Novel Therapies for Treating Familial Hypercholesterolemia

  • Salman J. Bandeali
  • Jad Daye
  • Salim S. Virani
Nonstatin Drugs (WB Borden, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Nonstatin Drugs


Familial hypercholesterolemia is an inherited disorder associated with early accelerated atherosclerosis with morbidity and mortality resulting from premature cardiovascular disease. Affected individuals have extreme elevations in low-density lipoprotein cholesterol levels. Patients usually do not achieve target reductions in cholesterol levels with conventional antihyperlipidemic pharmacotherapy. This unmet need has resulted in the recent development and approval of novel therapies targeting different cholesterol pathways. This article briefly summarizes familial hypercholesterolemia and then discusses the newer pharmacotherapies available in the management of familial hypercholesterolemia.


Familial hypercholesterolemia Mipomersen Proprotein convertase subtilisin/kexin 9 inhibitors Lomitapide 



Salim S. Virani is supported by a Department of Veterans Affairs Health Services Research and Development Service Career Development Award.

Conflict of Interest

Salman J. Bandeali, Jad Daye, and Salim S. Virani declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of outstanding importance

  1. 1.
    Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis. 2012;223(2):262–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356(2):148–56.PubMedCrossRefGoogle Scholar
  3. 3.
    Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Sly WS, Childs B, Beaudet AL, Valle C, Kinzler KW, Vogelstein B, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 2863–913.Google Scholar
  4. 4.
    Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445–66.PubMedCrossRefGoogle Scholar
  5. 5.
    Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111(12):1795–803.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Robinson JG. Management of familial hypercholesterolemia: a review of the recommendations from the national lipid association expert panel on familial hypercholesterolemia. J Manag Care Pharm. 2013;19(2):139–49.PubMedGoogle Scholar
  7. 7.
    Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, et al. Familial hypercholesterolemia: 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(3):133–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Widhalm K, Binder CB, Kreissl A, Aldover-Macasaet E, Fritsch M, Kroisboeck S, et al. Sudden death in a 4-year-old boy: a near-complete occlusion of the coronary artery caused by an aggressive low-density lipoprotein receptor mutation (W556R) in homozygous familial hypercholesterolemia. J Pediatr. 2011;158(1):167.PubMedCrossRefGoogle Scholar
  9. 9.
    Smith RJ, Hiatt WR. Two new drugs for homozygous familial hypercholesterolemia: managing benefits and risks in a rare disorder. JAMA Intern Med. 2013;6:1–3.Google Scholar
  10. 10.
    Moorjani S, Roy M, Torres A, Betard C, Gagne C, Lambert M, 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(8856):1303–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Kim YR, Han KH. Familial hypercholesterolemia and the atherosclerotic disease. Korean Circ J. 2013;43(6):363–7.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia 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. doi: 10.1093/eurheartj/eht273.Google Scholar
  13. 13.
    Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105(21):2469–75.PubMedCrossRefGoogle Scholar
  14. 14.••
    Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, et al. Efficacy 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):40–6. This was the first phase 3 dose-escalation study that evaluated the efficacy and safety of lomitapide in HoFH patients. The beneficial results of the study led to the FDA approval for lomitapide..PubMedCrossRefGoogle Scholar
  15. 15.
    Raal FJ, Pilcher GJ, Illingworth DR, Pappu AS, Stein EA, Laskarzewski P, et al. Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia. Atherosclerosis. 1997;135(2):249–56.PubMedCrossRefGoogle Scholar
  16. 16.
    Raal FJ, Pappu AS, Illingworth DR, Pilcher GJ, Marais AD, Firth JC, et al. Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia. Atherosclerosis. 2000;150(2):421–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Marais AD, Raal FJ, Stein EA, Rader DJ, Blasetto J, Palmer M, et al. A dose-titration and comparative study of rosuvastatin and atorvastatin in patients with homozygous familial hypercholesterolaemia. Atherosclerosis. 2008;197(1):400–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Thompson GR, Barbir M, Davies D, Dobral P, Gesinde M, Livingston M, et al. Efficacy criteria and cholesterol targets for LDL apheresis. Atherosclerosis. 2010;208(2):317–21.PubMedCrossRefGoogle Scholar
  19. 19.
    Hudgins LC, Kleinman B, Scheuer A, White S, Gordon BR. Long-term safety and efficacy of low-density lipoprotein apheresis in childhood for homozygous familial hypercholesterolemia. Am J Cardiol. 2008;102(9):1199–204.PubMedCrossRefGoogle Scholar
  20. 20.
    Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012;380(9836):29–36.PubMedCrossRefGoogle Scholar
  21. 21.
    Stein EA, Ose L, Retterstol K, Tonstad S, Schleman M, Harris S, et al. Further reduction of low-density lipoprotein cholesterol and C-reactive protein with the addition of ezetimibe to maximum-dose rosuvastatin in patients with severe hypercholesterolemia. J Clin Lipidol. 2007;1(4):280–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Pijlman AH, Huijgen R, Verhagen SN, Imholz BP, Liem AH, Kastelein JJ, et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis. 2010;209(1):189–94.PubMedCrossRefGoogle Scholar
  23. 23.
    US Food and Drug Administration. FDA approves new orphan drug for rare cholesterol disorder. 2012.
  24. 24.
    Aegerion Pharmaceuticals. FDA approves Aegerion Pharmaceuticals’ JUXTAPID(TM) (lomitapide) capsules for homozygous familial hypercholesterolemia (HoFH). 2012.
  25. 25.••
    Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9719):998–1006. This reports a phase 3 trial showing the effect of mipomersen on lowering LDL-C levels in HoFH patients..PubMedCrossRefGoogle Scholar
  26. 26.••
    McGowan MP, Tardif JC, Ceska R, Burgess LJ, Soran H, Gouni-Berthold I, et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7(11):e49006. This reports a randomized placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia that showed an increase in cardiovascular incidents in the mipomersen arm..PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Stein EA, Dufour R, Gagne C, Gaudet D, East C, Donovan JM, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012;126(19):2283–92.PubMedCrossRefGoogle Scholar
  28. 28.
    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 Opini Pharmacother. 2013;14(6):691–7.CrossRefGoogle Scholar
  29. 29.•
    Visser ME, Wagener G, Baker BF, Geary RS, Donovan JM, Beuers UH, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2012;33(9):1142–9. This reports a randomized double-blind placebo-controlled study of mipomersen in statin-intolerant patients with high risk of cardiovascular disease..PubMedCrossRefGoogle Scholar
  30. 30.
    US Food and Drug Administration. KYNAMRO (mipomersen sodium) injection. 2013.
  31. 31.•
    Genzyme. A Study of the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol (FOCUS FH). 2011–2013. Available from This is a randomized placebo-controlled trial currently being done to determine the effect of mipomersen in severe HeFH.
  32. 32.••
    Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12):1108–18. This reported a phase 1 trial of PCSK9-inhibiting monoclonal antibody (REGN727) showing a significant decrease in LDL-C levels in blood of HeFH patients..PubMedCrossRefGoogle Scholar
  33. 33.
    Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem. 2004;279(48):50630–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A. 2004;101(18):7100–5.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Farnier M. PCSK9 inhibitors. Curr Opin Lipidol. 2013;24(3):251–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Goldberg AC. Novel therapies and new targets of treatment for familial hypercholesterolemia. J Clin Lipidol. 2010;4(5):350–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–72.PubMedCrossRefGoogle Scholar
  39. 39.
    Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol. 2010;55(25):2833–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res. 2007;48(4):763–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Orum H, et al. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS One. 2010;5(5):e10682.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci U S A. 2008;105(33):11915–20.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Ason B, Tep S, Davis Jr HR, Xu Y, Tetzloff G, Galinski B, et al. Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9. J Lipid Res. 2011;52(4):679–87.PubMedCrossRefGoogle Scholar
  44. 44.
    Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012;53(12):2515–24.PubMedCrossRefGoogle Scholar
  45. 45.•
    Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B, Stolman D, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012;60(19):1888–98. This reported a phase 1 study that evaluated the safety and effects of AMG145 (PCSK9 antibody) in healthy and hypercholesterolemic subjects receiving statin therapy..PubMedCrossRefGoogle Scholar
  46. 46.••
    Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 2012;126(20):2408–17. This reported a multicenter, phase 2 randomized trial that tested the safety and efficacy of AMG145 (PCSK9 antibody) in HeFH patients already receiving intensive antihyperlipidemic therapy..PubMedCrossRefGoogle Scholar
  47. 47.•
    Amgen. Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities (TESLA). 2012–2013. Available from This is a multicenter randomized trial that is currently being done to test the safety and efficacy of AMG145 (PCSK9 antibody) in HoFH patients.
  48. 48.
    Grossman M, Raper SE, Wilson JM. Transplantation of genetically modified autologous hepatocytes into nonhuman primates: feasibility and short-term toxicity. Hum Gene Ther. 1992;3(5):501–10.PubMedCrossRefGoogle Scholar
  49. 49.
    Chowdhury JR, Grossman M, Gupta S, Chowdhury NR, Baker Jr JR, Wilson JM. Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits. Science. 1991;254(5039):1802–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Grossman M, Rader DJ, Muller DW, Kolansky DM, Kozarsky K, Clark 3rd BJ, et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med. 1995;1(11):1148–54.PubMedCrossRefGoogle Scholar
  51. 51.
    Grossman M, Raper SE, Kozarsky K, Stein EA, Engelhardt JF, Muller D, et al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat Genet. 1994;6(4):335–41.PubMedCrossRefGoogle Scholar
  52. 52.
    Fattahi F, Asgari S, Pournasr B, Seifinejad A, Totonchi M, Taei A, et al. Disease-corrected hepatocyte-like cells from familial hypercholesterolemia-induced pluripotent stem cells. Mol Biotechnol. 2013;54(3):863–73.PubMedCrossRefGoogle Scholar
  53. 53.
    Davidson MH. Novel nonstatin strategies to lower low-density lipoprotein cholesterol. Curr Atheroscler Rep. 2009;11(1):67–70.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  • Salman J. Bandeali
    • 1
  • Jad Daye
    • 2
  • Salim S. Virani
    • 2
    • 3
    • 4
    • 5
    • 6
    • 7
  1. 1.Section of Cardiology, Department of Medicine, Texas Heart InstituteSt. Luke’s Episcopal HospitalHoustonUSA
  2. 2.Department of MedicineBaylor College of MedicineHoustonUSA
  3. 3.Health Policy, Quality, and Informatics ProgramMichael E. DeBakey Veteran Affairs Medical Center Health Services Research and Development Center of ExcellenceHoustonUSA
  4. 4.Section of Cardiovascular Research, Department of MedicineBaylor College of MedicineHoustonUSA
  5. 5.Center for Cardiovascular Disease PreventionHouston Methodist DeBakey Heart and Vascular CenterHoustonUSA
  6. 6.Section of CardiologyMichael E. DeBakey Veterans Affairs Medical CenterHoustonUSA
  7. 7.Health Services Research and Development (152)Michael E. DeBakey Veterans Affairs Medical CenterHoustonUSA

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