widespread implementation of this programme) in order to make prevention of cardiovascular diseases and other chronic diseases in Poland real at long last. The scope of possible tests is presented in Table XLII. The authors of these guidelines encourage the dissemination of information on the programme, promotion of the programme among patients, and continuation of work with the Ministry of Health and the payer to extend this programme to a full-fledged programme of coordinated care for primary prevention of cardiovascular and chronic diseases in Poland. Table XLII Scope of tests that can be performed in the Prevention 40 PLUS programme The diagnostic test package for women contains: Peripheral blood cell count with differential white blood cells (WBC) count and platelets Total cholesterol concentration or control lipid profile Blood glucose concentration ALT, AST, γ-glutamyl transpeptidase (GGTP) Blood creatinine level General urine test Blood uric acid level Immunochemical faecal occult blood test (iFOBT) The diagnostic test package for men contains: Peripheral blood cell count with differential WBC count and platelets Total cholesterol concentration or control lipid profile Blood glucose concentration ALT, AST, GGTP Blood creatinine level General urine test Blood uric acid level Immunochemical faecal occult blood test (iFOBT) Total prostate-specific antigen (PSA) Common diagnostic test package: Arterial blood pressure measurement Measurement of body weight, height, waist circumference, and calculation of body mass index (BMI) Heart rhythm assessment KEY POINTS TO REMEMBER The main burden of prevention as well as diagnostics and treatment of lipid disorders lies with family physicians (PHC physicians). Treatment of lipid disorders requires cooperation between primary care physicians and specialist care physicians.