Managing recalcitrant hypercholesterolemia in patients on current best standard of care: Efficacy and safety of novel pharmacotherapies

Clinical Lipidology

Volumn 9, Issue 2, 2014, Pages 221-233

  Sahebkar, Amirhossein ^a,b   Watts, Gerald F ^c  

^a MASHHAD UNIVERSITY OF MEDICAL SCIENCES   (Iran)

^b MASHHAD UNIVERSITY OF MEDICAL SCIENCES   (Iran)

^c UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

Author keywords

antisense oligonucleotide; cardiovascular disease; CETP; cholesteryl ester transfer protein; familial and nonamilial hypercholesterolemia; microsomal triglyceride transfer protein; MTTP; PCSK9; proprotein convertase subtilisin kexin type 9

Indexed keywords

ALIROCUMAB; ALN PCS; ANACETRAPIB; ATORVASTATIN; BOCOCIZUMAB; CHOLESTEROL ESTER TRANSFER PROTEIN; EVACETRAPIB; EVOLOCUMAB; EZETIMIBE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOMITAPIDE; MIPOMERSEN; PROTEIN PCSK9; ROSUVASTATIN; SERINE PROTEINASE; SIMVASTATIN; SMALL INTERFERING RNA; TORCETRAPIB; UNCLASSIFIED DRUG;

DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG RESPONSE; DRUG SAFETY; DRUG TOLERABILITY; FAMILIAL HYPERCHOLESTEROLEMIA; FEVER; GASTROINTESTINAL DISEASE; HEALTH CARE QUALITY; HUMAN; HYPERCHOLESTEROLEMIA; HYPERSENSITIVITY; INJECTION SITE REACTION; LOW DRUG DOSE; MALAISE; MYALGIA; NAUSEA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RASH; REVIEW; SINGLE DRUG DOSE; STEATOSIS; SYSTEMATIC REVIEW; UNSPECIFIED SIDE EFFECT;

EID: 84902278734     PISSN: 17584299     EISSN: 17584302     Source Type: Journal    
DOI: 10.2217/clp.14.14     Document Type: Review

References (75)

1. Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation 112(22), 3375-3383 (2005).
2. Watts GF, Gidding S, Wierzbicki AS et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int. J. Cardiol. 171(3), 309-325 (2014).
3. Nordestgaard BG, Chapman MJ, Humphries SE 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. 34(45), 3478-3490 (2013).
4. WHO. Familial hypercholesterolaemia: report of a WHO consultation. WHO, Paris, France (1997).
5. Fahed AC, Nemer GM. Familial hypercholesterolemia: the lipids or the genes? Nutr. Metab. (Lond.) 8(1), 23 (2011).
6. Neefjes LA, Ten Kate GJ, Rossi A et al. CT coronary plaque burden in asymptomatic patients with familial hypercholesterolaemia. Heart 97(14), 1151-1157 (2011).
7. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am. J. Cardiol. 81(5), 582-587 (1998).
8. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J. Am. Coll. Cardiol. 46(8), 1411-1416 (2005).
9. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J. Am. Coll. Cardiol. 57(16), 1666-1675 (2011).
10. Choumerianou DM, Dedoussis GV. Familial hypercholesterolemia and response to statin therapy according to LDLR genetic background. Clin. Chem. Lab. Med. 43(8), 793-801 (2005).
11. 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 209(1), 189-194 (2010).
12. Versmissen J, Oosterveer DM, Yazdanpanah M et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 337, a2423 (2008).
13. Neil A, Cooper J, Betteridge J et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur. Heart J. 29(21), 2625-2633 (2008).
14. Harada-Shiba M, Sugisawa T, Makino H et al. Impact of statin treatment on the clinical fate of heterozygous familial hypercholesterolemia. J. Atheroscler. Thromb. 17(7), 667-674 (2010).
15. Raal FJ, Pilcher GJ, Panz VR et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 124(20), 2202-2207 (2011).
16. Elis A, Zhou R, Stein EA. Effect of lipid-lowering treatment on natural history of heterozygous familial hypercholesterolemia in past three decades. Am. J. Cardiol. 108(2), 223-226 (2011).
17. Fruchart JC, Sacks F, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am. J. Cardiol. 102(10 Suppl.), 1K-34K (2008).
18. Bell DS, Dinicolantonio JJ, O'Keefe JH. Is statin-induced diabetes clinically relevant? A comprehensive review of the literature. Diabetes Obes. Metab. doi:10.1111/dom.12254 (2013) (Epub ahead of print).
19. Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr. Opin. Lipidol. 18(4), 401-408 (2007).
20. Artenstein AW, Opal SM. Proprotein convertases in health and disease. N. Engl. J. Med. 365(26), 2507-2518 (2011).
21. Abifadel M, Varret M, Rabes JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34(2), 154-156 (2003).
22. Dowdall M. Highlighting the future potential of PCSK9- targeted therapeutics. Clin. Lipidol. 7(6), 599-601 (2012).
23. Rhainds D, Arsenault BJ, Tardif JC. PCSK9 inhibition and LDL cholesterol lowering: the biology of an attractive therapeutic target and critical review of the latest clinical trials. Clin. Lipidol. 7(6), 621-640 (2012).
24. Garber K. Biologics inch toward cholesterol-lowering market. Nat. Biotechnol. 30(4), 302-304 (2012).
25. Dias CS, Shaywitz AJ, Wasserman SM 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. 60(19), 1888-1898 (2012).
26. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 128(19), 2113-2120 (2013).
27. Raal F, Scott R, Somaratne R 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 126(20), 2408-2417 (2012).
28. Stein EA, Mellis S, Yancopoulos GD et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366(12), 1108-1118 (2012).
29. Stein EA, Gipe D, Bergeron J 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 380(9836), 29-36 (2012).
30. Sullivan D, Olsson AG, Scott R et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 308(23), 2497-2506 (2012).
31. Giugliano RP, Desai NR, Kohli P et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACETIMI 57): a randomised, placebo-controlled, dose-ranging, Phase 2 study. Lancet 380(9858), 2007-2017 (2012).
32. Koren MJ, Scott R, Kim JB et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, Phase 2 study. Lancet 380(9858), 1995-2006 (2012).
33. Koren MJ, Giugliano RP, Raal FJ et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the open-label study of long-term evaluation against LDL-C (OSLER) randomized trial. Circulation 129(2), 234-243 (2013).
34. Roth EM, Mckenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N. Engl. J. Med. 367(20), 1891-1900 (2012).
35. AHA. Effects of 12 Weeks of Treatment with RN316 (PF- 04950615), a Humanized IgG2a Monoclonal Antibody Binding Proprotein Convertase Subtilisin Kexin Type 9, in Hypercholesterolemic Subjects on High and Maximal Dose Statins. http://my.americanheart.org/idc/groups/ahamahpublic/@wcm/@sop/@scon/documents/ downloadable/ucm-446310.pdf
36. Gumbiner B, Udata C, Joh T et al. The effects of multiple dose administration of RN316 (PF-04950615), a humanized IgG2a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects. Circulation 126, A13524 (2012).
37. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, Phase 1 trial. Lancet 383(9911), 60-68 (2014).
38. Crooke RM, Baker BF, Wedel M. Cardiovascular Therapeutic Applications in Antisense Drug Technology; Principles, Strategies and Applications (2nd Edition). CRC Press, FL, USA, 601-639 (2007).
39. Kohli P, Cannon CP. A new approach to managing the 'statin-intolerant' patient? Eur. Heart J. 33(9), 1040-1043 (2012).
40. 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. 105(10), 1413-1419 (2010).
41. 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 hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 375(9719), 998-1006 (2010).
42. Kastelein JJ, Wedel MK, Baker BF et al. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 114(16), 1729-1735 (2006).
43. Akdim F, Stroes ES, Sijbrands EJ et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J. Am. Coll. Cardiol. 55(15), 1611-1618 (2010).
44. Akdim F, Tribble DL, Flaim JD et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur. Heart J. 32(21), 2650-2659 (2011).
45. Visser ME, Wagener G, Baker BF 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. 33(9), 1142-1149 (2012).
46. Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J. Am. Coll. Cardiol. 62(23), 2178-2184 (2013).
47. Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in ApoB-lipoprotein assembly. J. Lipid Res. 44(1), 22-32 (2003).
48. Sankatsing RR, Fouchier SW, De Haan S et al. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler. Thromb. Vasc. Biol. 25(9), 1979-1984 (2005).
49. Joy TR. Novel therapeutic agents for lowering low density lipoprotein cholesterol. Pharmacol. Ther. 135(1), 31-43 (2012).
50. Cuchel M, Bloedon LT, Szapary PO et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N. Engl. J. Med. 356(2), 148-156 (2007).
51. Cuchel M, Meagher EA, Du Toit Theron H 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 381(9860), 40-46 (2013).
52. Samaha FF, Mckenney J, Bloedon LT, Sasiela WJ, Rader DJ. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat. Clin. Pract. Cardiovasc. Med. 5(8), 497-505 (2008).
53. Durrington PN. Hyperlipidaemia Diagnosis and Management (3rd Edition). Hodder Arnold, London, UK (2008).
54. Bishop BM. Systematic review of CETP inhibitors for increasing high-density lipoprotein cholesterol: where do these agents stand in the approval process? Am. J. Ther. doi:10.1097/MJT.0b013e31828b8463 (2013) (Epub ahead of print).
55. Krishna R, Anderson MS, Bergman AJ et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled Phase I studies. Lancet 370(9603), 1907-1914 (2007).
56. Cannon CP, Shah S, Dansky HM et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N. Engl. J. Med. 363(25), 2406-2415 (2010).
57. Bloomfield D, Carlson GL, Sapre A et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am. Heart J. 157(2), 352-360.e352 (2009).
58. Teramoto T, Shirakawa M, Kikuchi M, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with dyslipidaemia. Atherosclerosis 230(1), 52-60 (2013).
59. Gotto AM Jr, Cannon CP, Li XS et al. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am. J. Cardiol. 113(1), 76-83 (2014).
60. Nicholls SJ, Brewer HB, Kastelein JJ et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 306(19), 2099-2109 (2011).
61. Gotto AM Jr, Cannon CP, Li XS et al. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am. J. Cardiol. 113(1), 76-83 (2014).
62. Sahebkar A, Watts GF. New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin. Ther. 35(8), 1082-1098 (2013).
63. Sahebkar A, Watts GF. New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: what can the clinician expect?. Cardiovasc. Drugs Ther. 27(6), 559-567 (2013).
64. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J. Am. Coll. Cardiol. 44(3), 720-732 (2004).
65. Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr. Opin. Lipidol. 18(4), 401-408 (2007).
66. Nielsen LB. Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux. Atherosclerosis 143(2), 229-243 (1999).
67. Tsimikas S, Brilakis ES, Miller ER et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 353(1), 46-57 (2005).
68. Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J. Am. Coll. Cardiol. 60(8), 716-721 (2012).
69. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301(22), 2331-2339 (2009).
70. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31(23), 2844-2853 (2010).
71. 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. Int. J. Med. 256(6), 482-490 (2004).
72. Alagona P Jr. Beyond LDL cholesterol: the role of elevated triglycerides and low HDL cholesterol in residual CVD risk remaining after statin therapy. Am. J. Manag. Care 15(3 Suppl.), S65-S73 (2009).
73. Le NA, Walter MF. The role of hypertriglyceridemia in atherosclerosis. Curr. Atheroscler. Rep. 9(2), 110-115 (2007).
74. Nakaya N. Hypertriglyceridemia as a cause of atherosclerosis. Nihon Rinsho 60(5), 860-867 (2002).
75. Hussain MM, Rava P, Walsh M, Rana M, Iqbal J. Multiple functions of microsomal triglyceride transfer protein. Nutr. Metab. (Lond.) 9, 14 (2012).