The genetics of familial hypercholesterolemia and emerging therapies

Application of Clinical Genetics

Volumn 8, Issue , 2015, Pages 27-36

  Vogt, Anja ^a  

^a LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

Author keywords

Atherosclerosis; Familial hypercholesterolemia; Genetics; LDL cholesterol; Mipomersen; New therapies

Indexed keywords

BILE ACID SEQUESTRANT; EZETIMIBE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LIPOPROTEIN A; LOMITAPIDE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN INHIBITOR; MIPOMERSEN; NICOTINIC ACID; PLACEBO; TRIACYLGLYCEROL;

APHERESIS; ARTICLE; CARDIOVASCULAR MAGNETIC RESONANCE; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; DIETARY INTAKE; DRUG EFFICACY; DRUG HYPERSENSITIVITY; DRUG RESPONSE; DRUG SAFETY; ECHOCARDIOGRAPHY; ECHOGRAPHY; EXERCISE; FAMILIAL HYPERCHOLESTEROLEMIA; FAMILY PLANNING; FIRST DEGREE RELATIVE; FLU LIKE SYNDROME; GASTROINTESTINAL SYMPTOM; GENETIC ANALYSIS; HEADACHE; HETEROZYGOSITY; HOMOZYGOSITY; HUMAN; INJECTION SITE REACTION; LIFESTYLE MODIFICATION; MYOPATHY; NAUSEA; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL (TOPIC); SYMPTOMATOLOGY; TREATMENT DURATION; TREATMENT INDICATION; TRIACYLGLYCEROL BLOOD LEVEL; XANTHOMA;

EID: 84922178425     PISSN: None     EISSN: 1178704X     Source Type: Journal    
DOI: 10.2147/TACG.S44315     Document Type: Article

References (68)

1. Nordestgaard BG, Chapman MJ, Humphries SE, et al; European Atherosclerosis Society Consensus Panel. Familial hypercholestero-laemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478–3490a.
2. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group. Atherosclerosis. 1999;142(1):105–112.
3. National Institute for Health and Care Excellence [webpage on the Internet]. Identification and management of familial hypercholestero-laemia. London, UK: National Institute for Health Care and Excellence; 2008. Available from: http://www.nice.org.uk/CG071. Accessed
4. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012;97(11):3956–3964.
5. Goldberg AC, Hopkins PN, Toth P P, et al; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholes-terolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(Suppl 3): S1–S8.
6. Catapano AL, Chapman J, Wiklund O, Taskinen MR. The new joint EAS/ ESC guidelines for the management of dyslipidaemias. Atherosclerosis. 2011;217(1):1.
7. Watts GF, Gidding S, Wierzbicki AS, et al. Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation. J Clin Lipidol. 2014;8(2):148–172.
8. Goldstein JL, Brown MS. Molecular medicine. The cholesterol quartet. Science. 2001;292(5520):1310–1312.
9. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. Epub Feburary 28, 2014.
10. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1–S45.
11. 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 U S A. 1973;70(10):2804–2808.
12. Brown MS, Goldstein JL. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fbroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Proc Natl Acad Sci U S A. 1974;71(3):788–792.
13. Usifo E, Leigh SE, Whittall RA, et al. Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Ann Hum Genet. 2012;76(5):387–401.
14. Innerarity TL, Mahley RW, Weisgraber KH, et al. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res. 1990;31(8):1337–1349.
15. Souf M, Sattler AM, Maerz W, et al. A new but frequent mutation of apoB-100-apoB His3543Tyr. Atherosclerosis. 2004;174(1):11–16.
16. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–1272.
17. Garuti R, Jones C, Li W P, et al. The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipo-protein receptor clustering into clathrin-coated pits. J Biol Chem. 2005;280(49):40996–41004.
18. Cuchel M, Bruckert E, Ginsberg HN, et al; For the 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 Hypercho-lesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35(32):2146–2157.
19. Vogt A, Keller C, Heigl C, Weiss N, Zöllner N. Two forms of familial hypercholesterolemia: differences in cardiovascular risk factors, cardiac and extracardiac atherosclerosis. Dtsch Med Wochenschr. Epub August 15, 2014. German.
20. Wang J, Joy T, Mymin D, Frohlich J, Hegele RA. Phenotypic heterogeneity of sitosterolemia. J Lipid Res. 2004;45(12):2361–2367.
21. Allen JM, Thompson GR, Myant NB, Steiner R, Oakley CM. Cadiovascular complications of homozygous familial hypercholestero-laemia. Br Heart J. 1980;44(4):361–368.
22. Nenseter MS, Lindvig H W, Ueland T, et al. Lipoprotein(a) levels in coronary heart disease-susceptible and -resistant patients with familial hypercholesterolemia. Atherosclerosis. 2011;216(2):426–432.
23. Jansen AC, van Aalst-Cohen ES, Tanck MW, et al. The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. J Intern Med. 2004;256(6):482–490.
24. Williams RR, Hunt SC, Schumacher MC, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993;72(2):171–176.
25. Sprecher DL, Schaefer EJ, Kent KM, et al. Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients. Am J Cardiol. 1984;54(1):20–30.
26. Rafeiyian S, Mojtahedzadeh S, Hekmat M, et al. Supravalvular and valvular aortic stenosis in heterozygous familial hypercholesterolemia. Med Princ Pract. 2007;16(4):315–317.
27. Wiegman A, de Groot E, Hutten BA, et al. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 2004;363(9406):369–370.
28. Gylling H, Plat J, Turley S, et al; European Atherosclerosis Society Consensus Panel on Phytosterols. Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis. 2014;232(2):346–360.
29. Baigent C, Keech A, Kearney PM, et al; Cholesterol Treatment Trialists’ (CTT) Collaborators. Effcacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493): 1267–1278.
30. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolemia: a long term cohort study. BMJ. 2008;337:a2423.
31. van der Graaf A, Cuffe-Jackson C, Vissers MN, et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol. 2008;52(17):1421–1429.
32. Elis A, Zhou R, Stein EA. Treatment of familial hypercholesterolaemia in children and adolescents in the last three decades. Cardiol Young. 2014;24(3):437–441.
33. Tonstad S, Sivertsen M, Aksnes L, Ose L. Low dose colestipol in adolescents with familial hypercholesterolaemia. Arch Dis Child. 1996;74(2):157–160.
34. Huijgen R, Abbink EJ, Bruckert E, et al; Triple Study Group. Coleseve-lam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial. Clin Ther. 2010;32(4):615–625.
35. Nordestgaard BG, Chapman MJ, Ray K, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844–2853.
36. Pijlman AH, Huijgen R, Verhagen SN, et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis. 2010;209(1):189–194.
37. Thompson GR. Lipoprotein apheresis. Curr Opin Lipidol. 2010;21(6):487–491.
38. Kroon AA, Aengevaeren WR, van der Werf T, et al. LDL-Apheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation. 1996;93(10):1826–1835.
39. Winters JL. Lipid apheresis, indications, and principles. J Clin Apher. 2011;26(5):269–275.
40. Gemeinsamer Bundesausschuss. Richtlinie des Gemeinsamen Bunde-sausschusses zu Untersuchungs- und Behandlungsmethoden der ver-tragsärztlichen Versorgung. Berlin, Germany: Bundesanzeiger; 2014. German.
41. Thompson GR, Lowenthal R, Myant NB. Plasma exchange in the management of homozygous familial hypercholesterolaemia. Lancet. 1975;1(7918):1208–1211.
42. Thompson GR; HEART-UK LDL Apheresis Working Group. Recommendations for the use of LDL apheresis. Atherosclerosis. 2008;198(2):247–255.
43. Græsdal A, Bogsrud M P, Holven KB, et al. Apheresis in homozygous familial hypercholesterolemia: the results of a follow-up of all Norwegian patients with homozygous familial hypercholesterolemia. J Clin Lipidol. 2012;6(4):331–339.
44. Keller C. LDL-apheresis in homozygous LDL-receptor-defective familial hypercholesterolemia: the Munich experience. Atheroscler Suppl. 2009;10(5):21–26.
45. Mabuchi H, Koizumi J, Shimizu M, et al. Long-term efficacy of low-density lipoprotein apheresis on coronary heart disease in familial hypercholesterolemia. Hokuriku-FH-LDL-Apheresis Study Group. Am J Cardiol. 1998;82(12):1489–1495.
46. Norata GD, Ballantyne CM, Catapano AL. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs. Eur Heart J. 2013;34(24):1783–1789.
47. Kramer W. Novel drug approaches in development for the treatment of lipid disorders. Exp Clin Endocrinol Diabetes. 2013;121(10):567–580.
48. Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129(9):1022–1032.
49. Parhofer KG. Mipomersen: evidence-based review of its potential in the treatment of homozygous and severe heterozygous familial hypercholesterolemia. Core Evid. 2012;7:29–38.
50. Yu RZ, Geary RS, Flaim JD, et al. Lack of pharmacokinetic interaction of mipomersen sodium (ISIS 301012), a 2′-O-methoxyethyl modifed antisense oligonucleotide targeting apolipoprotein B-100 messenger RNA, with simvastatin and ezetimibe. Clin Pharmacokinet. 2009;48(1):39–50.
51. Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol. 2010;105(10):1413–1419.
52. Akdim F, Tribble DL, Flaim JD, et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur Heart J. 2011;32(21):2650–2659.
53. Akdim F, Stroes ES, Sijbrands EJ, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercho-lesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol. 2010;55(15):1611–1618.
54. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolae-mia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9719):998–1006.
55. Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholester-olemia: results of a randomized, double-blind, placebo-controlled trial to assess effcacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012;126(19):2283–2292.
56. Sanof (Genzyme, a Sanof Company). A study of the safety and efficacy of two different regimens of mipomersen in patients with familial hypercholes-terolemia and inadequately controlled low-density lipoprotein cholesterol (FOCUS FH). Available from: http://clinicaltrials.gov/show/NCT01475825. NLM identifer: NCT01475825. Accessed October 20, 2014.
57. Vogt A, Parhofer KG. The potential of mipomersen, an ApoB synthesis inhibitor, to reduce necessity for LDL-apheresis in patients with heterozygous familial hypercholesterolemia and coronary artery disease. Expert Opin Pharmacother. 2013;14(6):691–697.
58. Ludwig-Maximilians – University of Munich. Effect of mipomersen on LDL-cholesterol in patients treated by regular apheresis (MICA). Available from: http://clinicaltrials.gov/ct2/show/NCT01598948. NLM identifer: NCT01598948. Accessed October 20, 2014.
59. Genzyme, A Sanof Company [webpage on the Internet]. KYNAMRO risk evaluation and mitigation strategy (REMS). Cambridge, MA: Genzyme Corporation; 2013. Available from: http://www.kynamrorems.com. Accessed October 20, 2014.
60. Cuchel M, Meagher EA, du Toit Theron H, et al; Phase 3 HoFH Lomitapide Study investigators. Effcacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381(9860):40–46.
61. Aegerion Pharmaceuticals, Inc. [webpage on the Internet]. JUXTAPID REMS Program. Cambridge, MA: Aegerion Pharmaceuticals; 2012. Available from: http://www.juxtapidremsprogram.com. Accessed
62. Rodenburg J, Vissers MN, Wiegman A, et al. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation. 2007;116(6):664–668.
63. Vuorio A, Kuoppala J, Kovanen PT, et al. Statins for children with familial hypercholesterolemia. Cochrane Database Syst Rev. 2014;7:CD006401.
64. Tonstad S, Nøvik TS, Vandvik IH. Psychosocial function during treatment for familial hypercholesterolemia. Pediatrics. 1996;98(2 Pt 1):249–255.
65. Tonstad S. Familial hypercholesterolaemia: a pilot study of parents’ and children’s concerns. Acta Paediatr. 1996;85(11):1307–1313.
66. Hyttinen L, Kekäläinen P, Vuorio A F, Sintonen H, Strandberg TE. Health-related quality of life in elderly patients with familial hypercholesterolemia. Int J Technol Assess Health Care. 2008;24(2): 228–234.
67. Vogt A. Diagnostik und Therapie. Schwere, asymptotische Hypercho-lesterinämie im jungen Lebensalter [Diagnosis and therapy. Severity, asymptotic hypercholesterolemia at a young age]. CardioVasc. 2013; 13(6):39–43. German.
68. Vogt A. Schwere, asymptotische Hypercholesterinämie im jungen Leb-ensalter. Diagnostik und Therapie. Cardiovasc. 2013;13(6):39–44.