Mipomersen, an Antisense Oligonucleotide to Apolipoprotein B-100, Reduces Lipoprotein(a) in Various Populations with Hypercholesterolemia: Results of 4 Phase III Trials

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 35, Issue 3, 2015, Pages 689-699

  Santos, Raul D ^a   Raal, Frederick J ^b   Catapano, Alberico L ^c   Witztum, Joseph L ^e   Steinhagen Thiessen, Elisabeth ^d   Tsimikas, Sotirios ^e  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b UNIVERSITY OF THE WITWATERSRAND   (South Africa)

^c UNIVERSITY OF MILAN   (Italy)

^d CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^e UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

antisense oligonucleotide; coronary artery disease; dyslipidemias; hyperlipoproteinemia type II; hypolipidemic agents

Indexed keywords

APOLIPOPROTEIN B100; LIPOPROTEIN A; LOW DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MIPOMERSEN; PLACEBO; ANTISENSE OLIGODEOXYNUCLEOTIDE; APOB PROTEIN, HUMAN; BIOLOGICAL MARKER; HYPOCHOLESTEROLEMIC AGENT; OLIGONUCLEOTIDE;

ADULT; APHERESIS; ARTICLE; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DIAGNOSIS; DOUBLE BLIND PROCEDURE; FAMILIAL HYPERCHOLESTEROLEMIA; FEMALE; HUMAN; HYPERCHOLESTEROLEMIA; LIPID BLOOD LEVEL; LIPOPROTEIN BLOOD LEVEL; MAJOR CLINICAL STUDY; MALE; MIDDLE AGED; PHARMACEUTICAL CARE; PHASE 3 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; AGED; BLOOD; CARDIOVASCULAR DISEASES; COMPLICATION; DOWN REGULATION; GENETICS; HYPERLIPOPROTEINEMIA TYPE II; META ANALYSIS; PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); RISK ASSESSMENT; RISK FACTOR; TREATMENT OUTCOME;

ADULT; AGED; ANTICHOLESTEREMIC AGENTS; APOLIPOPROTEIN B-100; BIOMARKERS; CARDIOVASCULAR DISEASES; CLINICAL TRIALS, PHASE III AS TOPIC; DOWN-REGULATION; FEMALE; HUMANS; HYPERLIPOPROTEINEMIA TYPE II; LIPOPROTEIN(A); MALE; MIDDLE AGED; OLIGODEOXYRIBONUCLEOTIDES, ANTISENSE; OLIGONUCLEOTIDES; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RISK ASSESSMENT; RISK FACTORS; TREATMENT OUTCOME;

EID: 84921866616     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.114.304549     Document Type: Article

References (68)

1. 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 2012 60 716 721. doi: 10.1016/j.jacc.2012.04.038
2. Kronenberg F, Utermann G, Lipoprotein(a): resurrected by genetics. J Intern Med 2013 273 6 30. doi: 10.1111/j.1365-2796.2012.02592.x
3. Marcovina SM, Albers JJ, Wijsman E, Zhang Z, Chapman NH, Kennedy H, Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J Lipid Res 1996 37 2569 2585
4. Tsimikas S, Clopton P, Brilakis ES, Marcovina SM, Khera A, Miller ER, de Lemos JA, Witztum JL, Relationship of oxidized phospholipids on apolipoprotein B-100 particles to race/ethnicity, apolipoprotein(a) isoform size, and cardiovascular risk factors: results from the Dallas Heart Study. Circulation 2009 119 1711 1719. doi: 10.1161/CIRCULATIONAHA.108.836940
5. Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J, Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009 302 412 423. doi: 10.1001/jama.2009.1063
6. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG, Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009 301 2331 2339. doi: 10.1001/jama.2009.801
7. Li Y, Luke MM, Shiffman D, Devlin JJ, Genetic variants in the apolipoprotein(a) gene and coronary heart disease. Circ Cardiovasc Genet 2011 4 565 573. doi: 10.1161/CIRCGENETICS.111.959601
8. Gurdasani D, Sjouke B, Tsimikas S, Hovingh GK, Luben RN, Wainwright NW, Pomilla C, Wareham NJ, Khaw KT, Boekholdt SM, Sandhu MS, Lipoprotein(a) and risk of coronary, cerebrovascular, and peripheral artery disease: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol 2012 32 3058 3065. doi: 10.1161/ATVBAHA.112.255521
9. Bertoia ML, Pai JK, Lee JH, Taleb A, Joosten MM, Mittleman MA, Yang X, Witztum JL, Rimm EB, Tsimikas S, Mukamal KJ, Oxidation-specific biomarkers and risk of peripheral artery disease. J Am Coll Cardiol 2013 61 2169 2179. doi: 10.1016/j.jacc.2013.02.047
10. Thanassoulis G, Campbell CY, Owens DS, CHARGE Extracoronary Calcium Working Group Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013 368 503 512. doi: 10.1056/NEJMoa1109034
11. Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG, Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2014 63 470 477. doi: 10.1016/j.jacc.2013.09.038
12. Kraft HG, Lingenhel A, Raal FJ, Hohenegger M, Utermann G, Lipoprotein(a) in homozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000 20 522 528
13. Seed M, Hoppichler F, Reaveley D, McCarthy S, Thompson GR, Boerwinkle E, Utermann G, Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med 1990 322 1494 1499. doi: 10.1056/NEJM199005243222104
14. Hopkins PN, Stephenson S, Wu LL, Riley WA, Xin Y, Hunt SC, Evaluation of coronary risk factors in patients with heterozygous familial hypercholesterolemia. Am J Cardiol 2001 87 547 553
15. Holmes DT, Schick BA, Humphries KH, Frohlich J, Lipoprotein(a) is an independent risk factor for cardiovascular disease in heterozygous familial hypercholesterolemia. Clin Chem 2005 51 2067 2073. doi: 10.1373/clinchem.2005.055228
16. Orsó E, Ahrens N, Kilalić D, Schmitz G, Familial hypercholesterolemia and lipoprotein(a) hyperlipidemia as independent and combined cardiovascular risk factors. Atheroscler Suppl 2009 10 74 78. doi: 10.1016/S1567-5688(09)71816-1
17. Jansen AC, van Aalst-Cohen ES, Tanck MW, Trip MD, Lansberg PJ, Liem AH, van Lennep HW, Sijbrands EJ, Kastelein JJ, The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. J Intern Med 2004 256 482 490. doi: 10.1111/j.1365-2796.2004.01405.x
18. Nenseter MS, Lindvig HW, Ueland T, Langslet G, Ose L, Holven KB, Retterstøl K, Lipoprotein(a) levels in coronary heart disease-susceptible and-resistant patients with familial hypercholesterolemia. Atherosclerosis 2011 216 426 432. doi: 10.1016/j.atherosclerosis.2011.02.007
19. Alonso R, Andres E, Mata N, Fuentes-Jimenez F, Badimon L, Lopez-Miranda J, Padro T, Muniz O, Diaz-Diaz JL, Mauri M, Ordovas JM, Mata P, SAFEHEART Investigators Lipoprotein(a) levels in familial hypercholesterolaemia: an important predictor for cardiovascular disease independent of the type of LDL-receptor mutation. J Am Coll Cardiol 2014 63 1982 1989. doi: 10.1016/j.jacc.2014.01.063
20. Jamieson DG, Usher DC, Rader DJ, Lavi E, Apolipoprotein(a) deposition in atherosclerotic plaques of cerebral vessels. A potential role for endothelial cells in lesion formation. Am J Pathol 1995 147 1567 1574
21. Cain WJ, Millar JS, Himebauch AS, Tietge UJ, Maugeais C, Usher D, Rader DJ, Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]. J Lipid Res 2005 46 2681 2691. doi: 10.1194/jlr.M500249-JLR200
22. Leebmann J, Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breitenberger P, Maerz W, Lehmacher W, Heibges A, Klingel R, Pro(a)LiFe Study Group∗ Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation 2013 128 2567 2576. doi: 10.1161/CIRCULATIONAHA.113.002432
23. Willeit P, Kiechl S, Kronenberg F, Witztum JL, Santer P, Mayr M, Xu Q, Mayr A, Willeit J, Tsimikas S, Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 2014 64 851 860. doi: 10.1016/j.jacc.2014.03.061
24. Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, Lachmann RH, Gaudet D, Tan JL, Chasan-Taber S, Tribble DL, Flaim JD, Crooke ST, 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 375 998 1006. doi: 10.1016/S0140-6736(10)60284-X
25. McGowan MP, Tardif JC, Ceska R, Burgess LJ, Soran H, Gouni-Berthold I, Wagener G, Chasan-Taber S, Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One 2012 7 e49006. doi: 10.1371/journal.pone.0049006
26. Stein EA, Dufour R, Gagne C, Gaudet D, East C, Donovan JM, Chin W, Tribble DL, McGowan M, 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 2283 2292. doi: 10.1161/CIRCULATIONAHA.112.104125
27. 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 2013 62 2178 2184. doi: 10.1016/j.jacc.2013.07.081
28. Nordestgaard BG, Chapman MJ, Ray K, European Atherosclerosis Society Consensus Panel Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010 31 2844 2853. doi: 10.1093/eurheartj/ehq386
29. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S, Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions. Clin Chem 2003 49 1785 1796
30. Trégouët DA, König IR, Erdmann J, Wellcome Trust Case Control Consortium; Cardiogenics Consortium Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet 2009 41 283 285. doi: 10.1038/ng.314
31. Clarke R, Peden JF, Hopewell JC, PROCARDIS Consortium Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009 361 2518 2528. doi: 10.1056/NEJMoa0902604
32. Erqou S, Thompson A, Di Angelantonio E, Saleheen D, Kaptoge S, Marcovina S, Danesh J, Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol 2010 55 2160 2167. doi: 10.1016/j.jacc.2009.10.080
33. Schunkert H, König IR, Kathiresan S, Cardiogenics; CARDIoGRAM Consortium Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 2011 43 333 338. doi: 10.1038/ng.784
34. Helgadottir A, Gretarsdottir S, Thorleifsson G, Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol 2012 60 722 729. doi: 10.1016/j.jacc.2012.01.078
35. Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG, Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol 2013 61 1146 1156. doi: 10.1016/j.jacc.2012.12.023
36. Hung MY, Witztum JL, Tsimikas S, New therapeutic targets for calcific aortic valve stenosis: the lipoprotein(a)-lipoprotein-associated phospholipase A2-oxidized phospholipid axis. J Am Coll Cardiol 2014 63 478 480. doi: 10.1016/j.jacc.2013.08.1639
37. Taleb A, Witztum JL, Tsimikas S, Oxidized phospholipids on apoB-100-containing lipoproteins: a biomarker predicting cardiovascular disease and cardiovascular events. Biomark Med 2011 5 673 694. doi: 10.2217/bmm.11.60
38. Spence JD, Koschinsky ML, Mechanisms of lipoprotein(a) pathogenicity. Arterioscler Thromb Vasc Biol 2012 32 1550 1551. doi: 10.1161/ATVBAHA.112.251306
39. Leibundgut G, Witztum JL, Tsimikas S, Oxidation-specific epitopes and immunological responses: Translational biotheranostic implications for atherosclerosis. Curr Opin Pharmacol 2013 13 168 179. doi: 10.1016/j.coph.2013.02.005
40. Ravandi A, Leibundgut G, Hung MY, Patel M, Hutchins PM, Murphy RC, Prasad A, Mahmud E, Miller YI, Dennis EA, Witztum JL, Tsimikas S, Release and capture of bioactive oxidized phospholipids and oxidized cholesteryl esters during percutaneous coronary and peripheral arterial interventions in humans. J Am Coll Cardiol 2014 63 1961 1971. doi: 10.1016/j.jacc.2014.01.055
41. van Dijk RA, Kolodgie F, Ravandi A, Leibundgut G, Hu PP, Prasad A, Mahmud E, Dennis E, Curtiss LK, Witztum JL, Wasserman BA, Otsuka F, Virmani R, Tsimikas S, Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions. J Lipid Res 2012 53 2773 2790. doi: 10.1194/jlr.P030890
42. Choi SH, Yin H, Ravandi A, Armando A, Dumlao D, Kim J, Almazan F, Taylor AM, McNamara CA, Tsimikas S, Dennis EA, Witztum JL, Miller YI, Polyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages. PLoS One 2013 8 e83145. doi: 10.1371/journal.pone.0083145
43. Myers GL, Christenson RH, Cushman M, Ballantyne CM, Cooper GR, Pfeiffer CM, Grundy SM, Labarthe DR, Levy D, Rifai N, Wilson PW, National academy of clinical biochemistry laboratory medicine practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem 2009 55 378 384. doi: 10.1373/clinchem.2008.115899
44. Catapano AL, Chapman J, Wiklund O, Taskinen MR, The new joint EAS/ESC guidelines for the management of dyslipidaemias. Atherosclerosis 2011 217 1. doi: 10.1016/j.atherosclerosis.2011.06.011
45. Davidson MH, Ballantyne CM, Jacobson TA, Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol 2011 5 338 367. doi: 10.1016/j.jacl.2011.07.005
46. Nordestgaard BG, Chapman MJ, Humphries SE, European Atherosclerosis Society Consensus Panel 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 34 3478a 3490a. doi: 10.1093/eurheartj/eht273
47. Hoover-Plow J, Huang M, Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism 2013 62 479 491. doi: 10.1016/j.metabol.2012.07.024
48. Tsimikas S, Bergmark C, Beyer RW, Patel R, Pattison J, Miller E, Juliano J, Witztum JL, Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes. J Am Coll Cardiol 2003 41 360 370
49. Tsimikas S, Lau HK, Han KR, Shortal B, Miller ER, Segev A, Curtiss LK, Witztum JL, Strauss BH, Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein. Circulation 2004 109 3164 3170. doi: 10.1161/01.CIR.0000130844.01174.55
50. MBewu AD, Durrington PN, Bulleid S, Mackness MI, The immediate effect of streptokinase on serum lipoprotein(a) concentration and the effect of myocardial infarction on serum lipoprotein(a), apolipoproteins A1 and B, lipids and C-reactive protein. Atherosclerosis 1993 103 65 71
51. Faghihnia N, Tsimikas S, Miller ER, Witztum JL, Krauss RM, Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet. J Lipid Res 2010 51 3324 3330. doi: 10.1194/jlr.M005769
52. Silaste ML, Rantala M, Alfthan G, Aro A, Witztum JL, Kesäniemi YA, Hörkkö S, Changes in dietary fat intake alter plasma levels of oxidized low-density lipoprotein and lipoprotein(a). Arterioscler Thromb Vasc Biol 2004 24 498 503. doi: 10.1161/01.ATV.0000118012.64932.f4
53. Budoff MJ, Ahmadi N, Gul KM, Liu ST, Flores FR, Tiano J, Takasu J, Miller E, Tsimikas S, Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: a randomized clinical trial. Prev Med 2009 49 101 107. doi: 10.1016/j.ypmed.2009.06.018
54. Ahmadi N, Tsimikas S, Hajsadeghi F, Saeed A, Nabavi V, Bevinal MA, Kadakia J, Flores F, Ebrahimi R, Budoff MJ, Relation of oxidative biomarkers, vascular dysfunction, and progression of coronary artery calcium. Am J Cardiol 2010 105 459 466. doi: 10.1016/j.amjcard.2009.09.052
55. Tsimikas S, Witztum JL, Miller ER, Sasiela WJ, Szarek M, Olsson AG, Schwartz GG, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial. Circulation 2004 110 1406 1412. doi: 10.1161/01.CIR.0000141728.23033.B5
56. Choi SH, Chae A, Miller E, Messig M, Ntanios F, DeMaria AN, Nissen SE, Witztum JL, Tsimikas S, Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Am Coll Cardiol 2008 52 24 32. doi: 10.1016/j.jacc.2008.02.066
57. Ky B, Burke A, Tsimikas S, Wolfe ML, Tadesse MG, Szapary PO, Witztum JL, FitzGerald GA, Rader DJ, The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am Coll Cardiol 2008 51 1653 1662. doi: 10.1016/j.jacc.2008.01.026
58. Yoshida H, Shoda T, Yanai H, Ikewaki K, Kurata H, Ito K, Furutani N, Tada N, Witztum JL, Tsimikas S, Effects of pitavastatin and atorvastatin on lipoprotein oxidation biomarkers in patients with dyslipidemia. Atherosclerosis 2013 226 161 164. doi: 10.1016/j.atherosclerosis.2012.10.069
59. Kostner GM, Gavish D, Leopold B, Bolzano K, Weintraub MS, Breslow JL, HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation 1989 80 1313 1319
60. Rodenburg J, Vissers MN, Wiegman A, Miller ER, Ridker PM, Witztum JL, Kastelein JJ, Tsimikas S, Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin. J Am Coll Cardiol 2006 47 1803 1810. doi: 10.1016/j.jacc.2005.12.047
61. Frischmann ME, Ikewaki K, Trenkwalder E, Lamina C, Dieplinger B, Soufi M, Schweer H, Schaefer JR, König P, Kronenberg F, Dieplinger H, In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a). Atherosclerosis 2012 225 322 327. doi: 10.1016/j.atherosclerosis.2012.09.031
62. Merki E, Graham MJ, Mullick AE, Miller ER, Crooke RM, Pitas RE, Witztum JL, Tsimikas S, Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation 2008 118 743 753. doi: 10.1161/CIRCULATIONAHA.108.786822
63. Viney NJ, Graham M, Crooke R, Hughes S, Singleton W, Evaluation of isis apo(a)rx, an antisense inhibitor to apolipoprotein(a), in healthy volunteers. Circulation 2013 128 A14196
64. Tsimikas S, Duff GW, Berger PB, Rogus J, Huttner K, Clopton P, Brilakis E, Kornman KS, Witztum JL, Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 2014 63 1724 1734. doi: 10.1016/j.jacc.2013.12.030
65. Sniderman AD, Tsimikas S, Fazio S, The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies. J Am Coll Cardiol 2014 63 1935 1947. doi: 10.1016/j.jacc.2014.01.060
66. Santos RD, Duell PB, East C, Guyton JR, Moriarty PM, Chin W, Mittleman RS, Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension [published online ahead of print December 23, 2013]. Eur Heart J doi:10.1093/eurheartj/eht549. http://eurheartj.oxfordjournals.org/content/early/2013/12/21/eurheartj.eht549.long
67. Kolski B, Tsimikas S, Emerging therapeutic agents to lower lipoprotein (a) levels. Curr Opin Lipidol 2012 23 560 568. doi: 10.1097/MOL.0b013e3283598d81
68. McGowan MP, Emerging low-density lipoprotein (LDL) therapies: management of severely elevated LDL cholesterol-the role of LDL-apheresis. J Clin Lipidol 2013 7 suppl 3 S21 S26. doi: 10.1016/j.jacl.2013.03.002