**4. Long-term studies of the effectiveness of statins in childhood**

The need for long-term studies to assess the effectiveness of statins in childhood has been repeatedly emphasized. In October 2019, a group of scientists published the results of the longest to date follow-up of children with familial hypercholesterolemia taking statins [8]. 214 patients with this disease and their 95 healthy brothers and sisters were under observation for 20 years. It was found that patients taking statins did not significantly differ from their healthy siblings in terms of an increase in the thickness of the intima-media complex. At the same time, the incidence of cardiovascular diseases and mortality from them at the age of 39 years among patients with familial hypercholesterolemia was lower than among their parents suffering from this disease, and amounted to 1% versus 26% and 0 versus 7%, respectively. These studies make it possible to substantiate the need for the use of statins for the primary prevention of complications and increase life expectancy in children with familial hypercholesterolemia. The effectiveness of treatment depends on the dose of drugs and the age of initiation of therapy. The authors of these and a number of other clinical studies emphasize the need to start statin therapy at the age of 8–10 years [9, 20–23].

#### **5. Features of statins usage in children with FH in clinical practice**

In clinical practice, along with an increase in the frequency of statin use, their side effects are increasingly the subject of research. In adults, statin-related side effects include elevated liver transaminases, creatine kinase, and rhabdomyolysis [24]. The main concerns in the pediatric population are the risk of developing myalgias, as well as the possible effect of statins on liver function [13, 19], cholesterol-dependent production of steroid hormones in the gonads and adrenal glands [24] and energy metabolism [25], as well as the child's growth [26].

In a number of studies, when using statins in children with familial hypercholesterolemia, it is noted the occurrence of muscle pain: when taking pitavastatin, they

developed within 3 months in 9.3% cases [18], and when taking pravastatin and atorvasttin - for 48 months in 12.2% of cases [12]. This prevalence of side effects in the form of muscle damage is higher than in adults, who experience myalgia in only 1.5–5% of cases [27]. In this regard, the authors concluded that most of the presented cases of side effects of statins on skeletal muscles in children may not be myalgias directly related to taking statins, but "growing pains" and subjective feelings of the child. A meta-analysis of 6 studies evaluating the efficacy and safety of statins in children with familial hypercholesterolemia with a total of 798 study participants with statin treatment durations from 12 to 104 weeks did not reveal a statistically significant increase in the number of side effects, including myalgias, when prescribing statins compared with placebo [28]. The European Society of Atherosclerosis recommends measuring the level of creatine phosphokinase (CPK) before treatment and 1–3 months after the start of statin therapy [29] in order to control the possible occurrence of myalgias.

The studied side effects, in respect of which remain alert, is hepatotoxicity. Several studies with a total of 943 children with familial hypercholesterolemia taking statins have examined the effect of statins on liver function [30, 31]. The authors emphasize the absence of significant differences in the incidence of violations of the activity of hepatic transaminases in treatment with statins and taking placebo. This confirms the good tolerability of the drugs. The European Society of Atherosclerosis recommends measuring the levels of alanine and aspartate aminotransferases (ALT and AST) before starting statin therapy, and then every 3 months during treatment if there is a history of liver disease or an increase in the level of hepatic transaminases by more than 3 times from the upper limit of normal [32].

Other discussed potential side effects of statins include puberty disorders. Randomized studies evaluating the efficacy and safety of statins in children with familial hypercholesterolemia found no signs of impaired puberty when pravastatin was used at a dose of 20–40 mg/day for 104 weeks [9] and pitavastatin at a dose of 1 mg/2 mg/4 mg/days for 12 weeks [18]. S.B. Clauss (2005) [10] in his article expressed theoretical concerns regarding the use of statins in adolescent girls with potential effects on pituitary hormones (luteinizing hormone and folliclestimulating hormone), menstrual cycle and physical development. However, in a 24-week study in which adolescent girls with familial hypercholesterolemia took lovastatin 20–40 mg/day, these side effects were not reported [33]. A number of researchers have also demonstrated the safety of using drugs (pravastatin, atorvastatin, rosuvastatin) in children over a similar 2-year period [10, 19, 34].

In recent years, the likelihood of an increase in the risk of developing type 2 diabetes mellitus with prolonged use of statins in adults in the general population has been actively discussed. In a study by J. Besseling et al. (2015), including more than 63 thousand patients with familial hypercholesterolemia taking statins, showed that the prevalence of type 2 diabetes in this group was significantly lower than that of their relatives (1.75% versus 2.93%; p < 0.05) [35]. A 10-year prospective follow-up of 194 children with familial hypercholesterolemia receiving statins revealed one new case of type 2 diabetes mellitus without significant differences in morbidity in their 83 siblings without familial hypercholesterolemia [36]. N. Joyce et al. (2017) [37] also showed no significant differences in the incidence of type 2 diabetes mellitus among children taking statins compared with children not receiving drugs in this group.

Thus, it should be noted that the occurrence of side effects when using statins in children cannot be completely ruled out. However, the analysis of studies carried out in this direction emphasizes the low probability of their occurrence. The key when prescribing statins to a child with familial hypercholesterolemia is careful

**123**

heterozygous disease.

of LDL cholesterol [40].

**6. Conclusions**

hypercholesterolemia.

*Statins for Children with Familial Hypercholesterolemia DOI: http://dx.doi.org/10.5772/intechopen.96007*

monitoring of complaints, clinical condition, and a number of biochemical markers in the blood (ALT, AST, CPK). It is also necessary to monitor the patient's condition

Separate sections devoted to the use of statins in childhood are presented in the most frequently cited clinical guidelines for the diagnosis and treatment of dyslipidemia: American [38], Japanese [20] and Australian [21]. In 2019, the results of a study conducted in 8 European countries (Norway, Great Britain, Czech Republic, Portugal, Greece, Austria, the Netherlands, Belgium) were published, which compared the tactics and results of treatment of familial hypercholesterolemia in a total sample of 3064 children. It has been shown that the proportion of children taking statins increases with age and by the age of 15, already 79% of patients in these countries are taking statins [39]. The goals for children over 10 years of age are to achieve LDL cholesterol <3.5 mmol/L (<135 mg/dL), at a younger age - to reduce this indicator by ≥50%. In the United States and Europe, simvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, and rosuvastatin are approved for use in children with familial hypercholesterolemia. In the United States, all of these statins are approved from the age of 10, with the exception of pravastatin, which is recommended from the age of 8. In Europe, rosuvastatin is approved from 6 years old, in Australia atorvastatin is approved in children from 6 years old. It is recommended to start statin therapy with low doses and increase it until the set goals are achieved [29] with a possible increase to the maximum admissible dose in childhood established for each of the drugs. This dose is 20 mg for pravastatin for children under 13 years of age and 40 mg for children under 18; for rosuvastatin - 10 mg up to 9 years and 20 mg - up to 18 years; for atorvastatin - 40 mg regardless of age [12]. The results of recent randomized studies on the efficacy and safety of statins in children with familial hypercholesterolemia formed the basis for the joint recommendations of the European Society of Cardiology and the European Society of Atherosclerosis [29]. In 2018, Russian guidelines for the diagnosis and treatment of familial hypercholesterolemia were published [40]. These recommendations serve as the main document in the work of a pediatric cardiologist and pediatrician when monitoring children with familial hypercholesterolemia. According to these recommendations, statin therapy should be considered in children aged 8–10 years with

Particular vigilance should be shown in relation to children with a homozygous form of familial hypercholesterolemia, in which lipid-lowering therapy should be started as early as possible, immediately after the diagnosis. It is recommended to prescribe therapy with maximum tolerated doses of statins in combination with other lipid-lowering drugs in order to maximize the reduction

Thus, the initiation of lipid-lowering therapy in familial hypercholesterolemia from childhood is of great importance for reducing the cumulative effect of LDL cholesterol and increasing the patient's life expectancy. When answering questions regarding the treatment of children with dyslipidemia, one should take into account the compelling reasons to follow international recommendations and use statins for familial hypercholesterolemia from the age of 8–10 years, with monitoring of the recommended clinical and biochemical markers under the supervision of a physician. There is currently a need to continue randomized trials to prove the lifelong benefit of low LDL cholesterol in patients with familial

with prompt correction of the drug and the dose received by the child.

#### *Statins for Children with Familial Hypercholesterolemia DOI: http://dx.doi.org/10.5772/intechopen.96007*

*Management of Dyslipidemia*

normal [32].

control the possible occurrence of myalgias.

developed within 3 months in 9.3% cases [18], and when taking pravastatin and atorvasttin - for 48 months in 12.2% of cases [12]. This prevalence of side effects in the form of muscle damage is higher than in adults, who experience myalgia in only 1.5–5% of cases [27]. In this regard, the authors concluded that most of the presented cases of side effects of statins on skeletal muscles in children may not be myalgias directly related to taking statins, but "growing pains" and subjective feelings of the child. A meta-analysis of 6 studies evaluating the efficacy and safety of statins in children with familial hypercholesterolemia with a total of 798 study participants with statin treatment durations from 12 to 104 weeks did not reveal a statistically significant increase in the number of side effects, including myalgias, when prescribing statins compared with placebo [28]. The European Society of Atherosclerosis recommends measuring the level of creatine phosphokinase (CPK) before treatment and 1–3 months after the start of statin therapy [29] in order to

The studied side effects, in respect of which remain alert, is hepatotoxicity. Several studies with a total of 943 children with familial hypercholesterolemia taking statins have examined the effect of statins on liver function [30, 31]. The authors emphasize the absence of significant differences in the incidence of violations of the activity of hepatic transaminases in treatment with statins and taking placebo. This confirms the good tolerability of the drugs. The European Society of Atherosclerosis recommends measuring the levels of alanine and aspartate aminotransferases (ALT and AST) before starting statin therapy, and then every 3 months during treatment if there is a history of liver disease or an increase in the level of hepatic transaminases by more than 3 times from the upper limit of

Other discussed potential side effects of statins include puberty disorders. Randomized studies evaluating the efficacy and safety of statins in children with familial hypercholesterolemia found no signs of impaired puberty when pravastatin was used at a dose of 20–40 mg/day for 104 weeks [9] and pitavastatin at a dose of 1 mg/2 mg/4 mg/days for 12 weeks [18]. S.B. Clauss (2005) [10] in his article expressed theoretical concerns regarding the use of statins in adolescent girls with potential effects on pituitary hormones (luteinizing hormone and folliclestimulating hormone), menstrual cycle and physical development. However, in a 24-week study in which adolescent girls with familial hypercholesterolemia took lovastatin 20–40 mg/day, these side effects were not reported [33]. A number of researchers have also demonstrated the safety of using drugs (pravastatin, atorvas-

tatin, rosuvastatin) in children over a similar 2-year period [10, 19, 34].

In recent years, the likelihood of an increase in the risk of developing type 2 diabetes mellitus with prolonged use of statins in adults in the general population has been actively discussed. In a study by J. Besseling et al. (2015), including more than 63 thousand patients with familial hypercholesterolemia taking statins, showed that the prevalence of type 2 diabetes in this group was significantly lower than that of their relatives (1.75% versus 2.93%; p < 0.05) [35]. A 10-year prospective follow-up of 194 children with familial hypercholesterolemia receiving statins revealed one new case of type 2 diabetes mellitus without significant differences in morbidity in their 83 siblings without familial hypercholesterolemia [36]. N. Joyce et al. (2017) [37] also showed no significant differences in the incidence of type 2 diabetes mellitus among children taking statins compared with children not

Thus, it should be noted that the occurrence of side effects when using statins in children cannot be completely ruled out. However, the analysis of studies carried out in this direction emphasizes the low probability of their occurrence. The key when prescribing statins to a child with familial hypercholesterolemia is careful

**122**

receiving drugs in this group.

monitoring of complaints, clinical condition, and a number of biochemical markers in the blood (ALT, AST, CPK). It is also necessary to monitor the patient's condition with prompt correction of the drug and the dose received by the child.

Separate sections devoted to the use of statins in childhood are presented in the most frequently cited clinical guidelines for the diagnosis and treatment of dyslipidemia: American [38], Japanese [20] and Australian [21]. In 2019, the results of a study conducted in 8 European countries (Norway, Great Britain, Czech Republic, Portugal, Greece, Austria, the Netherlands, Belgium) were published, which compared the tactics and results of treatment of familial hypercholesterolemia in a total sample of 3064 children. It has been shown that the proportion of children taking statins increases with age and by the age of 15, already 79% of patients in these countries are taking statins [39]. The goals for children over 10 years of age are to achieve LDL cholesterol <3.5 mmol/L (<135 mg/dL), at a younger age - to reduce this indicator by ≥50%. In the United States and Europe, simvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, and rosuvastatin are approved for use in children with familial hypercholesterolemia. In the United States, all of these statins are approved from the age of 10, with the exception of pravastatin, which is recommended from the age of 8. In Europe, rosuvastatin is approved from 6 years old, in Australia atorvastatin is approved in children from 6 years old. It is recommended to start statin therapy with low doses and increase it until the set goals are achieved [29] with a possible increase to the maximum admissible dose in childhood established for each of the drugs. This dose is 20 mg for pravastatin for children under 13 years of age and 40 mg for children under 18; for rosuvastatin - 10 mg up to 9 years and 20 mg - up to 18 years; for atorvastatin - 40 mg regardless of age [12].

The results of recent randomized studies on the efficacy and safety of statins in children with familial hypercholesterolemia formed the basis for the joint recommendations of the European Society of Cardiology and the European Society of Atherosclerosis [29]. In 2018, Russian guidelines for the diagnosis and treatment of familial hypercholesterolemia were published [40]. These recommendations serve as the main document in the work of a pediatric cardiologist and pediatrician when monitoring children with familial hypercholesterolemia. According to these recommendations, statin therapy should be considered in children aged 8–10 years with heterozygous disease.

Particular vigilance should be shown in relation to children with a homozygous form of familial hypercholesterolemia, in which lipid-lowering therapy should be started as early as possible, immediately after the diagnosis. It is recommended to prescribe therapy with maximum tolerated doses of statins in combination with other lipid-lowering drugs in order to maximize the reduction of LDL cholesterol [40].
