Treatment of pediatric dyslipidemia

• Since the NCEP Pediatric Panel guidelines were published in 1992, new evidence from numerous studies has provided the impetus for their reevaluation and modification. In 2007, the American Heart Association (AHA) published a scientific statement with updated treatment recommendations for children and adolescents.¹ More recently, the American Academy of Pediatrics’ also published guidelines for the screening and management of lipid abnormalities in children.² In 2011 the Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents was published by the National Heart, Lung and Blood Institute (NHLBI) with detailed recommendations.³

• Children with dyslipidemia should be treated with aggressive lifestyle modification from age two and medication from age 10 onwards if the lipid goals and targets are not met with lifestyle modifications alone.^{2, 4, 5} However children with familial homozygous hypercholesterolemia (FH) who have very high LDL (> 500mg/dL) can be treated with medications as early as 8 years. It is worth noting that children as young as 18 months have received treatment, since coronary events begin in the first decade of life and lifespan is severely shortened in children with very high LDL levels.³ The report also recommended that children with diabetes  and LDL–C ≥130 mg/dL be considered for drug therapy.³

The Cardiovascular Health Integrated Lifestyle Diet (CHILD 1) 

• The NHLBI Expert Panel accepts the 2010 DGA (Dietary guidelines for Americans)  as containing appropriate recommendations for diet and nutrition in children 2 years and older.³

• Proven methods of primary prevention, namely maintenance of optimal body weight through physical activity and proper caloric balance, not smoking, and eating fresh fruits and vegetables, should be applied to all children, irrespective of their blood lipid levels, as part of an effective primary prevention approach. The need and dose of medications can be reduced by healthy lifestyle changes in children.⁴

• In normal children and in children with hypercholesterolemia, intake of total fat can be safely limited to 30% of total calories, saturated fat intake limited to 7-10% of calories, and dietary cholesterol limited to 300 mg/d without adversely affecting growth and nutrition.⁴ For those who do not respond adequately, a more stringent diet with saturated fat < 7% of calories and dietary cholesterol < 200 mg/d has been shown to be safe and modestly effective in lowering the LDL-C level.⁴

• 4-5 servings of fruits and 4-5 servings of vegetables are recommended (for a1800 cal diet).³

• The water-soluble fiber psyllium (Metamucil) can be added to a low saturated fat diet as at a dose of 6 g/d for children 2–12 years, and 12 g/d for those ≥12 years.³

• Use of dietary adjuncts such as plant sterol or stanol esters up to 20 g/d can safely lower LDL-C in children with FH. Food products containing plant stanol esters, such as some margarine, are marketed directly to the general public. In two short-term trials, they have been shown to be safe.³

• As in all children, 1 hour/day (h/d) of moderate to vigorous physical activity and <2 h/d of sedentary screen time are recommended. 

• Children with lipid abnormalities (other than LDL-C > 250 mg/dL or TG > 500 mg/dL) should be initially managed for 3-6 months with diet changes. If  overweight (BMI is > 85th percentile), add increased physical activity, reduced screen time, and calorie restriction 

Medications

• Decisions regarding the need for medication therapy should be based on the average of results from at least two fasting lipid profiles obtained at least 2 weeks but no more than 3 months apart.³

• The bile acid sequestrants are medications that bind bile salts within the intestinal lumen and prevent their enterohepatic reuptake in the terminal ileum, resulting in a depletion of bile salts in the liver and a signal for increased production. Since bile salts are synthesized from intracellular cholesterol in the liver, the intracellular pool of cholesterol becomes depleted, signaling increased production of LDL receptors and increased clearance of circulating LDL–C to replenish the intracellular cholesterol pool for increased production of bile salts.³

• Studies of bile acid sequestrants in children and adolescents ages 6–18 years have shown LDL–C reduction of 10–20 percent, sometimes with a modest elevation in triglyceride levels. The bile acid sequestrants are safe and moderately effective but adherence is limited in both children and adults due to gastrointestinal side effects.³ This agent can be used with statins for additive effects.

• Colesevelam but not ezetemibe or fibrates is indicated as monotherapy or with statin for LDL-C reduction in boys and postmenarchal girls ages 10-17 years with FH after diet trial if LDL-C levels remain elevated. Table 131A

• Statin medications which inhibit HMG coA reductase, the rate-limiting enzyme in the endogenous cholesterol synthesis pathway has now become the mainstay of treatment of elevated cholesterol in children and adults. Statins decreases the intracellular pool of cholesterol, which signals upregulation of LDL receptors and increased clearance of circulating LDL–C. As a group, statins have been shown to reduce LDL–C in children and adolescents with marked LDL–C elevation or FH (Table 132A).

Statin Trials Establishing Safety and Efficacy in Children3
Author	Number	Ages	Statin use	LDL-C reduction
McCrindle et al. 6	187	10-17 years	Atorvastatin 10-20 mg/d for 26 weeks	40%
Schanberg 7	221	10-21	Atorvastatin 10-20 mg/d for 36 months	Significant reduction
Van der Graaf et al8	189	10-16 years	Fluvastatin 80 mg/d for 2 years	34%
Van der Graaf et al8	189	10-17	Pravastatin 20-40 mg/d for 1year	45%
Lambert et al9	69	13 years	Lovastatin 10-40 mg/d for 8 weeks	21-36%
Stein et al10	132	10-17 years	Lovastatin 10-40 mg/d for 48 weeks	17-27%
Clauss et al11	54	10-17 years	Lovastatin 40 mg/d for 24 weeks	27%
Knipscheer et al.12	72	8-16 years	Pravastatin5-20 mg/d for 20 weeks	23-33%
Wiegman et al. 13	214	8-18 years	Pravastatin 20-40 mg/d for 2 years	24%
Rodenburg et al.14	178	8-18 years	Pravastatin 20-40 mg/d for4.5 years	29%
Hedman 15	30	4-19	Pravastatin 10-40 mg/d for 24 months	25-32%
de Jongh et al.	50	10-17 years	Simvastatin 10-40 mg/d for 48 weeks	40%
de Jongh et al.	173	9-18 years	Simvastatin 10-40 mg/d for  32 weeks	41%
Avis et al16	177	10-17 years	Rosuvastatin 5-20 mg/d for 52 weeks	38-50%
Avis et al17	798	8 to 18 years	12-104 weeks various statins	Significant reduction
Carreau et al18	85	11 years	26 months	21-24%

• The lower LDL–C level for eligibility into the statin trials was >190 mg/dl or > 160 mg/dl with 2 or more additional risk factors, after a trial period on diet. Trial subjects were monitored carefully throughout treatment; adverse impacts on growth, development, or sexual maturation were not seen, and adverse event profiles and efficacy were similar to those in studies of adults.³

• All statins currently marketed except pitavastatin are approved as an adjunct to diet to lower LDL-C in adolescent boys and postmenarchal girls ages 10-18 years (8+ years for pravastatin). The indications for statin therapy are given in the table below. Target levels for LDL-C are: Minimal < 130 mg/dL; Ideal < 110 mg/dL.

• Statin use should begin with the lowest available dose given once daily. If LDL-C target levels are not achieved with at least 3 months of compliant use, then the dose may be increased by one increment (usually 10 mg). If LDL-C target levels are still not achieved with at least 3 months of compliant use, then the dose may be further increased by one increment. The risk and effectiveness of dose escalation has been explored in several of the statin clinical trials in children with no additional safety issues identified. Alternatively, a second agent such as a bile acid sequestrant or cholesterol absorption inhibitor may be added under the direction of a lipid specialist.

Safety of Statins in Children

• Adverse effects from statins are rare at standard doses but include myopathy and hepatic enzyme elevation. In the meta-analysis of statin use in children, evidence of hepatic enzyme elevation and muscle toxicity did not differ between the statin and placebo groups. However, routine monitoring of hepatic enzymes and clinical assessment for muscle toxicity are strongly recommended for children and adolescents on statin therapy. The threshold for worrisome levels of ALT or AST is > 3 times the upper limit of normal.³

• The risk of adverse events increases with use of higher doses and interacting drugs, the latter occurring primarily with drugs that are metabolized by the cytochrome P–450 system, which is the primary mode of metabolism for the majority of statins. Drugs that potentially interact with statins include fibrates, Azole antifungals, macrolide antibiotics, antiarrhthymics, and protease inhibitors, none of which is used commonly in children.

• Adolescent females should be counseled about statin contraindications in pregnancy and the need for abstinence or use of appropriate contraceptive measures. Use of oral contraceptives is not contraindicated if medically appropriate.

• There is limited published experience in children with use of niacin and fibrates, or cholesterol absorption inhibitors, which have been useful in treating adult patients with combined dyslipidemias. Efficacy and safety data are limited, and no data are available regarding newer formulations.

• Children with lipid abnormalities should have a detailed family history taken and be assessed for causes of hyperlipidemia, additional risk factors, and risk condition.

FAQ

1.Can children Younger Than Age 10 Years be treated with a statin?

Children < age 10 years should not be treated with a medication unless they have a severe primary hyperlipidemia or a high-risk condition that is associated with serious medical morbidity (homozygous hypercholesterolemia with LDL-C > 400 mg/dL; primary hypertriglyceridemia with TG > 500 mg/dL; evident CVD in the first two decades of life; postcardiac transplantation.

For children ages 8 and 9 years with LDL-C persistently > 190 mg/dL after a trial of lifestyle/diet management, together with multiple first-degree family members with premature CVD/events, or the presence of at least one high-level risk factor or risk condition or the presence of at least two moderate-level risk factors or risk conditions, statin therapy might be considered.

2.How long children can be managed without medications?

If LDL-C remains > 130 mg/dL to < 190 mg/dL in a child age 10 years or older with a negative family history of premature CVD in first-degree relatives and no high-level or moderate-level risk factor or risk condition, management should continue to focus on diet and lifestyle changes with  weight management if overweight. Pharmacologic therapy is not generally indicated, but treatment with bile acid sequestrants might be considered, the latter in consultation with a lipid specialist.

3.When should Children (10-21years) be referred to a lipid specialist?

Children with average LDL-C > 250 mg/dL should be referred directly to a lipid specialist. If LDL-C remains > 190 mg/dL after a 6-month trial of lifestyle/diet management  for children ages 10 years and older, statin therapy should be considered (see table)

4.How should children be monitored while on statin therapy? 

Children taking a statin should have routine clinical monitoring for symptoms of muscle toxicity and assessment of hepatic transaminases and creatine kinase in the same way as is done in adults.

Pediatric care providers should be on the alert for, and children and their families should be counseled about, potential medication interactions.

Sources

1. McCrindle BW, Urbina EM, Dennison BA, et al. Summary of the American Heart Association’s scientific statement on drug therapy of high-risk lipid abnormalities in children and adolescents. Arterioscler Thromb Vasc Biol. May 2007;27(5):982-985.

2. Daniels SR, Greer FR. Lipid screening and cardiovascular health in childhood. Pediatrics. Jul 2008;122(1):198-208.

3. Daniels SR. Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Report from National Heart, Lung and Blood Institute.Bethesda ,http://www.nhlbi.nih.gov/guidelines/cvd_ped/index.htm2011.

4. McCrindle BW, Urbina EM, Dennison BA, et al. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation. Apr 10 2007;115(14):1948-1967.

5. Enas E.A., Hancy Chennikkara Pazhoor MD, Arun Kuruvila MBBS, Krishnaswami Vijayaraghavan MD F. Intensive Statin Therapy for Indians:Part I Benefits. Indian Heart J 2011; 63: 211-227.

6. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial. J Pediatr. Jul 2003;143(1):74-80.

7. Schanberg LE, Sandborg C, Barnhart HX, et al. Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum. Oct 26 2011.

8. van der Graaf A, Nierman MC, Firth JC, Wolmarans KH, Marais AD, de Groot E. Efficacy and safety of fluvastatin in children and adolescents with heterozygous familial hypercholesterolaemia. Acta Paediatr. Nov 2006;95(11):1461-1466.

9. Lambert M, Lupien PJ, Gagne C, et al. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group. Pediatrics. 1996;97(5):619-628.

10. Stein EA, Illingworth D, Kwiterovich P, Jr., et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. Jama. 1999;281(2):137-144.

11. Clauss SB, Holmes KW, Hopkins P, et al. Efficacy and safety of lovastatin therapy in adolescent girls with heterozygous familial hypercholesterolemia. Pediatrics. Sep 2005;116(3):682-688.

12. Knipscheer HC, Boelen CC, Kastelein JJ, et al. Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia. Pediatr Res. May 1996;39(5):867-871.

13. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. Jama. Jul 21 2004;292(3):331-337.

14. Rodenburg J, Vissers MN, Wiegman A, et al. Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin. J Am Coll Cardiol. May 2 2006;47(9):1803-1810.

15. Hedman M, Matikainen T, Fohr A, et al. Efficacy and safety of pravastatin in children and adolescents with heterozygous familial hypercholesterolemia: a prospective clinical follow-up study. The Journal of clinical endocrinology and metabolism. Apr 2005;90(4):1942-1952.

16. Avis  HJ, Hutten BA, Gagne C, et al. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. J Am Coll Cardiol. Mar 16 2010;55(11):1121-1126.

17. Avis HJ, Vissers MN, Stein EA, et al. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. Aug 2007;27(8):1803-1810.

18. Carreau V, Girardet JP, Bruckert E. Long-term follow-up of statin treatment in a cohort of children with familial hypercholesterolemia: efficacy and tolerability. Paediatr Drugs. Aug 1 2011;13(4):267-275.