US Pharm. 2014;39(5):52-56.
ABSTRACT: Guidelines for the screening and
management of dyslipidemias in children were published in November 2011
by the National Heart, Lung, and Blood Institute. They recommend
universal screening of all children aged 9 to 11 and 17 to 21 years
regardless of family history and risk factors. Despite this
recommendation, pediatric practitioners do not routinely screen children
without a family history or risk factor present. This article will
review current guidelines for screening and treatment of dyslipidemias
in children and adolescents.
Dyslipidemias are disorders of lipoproteins that include
high total cholesterol (TC), high low-density lipoprotein cholesterol
(LDL-C), low high-density lipoprotein cholesterol (HDL-C), and high
triglycerides (TG), all of which can contribute to atherosclerosis
development and cardiovascular disease (CVD), a common cause of death in
adults.1,2 The development of dyslipidemia often begins in childhood (TABLE 1),2 and as early as 9 years of age, such changes have been linked to adverse cardiac outcomes in adulthood.3 Results from several studies link development of dyslipidemias in childhood to development of CVD in adulthood.4-7
Risk factors for development of CVD in children and
adolescents include genetic disorders, such as familial combined
hyperlipidemia (FCH) and familial hypercholesterolemia (FH), obesity,
hypertension, and diabetes. These factors place a child at high risk of
subsequent development of CVD in adulthood (TABLE 2).2 Childhood obesity is a contributing factor in development of CVD risk factors.8 Moreover, prevalence of obesity in children aged 6 to 11 years has increased from 4% to over 20% in the past three decades.9
The increase in childhood obesity, along with diabetes and
hypertension, heightens the importance of treating and preventing
secondary causes of CVD in children and adolescents.
The National Heart, Lung, and Blood Institute (NHLBI),
which is part of the National Institutes of Health (NIH), began the
National Cholesterol Education Program (NCEP) in 1985 with a goal to
“reduce illness and death from coronary heart disease in the United
States by reducing the percent of Americans with high blood
cholesterol.”10 In 1992, guidelines recommended screening for
children and adolescents with a family history of premature CVD or
elevated serum cholesterol.11 In 2008, the American Academy
of Pediatrics (AAP) released guidelines for selected screening of
children aged 2 to 10 years who have a family history or identified risk
Most recently, the Expert Panel on Integrated Guidelines
for Cardiovascular Risk Reduction, under a directive from the NHLBI,
released guidelines for lipid screening in pediatric patients.2
Consequently, members of the expert panel decided that screening only
those with a family history of dyslipidemias would fail to capture
children and adolescents with atherosclerosis who are at risk for future
development of CVD. Therefore, the panel recommended universal
screening of all children aged 9 to 11 and 17 to 21 years (TABLE 3).2
The AAP endorsed the NHLBI guidelines, which differ from the U.S.
Preventive Services Task Force (USPSTF) guidelines that concluded there
was insufficient evidence to recommend universal screening.13,14
Criticisms to universal screening include lack of strong
evidence and evidence from long-term clinical trials assessing efficacy
of lipid-lowering therapies in children and adolescents, and potential
of conflict of interest among NHLBI panel members.11,15 The
USPSTF is currently revising guidelines to determine the diagnostic
value of selective and universal screening of children and adolescents
for treatment of dyslipidemias.16
Differences in recommendations for screening dyslipidemias
in children and adolescents provide a source of confusion among
practitioners. In 2012-2013, the University of Minnesota conducted an
online survey over 12 weeks to assess awareness and implementation of
lipid-screening guidelines among primary pediatric providers in
Minnesota. Results indicated that of the 548 respondents, 34% performed
no lipid screening, 50% screened selectively, and only 16% performed
Lifestyle Modifications and Diet
Lifestyle modifications remain the cornerstone of
dyslipidemia treatment. Goals include prompting dietary change,
increasing physical activity, limiting inactivity, and achieving weight
loss, if needed.2 The Cardiovascular Health Integrated
Lifestyle Diet (CHILD 1) promotes healthy eating and weight. Children
limit or avoid sugar-sweetened drinks, drink more water and fat-free
unflavored milk, avoid foods with high trans fat and sodium, and consume
high-fiber foods, fruits, vegetables, whole grains, fish, poultry,
beans, nuts, and seeds. Additionally, the diet stresses control of
portion sizes and overall healthy eating. If after 3 months of adherence
to the CHILD-1 diet, lipid levels fail to achieve desired targets, the
CHILD-2 diet specific to the abnormal lipid level is recommended. For
more information about these diets, consult the NHLBI guidelines.2
Lifestyle modifications alone often fail to achieve desired target lipid levels, not only in adults but also in children.2
If after 6 months of lifestyle modifications and diet, desired lipid
levels are not achieved, pharmacotherapy may be considered in children
and adolescents who meet specific criteria stated below2:
- No CVD risk factors but has LDL-C >190 mg/dL after 6 months of lifestyle/diet changes
- CVD risk factor(s) and LDL-C ≥160 mg/dL after 6 months of lifestyle/diet changes
- Diabetes and LDL-C ≥130 mg/dL despite lifestyle/diet changes
- Average fasting TG level ≥500 mg/dL or single level ≥1,000 mg/dL.
Statins: Considered first-line
therapy for treatment of dyslipidemias in children and adolescents,
statins inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase,
the enzyme responsible for the rate-limiting step in cholesterol
synthesis. Inhibition lowers intracellular cholesterol and increases
clearance of LDL-C through upregulation of LDL-C receptors. Statins
lower LDL-C serum levels an average of 20% to 50%. Currently seven of
the eight commercially available statins are FDA-approved as an adjunct
to diet to lower LDL-C concentrations in children aged 10 to 18 years
(≥8 years for pravastatin) (TABLE 4).2,8
Children and adolescents with hereditary FH and LDL-C ≥190
mg/dL or who have a family history of premature CVD and two or more CVD
risk factors and LDL-C ≥160 mg/dL are potential candidates for therapy.2,8
Pitavastatin is not FDA-approved for use in children or adolescents.18 Choice of statin depends upon the patient’s insurance coverage and physician preference.
Long-term safety of statins in children is unknown.
Results of a recent systematic review on safety of statins in children
≤18 years showed that these drugs were well tolerated.19,20
Adverse effects were mild and included headache, gastrointestinal (GI)
distress, and myalgia. Elevations in liver enzymes were infrequent,
occurring in 1% to 5% of patients receiving atorvastatin and simvastatin
and less frequently with lovastatin, pravastatin, and rosuvastatin.19,20
Results of a recent systematic Cochrane review in which authors
identified eight trials assessing the efficacy and safety of statins for
treatment of FH in children aged 7 to 17 years revealed no increased
risk of liver or muscle enzyme elevations.20 Trials ranged
from 6 months to 2 years. The lack of published long-term safety data
requires prudent prescribing and monitoring of children requiring such
therapy. Statin-induced myopathies may take weeks to months to develop.21,22
Any complaint of unusual muscle weakness or pain beginning several
weeks to months after initiation of a statin should be assessed.
Cholesterol Absorption Inhibitors: This
drug class inhibits cholesterol from the intestine, thereby decreasing
hepatic cholesterol, which causes upregulation of LDL-C receptors and
increased LDL-C clearance.2 Ezetimibe, the only cholesterol absorption inhibitor approved by the FDA, is indicated for children aged ≥10 years (TABLE 4).2,23 Addition of ezetimibe to a statin regimen lowers LDL-C levels more than statin monotherapy.23 When used in conjunction with statins, reductions in LDL-C levels of 14% to 18% may occur.2,23 Ezetimibe monotherapy when used in conjunction with diet has shown to similarly reduce LDL-C levels.24
Ezetimibe may be considered for children and adolescents who fail to
meet lipid target levels on statin monotherapy, but should be used under
direction of a lipid specialist. Ezetimibe is well tolerated, with
adverse effects of diarrhea, arthralgia, myalgia, and nasopharyngitis
reported most often.24
Fibric Acid Derivatives (Fibrates): These
agents increase oxidation of fatty acids in the liver and muscle,
thereby reducing the rate of hepatic lipogenesis and decreasing TG
production. Although fibrates are not FDA-approved in children and
adolescents (TABLE 4), use may be considered in consultation with a lipid specialist for children with TG levels >500 mg/dL.2
Fibrates should not be used in conjunction with statins unless the
patient is under the care of a lipid specialist because of the increased
risk of myopathy and rhabdomyolysis.2,8 In addition, gemfibrozil is a strong CYP450 inhibitor of CYP2C19, CYP2C8, and CYP2C9.25
Bile Acid Sequestrants: These medications bind bile
salts in the intestine, thereby increasing the conversion of
cholesterol to bile in the liver. Decreased hepatic cholesterol causes
upregulation of LDL-C receptors and increased LDL-C clearance.
Cholestyramine and colestipol are not FDA-approved for use in children
and adolescents (TABLE 4).2,8,26 Colesevelam is
indicated as monotherapy or in combination with a statin in children and
adolescents with hereditary FH who have LDL-C ≥190 mg/dL or who have a
family history of premature CVD and two or more CVD risk factors and
LDL-C ≥160 mg/dL.2,8
Since bile salts are not absorbed systematically, major
adverse effects are GI in nature and include bloating, nausea, diarrhea,
and constipation. Many patients cannot tolerate these effects and stop
Niacin: This form of vitamin B3
decreases hepatic metabolism of cholesterol and increases HDL-C
concentrations. Because of the potential intolerable adverse effects,
including flushing, rash, and headaches, and the limited data supporting
efficacy in children, niacin should be used with caution in children
and only in those under the care of a lipid specialist.2,8
Niacin may be considered for treatment of severe hypertriglyceridemia
(fasting TG≥≥500 mg/dL or any single measurement of ≥1,000 mg/dL).2
Extended-release niacin products are FDA-approved in
children ≥16 years. The effects of flushing, which occur more often with
immediate-release formulations, may be lessened with administration of
aspirin before therapy; however, routine use is linked to development of
Reye syndrome.27 In addition, changing to an extended-release formulation may alleviate flushing.
Omega-3 Fatty Acids: These essential
fatty acids reduce cholesterol and TG concentrations. In clinical trials
with adults, 2 to 4 g daily of omega-3 fatty acids lowered TG by 30% to
40% and raised HDL-C by 6% to 17%.2 However, data supporting
the use of omega-3s to treat dyslipidemias in children are sparse and
have not shown beneficial effects.2,8
Researchers conducted a randomized, controlled trial in
which 25 children aged 10 to 19 years with moderate-to-severe
hypertriglyceridemia received omega-3s, given as Lovaza 1 g, four
capsules daily or placebo for 6 months.28 Results showed a
reduction in serum TG levels at 3 and 6 months of 24% with Lovaza and
16% with placebo. The reductions in TG levels between Lovaza and placebo
were not statistically significant. It is worth noting that baseline TG
levels ranged from 150 to 1,000 mg/dL. With the small sample size and
the wide variation in baseline TG levels, more data are needed to
adequately assess the benefit of omega-3 fatty acids in children with
Other: In 2013, the FDA approved two drugs for the treatment of homozygous FH.29
Mipomersen (Kynamro) must be injected subcutaneously once weekly, and
lomitapide (Juxtapid) is taken orally once daily. Both medications
significantly lower LDL-C in patients with homozygous FH already taking
maximum dosages of other lipid-lowering drugs. Safety and effectiveness
have not been established in pediatric patients.29
PEDIATRIC VERSUS ADULT MANAGEMENT
The American College of Cardiology in conjunction with the
American Heart Association released updated guidelines in November 2013
for treatment of hyperlipidemia in adults.30 These new
guidelines eliminate LDL-C targets for monitoring therapy and identify
four groups of adults as candidates for statin therapy30:
- Those with atherosclerotic CVD who require secondary prevention
- Those with LDL-C ≥190 mg/dL without a secondary cause
- Those aged 40 to 75 years with diabetes but no established CVD who have an LDL-C of 70 to 189 mg/dL
- Those aged 40 to 75 years who do not have diabetes or
atherosclerotic CVD but who have an LDL-C of 70 to 189 mg/dL with a
calculated CVD risk of ≥7.5%.
With adults, healthcare providers can calculate individual
risk of CVD, which aids in guidance of lipid-lowering therapy. For
children, however, initiation of pharmacotherapy is most likely for
treatment of primary dyslipidemias, such as FH. The new guidelines for
adults complement those for children because both state initiation of
statin therapy for LDL-C ≥190 mg/dL.2,30 With the increase in
secondary causes of dyslipidemias in children and adolescents,
practitioners need to support lifestyle changes before initiation of
lifelong lipid-lowering therapy.
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