Cholesteryl ester transfer protein inhibitors: challenges and perspectives

Expert Review of Cardiovascular Therapy

Volumn 14, Issue 8, 2016, Pages 953-962

  Filippatos, T D ^a   Klouras, E ^a   Barkas, F ^a   Elisaf, M ^a  

^a UNIVERSITY OF IOANNINA   (Greece)

Author keywords

anacetrapib; cardiovascular disease; Cholesteryl ester transfer protein inhibitors; dalcetrapib; evacetrapib; TA 8995; torcetrapib

Indexed keywords

ALDOSTERONE; ANACETRAPIB; ATORVASTATIN; CARBOHYDRATE; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; DALCETRAPIB; EVACETRAPIB; EZETIMIBE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INSULIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; TORCETRAPIB; TRIACYLGLYCEROL; BENZODIAZEPINE DERIVATIVE; CETP PROTEIN, HUMAN; CHOLESTEROL ESTER TRANSFER PROTEIN; HIGH DENSITY LIPOPROTEIN; HYPOCHOLESTEROLEMIC AGENT; LIPID; LIPOPROTEIN A; OXAZOLIDINONE DERIVATIVE; QUINOLINE DERIVATIVE; TA-8995; THIOL DERIVATIVE;

ALDOSTERONE BLOOD LEVEL; CARBOHYDRATE METABOLISM; CARDIOVASCULAR EFFECT; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL TRANSPORT; CORONARY ARTERY ATHEROSCLEROSIS; DIABETIC PATIENT; DRUG BLOOD LEVEL; DRUG SAFETY; DRUG TREATMENT FAILURE; DRUG WITHDRAWAL; FAMILIAL HYPERCHOLESTEROLEMIA; HEART MUSCLE REVASCULARIZATION; HUMAN; HYPERTENSION; INSULIN RELEASE; LIPID BLOOD LEVEL; LIPID METABOLISM; META ANALYSIS (TOPIC); MONOTHERAPY; NONHUMAN; PARTICLE SIZE; PHARMACOGENOMICS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK REDUCTION; SIDE EFFECT; SYSTOLIC BLOOD PRESSURE; TRIACYLGLYCEROL BLOOD LEVEL; ANTAGONISTS AND INHIBITORS; BLOOD; METABOLISM;

ANTICHOLESTEREMIC AGENTS; BENZODIAZEPINES; CHOLESTEROL ESTER TRANSFER PROTEINS; CHOLESTEROL, HDL; CHOLESTEROL, LDL; HUMANS; LIPIDS; LIPOPROTEIN(A); LIPOPROTEINS, HDL; OXAZOLIDINONES; QUINOLINES; SULFHYDRYL COMPOUNDS;

EID: 84978653504     PISSN: 14779072     EISSN: 17448344     Source Type: Journal    
DOI: 10.1080/14779072.2016.1189327     Document Type: Review

References (99)

1. G.De Backer, E.Ambrosioni, K.Borch-Johnsen, et al. European guidelines on cardiovascular disease prevention in clinical practice. Third joint task force of European and other societies on cardiovascular disease prevention in clinical practice. Eur Heart J. 2003;24:1601–1610.
2. Z.Reiner, A.L.Catapano, G.De Backer, 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. 2011;32:1769–1818.
3. B.Mihaylova, J.Emberson, L.Blackwell, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–590.
4. C.Baigent, A.Keech, P.M.Kearney, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278.
5. A.A.Kei, T.D.Filippatos, M.S.Elisaf The safety of ezetimibe and simvastatin combination for the treatment of hypercholesterolemia. Expert Opin Drug Saf. 2016;15:559–569.
6. T.D.Filippatos, M.S.Elisaf. Statin-ezetimibe combination therapy in diabetic individuals. Angiology. 2016;67:507–509.
7. T.D.Filippatos, M.S.Elisaf. Effects of ezetimibe/simvastatin combination on metabolic parameters. Int J Cardiol. 2016;202:273–274.
8. T.D.Filippatos, M.S.Elisaf. Are lower levels of LDL-cholesterol really better? Looking at the results of IMPROVE-IT: opinions of three experts - III. Hellenic J Cardiol. 2015;56:7–9.
9. P.Barter, A.M.Gotto, J.C.LaRosa, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301–1310.
10. I.F.Gazi, T.D.Filippatos, V.Tsimihodimos, et al. The hypertriglyceridemic waist phenotype is a predictor of elevated levels of small, dense LDL cholesterol. Lipids. 2006;41:647–654.
11. V.Tsimihodimos, I.Gazi, T.Filippatos, et al. Plasma triglyceride levels and body mass index values are the most important determinants of prebeta-1 HDL concentrations in patients with various types of primary dyslipidemia. Atherosclerosis. 2010;208:506–511.
12. C.Aguiar, E.Alegria, R.C.Bonadonna, et al. A review of the evidence on reducing macrovascular risk in patients with atherogenic dyslipidaemia: A report from an expert consensus meeting on the role of fenofibrate-statin combination therapy. Ather Suppl. 2015;19:1–12.
13. D.J.Gordon, J.L.Probstfield, R.J.Garrison, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8–15.
14. E.Bruckert, J.Labreuche, P.Amarenco. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis. 2010;210:353–361.
15. W.E.Boden, J.L.Probstfield, T.Anderson, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–2267.
16. M.J.Landray, R.Haynes, J.C.Hopewell, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–212.
17. T.D.Filippatos, M.S.Elisaf. Fenofibrate plus simvastatin (fixed-dose combination) for the treatment of dyslipidaemia. Expert Opin Pharmacother. 2011;12:1945–1958.
18. T.D.Filippatos, M.S.Elisaf. Safety considerations with fenofibrate/simvastatin combination. Expert Opin Drug Saf. 2015;14:1481–1493.
19. H.N.Ginsberg, M.B.Elam, L.C.Lovato, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–1574.
20. C.E.Kosmas, E.DeJesus, D.Rosario, et al. CETP inhibition: Past failures and future hopes. Clin Med Insights Cardiol. 2016;10:37–42.
21. A.R.Tall. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993;34:1255–1274.
22. K.Ikewaki, H.Mabuchi, T.Teramoto, et al. Association of cholesteryl ester transfer protein activity and TaqIB polymorphism with lipoprotein variations in Japanese subjects. Metabolism. 2003;52:1564–1570.
23. N.J.Lewis-Barned, W.H.Sutherland, R.J.Walker, et al. Plasma cholesterol esterification and transfer, the menopause, and hormone replacement therapy in women. J Clin Endocrinol Metab. 1999;84:3534–3538.
24. T.Murakami, S.Michelagnoli, R.Longhi, et al. Triglycerides are major determinants of cholesterol esterification/transfer and HDL remodeling in human plasma. Arterioscler Thromb Vasc Biol. 1995;15:1819–1828.
25. J.A.Beentjes, A.Van Tol, W.J.Sluiter, et al. Decreased plasma cholesterol esterification and cholesteryl ester transfer in hypopituitary patients on glucocorticoid replacement therapy. Scand J Clin Lab Invest. 2000;60:189–198.
26. A.Inazu, X.C.Jiang, T.Haraki, et al. Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol. J Clin Invest. 1994;94:1872–1882.
27. J.Koizumi, H.Mabuchi, A.Yoshimura, et al. Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinaemia. Atherosclerosis. 1985;58:175–186.
28. A.Thompson, E.Di Angelantonio, N.Sarwar, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. Jama. 2008;299:2777–2788.• An analysis which showed that specific polymorphisms of CETP are associated with decreased cardiovascular risk.
29. T.H.Johannsen, R.Frikke-Schmidt, J.Schou, et al. Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects. J Am Coll Cardiol. 2012;60:2041–2048.
30. J.D.Curb, R.D.Abbott, B.L.Rodriguez, et al. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res. 2004;45:948–953.
31. T.Okamura, A.Sekikawa, T.Kadowaki, et al. Cholesteryl ester transfer protein, coronary calcium, and intima-media thickness of the carotid artery in middle-age Japanese men. Am J Cardiol. 2009;104:818–822.
32. J.J.Regieli, J.W.Jukema, D.E.Grobbee, et al. CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction. Eur Heart J. 2008;29:2792–2799.• An analysis which showed that genetically induced low CETP levels are associated with increased mortality in statin-treated men with coronary artery disease.
33. S.E.Borggreve, H.L.Hillege, B.H.Wolffenbuttel, et al. An increased coronary risk is paradoxically associated with common cholesteryl ester transfer protein gene variations that relate to higher high-density lipoprotein cholesterol: a population-based study. J Clin Endocrinol Metab. 2006;91:3382–3388.
34. S.E.Borggreve, H.L.Hillege, G.M.Dallinga-Thie, et al. High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides. Eur Heart J. 2007;28:1012–1018.
35. S.Zhong, D.S.Sharp, J.S.Grove, et al. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest. 1996;97:2917–2923.
36. M.E.Brousseau, E.J.Schaefer, M.L.Wolfe, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004;350:1505–1515.
37. S.E.Nissen, J.C.Tardif, S.J.Nicholls, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356:1304–1316.
38. J.J.Kastelein, S.I.Van Leuven, L.Burgess, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007;356:1620–1630.
39. M.L.Bots, F.L.Visseren, G.W.Evans, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet. 2007;370:153–160.
40. P.J.Barter, M.Caulfield, M.Eriksson, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–2122.•• An outcomes trial which showed that increased cardiovascular and total mortality with torcetrapib mainly due to off-target effects.
41. J.G.Robinson. Dalcetrapib: a review of phase II data. Expert Opin Investig Drugs. 2010;19:795–805.
42. C.M.Ballantyne, M.Miller, E.J.Niesor, et al. Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: results of a phase IIb dose-ranging study. Am Heart J. 2012;163:515–521,521 e511–513.
43. E.A.Stein, E.M.Roth, J.M.Rhyne, et al. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J. 2010;31:480–488.
44. G.G.Schwartz, A.G.Olsson, M.Abt, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–2099.•• An outcomes trial that reported futility of dalcetrapib treatment.
45. C.K.Ip, D.M.Jin, J.J.Gao, et al. Effects of add-on lipid-modifying therapy on top of background statin treatment on major cardiovascular events: a meta-analysis of randomized controlled trials. Int J Cardiol. 2015;191:138–148.
46. J.C.Tardif, E.Rheaume, L.P.Lemieux Perreault, et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet. 2015;8:372–382.
47. A.Sahebkar, L.E.Simental-Mendia, F.Guerrero-Romero, et al. Efficacy and safety of evacetrapib for modifying plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Curr Pharm Des. 2016;22:595–608.
48. S.J.Nicholls, A.M.Lincoff, P.J.Barter, et al. Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: rationale and design of the ACCELERATE trial. Am Heart J. 2015;170:1061–1069.
49. R.Krishna, M.S.Anderson, A.J.Bergman, 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. 2007;370:1907–1914.
50. D.Bloomfield, G.L.Carlson, A.Sapre, 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. 2009;157:352–360 e352.
51. J.J.Kastelein, J.Besseling, S.Shah, et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2015;385:2153–2161.
52. J.S.Millar, G.Reyes-Soffer, P.Jumes, et al. Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects. J Clin Invest. 2016;126:1603–1604.
53. B.Dong, A.B.Singh, C.Fung, et al. CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo through a SREBP2 dependent mechanism. Atherosclerosis. 2014;235:449–462.
54. E.A.Brinton, U.Kher, S.Shah, et al. Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (determining the efficacy and tolerability of CETP inhibition with AnacEtrapib) trial. J Clin Lipidol. 2015;9:65–71.•• A study that assessed the effect of anacetrapib on lipid profile and its safety.
55. C.P.Cannon, S.Shah, H.M.Dansky, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363:2406–2415.
56. A.M.GottoJr., U.Kher, M.S.Chatterjee, et al. Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with anacetrapib in the DEFINE study. J Cardiovasc Pharmacol Ther. 2014;19:543–549.
57. A.M.GottoJr., C.P.Cannon, X.S.Li, 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. 2014;113:76–83.
58. G.K.Hovingh, J.J.Kastelein, S.J.Van Deventer, 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. 2015;386:452–460.
59. P.Barter. Lessons learned from the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial. Am J Cardiol. 2009;104:10E–15E.
60. S.J.Nicholls, E.M.Tuzcu, D.M.Brennan, et al. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILLUSTRATE (investigation of lipid level management using coronary ultrasound to assess reduction of atherosclerosis by CETP inhibition and HDL elevation). Circulation. 2008;118:2506–2514.
61. L.Yvan-Charvet, F.Matsuura, N.Wang, et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol. 2007;27:1132–1138.
62. K.K.Ray, M.Ditmarsch, D.Kallend, et al. The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: the dal-ACUTE randomized trial. Eur Heart J. 2014;35:1792–1800.
63. S.J.Nicholls, G.Ruotolo, H.B.Brewer, et al. Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib. J Am Coll Cardiol. 2015;66:2201–2210.
64. L.Yvan-Charvet, J.Kling, T.Pagler, et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol. 2010;30:1430–1438.
65. D.Saleheen, R.Scott, S.Javad, et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. Lancet Diabetes Endocrinol. 2015;3:507–513.
66. A.Rohatgi, A.Khera, J.D.Berry, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371:2383–2393.
67. A.V.Khera, M.Cuchel, M.De La Llera-Moya, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–135.
68. C.Maugeais, A.Perez, E.Von Der Mark, et al. Evidence for a role of CETP in HDL remodeling and cholesterol efflux: role of cysteine 13 of CETP. Biochim Biophys Acta. 2013;1831:1644–1650.
69. F.Briand, Q.Thieblemont, A.Andre, et al. CETP inhibitor torcetrapib promotes reverse cholesterol transport in obese insulin-resistant CETP-ApoB100 transgenic mice. Clin Transl Sci. 2011;4:414–420.
70. E.J.Niesor, C.Magg, N.Ogawa, et al. Modulating cholesteryl ester transfer protein activity maintains efficient pre-beta-HDL formation and increases reverse cholesterol transport. J Lipid Res. 2010;51:3443–3454.
71. F.Briand, Q.Thieblemont, E.Muzotte, et al. Upregulating reverse cholesterol transport with cholesteryl ester transfer protein inhibition requires combination with the LDL-lowering drug berberine in dyslipidemic hamsters. Arterioscler Thromb Vasc Biol. 2013;33:13–23.
72. U.Tchoua, W.D’Souza, N.Mukhamedova, et al. The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse cholesterol transport. Cardiovasc Res. 2008;77:732–739.
73. J.Castro-Perez, F.Briand, K.Gagen, et al. Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters. J Lipid Res. 2011;52:1965–1973.
74. F.Briand, Q.Thieblemont, E.Muzotte, et al. Anacetrapib and dalcetrapib differentially alters HDL metabolism and macrophage-to-feces reverse cholesterol transport at similar levels of CETP inhibition in hamsters. Eur J Pharmacol. 2014;740:135–143.
75. W.Annema, U.J.Tietge. Regulation of reverse cholesterol transport - a comprehensive appraisal of available animal studies. Nutr Metab (Lond). 2012;9:25.
76. C.E.Kosmas, G.Christodoulidis, J.W.Cheng, et al. High-density lipoprotein functionality in coronary artery disease. Am J Med Sci. 2014;347:504–508.
77. L.Camont, M.J.Chapman, A.Kontush. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med. 2011;17:594–603.
78. M.Ishigami, S.Yamashita, N.Sakai, et al. Large and cholesteryl ester-rich high-density lipoproteins in cholesteryl ester transfer protein (CETP) deficiency can not protect macrophages from cholesterol accumulation induced by acetylated low-density lipoproteins. J Biochem. 1994;116:257–262.
79. A.Kontush. HDL particle number and size as predictors of cardiovascular disease. Front Pharmacol. 2015;6:218.
80. N.Rashedi, D.Brennan, J.J.Kastelein, et al. Impact of cholesteryl ester transfer protein inhibition on nuclear magnetic resonance derived lipoprotein particle prameters (abstract). Ather Suppl. 2011;12:48.
81. G.D.Sloop, J.J.Weidman, J.A.St Cyr. Perspective. The failure of cholesteryl ester transfer protein inhibitors: is it due to increased blood viscosity? Ther Adv Cardiovasc Dis. 2015;9:32–35.
82. W.A.Van Der Steeg, I.Holme, S.M.Boekholdt, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol. 2008;51:634–642.
83. R.G.Clerc, A.Stauffer, F.Weibel, et al. Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. J Hypertens. 2010;28:1676–1686.
84. X.Hu, J.D.Dietz, C.Xia, et al. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009;150:2211–2219.
85. M.J.Forrest, D.Bloomfield, R.J.Briscoe, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol. 2008;154:1465–1473.
86. F.J.Rios, K.B.Neves, A.Nguyen Dinh Cat, et al. Cholesteryl ester-transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through Nox-dependent processes. J Pharmacol Exp Ther. 2015;353:27–34.
87. M.A.Connelly, T.J.Parry, E.C.Giardino, et al. Torcetrapib produces endothelial dysfunction independent of cholesteryl ester transfer protein inhibition. J Cardiovasc Pharmacol. 2010;55:459–468.•• A study which showed that torcetrapib, dalcetrapib, and anacetrapib increase aldosterone biosynthesis in adipocytes.
88. B.Simic, M.Hermann, S.G.Shaw, et al. Torcetrapib impairs endothelial function in hypertension. Eur Heart J. 2012;33:1615–1624.
89. F.Rios, R.Alves, K.Neves, et al. Off-target vascular effects of cholesteryl ester transfer protein (CETP) inhibitors involve redox-sensitive and STAT3-dependent pathways. J Pharmacol Exp Ther. 2016;357:415–422.
90. W.Y.Craig, L.M.Neveux, G.E.Palomaki, et al. Lipoprotein(a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies. Clin Chem. 1998;44:2301–2306.
91. H.J.Milionis, T.D.Filippatos, T.Loukas, et al. Serum lipoprotein(a) levels and apolipoprotein(a) isoform size and risk for first-ever acute ischaemic nonembolic stroke in elderly individuals. Atherosclerosis. 2006;187:170–176.
92. P.R.Kamstrup, A.Tybjaerg-Hansen, B.G.Nordestgaard. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol. 2014;63:470–477.
93. P.J.Barter, K.-A.Rye, J.-C.Tardif, et al. Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial. Circulation. 2011;124:555–562.• A study which showed possible beneficial effects of CETP inhibition on carbohydrate metabolism variables.
94. A.L.Siebel, A.K.Natoli, F.Y.Yap, et al. Effects of high-density lipoprotein elevation with cholesteryl ester transfer protein inhibition on insulin secretion. Circ Res. 2013;113:167–175.
95. M.Hao, W.S.Head, S.C.Gunawardana, et al. Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction. Diabetes. 2007;56:2328–2338.
96. D.R.Nair, M.Sharifi, K.Al-Rasadi. Familial hypercholesterolaemia. Curr Opin Cardiol. 2014;29:381–388.
97. E.M.deGoma, Z.S.Ahmad, E.C.O’Brien, et al. Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH registry. Circ Cardiovasc Genet. 2016. [Epub ahead of print]
98. G.J.De Grooth, T.J.Smilde, S.Van Wissen, et al. The relationship between cholesteryl ester transfer protein levels and risk factor profile in patients with familial hypercholesterolemia. Atherosclerosis. 2004;173:261–267.
99. D.T.Holmes, B.A.Schick, K.H.Humphries, et al. Lipoprotein(a) is an independent risk factor for cardiovascular disease in heterozygous familial hypercholesterolemia. Clin Chem. 2005;51:2067–2073.