CETP inhibition: Past failures and future hopes

Clinical Medicine Insights: Cardiology

Volumn 10, Issue , 2016, Pages 37-42

  Kosmas, Constantine E ^a   Dejesus, Eddy ^b   Rosario, Digna ^c   Vittorio, Timothy J ^d  

^a MOUNT SINAI HOSPITAL   (United States)

^b BRONX LEBANON HOSPITAL CENTER   (United States)

^c Cardiology Unlimited   (United States)

^d ST FRANCIS HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ABC TRANSPORTER A1; ALDOSTERONE; ANACETRAPIB; APOLIPOPROTEIN A1; APOLIPOPROTEIN B; ATORVASTATIN; BICARBONATE; C REACTIVE PROTEIN; CHOLESTEROL ESTER TRANSFER PROTEIN; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; DALCETRAPIB; EVACETRAPIB; EZETIMIBE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; POTASSIUM; SODIUM; TA 8995; TORCETRAPIB; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ACUTE CORONARY SYNDROME; ARTERIAL WALL THICKNESS; ATHEROSCLEROSIS; CARDIOVASCULAR RISK; CHOLESTEROL TRANSPORT; CORONARY ARTERY ATHEROSCLEROSIS; CORONARY ARTERY DISEASE; DOSE RESPONSE; DYSLIPIDEMIA; ELECTROLYTE DISTURBANCE; ELEVATED BLOOD PRESSURE; FAMILIAL HYPERCHOLESTEROLEMIA; GENE MUTATION; HUMAN; HYPERALDOSTERONISM; HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIA; ISCHEMIC HEART DISEASE; MONOTHERAPY; NONHUMAN; REVERSE CHOLESTEROL TRANSPORT; REVIEW; RISK REDUCTION; SIDE EFFECT;

EID: 84960921437     PISSN: None     EISSN: 11795468     Source Type: Journal    
DOI: 10.4137/CMC.S32667     Document Type: Review

References (50)

1. O’Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43(11):2142-6.
2. LaRosa JC, Grundy SM, Waters DD, et al; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-35.
3. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-207.
4. Kosmas CE, Christodoulidis G, Cheng JW, Vittorio TJ, Lerakis S. High-density lipoprotein functionality in coronary artery disease. Am J Med Sci. 2014;347(6):504-8.
5. Castelli WP. Cholesterol and lipids in the risk of coronary artery disease-the Framingham Heart Study. Can J Cardiol. 1988;4(suppl A):5A-10A.
6. Barter P, Gotto AM, LaRosa JC, et al; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357(13):1301-10.
7. Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993-2000.
8. Wang Y, van der Tuin S, Tjeerdema N, et al. Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells. Hepatology. 2015;62(6):1710-22.
9. Marcel YL, McPherson R, Hogue M, et al. Distribution and concentration of cholesteryl ester transfer protein in plasma of normolipemic subjects. J Clin Invest. 1990;85(1):10-7.
10. Gurfinkel R, Joy TR. Anacetrapib: hope for CETP inhibitors? Cardiovasc Ther. 2011;29(5):327-39.
11. McPherson R, Mann CJ, Tall AR, et al. Plasma concentrations of cholesteryl ester transfer protein in hyperlipoproteinemia. Relation to cholesteryl ester transfer protein activity and other lipoprotein variables. Arterioscler Thromb. 1991;11(4):797-804.
12. Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993;34(8):1255-74.
13. Koizumi J, Mabuchi H, Yoshimura A, et al. Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinaemia. Atherosclerosis. 1985;58(1-3):175-86.
14. Inazu A, Brown ML, Hesler CB, et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990;323(18):1234-38.
15. Morehouse LA, Sugarman ED, Bourassa PA, et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J Lipid Res. 2007;48(6):1263-72.
16. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004;350(15):1505-15.
17. Clark RW, Sutfin TA, Ruggeri RB, et al. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol. 2004;24(3):490-7.
18. Barter PJ, Caulfield M, Eriksson M, et al; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109-22.
19. Kosmas CE, Frishman WH. New and emerging LDL cholesterol-lowering drugs. Am J Ther. 2015;22(3):234-41.
20. Nissen SE, Tardif JC, Nicholls SJ, et al; ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356(13):1304-16.
21. Kastelein JJ, van Leuven SI, Burgess L, et al; RADIANCE 1 Investigators. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007;356(16):1620-30.
22. Bots ML, Visseren FL, Evans GW, et al; RADIANCE 2 Investigators. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet. 2007;370(9582):153-60.
23. Stein EA, Stroes ES, Steiner G, et al. Safety and tolerability of dalcetrapib. Am J Cardiol. 2009;104(1):82-91.
24. Lüscher TF, Taddei S, Kaski JC, et al; dal-VESSEL Investigators. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. Eur Heart J. 2012;33(7):857-65.
25. Schwartz GG, Olsson AG, Abt M, et al; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089-99.
26. Tardif JC, Rhéaume E, Lemieux Perreault LP, et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet. 2015;8(2):372-82.
27. Simic B, Hermann M, Shaw SG, et al. Torcetrapib impairs endothelial function in hypertension. Eur Heart J. 2012;33(13):1615-24.
28. Rader DJ, Alexander ET, Weibel GL, Billheimer J, Rothblat GH. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res. 2009;50(suppl):S189-94.
29. Annema W, Tietge UJ. Regulation of reverse cholesterol transport-a comprehensive appraisal of available animal studies. Nutr Metab (Lond). 2012;9(1):25.
30. Briand F, Thieblemont Q, Muzotte E, Sulpice T. 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(1):13-23.
31. Regieli JJ, Jukema JW, Grobbee DE, et al. CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction. Eur Heart J. 2008;29(22):2792-9.
32. Mackey RH, Greenland P, Goff DC Jr, Lloyd-Jones D, Sibley CT, Mora S. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2012;60(6):508-16.
33. Rashedi N, Brennan D, Kastelein JJ, Nissen SE, Nicholls S. Impact of cholesteryl ester transfer protein inhibition on nuclear magnetic resonance derived lipoprotein particle parameters (abstr). Atheroscler Suppl. 2011;12:48.
34. Ballantyne CM, Miller M, Niesor EJ, Burgess T, Kallend D, Stein EA. 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(3):515-21.
35. Camont L, Chapman MJ, Kontush A. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med. 2011;17(10):594-603.
36. Kontush A, Chantepie S, Chapman MJ. Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress. Arterioscler Thromb Vasc Biol. 2003;23(10):1881-8.
37. Ishigami M, Yamashita S, Sakai N, 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(2):257-62.
38. Hirano K, Yamashita S, Nakajima N, et al. Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan. Marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity. Arterioscler Thromb Vasc Biol. 1997;17(6):1053-9.
39. Qi Y, Fan J, Liu J, et al. Cholesterol-overloaded HDL particles are independently associated with progression of carotid atherosclerosis in a cardiovascular disease-free population: a community-based cohort study. J Am Coll Cardiol. 2015;65(4):355-63.
40. Miller NE. CETP inhibitors and cardiovascular disease: time to think again. F1000Res. 2014;3:124.
41. Cannon CP, Shah S, Dansky HM, et al; Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363(25):2406-15.
42. Gotto AM Jr, Kher U, Chatterjee MS, et al; DEFINE Investigators. 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(6):543-9.
43. Millar JS, Reyes-Soffer G, Jumes P, et al. Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects. J Clin Invest. 2015;125(6):2510-22.
44. Kühnast S, van der Tuin SJ, van der Hoorn JW, et al. Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin. Eur Heart J. 2015;36(1):39-48.
45. Cao G, Beyer TP, Zhang Y, et al. Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure. J Lipid Res. 2011;52(12):2169-76.
46. Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306(19):2099-109.
47. Sahebkar A, Simental-Mendía LE, Guerrero-Romero F, Golledge J, Watts GF. Efficacy and safety of evacetrapib for modifying plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Curr Pharm Des. 2015;22(5):595-608.
48. Nicholls SJ, Ruotolo G, Brewer HB, 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(20):2201-10.
49. Rohatgi A, Khera A, Berry JD, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371(25):2383-93.
50. Hovingh GK, Kastelein JJ, van Deventer SJ, 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(9992):452-60.