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01-01-2000 | Review Article

Role of Lipid-Lowering Pharmacotherapy in Children

Author: Dr Serena Tonstad

Published in: Pediatric Drugs | Issue 1/2000

Abstract

For patients with coronary artery disease and healthy middle-aged or older individuals with elevated cholesterol levels, treatment with cholesterol-lowering drugs reduces morbidity and sometimes mortality. Treatment reverses established atherosclerotic lesions within a relatively short period of time, suggesting that starting cholesterol-lowering drugs in adulthood is adequate for most people at risk. Children with genetic lipid disorders, including familial hypercholesterolaemia and familial combined hyperlipidaemia, may be candidates for earlier therapy. A complete assessment of risk factors should be undertaken to determine which children are at highest risk.

Treatment should start with diet, because diet is an important independent protective factor for disease. The bile acid sequestrants (resins) are the only drugs approved for children and may reduce low density lipoprotein (LDL)-cholesterol levels by 15 to 20% at best. Long term tolerability is good, but many children will not take the resins because they find them unpalatable. Tablet formulations have higher acceptability. Some children require supplementation with fat soluble vitamins or folate.

Although hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have not been tested in long term studies in children, safety records are excellent in adults. Short term studies show that HMG-CoA reductase inhibitors reduce LDL-cholesterol levels similarly in children and in adults. Thus, the drugs may be used in low dosages to treat some adolescents with exceptional risk of disease.

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9

Sacks F, Pfefeer M, Moye LA, et al. The effects of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001–9PubMedCrossRef

Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333: 1301–7PubMedCrossRef

Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. AirForce/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279: 1615–22PubMedCrossRef

Newman TB, Garber AM, Holtzman NA, et al. Problems with the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Arch Pediatr Adolesc Med 1995; 149: 241–7PubMedCrossRef

Tonstad S. A rational approach to treating hypercholesterolaemia in children. Drug Saf 1997; 16: 330–41PubMedCrossRef

Ose L, Tonstad S. The detection and management of dyslipidaemia in children and adolescents. Acta Paediatr 1995; 84: 1213–5PubMed

Porkka KVK, Raitakari OT. Serum lipoproteins in children and young adults: determinants and treatment strategies. Curr Opin Lipidol 1996; 7: 183–7PubMedCrossRef

Hegele RA. The genetic basis of atherosclerosis. J Clin Lab Res 1997; 27: 2–13CrossRef

10.

Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis 1989; 9Suppl. I: 119–32

11.

Ballantyne CM, Herd JA, Dunn JK, et al. Effects of lipid lowering therapy on progression of coronary and carotid artery disease. Curr Opin Lipidol 1997; 8: 354–61PubMedCrossRef

12.

Levine GN, Keaney Jr JF, Vita JA. Cholesterol reduction in cardiovascular disease: clinical benefits and possible mechanisms. N Engl J Med 1995; 332: 512–21PubMedCrossRef

13.

Wilson DJ, Gahan M, Haddad L, et al. A world wide web site for low-density lipoprotein receptor gene mutations in familial hypercholesterolaemia: sequence-based, tabular, and direct submission data handling. Am J Cardiol 1998; 81: 1509–11PubMedCrossRef

14.

Slack J. Risk of ischaemic heart disease in familial hyperlipidaemic states. Lancet 1969; II: 1380–2CrossRef

15.

European Atherosclerosis Society International Task Force for Prevention of Coronary Heart Disease: prevention of coronary heart disease: scientific background and new clinical guidelines. Nutr Metabol Cardiovasc Dis 1992; 2: 113–56

16.

Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ 1991; 303: 893–6

17.

Gagné C, Moorjani S, Brun D, et al. Heterozygous familial hypercholesterolemia. Relationship between plasma lipids, lipoproteins, clinical manifestations and ischaemic heart disease in men and women. Atherosclerosis 1979; 34: 13–24PubMedCrossRef

18.

Moorjani S, Roy M, Torres A, et al. Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia. Lancet 1993; 341: 1303–6PubMedCrossRef

19.

Ferrières J, Lambert J, Lussier-Cacan S, et al. Coronary artery disease in heterozygous familial hypercholesterolemia patients with the same LDL receptor gene mutation. Circulation 1995; 92: 290–5PubMedCrossRef

20.

Hansen PS, Jensen HK, Meinertz H, et al. Apolipoprotein B and E gene polymorphisms and association with plasma lipids and atherosclerotic disease in familial hypercholesterolemia. Nutr Metab Cardiovasc Dis 1994; 4: 204–8

21.

Tonstad S, Joakimsen O, Stensland-Bugge E, et al. Risk factors related to carotid intima-media thickness and plaque in children with familial hypercholesterolemia and controls. Arterioscler Thromb Vasc Biol 1996; 16: 984–91PubMedCrossRef

22.

Carmena R, Lussier-Cacan S, Roy M, et al. Lp(a) levels and atherosclerotic vascular disease in a sample of patients with familial hypercholesterolemia sharing the same gene defect. Arterioscler Thromb Vasc Biol 1996; 16: 129–36PubMedCrossRef

23.

Hirobe K, Matsuzawa Y, Ishikawa K, et al. Coronary artery disease in heterozygous familial hypercholesterolemia. Atherosclerosis 1982; 44: 201–10PubMedCrossRef

24.

Moorjani S, Gagné C, Lupien PJ, et al. Plasma triglycerides related decrease in high-density lipoprotein cholesterol and its association with myocardial infarction in heterozygous familial hypercholesterolemia. Metabolism 1986; 35: 311–6PubMedCrossRef

25.

Hill JS, Hayden MR, Frohlich J, et al. Genetic and environmental factors affecting the incidence of coronary artery disease in heterozygous familial hypercholesterolemia. Arterioscler Thromb 1991; 11: 290–7PubMedCrossRef

26.

Hausmann D, Johnson JA, Sudhir K, et al. Angiographically silent atherosclerosis detected by intravascular ultrasound in patients with familial hypercholesterolemia and familial combined hyperlipidemia: correlation with high density lipoproteins. J Am Coll Cardiol 1996; 27: 1562–70PubMedCrossRef

27.

Seed M, Hoppichler F, Reaveley D, et al. Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med 1990; 322: 1494–9PubMedCrossRef

28.

Heiberg A, Slack J. Family similarities in the age at coronary death in familial hypercholesterolaemia. BMJ 1977; 2: 493–5PubMedCrossRef

29.

Pimstone SN, Sun XM, du Souich C, et al. Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada. Arterioscler Thromb Vasc Biol 1998; 18: 309–15PubMedCrossRef

30.

Beaumont V, Jacotot B, Beaumont JL. Ischaemic disease in men and women with familial hypercholesterolaemia and xanthomatosis. Atherosclerosis 1976; 24: 441–50PubMedCrossRef

31.

Vuorio AF, Turtola H, Piilahti K-M, et al. Familial hypercholesterolemia in the Finnish North Karelia: a molecular, clinical, and genealogical study. Arterioscler Thromb Vasc Biol 1997; 17: 3127–38PubMedCrossRef

32.

Gaudet D, Vohl MC, Perron P, et al. Relationships of abdominal obesity and hyperinsulinemia to angiographically assessed coronary artery disease in men with known mutations in the LDL receptor gene. Circulation 1998; 97: 871–7PubMedCrossRef

33.

Yanagi K, Yamashita S, Kihara S, et al. Characteristics of coronary artery disease and lipoprotein abnormalities in patients with heterozygous familial hypercholesterolemia associated with diabetes mellitus or impaired glucose tolerance. Atherosclerosis 1997; 132: 43–51PubMedCrossRef

34.

Kotze MJ, De Villiers WJS, Steyn K, et al. Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations. Arterioscler Thromb 1993; 13: 1460–8PubMedCrossRef

35.

Eto M, Watanabe K, Chonan N, et al. Familial hypercholesterolemia and apolipoprotein E4. Atherosclerosis 1988; 82: 123–8CrossRef

36.

Wittekoek ME, Pimstone SN, Reymer PWA, et al. A common mutation in the lipoprotein lipase gene (N291S) alters the lipoprotein phenotype and risk for cardiovascular disease in patients with familial hypercholesterolemia. Circulation 1998; 97: 729–35PubMedCrossRef

37.

O’Malley JP, Maslen CL, Illingworth DR. Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia. Circulation 1998; 97: 1780–3PubMedCrossRef

38.

Koivunen-Niemela T, Viikari J, Niinikoski H, et al. Sonography in the detection of achilles tendon xanthomata in children with familial hypercholesterolaemia. Acta Paediatr 1994; 83: 1178–81PubMedCrossRef

39.

Williams RR, Hunt SC, Schumacher C et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993; 72: 171–6PubMedCrossRef

40.

Tell GS, Mittelmark MB, Vellar OD. Cholesterol, high density lipoprotein cholesterol and triglycerides during puberty: the Oslo Youth Study. Am J Epidemiol 1985; 122: 750–61PubMed

41.

Marais AD, Nauomova RP, Firth JC, et al. Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia. J Lipid Res 1997; 38: 2071–8PubMed

42.

Pimstone SN, Defesche JC, Clee SM, et al. Differences in the phenotype between children with familial defective apolipoprotein B-100 and familial hypercholesterolaemia. Arterioscler Thromb Vasc Biol 1997; 17: 826–33PubMedCrossRef

43.

de Graaf J, Stalenhoef AFH. Defects of lipoprotein metabolism in familial combined hyperlipidaemia. Curr Opin Lipidol 1998; 9: 189–96PubMedCrossRef

44.

Porkka KV, Nuotio I, Pajukanta P, et al. Phenotype expression in familial combined hyperlipidemia. Atherosclerosis 1997; 133: 245–53PubMedCrossRef

45.

Pajukanta P, Nuotio I, Terwilliger JD, et al. Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23. Nature Genet 1998; 18: 369–73PubMedCrossRef

46.

Shamir R, Tershakovec AM, Gallagher PR, et al. The influence of age and relative weight on the presentation of familial combined hyperlipidemia in childhood. Atherosclerosis 1996; 121: 85–91PubMedCrossRef

47.

Cortner JA, Coates PM, Gallagher PR. Prevalence and expression of familial combined hyperlipidemia in childhood. J Pediatr 1990; 116: 514–9PubMedCrossRef

48.

Cortner JA, Coates PM, Liacouras CA, et al. Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management. J Pediatr 1993; 123: 177–84PubMedCrossRef

49.

Williams RR, Hopkins PN, Wu LL, et al. Guidelines for managing severe familial lipid disorders. Prim Cardiol 1995; 21: 47–53

50.

Nyamugunduru G, Roper H. Childhood onset insulin dependent diabetes presenting with severe hyperlipidaemia. BMJ 1997; 314: 62–5PubMedCrossRef

51.

Goren A, Stankiewicz H, Goldstein R, et al. Fish oil treatment of hyperlipidemia in children and adolescents receiving renal replacement therapy. Pediatrics 1991; 88: 265–8PubMed

52.

Coleman JE, Watson AR. Hyperlipidaemia, diet and simvastatin therapy in steroid-resistant nephrotic syndrome of childhood. Pediatr Nephrol 1996; 10: 171–4PubMed

53.

Trachtman H, Frank R, Gauthier B. Lovastatin treatment of hypercholesterolemia in children with steroid resistant nephrotic syndrome. Ped Res 1996; 39 Pt 2: 371

54.

Kwiterovich Jr PO. Prevention of coronary disease starting in childhood: what risk factors should be identified and treated? Coron Artery Dis 1993; 4: 611–30PubMedCrossRef

55.

Silberberg JS, Wlodarczyk J, Fryer J, et al. Risk associated with various definitions of family history of coronary heart disease. Am J Epidemiol 1998; 147: 1133–9PubMedCrossRef

56.

American Academy of Pediatrics. National Cholesterol Education Program. Report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics 1992; 89: 525–84

57.

Mouratidis B, Vaugha-Neil EF, Gilday DL, et al. Detection of silent coronary artery disease in adolescents and young adults with familial hypercholesterolemia by single-photon emission computed tomography thallium-201 scanning. Am J Cardiol 1992; 70: 1109–12PubMedCrossRef

58.

Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340: 1111–5PubMedCrossRef

59.

Sorensen KE, Celermajer DS, Georgakopoulos D, et al. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolaemia and is related to the lipoprotein(a) level. J Clin Invest 1994; 93: 50–5PubMedCrossRef

60.

Assouline L, Levy E, Feoli-Fonseca JC, et al. Familial hypercholesterolemia: molecular, biochemical, and clinical characterization of a French-Canadian pediatric population. Pediatrics 1995; 96: 239–46PubMed

61.

Efficacy and safety of lowering dietary intake of fat and cholesterol in children with elevated low-density lipoprotein cholesterol: the Dietary Intervention study in Children (DISC). The Writing Group for the DISC Collaborative Research Group. JAMA 1995; 273: 1429–35

62.

Niinikoski H, Viikari J, Rinnemaa T, et al. Prospective randomized trial of low-saturated-fat, low-cholesterol diet during the first 3 years of life. The STRIPBaby Project. Circulation 1996; 94: 1386–93PubMedCrossRef

63.

Mann J. Position statement: nutrition options when reducing saturated fat intake. J Am Coll Nutr 1992; 11 Suppl.: 82S–3SPubMed

64.

De Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid rich-diet in the secondary prevention of coronary heart disease. Lancet 1994; 343: 1454–9PubMedCrossRef

65.

Gould AL, Rossouw JE, Santanello NC, et al. Cholesterol reduction yields clinical benefit. Circulation 1998; 97: 946–52PubMedCrossRef

66.

Aurecchia S, Orloff D, Sobel S. Regulatory concerns at various phases of drug development. Am J Cardiol 1998; 81: 2F–4FPubMedCrossRef

67.

Dorr AE, Gundersen K, Schneider JC, et al. Colestipol hydrochloride in hypercholesterolemic patients: effect on serum cholesterol and mortality. J Chron Dis 1978; 31: 5–14PubMedCrossRef

68.

Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results: 1. Reduction in incidence of coronary heart disease. JAMA 1984; 251: 351–64CrossRef

69.

Tonstad S, Knudtzon J, Sivertsen M, et al. Efficacy and safety of cholestyramine in peripubertal and prepubertal children with familial hypercholesterolemia. J Pediatr 1996; 129: 42–9PubMedCrossRef

70.

Tonstad S, Sivertsen M, Aksnes L, et al. Low dose colestipol in adolescents with familial hypercholesterolaemia. Arch Dis Child 1996; 74: 157–60PubMedCrossRef

71.

Tonstad S, Ose L. Colestipol tablets in adolescents with familial hypercholesterolaemia. Acta Paediatr 1996; 85: 1080–2PubMedCrossRef

72.

McCrindle BW, O’Neill MB, Cullen-Dean G, et al. Acceptability and compliance with two forms of cholestyramine in the treatment of hypercholesterolemia in children: a randomized, crossover trial. J Pediatr 1997; 130: 266–73PubMedCrossRef

73.

Liacouras CA, Coates PM, Gallagher PR, et al. Use of cholestyramine in the treatment of children with familial combined hyerlipidemia. J Pediatr 1993; 122: 477–82PubMedCrossRef

74.

Tonstad S, Aksnes L. Fat soluble vitamin levels in familial hypercholesterolemia. J Pediatr 1997; 130: 274–80PubMedCrossRef

75.

Tonstad S, Refsum H, Ose L, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene predisposes to hyperhomocysteinemia in children with familial hypercholesterolemia treated with cholestyramine. J Pediatr 1998; 132: 365–8PubMedCrossRef

76.

Tonstad S, Refsum H, Ueland PM. Association between plasma total homocysteine and parental history of cardiovascular disease in children with familial hypercholesterolemia. Circulation 1997; 96: 1803–8PubMedCrossRef

77.

Ducobu J, Brasseur D, Chaudron JM, et al. Simvastatin use in children [letter]. Lancet 1992; 339: 1488PubMedCrossRef

78.

Sinzinger H, Schmid P, Pirich CH, et al. Treatment of hypercholesterolaemia in children. Lancet 1992; 340: 548–9PubMedCrossRef

79.

Sinzinger H, Mayr F, Schmid P, et al. Sleep disturbance and appetite loss after lovastatin. Lancet 1994; 343: 973PubMedCrossRef

80.

Knipscheer HC, Boelen CCA, Kastelein JJP, et al. Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia. Pediatr Res 1996; 39: 867–71PubMedCrossRef

81.

Lambert M, Lupien P-J, Gagné C, et al. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Pediatrics 1996; 97: 619–28PubMed

82.

Stein EA, Illingworth DR, Kwiterovich Jr PO, et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. JAMA 1999; 281: 137–44PubMedCrossRef

83.

Ericsson CG, Hamsten A, Nilsson J, et al. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 1996; 347: 849–53PubMedCrossRef

84.

Steinmetz J, Morin C, Panek E, et al. Biological variations in hyperlipidemic children and adolescents treated with fenofibrate. Clin Chim Acta 1981; 112: 43–53PubMedCrossRef

85.

Becker M, Staab D, Von Bergmann K. Long-term treatment of severe familial hypercholesterolemia in children: effect of sitosterol and bezafibrate. Pediatrics 1992; 89: 138–42PubMed

86.

Colletti RB, Neufeld EJ, Roff NK, et al. Niacin treatment of hypercholesterolemia in children. Pediatrics 1993; 92: 78–82PubMed

87.

Sanjurjo P, Martul P, Sasieta M, et al. Treatment with probucol of children with familial hypercholesterolaemia. Acta Paediatr Scand 1988; 77: 132–5PubMedCrossRef

88.

Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, et al., editors. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw-Hill Inc., 1995: 1981–2030

Title: Role of Lipid-Lowering Pharmacotherapy in Children
Author: Dr Serena Tonstad
Publication date: 01-01-2000
Publisher: Springer International Publishing
Published in: Pediatric Drugs / Issue 1/2000
Print ISSN: 1174-5878
Electronic ISSN: 1179-2019
DOI: https://doi.org/10.2165/00148581-200002010-00002

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Role of Lipid-Lowering Pharmacotherapy in Children

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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