Clinical Drug Investigation

, Volume 22, Issue 8, pp 533–540 | Cite as

Efficacy, Safety and Tolerability of Simvastatin in Children with Familial Hypercholesterolaemia

Rationale, Design and Baseline Characteristics
  • Saskia de Jongh
  • Anton F. H. Stalenhoef
  • Mary B. Tuohy
  • Michele Mercuri
  • Henk D. Bakker
  • John J. P. Kastelein
Original Research Article


Objective: To describe the rationale, design and baseline data of a study conducted to determine the efficacy, safety and tolerability of simvastatin in children and adolescents with heterozygous familial hypercholesterolaemia (heFH).

Methods: Patients were recruited from nine lipid clinics worldwide. After a 4-week diet/placebo run-in period, patients were randomised to receive either simvastatin or placebo. Simvastatin was started at 10 mg/day and titrated at 8-week intervals to 20 and then 40 mg/day. During a second 24-week extension period, patients continued to receive simvastatin 40mg or placebo daily according to the original allocation.

Results: A total of 173 patients [98 boys (average age 13.2 years), 75 girls (average age 14.5 years)] were included in the study. Baseline total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) were severely elevated in heFH boys and girls compared with 69 healthy non-affected controls who were not part of the study. In heFH boys and the male siblings, respectively, mean total-C was 6.78 ± 1.03 vs 3.80 ± 0.11 mmol/L (p < 0.001), and mean LDL-C was 5.09 ± 0.97 vs 2.53 ± 0.69 mmol/L (p < 0.001). In heFH girls and the female siblings, respectively, mean total-C was 7.44 ± 1.35 vs 4.24 ± 0.47 mmol/L (p < 0.001), and mean LDL-C was 5.68 ± 1.28 vs 2.44 ± 0.50 mmol/L (p < 0.001).

Conclusion: This is the first and largest randomised, controlled, long-term clinical study to test the efficacy, safety and tolerability of a statin in boys and girls with heFH. The baseline data suggest that the sample selected for this study is representative of patients with heFH.


Simvastatin Pravastatin Lovastatin DHEAS Probucol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was financially supported by Merck & Co., Inc., USA. The authors would like to thank the study site coordinators and investigators as well as the Merck subsidiary personnel. Special thanks are given to Laura Corsetti for project coordination. Dr Kastelein is an established investigator of the Netherlands Heart Foundation (grant no. 2000D039).


  1. 1.
    Goldstein JL, Hobbs HH, Brown HS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Valle D, editors. The metabolic basis of inherited disease. New York: McGraw-Hill, 2001: 2863–2913Google Scholar
  2. 2.
    Goldstein JL, Brown MS. Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme a reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci USA 1973; 70(10): 2804–8PubMedCrossRefGoogle Scholar
  3. 3.
    Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992; 1(6): 445–66PubMedCrossRefGoogle Scholar
  4. 4.
    Lansberg PJ, Tuzgol S, van de Ree MA, Defesche JC, Kastelein JJ. Higher prevalence of familiar hypercholesterolemia than expected in adult patients of four family practices in Netherlands. Ned Tijdschr Geneeskd 2000 July; 144(30): 1437–1440PubMedGoogle Scholar
  5. 5.
    Fouchier SW, Defesche JC, Umans-Eckenhausen MW, et al. The molecular basis of familial hypercholesterolemia in The Netherlands. Hum Genet 2001 Dec; 109(6): 602–15PubMedCrossRefGoogle Scholar
  6. 6.
    Stone NJ, Levy RI, Fredrickson DS, et al. Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation 1974 Mar; 49(3): 476–88PubMedCrossRefGoogle Scholar
  7. 7.
    Slack J. Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet 1969 Dec; 2(7635): 1380–2PubMedCrossRefGoogle Scholar
  8. 8.
    Bakker HD, Trump MJ, Defesche JC, et al. Familial hypercholesterolemia in Dutch children: past, present, and future. Int Pediatr 1994; 9(3): 157–64Google Scholar
  9. 9.
    Strong JP, Malcom GT, McMahan CA, et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the pathobiological determinants of atherosclerosis in youth study. JAMA 1999 Feb; 281(8): 727–35PubMedCrossRefGoogle Scholar
  10. 10.
    McGill HC Jr, McMahan CA. Determinants of atherosclerosis in the young: pathobiological determinants of atherosclerosis in youth (PDAY) research group. Am J Cardiol 1998 Nov; 82(10B): 30T–6TPubMedCrossRefGoogle Scholar
  11. 11.
    Berenson GS, Srinivasan SR, Bao W, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. New Engl J Med 1998 Jun; 338(23): 1650–6PubMedCrossRefGoogle Scholar
  12. 12.
    McGill HC Jr, McMahan CA, Zieske AW, et al. Association of coronary heart disease risk factors with microscopic qualities of coronary atherosclerosis in youth. Circulation 2000 Jul; 102(4): 374–9PubMedCrossRefGoogle Scholar
  13. 13.
    Poli A, Tremoli E, Colombo A, et al. Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients: a new model for the quantitation and follow-up of preclinical atherosclerosis in living human subjects. Atherosclerosis 1988 Apr; 70(3): 253–61PubMedCrossRefGoogle Scholar
  14. 14.
    Neunteufl T, Heher S, Katzenschlager R, et al. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol 2000 Jul; 86(2): 207–10PubMedCrossRefGoogle Scholar
  15. 15.
    de Groot E, Wiegman A, Wittekoek ME, et al. B-mode ultrasound imaging of carotid artery walls in children with familial hypercholesterolemia: its potential for atherosclerosis studies. [dissertation] Leiden: University of Leiden, 1999Google Scholar
  16. 16.
    Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992 Nov; 340(8828): 1111–5PubMedCrossRefGoogle Scholar
  17. 17.
    Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994 May; 89(5): 2462–78PubMedCrossRefGoogle Scholar
  18. 18.
    Kwiterovich PO Jr. Pediatric implications of heterozygous familial hypercholesterolemia: screening and dietary treatment. Arteriosclerosis 1989 Jan; 9 Suppl. 1: 111–20Google Scholar
  19. 19.
    Obarzanek E, Kimm SYS, Barton BA, et al. Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the dietary intervention study in children (DISC). Pediatrics 2001 Feb 2; 107: 256–64PubMedCrossRefGoogle Scholar
  20. 20.
    American Academy of Pediatrics. National cholesterol education program: report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics 1992 Mar; 89 (3 Pt 2): 525–84Google Scholar
  21. 21.
    Tonstad S, Knudtzon J, Sivertsen M, et al. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. J Pediatr 1996 Jul; 129(1): 42–9PubMedCrossRefGoogle Scholar
  22. 22.
    West RJ, Lloyd JK, Leonard JV. Long-term follow-up of children with familial hypercholesterolaemia treated with cholestyramine. Lancet 1980 Oct; 2(8200): 873–5PubMedCrossRefGoogle Scholar
  23. 23.
    Groot PH, Dijkhuis-Stoffelsma R, Grose WF, et al. The effects of colestipol hydrochloride on serum lipoprotein lipid and apolipoprotein B and A-I concentrations in children heterozygous for familial hypercholesterolemia. Acta Paediatr Scand 1983 Jan; 72(1): 81–5PubMedCrossRefGoogle Scholar
  24. 24.
    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 Nov; 333(20): 1301–7PubMedCrossRefGoogle Scholar
  25. 25.
    Scandinavian Simvastatin Survival Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 2000 Nov 19; 344: 1383–9Google Scholar
  26. 26.
    Ducobu J, Brasseur D, Chaudron S, et al. Simvastatin use in children [letter]. Lancet 1992 Jun; 339(8807): 1488PubMedCrossRefGoogle Scholar
  27. 27.
    Sinzinger H, Schmid P, Pirich C, et al. Treatment of hypercholesterolaemia in children. Lancet 1992 Aug; 340(8818): 548–9PubMedCrossRefGoogle Scholar
  28. 28.
    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 May; 97(5): 619–28PubMedGoogle Scholar
  29. 29.
    Knipscheer HC, Boelen CC, Kastelein JJ, et al. Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia [published erratum appears in Pediatr Res 1996 Dec; 40 (6): 866]. Pediatr Res 1996 May; 39(5): 867–71PubMedCrossRefGoogle Scholar
  30. 30.
    Stefanutti C, Lucani G, Vivenzio A, et al. Diet only and diet plus simvastatin in the treatment of heterozygous familial hypercholesterolemia in childhood. Drugs Exp Clin Res 1999; 25(1): 23–8PubMedGoogle Scholar
  31. 31.
    Stein EA, Illingworth DR, Kwiterovich PO Jr, et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. JAMA 1999 Jan; 281(2): 137–44PubMedCrossRefGoogle Scholar
  32. 32.
    Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969 Jun; 44(235): 291–303PubMedCrossRefGoogle Scholar
  33. 33.
    Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970 Feb; 45(239): 13–23PubMedCrossRefGoogle Scholar
  34. 34.
    Myers GL, Cooper GR, Winn CL, et al. The centers for disease control-national heart, lung and blood institute lipid standardization program: an approach to accurate and precise lipid measurements. Clin Lab Med 1989 Mar; 9(1): 105–35PubMedGoogle Scholar
  35. 35.
    Steiner P, Freidel J, Bremner W, et al. Standardization of micromethods for plasma cholesterol, triglycerides and HDL-cholesterol with the lipid clincs’ methodology. J Clin Chem 1981; 19: 850Google Scholar
  36. 36.
    Warnick GR, Albers JJ. A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high density lipoprotein cholesterol. J Lipid Res 1978 Jan; 19(1): 65–76PubMedGoogle Scholar
  37. 37.
    Friedewald WT. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18(6): 499–502PubMedGoogle Scholar
  38. 38.
    Santner SJ, Santen RJ, Kulin HE, et al. A model for validation of radioimmunoassay kit reagents: measurement of follitropin and lutropin in blood and urine. Clin Chem 1981 Nov; 27(11): 1892–5PubMedGoogle Scholar
  39. 39.
    Xing S, Cekan SZ, Diczfalusy U, et al. Validation of radioimmunoassay for estradiol-17 beta by isotope dilution-mass spectrometry and by a test of radiochemical purity. Clin Chim Acta 1983; 135(2): 189–201PubMedCrossRefGoogle Scholar
  40. 40.
    Tdx System Operator’s Manual, Abbot Diagnostics, Abbot Park (IL). 1993.Google Scholar
  41. 41.
    Newton WT, McGuigan JE, Jaffe BM. Radioimmunoassay of peptides lacking tyrosine. J Lab Clin Med 1970 May; 75(5): 886–92PubMedGoogle Scholar
  42. 42.
    Stein EA. Treatment of familial hypercholesterolemia with drugs in children. Arteriosclerosis 1989 Jan; 9 Suppl. 1: 1145–51Google Scholar
  43. 43.
    Dietz WH, Robinson TN. Use of the body mass index (BMI) as a measure of overweight in children and adolescents. J Pediatr 1998 Feb; 132(2): 191–3PubMedCrossRefGoogle Scholar
  44. 44.
    Edelman CHM, editor. Pediatric kidney disease. London: Little & Brown, 2001: 1890–2.2Google Scholar
  45. 45.
    Fagot-Campagna A, Saaddine JB, Flegal KM, et al. Diabetes, impaired fasting glucose, and elevated HbA1c in US adolescents: the Third National Health and Nutrition Examination Survey. Diabetes Care 2001 May; 24(5): 834–7PubMedCrossRefGoogle Scholar
  46. 46.
    Kwiterovich PO Jr. Biochemical, clinical, epidemiologic, genetic, and pathologic data in the pediatric age group relevant to the cholesterol hypothesis. Pediatrics 1986 Aug; 78(2): 349–62PubMedGoogle Scholar
  47. 47.
    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 control subjects. Arterioscler Thromb Vasc Biol 1996 Aug; 16(8): 984–91PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Saskia de Jongh
    • 1
    • 2
  • Anton F. H. Stalenhoef
    • 3
  • Mary B. Tuohy
    • 4
  • Michele Mercuri
    • 4
  • Henk D. Bakker
    • 2
  • John J. P. Kastelein
    • 1
  1. 1.Department of Vascular MedicineEmma Children’s Hospital, Academic Medical Center, University of AmsterdamAmsterdamThe Netherlands
  2. 2.Emma Children’s Hospital, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  3. 3.Department of MedicineUniversity Medical CenterNijmegenThe Netherlands
  4. 4.Merck Research LaboratoriesRahwayUSA

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