A 10-year experience using combined lipid-lowering pharmacotherapy in children and adolescents

María Beatriz Araujo; María Sol Pacce

doi:10.1515/jpem-2016-0117

Article

A 10-year experience using combined lipid-lowering pharmacotherapy in children and adolescents

María Beatriz Araujo and María Sol Pacce

Published/Copyright: October 8, 2016

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 29 Issue 11

Abstract

Background:

Current pediatric guidelines for heterozygous familial hypercholesterolemia (HeFH) propose pharmacotherapy (PT) with statins from age 8 to 10 years; however, schemes with absorption inhibitors combined with statins, could be started earlier. The aim of the study was to show the 10-year results of a combined treatment protocol.

Methods:

Prospective, descriptive and analytical study. Pediatric patients (n=70; mean age at PT initiation 9.3 years [range, 2–17.5]) with HeFH who required PT between 2005 and 2015 were included. All patients ≥10 years, with LDL >190 mg/dL or >160 mg/dL with one cardiovascular risk factor (CVRF) or >130 mg/dL with two or more CVRF; and those patients 5–10 years and with LDL-C >240 mg/dL or a family history of a cardiovascular event before 40 years, were medicated. After a period on a lipid-lowering diet (LLD), all patients were started on ezetimibe. Patients who did not achieve the treatment goal were given statins. The variables were: age, age at PT initiation, duration of PT, initial LDL-C, mean LDL-C during ezetimibe monodrug therapy, mean LDL-C during combined PT, and percentage of LDL decrease.

Results:

LDL-C levels were: Baseline: 235 mg/dL±55; after 3 months on ezetimibe: 167 mg/dL±47 (decrease: −27.62%). In 18 patients who did not reach the treatment goal atorvastatin was added and their LDL-C decreased −41.5% (p: 0.02). Overall, mean final LDL-C was 155 mg/dL±30.4 (range, 98–257) and treatment goals were reached in 74% of the patients. No severe side effects were reported.

Conclusions:

Combined and sequential treatment starting at early ages was shown to be safe and effective over this follow-up period.

Keywords: ezetimibe; heterozygous familial hypercholestrolemia; pediatrics; pharmacotherapy; statins

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Goldstein J, Hobbs H, Brown M. The online metabolic and molecular bases of inherited disease. Chapter 120. Familial hypercholesterolemia. http://ommbid.mhmedical.com/DOI:10.1036/ommbid.149.Search in Google Scholar

2. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232:34–47.10.1126/science.3513311Search in Google Scholar PubMed

3. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, et al. European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146–57.10.1093/eurheartj/ehu274Search in Google Scholar PubMed PubMed Central

4. Daniels SR, Gidding SS, de Ferranti SD. National lipid association expert panel on familial hypercholesterolemia. Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011;5(Suppl 3):S30–7.10.1016/j.jacl.2011.03.453Search in Google Scholar PubMed

5. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk. Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011;128(Suppl 5):S213–56.10.1542/peds.2009-2107CSearch in Google Scholar PubMed PubMed Central

6. Descamps OS, Tenoutasse S, Stephenne X, Gies I, Beauloye V, et al. Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis 2011;218:272–80.10.1016/j.atherosclerosis.2011.06.016Search in Google Scholar PubMed

7. Myśliwiec M, Walczak M, Małecka-Tendera E, Dobrzańska A, Cybulska B, et al. Management of familial hypercholesterolemia in children and adolescents. Positionpaper of the Polish Lipid Expert Forum. J Clin Lipidol 2014;8:173–80.10.1016/j.jacl.2014.01.001Search in Google Scholar PubMed

8. Kusters DM, Wiegman A, Kastelein JJ, Hutten BA. Carotid intima-media thickness in children with familial hypercholesterolemia. Circ Res 2014;114:307–10.10.1161/CIRCRESAHA.114.301430Search in Google Scholar PubMed

9. McNeal CJ, Wilson DP, Christou D, Bush RL, Shepherd LG, et al. The use of surrogate vascular markers in youth at risk for premature cardiovasculardisease. J Pediatr Endocrinol Metab 2009;22:195–211.10.1515/JPEM.2009.22.3.195Search in Google Scholar

10. Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, et al. The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. J Pediatr 2009;155:199–204.10.1016/j.jpeds.2009.02.022Search in Google Scholar PubMed

11. Choh SA, Choh NA, Rasool A, Yousuf R, Qureshi U. Homozygous familial hypercholesterolemia. J Pediatr Endocrinol Metab 2009;22:573–5.10.1515/JPEM.2009.22.6.573Search in Google Scholar PubMed

12. Davis HR Jr, Pula KK, Alton KB, Burrier RE, Watkins RW. The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs. Metabolism 2001;50:1234–41.10.1053/meta.2001.26737Search in Google Scholar PubMed

13. Lambert M, Lupien PJ, Gagné C, Lévy E, Blaichman S, et al. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group. Pediatrics 1996;97:619–28.10.1542/peds.97.5.619Search in Google Scholar

14. McCrindle BW, Helden E, Cullen-Dean G, Conner WT. A randomized crossover trial of combination pharmacologic therapy in children with familial hyperlipidemia. Pediatr Res 2002;51:715–21.10.1203/00006450-200206000-00009Search in Google Scholar PubMed

15. Clauss SB, Holmes KW, Hopkins P, Stein E, Cho M, et al. Efficacy and safety of lovastatin therapy in adolescent girls with heterozygous familial hypercholesterolemia. Pediatrics 2005;116:682–8.10.1542/peds.2004-2090Search in Google Scholar PubMed

16. Kusters DM, Hutten BA, McCrindle BW, Cassiman D, Francis GA, et al. Design and baseline data of a pediatric study with rosuvastatin in familial hypercholesterolemia. J Clin Lipidol 2013;7:408–13.10.1016/j.jacl.2013.06.010Search in Google Scholar PubMed

17. Kusters DM, Avis HJ, de Groot E, Wijburg FA, Kastelein JJ, et al. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. J Am Med Assoc 2014;312:1055–7.10.1001/jama.2014.8892Search in Google Scholar PubMed

18. O’Gorman CS, Higgins MF, O’Neill MB. Systematic review and metaanalysis of statins for heterozygous familial hypercholesterolemia in children: evaluation of cholesterol changes and side effects. Pediatr Cardiol 2009;30:482–9.10.1007/s00246-008-9364-3Search in Google Scholar PubMed

19. van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagné C, et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol 2008;52:1421–9.10.1016/j.jacc.2008.09.002Search in Google Scholar PubMed

20. Yeste D, Chacon P, Clemente M, Albisu MA, Gussinye M, et al. Ezetimibe as monotherapy in the treatment of hypercholesterolemia in children and adolescents. J Pediatr Endocrinol Metab 2009;22:487–92.10.1515/JPEM.2009.22.6.487Search in Google Scholar

21. Clauss S, Wai KM, Kavey RE, Kuehl K. Ezetimibe treatment of pediatric patients with hypercholesterolemia. J Pediatr 2009;154:869–72.10.1016/j.jpeds.2008.12.044Search in Google Scholar PubMed

22. Araujo MB, Botto PM, Mazza CS. Use of ezetimibe in the treatment of familial hypercholesterolemia in children and adolescents. AnPediatr (Barc) 2012;77:37–42.10.1016/j.anpedi.2011.11.007Search in Google Scholar PubMed

23. Kusters DM, Caceres M, Coll M, Cuffie C, Gagné C, et al. Efficacy and safety of ezetimibe monotherapy in children with heterozygous familial or nonfamilial hypercholesterolemia. J Pediatr 2015;166:1377–84.10.1016/j.jpeds.2015.02.043Search in Google Scholar PubMed

24. Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003;107:2409–15.10.1161/01.CIR.0000068312.21969.C8Search in Google Scholar PubMed

25. Ladeiras-Lopes R, Agewall S, Tawakol A, Staels B, Stein E, et al. Atherosclerosis: recent trials, new targets and future directions. Int J Cardiol 2015;192:72–81.10.1016/j.ijcard.2015.05.013Search in Google Scholar PubMed

26. Tyroler HA. Cholesterol and cardiovascular disease. An overview of Lipid Research Clinics (LRC) epidemiologic studies as background for the LRC Coronary Primary Prevention Trial. Am J Cardiol 1984;54:14C–19C.Search in Google Scholar

27. Magnussen CG, Venn A, Thomson R, Juonala M, Srinivasan SR, et al. The association of pediatric low- and high-density lipoprotein cholesterol dyslipidemia classifications and change in dyslipidemia status with carotid intima-media thickness in adulthood evidence from the cardiovascular risk in Young Finns study, the Bogalusa Heart study, and the CDAH (Childhood Determinants of Adult Health) study. J Am Coll Cardiol 2009;53:860–9.10.1016/j.jacc.2008.09.061Search in Google Scholar PubMed PubMed Central

28. Kologlu T, Ucar SK, Levent E, Akcay YD, Coker M, et al. Chitotriosidase as a possible marker of clinically evidenced atherosclerosis in dyslipidemic children. J Pediatr Endocrinol Metab 2014;27:701–8.10.1515/jpem-2013-0365Search in Google Scholar PubMed

29. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109(23 Suppl 1):III39–43.10.1161/01.CIR.0000131517.20177.5aSearch in Google Scholar PubMed

30. Kavalipati N, Shah J, Ramakrishan A, Vasnawala H. Pleiotropic effects ofstatins. Indian J Endocrinol Metab 2015;19:554–62.10.4103/2230-8210.163106Search in Google Scholar PubMed PubMed Central

31. Satoh M, Takahashi Y, Tabuchi T, Minami Y, Tamada M, et al. Cellular and molecular mechanisms of statins: an update onpleiotropic effects. Clin Sci (Lond) 2015;129:93–105.10.1042/CS20150027Search in Google Scholar PubMed

Received: 2016-4-1

Accepted: 2016-9-5

Published Online: 2016-10-8

Published in Print: 2016-11-1

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Articles in the same Issue

https://doi.org/10.1515/jpem-2016-0117

Keywords for this article

ezetimibe; heterozygous familial hypercholestrolemia; pediatrics; pharmacotherapy; statins