The National Heart, Lung and Blood Institute (NHLBI) recommends universal pediatric lipid screening to identify and treat children with serious genetic dyslipidemias.¹ Primary care providers should certainly identify children who will be candidates for statin therapy. One in 500 people are heterozygous for the autosomal co-dominant mutations causing familial hypercholesterolemia² (FH), making it one of the most common genetic diseases in Western populations. Still, a very low number of the children tested will reach the threshold for treatment.³ Statin therapy is recommended for otherwise healthy children older than 10 years with low-density lipoprotein cholesterol (LDL-C) > 190 mg/dL; this high cutpoint include only those with severe dyslipidemias such as FH.¹ Regardless of the low number of children who will require treatment, obstacles remain for these pediatric patients. Medications commonly associated with grandparents and secondary prevention of further cardiovascular disease may seem out of place in a child’s medicine cabinet. Even for willing prescribers, pediatricians historically have had little training in the management of lipid disorders, particularly pharmacotherapy.

Hesitation to use this class of drugs is unfortunate, because statins have proven highly effective and safe in adult primary and secondary prevention trials^4,5 and improve carotid medial thickness in children with FH.⁶ Furthermore, a recent meta-analysis of 135 studies involving ~250,000 adult patients showed that side effects of statins were rare.⁷ They are far more palatable and more effective at lowering LDL-C than the prior mainstay of pediatric treatment, bile-acid-binding resins.

Regardless of the agent used, reducing cholesterol in the pediatric population has caused concerns about decreasing the available substrate to form hormones that orchestrate pubertal development, and initiating a low-fat diet in at-risk children has been questioned because of the necessity of fats for healthy brain development. These concerns remain theoretical; a well-designed meta-analysis of six studies examining a total of 798 children showed no pubertal or growth concerns in children treated with statins.⁸ Smaller studies showed efficacy and safety of other agents, though none was powered to detect rare events.^9-12 Reversible elevations in transaminases were reported in from 1% to 5% of children in trials of simvastatin or atorvastatin, but none had clinical signs of liver injury.^11,12

Infrequent but significant adverse effects of statin therapy have been reported, including severe muscle injury leading to rhabdomyolysis. However, the more common issue in practice is statin intolerance, an inability to stay on the medication because of muscle complaints without objective signs or blood marker changes. Furthermore, recent studies showing a slight but statistically significant increase in risk for new onset diabetes have given many prescribers pause about statin use in patients of all ages.^7,13 Acute kidney injury with high doses,¹⁴ increased muscle injury and strains,¹⁵ reversible memory problems¹⁶ and decreased exercise tolerance¹⁷ also have been reported. Furthermore, the possible cumulative effect of statins is unknown. Young patients who start statin therapy for FH will likely take a pill for the rest of their lives. Statins are classified as a Category X medication for their potential teratogenic effects¹⁸ and should be used carefully in women of childbearing age, including teenage girls.

In the Vanderbilt University Medical Center pediatric lipid program, we first present lifestyle measures for lowering LDL-C and improving overall cardiovascular health, and each family meets with our dietitian. Following six months of optimal lifestyle efforts, we offer low-dose statin therapy and transparently discuss the risks and benefits of pharmacotherapy if LDL-C remains above the recommended threshold and continue close follow-up in our clinic. Only one patient in our practice, an obese but active girl, discontinued simvastatin based on complaints of muscle pain while performing ballet. There was no evidence of serious muscle injury, and a creatine phosphokinase level was normal at 114 IU/L (normal 26-140); following a brief medication holiday, she has had no complaints with rosuvastatin treatment for years now. A survey of our colleagues at three other pediatric lipid clinics at tertiary academic referral centers similarly revealed no knowledge of adverse effects requiring discontinuation of statin therapy.

One potential explanation for low rates of adverse effects in young patients is that children are generally healthy, without concomitant kidney or muscle disease. Furthermore, children are not usually taking other medications known to cause serious interactions, including gemfibrozil and digoxin.¹⁹ Polypharmacy increases the risk of toxicity because of competition with other cytochrome P450 isoform 3A4- metabolized substances.¹⁹ Lipid specialists also treat to less aggressive goals in children and use lower doses than for highrisk adult patients, and lower doses are associated with fewer adverse effects.⁷

In summary, statins are well tolerated in children when prescribed by specialists as recommended by the conservative guidelines given by the NHLBI. Early identification and treatment of serious dyslipidemias provide an important opportunity to prevent atherosclerotic disease later in life. Routine clinic visits with appropriate screening and counseling regarding adverse drug effects are necessary, but the knowledge of these potential rare complications should not limit the use of these powerful and effective lipid-lowering agents in appropriate patients. 

Disclosure statement: Dr. Lilley has no disclosures to report.

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