Progress in the care of common inherited atherogenic disorders of apolipoprotein B metabolism

Key Points

  • Familial hypercholesterolaemia, familial combined hyperlipidaemia and elevated lipoprotein(a) are inherited disorders of apo B-100 metabolism that are frequently encountered in clinical lipidology

  • Each of these inherited hyperlipidaemias markedly accelerates the onset of atherosclerotic cardiovascular disease (ASCVD)

  • To prevent premature ASCVD, these disorders must be accurately diagnosed and treated in index patients and at-risk family members

  • The supplementation of established lipid-lowering therapies with newly developed biological agents will be important for managing the most severe hyperlipidaemias, but long-term safety and cost-effectiveness need to be demonstrated

  • The promotion of public and clinical awareness of these disorders, and the establishment and maintenance of appropriate patient registries, are essential to facilitate research and improve clinical care

Abstract

Familial hypercholesterolaemia, familial combined hyperlipidaemia (FCH) and elevated lipoprotein(a) are common, inherited disorders of apolipoprotein B metabolism that markedly accelerate the onset of atherosclerotic cardiovascular disease (ASCVD). These disorders are frequently encountered in clinical lipidology and need to be accurately identified and treated in both index patients and their family members, to prevent the development of premature ASCVD. The optimal screening strategies depend on the patterns of heritability for each condition. Established therapies are widely used along with lifestyle interventions to regulate levels of circulating lipoproteins. New therapeutic strategies are becoming available, and could supplement traditional approaches in the most severe cases, but their long-term cost-effectiveness and safety have yet to be confirmed. We review contemporary developments in the understanding, detection and care of these highly atherogenic disorders of apolipoprotein B metabolism.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Proposed diagnostic protocol for cascade testing individuals for familial hypercholesterolaemia.
Figure 2: Algorithms for managing patients with familial hypercholesterolaemia.
Figure 3: Algorithm for managing patients with familial combined hyperlipidaemia.
Figure 4: Algorithm for the future management of patients with hyper-Lp(a).

References

  1. 1

    Adiels, M., Olofsson, S. O., Taskinen, M. R. & Borén, J. Diabetic dyslipidaemia. Curr. Opin. Lipidol. 17, 238–246 (2006).

  2. 2

    Marais, A. D., Solomon, G. A. & Blom, D. J. Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E. Crit. Rev. Clin. Lab. Sci. 51, 46–62 (2014).

  3. 3

    Nordestgaard, B. G. 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, 3478–3490a (2013).

  4. 4

    Watts, G. F. et al. Prevalence and treatment of familial hypercholesterolaemia in Australian communities. Int. J. Cardiol. 185, 69–71 (2015).

  5. 5

    Pang, J. et al. Frequency of familial hypercholesterolemia in patients with early-onset coronary artery disease admitted to a coronary care unit. J. Clin. Lipidol. 9, 703–708 (2015).

  6. 6

    De Backer, G. et al. Prevalence and management of familial hypercholesterolaemia in coronary patients: an analysis of EUROASPIRE IV, a study of the European Society of Cardiology. Atherosclerosis 241, 169–175 (2015).

  7. 7

    Watts, G. F. et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int. J. Cardiol. 171, 309–325 (2014).

  8. 8

    Horton, J. D. et al. PCSK9: a convertase that coordinates LDL catabolism. J. Lipid Res. 50 (Suppl.), S172–S177 (2009).

  9. 9

    Patel, J. et al. Coronary artery calcium improves risk assessment in adults with a family history of premature coronary heart disease: results from Multiethnic Study of Atherosclerosis. Circ. Cardiovasc. Imag. 8, e003186 (2015).

  10. 10

    Sijbrands, E. J., Nieman, K., Budoff, M. J. & FH CTA Consortium. Cardiac computed tomography imaging in familial hypercholesterolaemia: implications for therapy and clinical trials. Curr. Opin. Lipidol. 26, 586–592 (2015).

  11. 11

    Tardif, J. C., Lesage, F., Harel, F., Romeo, P. & Pressacco, J. Imaging biomarkers in atherosclerosis trials. Circ. Cardiovasc. Imag. 4, 319–333 (2011).

  12. 12

    Soutar, A. K. & Naoumova, R. P. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat. Clin. Pract. Cardiovasc. Med. 4, 214–225 (2007).

  13. 13

    Motazacker, M. M. et al. Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia. Eur. Heart J. 33, 1360–1366 (2012).

  14. 14

    Usifo, E. et al. Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Ann. Hum. Genet. 76, 387–401 (2012).

  15. 15

    Kotze, M. J. et al. Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations. Arterioscler. Thromb. 13, 1460–1468 (1993).

  16. 16

    Santos, P. C. et al. Presence and type of low density lipoprotein receptor (LDLR) mutation influences the lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia. Atherosclerosis 233, 206–210 (2014).

  17. 17

    Awan, Z. et al. APOE p.Leu167del mutation in familial hypercholesterolemia. Atherosclerosis 231, 218–222 (2013).

  18. 18

    Marduel, M. et al. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum. Mutat. 34, 83–87 (2013).

  19. 19

    Wintjens, R. et al. Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. J. Lipid Res. 7, 482–491 (2016).

  20. 20

    Fouchier, S. W. et al. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circ. Res. 115, 552–555 (2014).

  21. 21

    Johansen, C. T. et al. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias. J. Lipid Res. 55, 765–772 (2014).

  22. 22

    Maglio, C. et al. Genetic diagnosis of familial hypercholesterolaemia by targeted next-generation sequencing. J. Intern. Med. 276, 396–403 (2014).

  23. 23

    Page, M. M., Stefanutti, C., Sniderman, A. & Watts, G. F. Recent advances in the understanding and care of familial hypercholesterolaemia: significance of the biology and therapeutic regulation of proprotein convertase subtilisin/kexin type 9. Clin. Sci. (Lond.) 129, 63–79 (2015).

  24. 24

    Alonso, R. et al. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J. Am. Coll. Cardiol. 63, 1982–1989 (2014).

  25. 25

    Versmissen, J. et al. Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach. Eur. J. Hum. Genet. 23, 381–387 (2015).

  26. 26

    van Iperen, E. P. et al. Common genetic variants do not associate with CAD in familial hypercholesterolemia. Eur. J. Hum. Genet. 22, 809–813 (2014).

  27. 27

    Ademi, Z. et al. Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia. J. Clin. Lipidol. 8, 390–400 (2014).

  28. 28

    Morris, J. K., Wald, D. S. & Wald, N. J. The evaluation of cascade testing for familial hypercholesterolemia. Am. J. Med. Genet. A 158A, 78–84 (2012).

  29. 29

    Damgaard, D. et al. The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Atherosclerosis 180, 155–160 (2005).

  30. 30

    Harada-Shiba, M. et al. Guidelines for the management of familial hypercholesterolemia. J. Atheroscler. Thromb. 19, 1043–1060 (2012).

  31. 31

    Shi, Z. et al. Familial hypercholesterolemia in China: prevalence and evidence of underdetection and undertreatment in a community population. Int. J. Cardiol. 174, 834–836 (2014).

  32. 32

    Bell, D. A. et al. Familial hypercholesterolaemia in primary care: knowledge and practices among general practitioners in Western Australia. Heart Lung Circ. 23, 309–313 (2014).

  33. 33

    Pang, J. et al. Significant gaps in awareness of familial hypercholesterolemia among physicians in selected Asia-Pacific countries: a pilot study. J. Clin. Lipidol. 9, 42–48 (2015).

  34. 34

    Bell, D. A. et al. Impact of interpretative commenting on lipid profiles in people at high risk of familial hypercholesterolaemia. Clin. Chim. Acta 422, 21–25 (2013).

  35. 35

    Kirke, A. B. et al. Systematic detection of familial hypercholesterolaemia in primary health care: a community based prospective study of three methods. Heart Lung Circ. 24, 250–256 (2015).

  36. 36

    Weng, S. F., Kai, J., Andrew Neil, H., Humphries, S. E. & Qureshi, N. Improving identification of familial hypercholesterolaemia in primary care: derivation and validation of the familial hypercholesterolaemia case ascertainment tool (FAMCAT). Atherosclerosis 238, 336–343 (2015).

  37. 37

    Norsworthy, P. J. et al. Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study. BMC Med. Genet. 15, 70 (2014).

  38. 38

    Green, R. C. et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet. Med. 15, 565–574 (2013).

  39. 39

    Henneman, L., McBride, C. M., Cornel, M. C., Duquette, D. & Qureshi, N. Screening for familial hypercholesterolemia in children: what can we learn from adult screening programs? Healthcare 3, 1018–1030 (2015).

  40. 40

    Klancˇar, G. et al. Universal screening for familial hypercholesterolemia in children. J. Am. Coll. Cardiol. 66, 1250–1257 (2015).

  41. 41

    Talmud, P. J., Futema, M. & Humphries, S. E. The genetic architecture of the familial hyperlipidaemia syndromes: rare mutations and common variants in multiple genes. Curr. Opin. Lipidol. 25, 274–281 (2014).

  42. 42

    Futema, M. et al. Refinement of variant selection for the LDL-C genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from six countries. Clin. Chem. 61, 231–238 (2015).

  43. 43

    Talmud, P. J. et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 381, 1293–1301 (2013).

  44. 44

    Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013).

  45. 45

    Khera, A. V. et al. Diagnostic yield of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J. Am. Coll. Cardiol. http://dx.doi.org/10.1016/j.jacc.2016.03.520 (2016).

  46. 46

    Veerkamp, M. J., de Graaf, J., Hendriks, J. C., Demacker, P. N. & Stalenhoef, A. F. Nomogram to diagnose familial combined hyperlipidemia on the basis of results of a 5-year follow-up study. Circulation 109, 2980–2985 (2004).

  47. 47

    Civeira, F. et al. Frequency of low-density lipoprotein receptor gene mutations in patients with a clinical diagnosis of familial combined hyperlipidemia in a clinical setting. J. Am. Coll. Cardiol. 52, 1546–1553 (2008).

  48. 48

    Gidding, S. S. et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation 132, 2167–2192 (2015).

  49. 49

    Goldberg, A. C. 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. 5, 133–140 (2011).

  50. 50

    Wierzbicki, A. S., Humphries, S. E. & Minhas, R. Familial hypercholesterolaemia: summary of NICE guidance. BMJ 337, a1095 (2008).

  51. 51

    Vickery, A. W. et al. Optimising the detection and management of familial hypercholesterolaemia: central role of primary care and its integration with specialist services. Heart Lung Circ. 23, 1158–1164 (2014).

  52. 52

    Cuchel, M. et al. 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. 35, 2146–2157 (2014).

  53. 53

    Hammond, E. et al. Role of international registries in enhancing the care of familial hypercholesterolaemia. Int. J. Evid. Based Healthc. 11, 134–139 (2013).

  54. 54

    Sjouke, B. et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome. Eur. Heart J. 36, 560–565 (2015).

  55. 55

    Baum, S. J., Sijbrands, E. J., Mata, P. & Watts, G. F. The doctor's dilemma: challenges in the diagnosis and care of homozygous familial hypercholesterolemia. J. Clin. Lipidol. 8, 542–549 (2014).

  56. 56

    Besseling, J. et al. Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers. Atherosclerosis 233, 219–223 (2014).

  57. 57

    Reiner, Z. et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur. Heart J. 32, 1769–1818 (2011).

  58. 58

    Stone, N. J. 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 129 (25 Suppl. 2), S1–S45 (2014).

  59. 59

    Wiegman, A. et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur. Heart J. 36, 2425–2437 (2015).

  60. 60

    Leebmann, J. et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation 128, 2567–2576 (2013).

  61. 61

    Goldstein, J. L., Schrott, H. G., Hazzard, W. R., Bierman, E. L. & Motulsky, A. G. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J. Clin. Invest. 52, 1544–1568 (1973).

  62. 62

    Brouwers, M. C., van Greevenbroek, M. M., Stehouwer, C. D., de Graaf, J. & Stalenhoef, A. F. The genetics of familial combined hyperlipidaemia. Nat. Rev. Endocrinol. 8, 352–362 (2012).

  63. 63

    Wiesbauer, F. et al. Familial-combined hyperlipidaemia in very young myocardial infarction survivors (< or =40 years of age). Eur. Heart J. 30, 1073–1079 (2009).

  64. 64

    Genest, J. J. Jr et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 85, 2025–2033 (1992).

  65. 65

    Voors-Pette, C. & de Bruin, T. W. Excess coronary heart disease in familial combined hyperlipidemia, in relation to genetic factors and central obesity. Atherosclerosis 157, 481–489 (2001).

  66. 66

    Hopkins, P. N. et al. Coronary artery disease risk in familial combined hyperlipidemia and familial hypertriglyceridemia: a case-control comparison from the National Heart, Lung, and Blood Institute Family Heart Study. Circulation 108, 519–523 (2003).

  67. 67

    Rosenthal, E. A. et al. Joint linkage and association analysis with exome sequence data implicates SLC25A40 in hypertriglyceridemia. Am. J. Hum. Genet. 93, 1035–1045 (2013).

  68. 68

    Abifadel, M. et al. A PCSK9 variant and familial combined hyperlipidaemia. J. Med. Genet. 45, 780–786 (2008).

  69. 69

    Marcil, M. et al. Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia. Arterioscler. Thromb. Vasc. Biol. 26, 1619–1625 (2006).

  70. 70

    Veerkamp, M. J. et al. Diagnosis of familial combined hyperlipidemia based on lipid phenotype expression in 32 families: results of a 5-year follow-up study. Arterioscler. Thromb. Vasc. Biol. 22, 274–282 (2002).

  71. 71

    Miller, W. G. et al. Seven direct methods for measuring HDL and LDL cholesterol compared with ultracentrifugation reference measurement procedures. Clin. Chem. 56, 977–986 (2010).

  72. 72

    Sniderman, A. D., Lamarche, B., Contois, J. H. & de Graaf, J. Discordance analysis and the Gordian Knot of LDL and non-HDL cholesterol versus apoB. Curr. Opin. Lipidol. 25, 461–467 (2014).

  73. 73

    Emerging Risk Factors Collaboration et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009).

  74. 74

    Charlton-Menys, V. et al. Targets of statin therapy: LDL cholesterol, non-HDL cholesterol, and apolipoprotein B in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS). Clin. Chem. 55, 473–480 (2009).

  75. 75

    Boekholdt, S. M. et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 307, 1302–1309 (2012).

  76. 76

    Cruz-Bautista, I. et al. Determinants of VLDL composition and apo B-containing particles in familial combined hyperlipidemia. Clin. Chim. Acta 438, 160–165 (2015).

  77. 77

    Fredenrich, A. et al. Plasma lipoprotein distribution of apoC-III in normolipidemic and hypertriglyceridemic subjects: comparison of the apoC-III to apoE ratio in different lipoprotein fractions. J. Lipid Res. 38, 1421–1432 (1997).

  78. 78

    Cohn, J. S., Patterson, B. W., Uffelman, K. D., Davignon, J. & Steiner, G. Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity. J. Clin. Endocrinol. Metab. 89, 3949–3955 (2004).

  79. 79

    Ribas, V. et al. Human apolipoprotein A-II enrichment displaces paraoxonase from HDL and impairs its antioxidant properties: a new mechanism linking HDL protein composition and antiatherogenic potential. Circ. Res. 95, 789–797 (2004).

  80. 80

    Julve, J. et al. Human apolipoprotein A-II determines plasma triglycerides by regulating lipoprotein lipase activity and high-density lipoprotein proteome. Arterioscler. Thromb. Vasc. Biol. 30, 232–238 (2010).

  81. 81

    Brouwers, M. C. et al. Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia. Clin. Sci. (Lond.) 121, 397–403 (2011).

  82. 82

    Chan, D. C. et al. Plasma proprotein convertase subtilisin/kexin type 9: a marker of LDL apolipoprotein B-100 catabolism? Clin. Chem. 55, 2049–2052 (2009).

  83. 83

    Melone, M., Wilsie, L., Palyha, O., Strack, A. & Rashid, S. Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. J. Am. Coll. Cardiol. 59, 1697–1705 (2012).

  84. 84

    Baratta, R. et al. Adiponectin relationship with lipid metabolism is independent of body fat mass: evidence from both cross-sectional and intervention studies. J. Clin. Endocrinol. Metab. 89, 2665–2671 (2004).

  85. 85

    Koenen, T. B. et al. Adiponectin multimer distribution in patients with familial combined hyperlipidemia. Biochem. Biophys. Res. Commun. 376, 164–168 (2008).

  86. 86

    Sarwar, N. et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 379, 1205–1213 (2012).

  87. 87

    Castro Cabezas, M. et al. Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance. J. Clin. Invest. 92, 160–168 (1993).

  88. 88

    Aitman, T. J. et al. Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia. Arterioscler. Thromb. 17, 748–754 (1997).

  89. 89

    Veerkamp, M. J., de Graaf, J. & Stalenhoef, A. F. Role of insulin resistance in familial combined hyperlipidemia. Arterioscler. Thromb. Vasc. Biol. 25, 1026–1031 (2005).

  90. 90

    Purnell, J. Q., Kahn, S. E., Schwartz, R. S. & Brunzell, J. D. Relationship of insulin sensitivity and ApoB levels to intra-abdominal fat in subjects with familial combined hyperlipidemia. Arterioscler. Thromb. 21, 567–572 (2001).

  91. 91

    Miller, M. et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 123, 2292–2333 (2011).

  92. 92

    Chapman, M. J. et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur. Heart J. 32, 1345–1361 (2011).

  93. 93

    Watts, G. F., Ooi, E. M. & Chan, D. C. Demystifying the management of hypertriglyceridaemia. Nat. Rev. Cardiol. 10, 648–661 (2013).

  94. 94

    Rumawas, M. E., Meigs, J. B., Dwyer, J. T., McKeown, N. M. & Jacques, P. F. Mediterranean-style dietary pattern, reduced risk of metabolic syndrome traits, and incidence in the Framingham Offspring Cohort. Am. J. Clin. Nutr. 90, 1608–1614 (2009).

  95. 95

    Esposito, K. & Giugliano, D. Mediterranean diet for primary prevention of cardiovascular disease. N. Engl. J. Med. 369, 674–675 (2013).

  96. 96

    Eckel, R. H. et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, 2960–2984 (2014).

  97. 97

    Dattilo, A. M. & Kris-Etherton, P. M. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am. J. Clin. Nutr. 56, 320–328 (1992).

  98. 98

    Mateo-Gallego, R. et al. Serum lipid responses to weight loss differ between overweight adults with familial hypercholesterolemia and those with familial combined hyperlipidemia. J. Nutr. 144, 1219–1226 (2014).

  99. 99

    Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members. An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia — full report. J. Clin. Lipidol. 8, 29–60 (2014).

  100. 100

    Chan, D. C., Barrett, P. H. & Watts, G. F. The metabolic and pharmacologic bases for treating atherogenic dyslipidaemia. Best Pract. Res. Clin. Endocrinol. Metab. 28, 369–385 (2014).

  101. 101

    Hegele, R. A. et al. Nonstatin low-density lipoprotein-lowering therapy and cardiovascular risk reduction-statement from ATVB council. Arterioscler. Thromb. 35, 2269–2280 (2015).

  102. 102

    Catapano, A. L. et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 217, 3–46 (2011).

  103. 103

    Jacobson, T. A. et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 — executive summary. J. Clin. Lipidol. 8, 473–488 (2014).

  104. 104

    Mata, P. et al. [Familial combined hyperlipidemia: Consensus document]. Semergen 40, 374–380 (in Spanish) (2014).

  105. 105

    Jun, M. et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 375, 1875–1884 (2010).

  106. 106

    Ginsberg, H. N. et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1563–1574 (2010).

  107. 107

    Inzucchi, S. E. et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38, 140–149 (2015).

  108. 108

    Mancia, G. et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood Pressure 22, 193–278 (2013).

  109. 109

    Brunzell, J. D. et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J. Am. Coll. Cardiol. 51, 1512–1524 (2008).

  110. 110

    Kronenberg, F. & Utermann, G. Lipoprotein(a): resurrected by genetics. J. Intern. Med. 273, 6–30 (2013).

  111. 111

    Chretien, J. P. et al. Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans. J. Med. Genet. 43, 917–923 (2006).

  112. 112

    Virani, S. S. et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 125, 241–249 (2012).

  113. 113

    Kraft, H. G. et al. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Arterioscler. Thromb. Vasc. Biol. 16, 713–719 (1996).

  114. 114

    Kamstrup, P. R., Tybjaerg-Hansen, A., Steffensen, R. & Nordestgaard, B. G. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301, 2331–2339 (2009).

  115. 115

    Erqou, S. et al. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J. Am. Coll. Cardiol. 55, 2160–2167 (2010).

  116. 116

    Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).

  117. 117

    Schunkert, H. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333–338 (2011).

  118. 118

    Maranhão, R. C., Carvalho, P. O., Strunz, C. C. & Pileggi, F. Lipoprotein (a): structure, pathophysiology and clinical implications. Arq. Bras. Cardiol. 103, 76–84 (2014).

  119. 119

    Koschinsky, M. L., Côté, G. P., Gabel, B. & van der Hoek, Y. Y. Identification of the cysteine residue in apolipoprotein(a) that mediates extracellular coupling with apolipoprotein B-100. J. Biol. Chem. 268, 19819–19825 (1993).

  120. 120

    McCormick, S. P. et al. Mutagenesis of the human apolipoprotein B gene in a yeast artificial chromosome reveals the site of attachment for apolipoprotein(a). Proc. Natl Acad. Sci. USA 92, 10147–10151 (1995).

  121. 121

    Weisel, J. W. et al. The structure of lipoprotein(a) and ligand-induced conformational changes. Biochemistry 40, 10424–10435 (2001).

  122. 122

    Marcovina, S. M. et al. Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin. Chem. 46, 1956–1967 (2000).

  123. 123

    Brown, W. V., Ballantyne, C. M., Jones, P. H. & Marcovina, S. Management of Lp(a). J. Clin. Lipidol. 4, 240–247 (2010).

  124. 124

    McConnell, J. P. et al. Lipoprotein(a) mass: a massively misunderstood metric. J. Clin. Lipidol. 8, 550–553 (2014).

  125. 125

    Kronenberg, F., Lobentanz, E. M., König, P., Utermann, G. & Dieplinger, H. Effect of sample storage on the measurement of lipoprotein[a], apolipoproteins B and A-IV, total and high density lipoprotein cholesterol and triglycerides. J. Lipid Res. 35, 1318–1328 (1994).

  126. 126

    Kyriakou, T. et al. A common LPA null allele associates with lower lipoprotein(a) levels and coronary artery disease risk. Arterioscler. Thromb. Vasc. Biol. 34, 2095–2099 (2014).

  127. 127

    Lamon-Fava, S., Diffenderfer, M. R. & Marcovina, S. M. Lipoprotein(a) metabolism. Curr. Opin. Lipidol. 25, 189–193 (2014).

  128. 128

    Jenner, J. L. et al. The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a) in human beings. Metabolism 54, 361–369 (2005).

  129. 129

    Cain, W. J. et al. Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]. J. Lipid Res. 46, 2681–2691 (2005).

  130. 130

    Rader, D. J. et al. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans. J. Clin. Invest. 95, 1403–1408 (1995).

  131. 131

    Romagnuolo, R. et al. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J. Biol. Chem. 290, 11649–11662 (2015).

  132. 132

    Niemeier, A. et al. Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro. Arterioscler. Thromb. 19, 552–561 (1999).

  133. 133

    Yang, X. P. et al. Scavenger receptor-BI is a receptor for lipoprotein(a). J. Lipid Res. 54, 2450–2457 (2013).

  134. 134

    Poirier, S. et al. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem. 283, 2363–2372 (2008).

  135. 135

    Kronenberg, F., Utermann, G. & Dieplinger, H. Lipoprotein(a) in renal disease. Am. J. Kidney Dis. 27, 1–25 (1996).

  136. 136

    Nordestgaard, B. G. et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31, 2844–2853 (2010).

  137. 137

    Albers, J. J. et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J. Am. Coll. Cardiol. 62, 1575–1579 (2013).

  138. 138

    Khera, A. V. et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation 129, 635–642 (2014).

  139. 139

    Willeit, P. et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J. Am. Coll. Cardiol. 64, 851–860 (2014).

  140. 140

    Dubé, J. B., Boffa, M. B., Hegele, R. A. & Koschinsky, M. L. Lipoprotein(a): more interesting than ever after 50 years. Curr. Opin. Lipidol. 23, 133–140 (2012).

  141. 141

    Jansen, A. C. et al. The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. J. Intern. Med. 256, 482–490 (2004).

  142. 142

    Chan, D. C. et al. Elevated lipoprotein(a), hypertension and renal insufficiency as predictors of coronary artery disease in patients with genetically confirmed heterozygous familial hypercholesterolemia. Int. J. Cardiol. 201, 633–638 (2015).

  143. 143

    Hopkins, P. N. et al. Evaluation of coronary risk factors in patients with heterozygous familial hypercholesterolemia. Am. J. Cardiol. 87, 547–553 (2001).

  144. 144

    de Sauvage Nolting, P. R. et al. Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemia. J. Intern. Med. 253, 161–168 (2003).

  145. 145

    Neil, H. A. et al. Established and emerging coronary risk factors in patients with heterozygous familial hypercholesterolaemia. Heart 90, 1431–1437 (2004).

  146. 146

    Watts, G. F. et al. Familial hypercholesterolaemia: a model of care for Australasia. Atheroscler. Suppl. 12, 221–263 (2011).

  147. 147

    Tsimikas, S. et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386, 1472–1483 (2015).

  148. 148

    Graham, M. J., Viney, N., Crooke, R. & Tsimikas, S. Antisense inhibition of apolipoprotein(a) to lower plasma lipoprotein(a) levels in humans. J. Lipid Res. 57, 340–351 (2016).

  149. 149

    Bos, S., Yayha, R. & van Lennep, J. E. Latest developments in the treatment of lipoprotein (a). Curr. Opin. Lipidol. 25, 452–460 (2014).

  150. 150

    Hoover-Plow, J. & Huang, M. Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism 62, 479–491 (2013).

  151. 151

    Kolski, B. & Tsimikas, S. Emerging therapeutic agents to lower lipoprotein (a) levels. Curr. Opin. Lipidol. 23, 560–568 (2012).

  152. 152

    Guyton, J. R. et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J. Am. Coll. Cardiol. 62, 1580–1584 (2013).

  153. 153

    Page, M. M., Bell, D. A., Hooper, A. J., Watts, G. F. & Burnett, J. R. Lipoprotein apheresis and new therapies for severe familial hypercholesterolemia in adults and children. Best Pract. Res. Clin. Endocrinol. Metab. 28, 387–403 (2014).

  154. 154

    Stein, E. A., Lane, M. & Laskarzewski, P. Comparison of statins in hypertriglyceridemia. Am. J. Cardiol. 81, 66B–69B (1998).

  155. 155

    Cholesterol Treatment Trialists (CTT) Collaboration et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376, 1670–1681 (2010).

  156. 156

    Elis, A., Zhou, R. & Stein, E. A. Effect of lipid-lowering treatment on natural history of heterozygous familial hypercholesterolemia in past three decades. Am. J. Cardiol. 108, 223–226 (2011).

  157. 157

    Smilde, T. J. et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 357, 577–581 (2001).

  158. 158

    Raal, F. J. et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 124, 2202–2207 (2011).

  159. 159

    Pijlman, A. H. et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis 209, 189–194 (2010).

  160. 160

    Pandor, A. et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J. Intern. Med. 265, 568–580 (2009).

  161. 161

    Baigent, C. et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 377, 2181–2192 (2011).

  162. 162

    Tsujita, K. et al. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial. J. Am. Coll. Cardiol. 66, 495–507 (2015).

  163. 163

    Knopp, R. H. Drug treatment of lipid disorders. N. Engl. J. Med. 341, 498–511 (1999).

  164. 164

    Handelsman, Y. Role of bile acid sequestrants in the treatment of type 2 diabetes. Diabetes Care 34 (Suppl. 2), S244–S250 (2011).

  165. 165

    [No authors listed.] The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 251, 365–374 (1984).

  166. 166

    [No authors listed.] The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 251, 351–364 (1984).

  167. 167

    Davidson, M. The efficacy of colesevelam HCl in the treatment of heterozygous familial hypercholesterolemia in pediatric and adult patients. Clin. Ther. 35, 1247–1252 (2013).

  168. 168

    Huijgen, R. et al. Colesevelam 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. 32, 615–625 (2010).

  169. 169

    Sattar, N. et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375, 735–742 (2010).

  170. 170

    Reiner, Z. Management of patients with familial hypercholesterolaemia. Nat. Rev. Cardiol. 12, 565–575 (2015).

  171. 171

    Staels, B. et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98, 2088–2093 (1998).

  172. 172

    Chapman, M. J., Redfern, J. S., McGovern, M. E. & Giral, P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol. Ther. 126, 314–345 (2010).

  173. 173

    Frick, M. H. et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 317, 1237–1245 (1987).

  174. 174

    Bezafibrate Infarction Prevention (BIP) Study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 102, 21–27 (2000).

  175. 175

    Keech, A. et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366, 1849–1861 (2005).

  176. 176

    Keech, A. C. et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370, 1687–1697 (2007).

  177. 177

    ACCORD Study Group. et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N. Engl. J. Med. 363, 233–244 (2010).

  178. 178

    Creider, J. C., Hegele, R. A. & Joy, T. R. Niacin: another look at an underutilized lipid-lowering medication. Nat. Rev. Endocrinol. 8, 517–528 (2012).

  179. 179

    Canner, P. L. et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J. Am. Coll. Cardiol. 8, 1245–1255 (1986).

  180. 180

    AIM-HIGH Investigators et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).

  181. 181

    HPS2-THRIVE Collaborative Group et al. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371, 203–212 (2014).

  182. 182

    Mozaffarian, D. & Wu, J. H. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J. Am. Coll. Cardiol. 58, 2047–2067 (2011).

  183. 183

    Roth, E. M. ω-3 carboxylic acids for hypertriglyceridemia. Expert Opin. Pharmacother. 16, 123–133 (2015).

  184. 184

    Ballantyne, C. M. et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am. J. Cardiol. 110, 984–992 (2012).

  185. 185

    ORIGIN Trial Investigators et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N. Engl. J. Med. 367, 309–318 (2012).

  186. 186

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02104817 (2015).

  187. 187

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01492361 (2016).

  188. 188

    Davidson, M. H., Armani, A., McKenney, J. M. & Jacobson, T. A. Safety considerations with fibrate therapy. Am. J. Cardiol. 99, 3C–18C (2007).

  189. 189

    Brasky, T. M. et al. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J. Natl Cancer Inst. 105, 1132–1141 (2013).

  190. 190

    Giugliano, R. P. Niacin at 56 years of age — time for an early retirement? N. Engl. J. Med. 365, 2318–2320 (2011).

  191. 191

    HPS2-THRIVE Collaborative Group et al. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur. Heart J. 34, 1279–1291 (2013).

  192. 192

    Jacobson, T. A. Combination lipid-altering therapy: an emerging treatment paradigm for the 21st century. Curr. Atheroscler. Rep. 3, 373–382 (2001).

  193. 193

    Blazing, M. A. et al. Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: final baseline characteristics of the IMPROVE-IT study population. Am. Heart J. 168, 205–212.e1 (2014).

  194. 194

    Rubenfire, M., Brook, R. D. & Rosenson, R. S. Treating mixed hyperlipidemia and the atherogenic lipid phenotype for prevention of cardiovascular events. Am. J. Med. 123, 892–898 (2010).

  195. 195

    Robinson, J. G. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1489–1499 (2015).

  196. 196

    Blom, D. J. et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N. Engl. J. Med. 370, 1809–1819 (2014).

  197. 197

    Raal, F. J. et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 385, 341–350 (2015).

  198. 198

    Navarese, E. P. et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann. Intern. Med. 163, 40–51 (2015).

  199. 199

    Sabatine, M. S. et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1500–1509 (2015).

  200. 200

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01975389 (2016).

  201. 201

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01975376 (2016).

  202. 202

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01663402 (2016).

  203. 203

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01764633 (2016).

  204. 204

    Stein, E. A. et al. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur. Heart J. 35, 2249–2259 (2014).

  205. 205

    Stroes, E. et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J. Am. Coll. Cardiol. 63, 2541–2548 (2014).

  206. 206

    Stein, E. A. & Raal, F. J. New therapies for reducing low-density lipoprotein cholesterol. Endocrinol. Metab. Clin. North Am. 43, 1007–1033 (2014).

  207. 207

    Raal, F. J. 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, 998–1006 (2010).

  208. 208

    Stein, E. A. 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 126, 2283–2292 (2012).

  209. 209

    Thomas, G. S. et al. 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, 2178–2184 (2013).

  210. 210

    McGowan, M. P. et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS ONE 7, e49006 (2012).

  211. 211

    Gaudet, D. et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373, 438–447 (2015).

  212. 212

    Cuchel, M. 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, 40–46 (2013).

  213. 213

    Tuteja, S. et al. Pharmacokinetic interactions of the microsomal triglyceride transfer protein inhibitor, lomitapide, with drugs commonly used in the management of hypercholesterolemia. Pharmacotherapy 34, 227–239 (2014).

  214. 214

    Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2022 (2007).

  215. 215

    Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).

  216. 216

    Tardif, J. C. et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ. Cardiovasc. Genet. 8, 372–382 (2015).

  217. 217

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01687998 (2016).

  218. 218

    MacGregor, J. S. Lilly to discontinue development of evacetrib for high-risk atherosclerotic cardiovascular disease. PR Newswire, http://www.prnewswire.com/news-releases/lilly-to-discontinue-development-of-evacetrapib-for-high-risk-atherosclerotic-cardiovascular-disease-300157604.html (2015).

  219. 219

    Cannon, C. P. et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N. Engl. J. Med. 363, 2406–2415 (2010).

  220. 220

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01252953 (2015).

  221. 221

    Hovingh, G. K. et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet 386, 452–460 (2015).

  222. 222

    Pinkosky, S. L. et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J. Lipid Res. 54, 134–151 (2013).

  223. 223

    Filippov, S., Pinkosky, S. L. & Newton, R. S. LDL-cholesterol reduction in patients with hypercholesterolemia by modulation of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase. Curr. Opin. Lipidol. 25, 309–315 (2014).

  224. 224

    Stein, E. A. & Raal, F. J. Lipid-lowering drug therapy for CVD prevention: looking into the future. Curr. Cardiol. Rep. 17, 104 (2015).

  225. 225

    Bays, H. E. et al. MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J. Clin. Endocrinol. Metab. 96, 2889–2897 (2011).

  226. 226

    Ellis, J. M., Frahm, J. L., Li, L. O. & Coleman, R. A. Acyl-coenzyme A synthetases in metabolic control. Curr. Opin. Lipidol. 21, 212–217 (2010).

  227. 227

    Bays, H. E. et al. Effectiveness and tolerability of a new lipid-altering agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol. Am. J. Cardiol. 92, 538–543 (2003).

  228. 228

    Mandema, J. W. et al. Model-based development of gemcabene, a new lipid-altering agent. AAPS J. 7, E513–E522 (2005).

  229. 229

    Bell, D. A. & Watts, G. F. Response to familial hypercholesterolemia: an under-recognized but significant concern in cardiology practice. Clin. Cardiol. 37, 386–387 (2014).

Download references

Author information

Affiliations

Authors

Contributions

All authors researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Gerald F. Watts.

Ethics declarations

Competing interests

G.F.W. has received research grants and advisory board honouraria from Amgen and Sanofi. The other authors declare no competing interests.

Related links

FURTHER INFORMATION

ClinicalTrials.gov

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

Dutch Lipid Clinic Network Score for making a diagnosis of familial hypercholesterolaemia in an index patient. (PDF 332 kb)

Supplementary information S2 (box)

Indications for measuring lipoprotein(a) (PDF 68 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ellis, K., Hooper, A., Burnett, J. et al. Progress in the care of common inherited atherogenic disorders of apolipoprotein B metabolism. Nat Rev Endocrinol 12, 467–484 (2016). https://doi.org/10.1038/nrendo.2016.69

Download citation

Further reading