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biomedicines
Review
Treatment of Dyslipidaemia in Children
Riccardo Fiorentino * and Francesco Chiarelli
Citation: Fiorentino, R.; Chiarelli, F.
Treatment of Dyslipidaemia in
Children. Biomedicines 2021,9, 1078.
https://doi.org/10.3390/
biomedicines9091078
Academic Editor: Matteo Di Minno
Received: 19 July 2021
Accepted: 21 August 2021
Published: 24 August 2021
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Department of Paediatrics, University of Chieti, 66100 Chieti, Italy; chiarelli@unich.it
*Correspondence: riccardo.fiorentino8@gmail.com
Abstract:
Childhood dyslipidaemia is one of the main traditional cardiovascular risk factors that
initiate and exacerbate the atherosclerotic process. Healthcare providers may play a key role in
the management of children with lipid abnormalities; however, they have to properly evaluate the
normal lipid values and know the available treatment options in children and adolescents. Current
guidelines recommend healthy behaviours as the first-line treatment for childhood dyslipidaemia.
The therapeutic lifestyle changes should focus on dietary modifications, daily physical activity,
reduction in body weight and tobacco smoking cessation. Parents play a key role in promoting their
children’s healthy habits. In children with more severe forms of lipid abnormalities and in those who
do not benefit from healthy behaviours, pharmacological therapy should be considered. Safe and
effective medications are already available for children and adolescents. Statins represent the first-line
pharmacological option, while ezetimibe and bile acid sequestrants are usually used as second-line
drugs. Despite their limited use in children, other lipid-lowering agents (already approved for adults)
are currently available or under study for certain categories of paediatric patients (e.g., familial
hypercholesterolemia). Further studies are needed to evaluate the long-term efficacy, safety and
tolerability of novel lipid-lowering drugs, especially in children.
Keywords:
children; dyslipidaemia; management; non-pharmacological approach; pharmacotherapy
1. Introduction
Atherosclerotic cardiovascular disease remains the leading cause of death and a major
cause of morbidity [
1
,
2
]. Although clinical outcomes (e.g., death, stroke, myocardial
infarction) rarely occur in youth, mounting evidence suggests that atherosclerotic lesions
can begin in childhood [3].
The insidious atherosclerotic process is sped up by exposure to cardiovascular risk
factors, which may be present early on in life [
4
]. Childhood dyslipidaemia represents
one of the main traditional cardio-metabolic risk factors that exacerbate this process: lipid
accumulation over time induces vascular inflammation and the development of fatty
streaks, which gradually progresses to atherosclerotic plaque [
5
]. Interestingly, greater lipid
concentrations and longer lifetime exposure to lipid abnormalities significantly correlate
with the severity of atherosclerotic lesions [6].
The prevalence of children with an altered lipid profile is high: familial hyper-
cholesterolemia (FH) affects 1 in every 250 children, while around 1 in 5 children
meets the criteria for childhood overweight or obesity, which are often associated with
lipid abnormalities [
7
–
9
]. Moreover, it is important to note that cardiovascular risk
factors tend to progress from youth to adulthood [
10
]; several studies demonstrated
that childhood lipid concentrations correlate with future adult measurements [
11
]. In
view of this observation, it has become impossible to ignore the relevance of childhood
dyslipidaemia and the need for early identification and treatment in youths with lipid
abnormalities seems clear. This is very important in order to slow the atherosclerotic
process and to prevent future atherosclerotic cardiovascular disease.
Given that dyslipidaemia is a modifiable cardiovascular risk factor, healthcare providers
may play a key role in the management of children with lipid abnormalities. However, it is
Biomedicines 2021,9, 1078. https://doi.org/10.3390/biomedicines9091078 https://www.mdpi.com/journal/biomedicines
Biomedicines 2021,9, 1078 2 of 17
imperative to know very well the normal lipid reference values, the current recommen-
dation and available treatment options in children and adolescents. This review aimed
to outline the current status of the management of childhood dyslipidaemia, while also
providing an update on the advances in the field of lipid-lowering strategies.
2. Pathophysiology
Dyslipidaemia is a clinical condition that is characterised by disorders of lipid
metabolism. Although lipids are essential for maintaining health, abnormal lipid and
lipoprotein concentrations in the blood may be dangerous. Depending on the under-
lying cause, childhood dyslipidaemia may be classified into primary and secondary
dyslipidaemia [
3
]. Primary dyslipidaemia is usually caused by inherited disorders in
lipid metabolism: single or multiple gene mutations (e.g., gene mutations in low-density
lipoprotein receptors) may alter both lipid production and removal. Among the forms
of primary dyslipidaemia, familial combined hyperlipidaemia and familial hypercholes-
terolemia are the most common genetic causes of dyslipidaemia. It is important to note
that genetic causes are often responsible for the most severe lipid abnormalities [
6
]. In
contrast, secondary dyslipidaemia typically occurs as the result of specific conditions,
diseases or drugs that may interfere with lipid concentrations over time. The causes
of secondary dyslipidaemia include obesity, diabetes, renal and chronic inflammatory
diseases and corticosteroids. Secondary causes of dyslipidaemia should always be
evaluated and treated; in fact, the correct management of the causative disease may
often result in lipid abnormalities resolution [10].
3. Paediatric Guidelines
Clinical practice guidelines are designed to provide a synthesis of evidence and to
translate the evidence into graded recommendations; these recommendations may be
helpful in improving clinical decision making [
12
]. Paediatric guidelines for dyslipidaemia
have undergone several modifications in recent years. The first paediatric guidelines for
dyslipidaemia were published in 1992 by the National Cholesterol Education Program
(NCEP) following guidelines for adults that were developed by the same NCEP [
13
].
Although many of the recommendations were mainly based on expert opinion rather
than on systematic evidence review, these guidelines were adopted by several paediatric
scientific societies. Undoubtedly, these initial guidelines engendered some controversy;
however, they were important for increasing the awareness of childhood dyslipidaemia
and for stimulating the research on this important topic. Moreover, the cut-off points
for acceptable, borderline and high plasma lipid concentrations based on percentiles
from the Lipid Research Clinical Prevalence Study were the first to be presented [
14
].
As new data and new evidence became available, organisations such as the American
Heart Association (AHA) and the American Academy of Pediatrics (AAP) updated the
original guidelines. In 1998, the AAP Committee on Nutrition produced a statement
on cholesterol in childhood [
15
], which was followed by an additional clinical report
in 2008 [
16
]. Furthermore, the AHA first published a consensus statement on dietary
recommendations for children and then a scientific statement on drug therapy for high-risk
lipid abnormalities in children and adolescents [
17
,
18
]. The most up-to-date guidelines
for the management of childhood dyslipidaemia were published in 2011 by the National
Heart Lung and Blood Institute (NHLBI) after performing a systematic review and grading
the best available evidence [
3
]. The 2011 Guidelines constitute a part of an integrated
approach with a focus on all cardiovascular risk factors in children and adolescents; they
represent a cornerstone for cardio-metabolic risk reduction and cardiovascular health
in youth. As regards lipid abnormalities, the NHLBI Guidelines outlined the currently
used references values for plasma lipid, lipoprotein and apolipoprotein concentrations in
children and adolescents (Table 1); moreover, they give recommendations concerning both
lipid assessments in youth and the management of paediatric lipid disorders.
Biomedicines 2021,9, 1078 3 of 17
Table 1.
Lipid and lipoprotein reference values and corresponding centile in children and adolescents.
ACCEPTABLE BORDERLINE HIGH
mg/dL Percentile mg/dL Percentile mg/dL Percentile
Children and Adolescents
TC <170 <75th 170–199 75–95th >200 >95th
LDL-C <110 <75th 110–129 75–95th >130 >95th
TG
0–9 years <75 <75th 75–99 75–95th >100 >95th
10–19 years <90 <75th 90–129 75–95th >130 >95th
HDL-C >45 >10th 40–45 <40 <10th
Non-HDL-C <120 <75th 120–144 75–95th >145 >95th
Adapted from the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in
Children and Adolescents.
In accordance with previous guidelines, the non-pharmacological approach (includ-
ing dietary and lifestyle modifications) remained an integral part of the treatment for
dyslipidaemia in children and adolescents; on the other hand, the recommendations for
pharmacotherapy substantially changed in comparison with previous guidelines [
19
]. Due
to the increasing data on efficacy and safety, along with the Food and Drug Administration
(FDA) approval for the use of several lipids lowering drugs in children, the therapeutic
options for children with dyslipidaemia have expanded and, nowadays, statins are the
preferred drugs in paediatrics [3,20].
4. Management of Dyslipidaemia in Children
4.1. Non-Pharmacological Approaches
Although several pharmacological treatments are available or under development,
current guidelines recommend healthy behaviours as the first-line treatment for childhood
dyslipidaemia. It is important that healthy behaviours should be recommended for all
children and adolescents; however, they should be strongly encouraged in those children
with borderline or high plasma lipid and lipoprotein concentrations.
For children with an altered lipid profile, the initial management should consist of
therapeutic lifestyle changes that focus on dietary modifications, daily physical activity,
improving body weight and tobacco smoking cessation [
21
]. Moreover, in order to prevent
obesity in children, they should be encouraged to sleep for a decent amount of hours per
day and to limit screen time (including television, cell phone, computer use, videogames,
handheld electronics) to less than 2 h per day. In 2016, The AAP consensus groups rec-
ommended adequate daily hours of sleep (including naps) for children and adolescents,
depending on their age [
22
]. As regards sedentary activities, in a recent study, it was
observed that every additional hour of watching television was correlated with increased
triglycerides (TG) and decreased high-density lipoprotein (HDL-C) levels [
23
]. Several pos-
sible reasons were proposed: among them, the lower energy expenditure and the increased
intake of energy-dense foods (e.g., soft drinks, fast food) while watching television.
Although dietary treatment remains under debate, a modified diet can improve abnor-
mal lipid profiles by inducing a lipid-lowering effect, mainly on triglycerides (TG) levels,
but it also has a modest impact on total cholesterol (TC) and low-density lipoprotein (LDL-
C). In adults, the PREDIMED study (the largest dietary prevention trial) demonstrated
that the Mediterranean diet is beneficial in reducing the incidence of major cardiovas-
cular events. Similarly, adherence to the Mediterranean diet in children may improve
the carotid intima-media thickness test (CIMT), which is an early marker of atherosclero-
sis [
24
,
25
]. In view of these observations, it is likely that dietary modifications are relevant
for the prevention of atherosclerotic cardiovascular disease in both children and adults.
The specific dietary changes should emphasise decreasing total, trans and saturated fats;
decreasing cholesterol amounts; and increasing the intake of fibre. The NCEP suggests
Biomedicines 2021,9, 1078 4 of 17
two approaches for proposing a modified diet: the population approach is a group of
recommendations for all youths in order to prevent an abnormal lipid profile and the
atherosclerotic process. In contrast, the individual approach consists of suggestions for
children with confirmed dyslipidaemia and an increased risk for cardiovascular disease. It
is important to note that this latter approach uses a two-step nutritional change (CHILD-1
and CHILD-2) and that CHILD-1 recommendations coincide with those of the population
approach [
26
]. The recommended population diet, as well as the diet Cardiovascular
Health Integrated Lifestyle Diet-1 (CHILD-1), should limit the total fat consumption to
20–30% of total calories, saturated fat intake to less than 10% of total calories and average
cholesterol ingestion to less than 300 mg/day. Children should also avoid trans-fatty acids
(<1%), preferring polyunsaturated fatty acids and monounsaturated fatty acids, which
should be up to 10% and between 10 and 15% of total daily calories, respectively. It is
also recommended to increase the intake of dietary fibre through whole grains, vegetables
and fruit (five or more a day). For children at an increased cardiovascular risk and for
children with confirmed dyslipidaemia who have failed to achieve the lipid goals after
3 months
of the CHILD-1 diet, more intensive restrictions are needed. The Cardiovascular
Health Integrated Lifestyle Diet-2 (CHILD-2) requires limiting saturated fat intake to less
than 7% and cholesterol average ingestion to less than 200 mg/day [
3
,
27
]. The other step
1 recommendations should not be interrupted through the step 2 diet.
It is noteworthy that the NCEP recommends dietary modifications in children from
2 years of age: the first two years of life are critical for the development and the growth
of children and it is important to provide them with an adequate amount of calories and
nutrients [
28
]. This also applies to children older than 2 years old and both CHILD-1
and CHILD-2 should ensure adequate daily caloric intake for normal growth and devel-
opment: as a consequence, these diets should consist of 50–60% of total daily calories
from carbohydrates and 10–20% from proteins [
27
]. It is never suggested to limit protein
consumption, while in children with elevated TG, it is recommended to decrease simple
sugar consumption (including fruit juices and sugar drinks) and replace them with complex
carbohydrates [28].
For children with hypertriglyceridemia, an increase in omega-3 fatty acid dietary
intake should also be encouraged by increasing the consumption of fish. Long-chain
omega-3 fatty acids are also available in the form of unregulated fish oil products and
prescription drugs; although it is not clear the exact mechanisms by which they reduce TG
concentrations and limited data exist in children and adolescents, prescription products
seem to lower TG levels and have been safely used in children [
20
,
29
,
30
]. However, they
lack the approval for use in children and should be used in consultation with a lipid
specialist. For patients with increased LDL-C values, the CHILD-2 diet also recommends
dietary adjuncts, such as plant stanol and sterol esters and water-soluble fibre psyllium.
Plant sterol and stanol, when taken up to 2 g per day, were shown to inhibit intestinal
cholesterol absorption, leading to a reduction in LDL-C levels by approximately 9% [31].
Although the effectiveness of dietary changes is variable, it is important to remember
that the above-mentioned dietary modifications are safe and well tolerated over time.
Several studies, such as the Special Turku Coronary Risk Factor Intervention Project (STRIP)
and the Dietary Intervention Study in Children (DISC) showed that reducing fat intake
(total fat, saturated fat and cholesterol) was not significantly associated with changes in
somatic growth, pubertal development, mean body mass index, nutritional sufficiency and
psychological/social features [
32
,
33
]. Moreover, a recent study concluded that beneficial
nutritional interventions can be safely introduced in youth and sustained over 20 years [
34
].
Consultation with a registered nutritionist may help with promoting long-term ad-
herence to a diet; a study of 1062 children (540 children in the intervention group and
522 controls
) showed that repeated dietary counselling was helpful in reducing both satu-
rated fat consumption and LDL-C concentrations [
35
]. In addition, a paediatric dietitian
plays a key role in setting goals, tracking progress, making dietary adjustments and educat-
ing parents about nutritional plans inside and outside of the home [
21
]. It is important to
Biomedicines 2021,9, 1078 5 of 17
set realistic short-term dietary goals and to consider social, parental and cultural factors in
order to ensure the effective implementation of nutritional changes [
36
]. It is also important
that dietary modifications should never be portrayed as punitive, but rather in terms of
the child’s education, and that adequate non-food-based rewards should be given when
accomplishing the goals. Improving the quantity and the quality of nutrition is equally
important: children with obesity often consume exaggerated portions and large quantities
of non-nutritive but calorie-dense food. Common sources of non-nutritive foods include
ultra-processed products, soft and energy drinks, snacks and fast food [
27
]. The elimination
of these foods and limitation of portion sizes should be strongly encouraged to improve the
nutritional status. Furthermore, it is crucial that children and adolescents avoid skipping
meals (in particular breakfast); in accordance with a retrospective, observational study,
children who consumed fewer than two meals per day had higher levels of TC and LDL-C
compared with those eating three times or more per day [37].
In addition to nutritional changes, physical activity and weight reduction are the
cornerstones of preventing and treating lipid abnormalities in children. Physical activity is
associated with a variety of health benefits, both in healthy children and in youths with
chronic disease [
38
]. The benefits of physical activity were widely documented and include
improved musculoskeletal, mental, behavioural and cardiovascular health. In particular,
being physically active has a positive effect on cardiorespiratory fitness, serum glucose
concentrations and insulin sensitivity, blood pressure, bone density and lipid profile [
39
].
As a consequence, regular physical activity should always be encouraged in children
with dyslipidaemia; it may be useful in lowering TC, TG and LDL-C levels, increasing
HDL-C and, more importantly, it may assist with body fat and body mass index (BMI)
reduction. Therefore, it is critical that all children and adolescents should engage in at
least 1 h of moderate-to-vigorous physical activity every day [
3
]. Interestingly, a study of
1235 adolescents
showed a dose–response relationship between an increased number of
minutes of physical activity and improved lipid concentrations (HDL-C and TG values) [
40
].
It is important that physical activity is age appropriate, various (including unstructured and
structured activities) and enjoyable to the child. Further recommendations are available in
the 2018 Physical Activity Guidelines; these guidelines, released by the US Department
of Health and Human Services, provide important guidance on the amounts and types of
physical activity for multiple paediatric populations groups [41].
Weight management is another important recommendation for children with an al-
tered lipid profile and represents the primary treatment goal for obese or overweight
children with dyslipidaemia. The excess adiposity adversely affects not only the lipid pro-
files but the entire cardio-metabolic health of young people [
42
]; it is, therefore, necessary to
maintain a healthy BMI. A 5 to 10% reduction in body weight through dietary modifications
and increased physical activity is beneficial for reducing cardiovascular risk and improving
lipid abnormalities. Via different mechanisms (improved insulin sensitivity, enhanced activ-
ity of lipoprotein lipase, reduced free fatty acids release from adipose tissues), weight loss
is expected to increase the TG catabolism and removal by approximately 20% [
43
,
44
]. Only
when obesity-related comorbidities (such as dyslipidaemia) are not sufficiently reduced
with adequate weight reduction, they should be treated independently [6].
4.2. Family-Based Approach
Parents play a key role in promoting healthier eating habits and adequate activity
levels in their children and several authors consider parents one of the main focuses of
childhood dyslipidaemia prevention and treatment [
45
]. This is a critical point, although it
is often overlooked. Therapeutic lifestyle changes should be adopted by the entire family:
if the whole family does not change their habits, dyslipidaemia is unlikely to improve [
28
].
First, parents are responsible for the portions served to the child and for food and beverages
that enter the home. It is important to note that the food available in the home is often the
food that children learn to consume and that children’s consumption of fruit and vegetables
is predicted by their availability [
46
]. Second, parents play a role in creating a healthy home
Biomedicines 2021,9, 1078 6 of 17
environment (e.g., a smoke-free environment) and promoting healthy habits (e.g., a healthy
sleep routine); important factors that may affect children’s lipid profile are the sources of
food (prepackaged or homemade meals), TV watching during the meal and the frequency
of family meals [
47
]; the promotion of regular family meals is protective for obesity and its
related consequences, such as dyslipidaemia [
48
]. Third, considering that children often
mimic their close family members, parents serve as models for healthy behaviours and
are very important for children’s education in terms of the amount of physical activity
and eating habits [
49
]. In view of this, and considering that the introduction of healthy
behaviours at a young age may be carried throughout adult life, families must promote a
healthy lifestyle.
4.3. Pharmacological Treatment
Although secondary dyslipidaemia (e.g., obesity-related dyslipidaemia) is usually
successfully treated with the management of the underlying disorder and therapeutic
lifestyle changes, the adoption of healthy habits and long-term adherence to lifestyle
modifications may be challenging. Moreover, children with primary dyslipidaemia (e.g.,
FH) do not equally benefit from healthy behaviours: in children with FH, a low-fat diet
was shown to have only modest effects, leading to an LDL-C reduction by approximately
10% [
50
,
51
]. In such cases, as well as in children with more severe forms of lipid
abnormalities, the use of pharmacological therapy should be considered. This could
be possible thanks to the approval in children of safe and efficient pharmacological
options. According to the NHLBI Guidelines, decisions regarding the need for drug
treatment should take account of the baseline lipid levels, the child’s age, the presence
of moderate-to-high cardiovascular risk factors or condition and the familial history of
premature cardiovascular disease [
3
]. In particular, the NHLBI Guidelines state that
children with LDL-C > 250 mg/dL or TG > 500 mg/dL should consult a lipid specialist
in order to promptly start the pharmacological treatment. In children with less severe
lipid abnormalities, medication therapy should be recommended after at least 6 months
of therapeutic lifestyle changes if LDL-C > 130–190 mg/dL; the LDL-C threshold at
which statin therapy should be initiated may depend on the number of cardiovascular
risk factors or condition and the familial history of premature cardiovascular disease.
Basically, the goal of pharmacological therapy in children is to obtain acceptable values
of LDL-C (<130 mg/dL); however, children with high-risk cardiovascular conditions
(e.g., FH), may require stricter LDL-C targets (<100 mg/dL) [
3
,
6
]. It is important that
healthy behaviours should be implemented even though medications are initiated:
therapeutic lifestyle changes may be useful as a synergic mechanism to improve the
lipid profile and for the lowering dosages of lipid-lowering drugs [52].
4.3.1. Approved Pharmacological Treatment for Children
Statins
At present, statins have supplanted bile acid sequestrants as the first-line pharmaco-
logical therapy for children with dyslipidaemia. By inhibiting 3-hydroxy-3-methylglutaryl-
CoA reductase (HMG-CoA reductase, which is the rate-limiting enzyme of the hepatic
cholesterol production), statins reduce the intracellular cholesterol amount, which leads to
the upregulation of the LDL-C receptor on the hepatocyte’s surface and increases LDL-C
catabolism [
53
]. In adults, it is well known that statins are safe and effective at reducing
cardiovascular morbidity and mortality in both primary and secondary prevention [
54
].
As with adults, there is growing evidence that statin therapy is safe, well tolerated and
efficient at lowering lipids levels in children and adolescents with dyslipidaemia. Over
time, several studies were published on this issue [
55
–
59
]. A recent meta-analysis showed
that statins were effective at reducing TC, LDL-C and TG by approximately 25%, 33% and
8%, respectively; moreover, they led to a mean relative increase in HDL-C of approximately
3%. Although the available statins had a variable lipid-lowering efficacy throughout the
trials (being rosuvastatin and atorvastatin the most potent statins), the results indicated
Biomedicines 2021,9, 1078 7 of 17
a dose-dependent effect [
58
]. In the study of Luirink et al., it was also demonstrated that
statins were helpful in slowing the progression of CIMT and reducing cardiovascular mor-
bidity and mortality when used early in children with FH. Interestingly, the beneficial effect
was present even though the lipid target goals were not achieved [
59
]. As regards the safety
profile, no significant differences in short and long-term adverse events were described
when statins were compared to a placebo. In a 10-year follow-up study, Kusters et al. did
not note any differences in growth, maturation (including sexual development, as assessed
by Tanner staging) or educational level between treatment and placebo groups [
56
]; in a
study in which a 20-year follow-up was performed, no differences in transaminases (over
3-fold increase) and creatine kinase (over 10-fold increase) levels or serious adverse events
were described between statin therapy and placebo [
59
]. It is interesting to note that only
2% of children permanently discontinued the treatment due to adverse events and more
than 80% of the youths were regularly using statins [
59
]. These results suggest that statins
are generally well tolerated and that patients have good long-term compliance.
There are currently seven approved statins for use in children and adolescents:
lovastatin (the first HMG-CoA reductase inhibitor), simvastatin, atorvastatin and flu-
vastatin are indicated for children and adolescents
≥
10 years old; pitavastatin and
pravastatin have been approved for use in children from 8 years old; rosuvastatin is
indicated in children as young as 6 years old [
53
]. The choice of the statin can be influ-
enced by healthcare provider preferences, baseline LDL-C concentrations, treatment
goals and expected LDL-C reduction with a particular formulation [
10
]. When using a
statin, it is recommended to start with the lowest available dose once daily (at bedtime)
and subsequently increase the dose up to the maximally tolerated/age-appropriate
dose, if necessary [
3
]. It is also advised to increase the dose by one increment (doubling
the dose), without adjusting the dose based on body weight.
All statins, available at varying dosages, were approved for children with FH. Several
scientific societies provided recommendations regarding statin treatments for children with
both heterozygous FH (HeFH) and homozygous FH (HoFH) [
3
,
6
,
60
–
62
]. Depending on
the guidelines we use, children from 6-10 years old with HeFH are potential candidates
for pharmacological treatment in order to achieve LDL-C values < 100–130 mg/dL or a
50% reduction in LDL-C from baseline concentrations. As regards children with HoFH,
the common denominator that guidelines share is that statin treatment should be started
at the time of diagnosis, regardless of age. When used early, statins considerably reduce
the cardiovascular risk of HoFH patients, changing the natural history of the disease and
improving the prognosis. Although statins alone are rarely sufficient for achieving the
LDL-C goals, they represent the pillar of the treatment of HoFH patients [53].
Although it was shown that statins are safe, all children and adolescents on statin
treatment should always be monitored: growth, maturation, pubertal development and
possible adverse effects should be regularly assessed. In addition, baseline transaminases
and creatine kinase levels should be evaluated before starting the treatment and then
repeated over time (when the dose of statin is modified, muscle symptoms occur and at
regular intervals). If symptoms or laboratory abnormalities are reported, statin treatment
should be temporary interrupted and restarted after the resolution. For those patients
that are intolerant to statins, it is possible to try another statin formulation before using a
non-statin pharmacological treatment [63].
As a major substrate of cytochrome P450, it is important to know that statin therapy is
associated with various drug interactions; macrolides and antifungal azoles, which are com-
monly prescribed to children, are metabolised by the same enzyme and may be responsible
for increasing serum statin levels and its associated adverse effects [
19
]. Even in children
with chronic kidney diseases, statins should be used carefully: dose adjustment is needed
and only simvastatin and atorvastatin can be prescribed, as they are only metabolised in
the liver [
64
]. In addition, statins are contraindicated in pregnancy and lactation due to
their possible teratogenicity: as a consequence, all post-pubertal girls on statin treatment
should be adequately counselled and receive appropriate contraception [65].
Biomedicines 2021,9, 1078 8 of 17
Ezetimibe and Bile Acid Sequestrants
Although a majority of children usually benefit from statin treatment, some children
with the most severe lipid abnormalities (e.g., HoFH) may require other lipid-lowering
drugs in order to achieve the LDL-C therapeutic target [
66
]. This also applies to those rare
patients who develop an intolerance to HMG-CoA reductase inhibitor. If the LDL-C goals
are not attained, before adding second-line therapeutic drugs, it is possible to increase the
dose of statin or switch to a more potent statin, such as rosuvastatin or atorvastatin [
53
].
Moreover, it is extremely important to closely monitor the adherence to treatment among
patients with a poor response [67].
At present, bile-acid-binding resins (or sequestrants) and ezetimibe are the only
approved non-statin treatment for children and adolescents.
Due to its inhibition of intestinal cholesterol absorption (blocking the Niemann-Pick
C1-Like Intracellular Cholesterol Transporter 1), ezetimibe is the most frequently used
second-line agent [
68
]. It may be used as a monotherapy or combined with statins if the
maximal dose of statins is insufficient for achieving the LDL-C target. A 12-week trial of
ezetimibe as a monotherapy showed a significant reduction in LDL-C (by 27%) and TC
(by 21%) when compared to a placebo [
69
]. As regards the statin–ezetimibe association,
another long-term trial showed that the combination treatment led to a greater reduction
in LDL-C by 10–15% compared to a statin monotherapy [
70
]. In children and adolescents
with HeFH, the statin–ezetimibe association makes it possible to achieve the LDL-C goal
in approximately 69% of children [
71
]. Although data in children is limited, ezetimibe
is generally safe and well tolerated: no clinically significant adverse events, laboratory
abnormalities (transaminases and muscular creatine kinase increase) nor impacts on growth
and maturation have been associated with ezetimibe. Transient diarrhoea is probably the
most common adverse effect of ezetimibe [
52
,
69
–
71
]. Ezetimibe is currently approved for
children with FH from 10 years of age; the licensed formulation is 10 mg. Contrary to
statins, which are usually taken at bedtime, ezetimibe should be administrated without
regard to time of day or meals.
Bile acid sequestrants, such as cholestyramine and colesevelam, represent additional
lipid-lowering drugs. As mentioned above, they were the only pharmacological treatment
recommended by the first paediatric guidelines; however, they are no longer a first-line
therapy [
13
]. Bile acid sequestrants, while not being adsorbed, are able to bind to bile salt in
the gut and decrease intestinal cholesterol absorption. This results in greater hepatic conver-
sion of cholesterol to bile, upregulation of the LDL-C receptor and a consequent reduction
in TC and LDL-C concentrations. Their efficacy on lipid profiles varied between studies.
Cholestyramine (when taken at 8 g per day) reduces LDL-C values by approximately 15%;
colesevelam (3.75 g/day) has a similar effect, reducing LDL-C by 12–13% [72,73]. Despite
the additive lipid-lowering effect of bile acid sequestrants upon statins, these drugs are
not frequently used. Cholestyramine, in particular, is associated with poor palatability
and gastrointestinal effects (diarrhoea, nausea, abdominal pain, vomiting), and poor tol-
erance as a consequence [
53
]. It is also important to note that, contrary to ezetimibe, bile
acid sequestrants may also affect the intestinal absorption of fat-soluble vitamins, such as
vitamin D [
73
]. In view of this, they are generally used as additional agents in children
with an LDL-C that has not reached the target level despite the optimised statin–ezetimibe
combination [
3
]. Colesevelam is the only bile acid sequestrant that is approved by the FDA
for FH children over 10 years of age.
4.3.2. Non-Approved Pharmacological Treatment for Children
Fibrates and Niacin
Because limited data exist on the use of niacin and fibrates in children, these lipid-
lowering drugs lack FDA approval. According to Colletti et al., niacin (or vitamin B3)
may be helpful for reducing LDL-C and TC and increasing HDL-C values; this is mainly
due to the reduced hepatic production of very low-density lipoprotein (VLDL-C) [
74
].
However, the tolerance is poor and side-effects may be very common and serious (including
Biomedicines 2021,9, 1078 9 of 17
headache, flushing, abdominal pain, liver failure, myopathy, impaired glucose tolerance).
As a consequence, the use of niacin is usually reserved as an adjunct option for children
with severe dyslipidaemia (e.g., HoFH) that are not achieving the LDL-C goals [51].
Fibrates work by activating the transcription factor named peroxisome proliferator-
activated receptor alpha (PPAR
α
), which plays a key role in regulating hepatic lipid
metabolism. Via different mechanisms, fibrates lower the hepatic TG production, inhibit
the production of VLDL-C and reduce peripheral lipolysis [
20
]. Although they have
variable effects on LDL-C, fibrates may be beneficial in reducing TG in children and
adolescents. In particular, they are often the first-line treatment in children with severe
TG abnormalities (e.g., primary hypertriglyceridemia) in order to reduce the risk of
pancreatitis. Depending on the baseline TG concentrations, fibrates are able to reduce
serum TG by 40–60% [
10
]. The adverse effects that are associated with fibrate treatment
are similar to those with statins.
Due to the limited experience in children and the insufficient evidence on its safety and
dosage, it is recommended that niacin and fibrates should be initiated by a lipid specialist.
4.3.3. Additional Lipid-Lowering Options
In children with more severe forms of dyslipidaemia, such as HoFH, given the relevant
cardiovascular morbidity and mortality (the age of death is approximately 18 years in
untreated patients with HoFH), it is extremely important to keep lipid concentrations in
range, whenever possible [
52
]. In order to achieve this goal, as mentioned above, the
prompt detection of the disease represents a cornerstone of the treatment, as well as the
early start of lipid-lowering drugs (at diagnosis) [
53
]. However, children with HoFH
respond poorly to conventional treatment despite receiving the maximally tolerated statin
dose or combination therapy with bile acid sequestrants and/or ezetimibe [
75
]. Therefore,
additional therapeutic options may be considered.
Lipoprotein apheresis represents an additional option that is recommended for chil-
dren with HoFH. Even though it is expensive and difficult in practice, weekly or bi-weekly
LDL-C apheresis is effective at lowering LDL-C levels by 50–70%, improving cardiovascu-
lar health and providing clinical benefits (regression of xanthomas) [
64
]. Nevertheless, it is
important to note that the effect on LDL-C concentrations is temporary and the desired
frequency of lipoprotein apheresis should be every 1–2 weeks [76]. Lipoprotein apheresis
should be started as early as possible; however, being an invasive procedure, it cannot
always be performed due to several difficulties. Therefore, it should be considered from the
age of 5 years old and initiated before the age of 8 years [
77
]. In a recent study, it was found
that LDL-C apheresis is safe and is mainly associated with minor side effects; possible
adverse events include abdominal pain, hypotension and iron deficiency [64,78].
More recently, novel lipid-lowering drugs were developed and others are in the
process of human experimentation (Table 2).
Table 2. Novel lipid-lowering drugs.
Mechanism of Action Mean LDL-C
% Reduction
Currently Approval
Status Trials in Children Studies
Evolocumab PCSK9 inhibitor 20–55% FH from 12 years of
age
HoFH or severe
HeFH from
12 years of age
Santos et al. [79]
Hovingh et al. [80]
Santos et al. [81]
Alirocumab PCSK9 inhibitor 21–62% FH in adults Severe HeFH from
8 years of age
Blom et al. [82]
Hartgers et al. [83]
Daniels et al. [84]
Inclisiran
Small interfering RNA
directed against
PCSK9
35–43%
Primary hyperc-
holesterolemia or
mixed dyslipidaemia
in adults
Will be tested in
paediatric HeFH in
the ORION-16
study.
Raal et al. [85]
Biomedicines 2021,9, 1078 10 of 17
Table 2. Cont.
Mechanism of Action Mean LDL-C
% Reduction
Currently Approval
Status Trials in Children Studies
Evinacumab ANGPTL3 inhibitor 42–51% HoFH from 12 years
of age
HoFH from
12 years old Raal et al. [86]
Mipomersen Antisense APO-B
synthesis inhibitor 28% FH from 12 years of
age
HoFH and severe
HeFH from
12 years of age
Blom et al. [87]
Raal et al. [88]
Lomitapide MTTP inhibitor 51% FH in adults
HoFH from 7 years
of age
Stefanutti [89]
Ben-Omran et al. [90]
Chacra et al. [91]
Bempedoic
acid ACL inhibitor 17–38%
Primary hyperc-
holesterolemia or
mixed dyslipidaemia
in adults
Goldberg et al. [92]
Ballantyne et al. [93]
Anacetrapib CEPT inhibitor 40% Not approved Filippatos et al. [94]
Armitage et al. [95]
Both evolocumab and alirocumab are direct monoclonal antibodies that target the
proprotein convertase subtilisin/kexin type 9 (PCSK9). By inhibiting PCSK9, they prevent
the degradation of LDL-C receptors and favour its recycling on the hepatocyte surface,
resulting in greater expression of LDL-C receptors on the cell membrane and improved
LDL-C catabolism [
96
]. In adults, evolocumab and alirocumab were helpful in reducing
LDL-C by approximately 20–25% and 55–60% in patients with HoFH and severe HeFH,
respectively [
79
,
80
,
82
,
83
,
97
]. As regards children, evolocumab was used with HoFH and
HeFH before the age of 18 years and was shown to be as well tolerated and effective as in
adults [
79
,
81
]; similarly, when initiated in children with HeFH, alirocumab demonstrated
significant reductions in LDL-C and a good safety profile [
84
]. PCSK9 inhibitors are very
promising and should be considered in children from the age of 12 years old who are
intolerant to statins or not responding to conventional treatment; however, the presence
of the null mutation of LDL-C receptors may limit their utility [
98
]. A similar approach
may consist of the use of inclisiran, which is a gene-silencing drug that inhibits the hepatic
production of PCSK9 through a small interference RNA [
53
]. In adults, it seems to be
effective, safe and well tolerated thanks to the possibility of being administered at long
time intervals [85]. For paediatric patients, inclisiran is still under evaluation.
Evinacumab is a monoclonal antibody that binds and inhibits the function of
angiopoietin-like 3 (ANGPTL3). ANGPTL3 plays a key regulatory role in lipid
metabolism and is an inhibitor of lipoprotein-lipase. ANGPTL3 deficiency is tradition-
ally associated with reduced cardiovascular risk and serum lipid concentrations; as a
consequence, the inhibition of ANGPTL3 by evinacumab may be a new therapeutic
option for the management of dyslipidaemia [
99
]. In adults with HoFH, evinacumab
has documented potential benefits, leading to an average reduction in LDL-C by 47%.
Interestingly, evanicumab was effective regardless of the presence of a null variant of
LDL-C receptors [
86
]. Although it presented similar adverse effects to placebo in adults,
further investigations are needed in children and adolescents. It was recently approved
by the FDA as an add-on treatment for patients with HoFH from the age of 12 years
old. Novel pharmacological options include mipomersen, lomitapide, bempedoic acid
and anacetrapib. Mipomersen is an anti-sense oligonucleotide that is responsible for
the degradation of mRNA translation in apolipoprotein B (APO-B). This drug inhibits
the hepatic production of APO-B and reduces the assemblage of VLDL-C and other
atherogenic lipoproteins [
87
]. Mipomersen is associated with an average reduction in
LDL-C of 28% from baseline in addition to conventional therapy (e.g., maximum dose
of statin) and is currently approved by the FDA for patients with HoFH and severe
Biomedicines 2021,9, 1078 11 of 17
HeFH from the age of 12 years [
64
,
87
]. In children with HoFH, it was shown to be
effective in reducing LDL-C but was poorly tolerated due to side effects, such as flu-like
symptoms and reactions at the injection site [88].
On the other hand, lomitapide is a microsomal transfer protein of triglycerides (MTTP)
inhibitor; given that MTTP mainly acts by binding TG to APO-B in the liver, lomitapide
interferes with VLDL-C assembly and production [
87
]. Although adverse effects (e.g.,
gastrointestinal symptoms and fatty liver) occur frequently, lomitapide may lead to sig-
nificant reductions in VLDL-C, LDL-C and TG by approximately 65%, 51% and 56%,
respectively [
89
]. At present, it is only approved for adult patients with HoFH; however, it
has been used on a compassionate basis in few paediatric patients. In children with HoFH,
the administration of lomitapide reduced the LDL-C values by 58.4% and target LDL-C
goals were achieved in more than half of the patients [90,91].
Bempedoic acid is a targeted therapy that is designed to reduce cholesterol biosyn-
thesis, by inhibiting the adenosine triphosphate-citrate-lyase (ACL). In adults with FH,
it is approved as a monotherapy or in combination with ezetimibe, in addition to diet
and statin therapy [
100
]. When used as a monotherapy, it may further reduce LDL-C by
17% [
92
]; the combination of ezetimibe–bempedoic acid makes an additional reduction in
LDL-C by 38% possible [
93
]. Trials using children are not yet available. Lastly, anacetrapib
and other cholesterol ester transfer protein (CEPT) inhibitors may be a useful tool for the
management of dyslipidaemia in the future. By reducing the movement of cholesterol
esters from HDL-C to VLDL-C and LDL-C in exchange for TG, CEPT inhibitors signif-
icantly increase HDL-C and reduce VLDL, LDL-C and TG. Anacetrapib was shown to
be responsible for an increase in HDL-C by 140% and a decrease in LDL-C by 40%. It is
interesting to note that anacetrapib is also associated with improved glucose homeostasis
and decreased atherosclerotic cardiovascular events [
94
,
95
]. Although CEPT inhibitors
are not approved by the FDA in children or adults, the potential utility of anacetrapib
and the emerging data from genomic analyses may suggest their potential role in clinical
practice [101].
5. Conclusions
An altered lipid profile over time plays a key role in the initiation and progression
of atherosclerotic process in children and adolescents. Given that atherosclerosis is a
“paediatric problem” that correlates with future cardiovascular health, it seems neces-
sary to recognise it early and promptly treat children with modifiable cardiovascular risk
factors, such as dyslipidaemia. It is important to act when atherosclerosis is reversible.
Several guidelines and recommendations were published regarding the management of
lipid abnormalities in children; however, knowledge and uptake of these guidelines and
recommendations are not optimal in both patients and clinical practitioners. It is therefore
important to promote and increase awareness of them in this field. A graduated, indi-
vidualised and multidisciplinary approach is the basis of the treatment of dyslipidaemia:
therapeutic programs should combine behavioural modifications, dietary changes, physical
activity, drugs and other measures. Several figures may be involved in the management of
children with dyslipidaemia: parents, personal trainers, nutritionists, clinical practitioners,
lipid specialists and the patients themselves; among them, the family plays a very impor-
tant role in educating the children and creating a healthy environment. Although there
can be difficulties in adopting and sustaining therapeutic lifestyle changes, they represent
the cornerstone of the treatment and should be adopted all the time, regardless of drug
therapies. As regards pharmacological treatment, approved safe and effective medications
are already available for children and adolescents. As a consequence, physicians and
patients should not hesitate to consider lipid-lowering drugs in children, where statins
represent the first-line option; there is growing evidence that statin therapy in children may
change the natural history of atherosclerosis, even if lipid target goals are not achieved. In
addition to statins, there are other therapeutic strategies. Figure 1illustrates the algorithm
for the treatment of childhood dyslipidaemia.
Biomedicines 2021,9, 1078 12 of 17
Figure 1. Treatment algorithm of childhood dyslipidaemia.
Out of the traditional options (ezetimibe, bile acid sequestrants, fibrates, niacin, LDL-
C apheresis), additional lipid-lowering agents are currently available or under study for
certain categories of patients (e.g., FH). At present, the prescription of novel lipid-lowering
drugs beyond their licence should be considered on a case-by-case basis for the most severe
lipid abnormalities or for preventing risky invasive procedures (e.g., lipid apheresis). A
multidisciplinary team that includes lipid specialists should be involved. In the future,
novel lipid-lowering drugs may be promising options for the management of paediatric
dyslipidaemia; however, further studies are needed to evaluate their long-term efficacy,
safety and tolerability.
Author Contributions:
Writing—Original Draft Preparation, R.F.; Writing—Review & Editing, R.F.
and F.C.; Supervision, F.C. Both authors read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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