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Do Cholesteryl Ester Transfer Protein Inhibitors Have a Role in the Treatment of Cardiovascular Disease?

  • Stephen J. NichollsEmail author
  • Adam J. Nelson
Leading Article
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Abstract

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism and has presented an attractive target for drug development, primarily resting on the hope that CETP inhibition would reduce cardiovascular events through its ability to increase levels of high-density lipoprotein cholesterol (HDL-C). However, clinical development of CETP inhibitors has proven disappointing, with a spectrum of results spanning from evidence of harm, to futility, to only modest benefit in large-scale cardiovascular outcomes trials. A number of additional insights from genomic studies have suggested potential benefits from these agents in specific clinical settings. We review the current state of CETP inhibitors as an approach to targeting cardiovascular risk.

Notes

Compliance with Ethical Standards

Funding

No external funds were used to prepare this manuscript.

Conflict of interest

SJN has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx, and Sanofi-Regeneron and is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron and Novo Nordisk. AJN has no conflicts of interest that are directly relevant to the content of this article.

References

  1. 1.
    Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005;46(7):1225–8.CrossRefGoogle Scholar
  2. 2.
    Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis. 1996;124(Suppl):11–20.CrossRefGoogle Scholar
  3. 3.
    Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79(1):8–15.CrossRefGoogle Scholar
  4. 4.
    Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62(5):707–14.CrossRefGoogle Scholar
  5. 5.
    Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004;95(8):764–72.CrossRefGoogle Scholar
  6. 6.
    Barter P, Rye KA. Cholesteryl ester transfer protein: its role in plasma lipid transport. Clin Exp Pharmacol Physiol. 1994;21(9):663–72.CrossRefGoogle Scholar
  7. 7.
    Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990;323(18):1234–8.CrossRefGoogle Scholar
  8. 8.
    de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002;105(18):2159–65.CrossRefGoogle Scholar
  9. 9.
    Vasan RS, Pencina MJ, Robins SJ, Zachariah JP, Kaur G, D’Agostino RB, et al. Association of circulating cholesteryl ester transfer protein activity with incidence of cardiovascular disease in the community. Circulation. 2009;120(24):2414–20.CrossRefGoogle Scholar
  10. 10.
    Johannsen TH, Frikke-Schmidt R, Schou J, Nordestgaard BG, Tybjaerg-Hansen A. Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects. J Am Coll Cardiol. 2012;60(20):2041–8.CrossRefGoogle Scholar
  11. 11.
    Morehouse LA, Sugarman ED, Bourassa PA, Sand TM, Zimetti F, Gao F, 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.CrossRefGoogle Scholar
  12. 12.
    Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000;406(6792):203–7.CrossRefGoogle Scholar
  13. 13.
    Rittershaus CW, Miller DP, Thomas LJ, Picard MD, Honan CM, Emmett CD, et al. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol. 2000;20(9):2106–12.CrossRefGoogle Scholar
  14. 14.
    Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, 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.CrossRefGoogle Scholar
  15. 15.
    Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004;350(15):1505–15.CrossRefGoogle Scholar
  16. 16.
    Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109–22.CrossRefGoogle Scholar
  17. 17.
    Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet. 2007;370(9582):153–60.CrossRefGoogle Scholar
  18. 18.
    Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007;356(16):1620–30.CrossRefGoogle Scholar
  19. 19.
    Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356(13):1304–16.CrossRefGoogle Scholar
  20. 20.
    Yvan-Charvet L, Matsuura F, Wang N, Bamberger MJ, Nguyen T, Rinninger F, et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol. 2007;27(5):1132–8.CrossRefGoogle Scholar
  21. 21.
    Nicholls SJ, Tuzcu EM, Brennan DM, Tardif JC, Nissen SE. 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(24):2506–14.CrossRefGoogle Scholar
  22. 22.
    Hermann M, Ruschitzka FT. The hypertension peril: lessons from CETP inhibitors. Curr Hypertens Rep. 2009;11(1):76–80.CrossRefGoogle Scholar
  23. 23.
    Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey AM, Ehrhart J, 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(7):1465–73.CrossRefGoogle Scholar
  24. 24.
    Simic B, Hermann M, Shaw SG, Bigler L, Stalder U, Dorries C, et al. Torcetrapib impairs endothelial function in hypertension. Eur Heart J. 2012;33(13):1615–24.CrossRefGoogle Scholar
  25. 25.
    Luscher TF, Taddei S, Kaski JC, Jukema JW, Kallend D, Munzel T, et al. 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.CrossRefGoogle Scholar
  26. 26.
    Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011;378(9802):1547–59.CrossRefGoogle Scholar
  27. 27.
    Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–99.CrossRefGoogle Scholar
  28. 28.
    Tardif JC, Rheaume E, Lemieux Perreault LP, Gregoire JC, Feroz Zada Y, Asselin G, et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet. 2015;8(2):372–82.CrossRefGoogle Scholar
  29. 29.
    Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, 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.CrossRefGoogle Scholar
  30. 30.
    Lincoff AM, Nicholls SJ, Riesmeyer JS, Barter PJ, Brewer HB, Fox KAA, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376(20):1933–42.CrossRefGoogle Scholar
  31. 31.
    Nissen SE, Pillai SG, Nicholls SJ, Wolski K, Riesmeyer JS, Weerakkody GJ, et al. ADCY9 genetic variants and cardiovascular outcomes with evacetrapib in patients with high-risk vascular disease: a nested case-control study. JAMA Cardiol. 2018;3(5):401–8.CrossRefGoogle Scholar
  32. 32.
    Bloomfield D, Carlson GL, Sapre A, Tribble D, McKenney JM, Littlejohn TW 3rd, 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(2):352–360 e2.CrossRefGoogle Scholar
  33. 33.
    Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363(25):2406–15.CrossRefGoogle Scholar
  34. 34.
    Group HTRC, Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377(13):1217–27.CrossRefGoogle Scholar
  35. 35.
    Gotto AM Jr, Kher U, Chatterjee MS, Liu Y, Li XS, Vaidya S, 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(6):543–9.CrossRefGoogle Scholar
  36. 36.
    Ford J, Lawson M, Fowler D, Maruyama N, Mito S, Tomiyasu K, et al. Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Br J Clin Pharmacol. 2014;78(3):498–508.CrossRefGoogle Scholar
  37. 37.
    Hovingh GK, Kastelein JJ, van Deventer SJ, Round P, Ford J, Saleheen D, 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.CrossRefGoogle Scholar
  38. 38.
    Hu X, Dietz JD, Xia C, Knight DR, Loging WT, Smith AH, et al. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009;150(5):2211–9.CrossRefGoogle Scholar
  39. 39.
    Clerc RG, Stauffer A, Weibel F, Hainaut E, Perez A, Hoflack JC, et al. Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. J Hypertens. 2010;28(8):1676–86.CrossRefGoogle Scholar
  40. 40.
    Brousseau ME, O’Connor JJ Jr, Ordovas JM, Collins D, Otvos JD, Massov T, et al. Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial. Arterioscler Thromb Vasc Biol. 2002;22(7):1148–54.CrossRefGoogle Scholar
  41. 41.
    Ridker PM, Pare G, Parker AN, Zee RY, Miletich JP, Chasman DI. Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: genomewide analysis among 18,245 initially healthy women from the Women’s Genome Health Study. Circ Cardiovasc Genet. 2009;2(1):26–33.CrossRefGoogle Scholar
  42. 42.
    Thompson A, Di Angelantonio E, Sarwar N, Erqou S, Saleheen D, Dullaart RP, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA. 2008;299(23):2777–88.CrossRefGoogle Scholar
  43. 43.
    Ference BA, Kastelein JJP, Ginsberg HN, Chapman MJ, Nicholls SJ, Ray KK, et al. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 2017;318(10):947–56.CrossRefGoogle Scholar
  44. 44.
    Nicholls SJ. CETP-inhibition and HDL-cholesterol: a story of CV risk or CV benefit, or both. Clin Pharmacol Ther. 2018;104(2):297–300.CrossRefGoogle Scholar
  45. 45.
    Masson W, Lobo M, Siniawski D, Huerin M, Molinero G, Valero R, et al. Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk. Diabetes Metab. 2018;44(6):508–18.CrossRefGoogle Scholar
  46. 46.
    Barter PJ, Rye KA, Tardif JC, Waters DD, Boekholdt SM, Breazna A, 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(5):555–62.CrossRefGoogle Scholar
  47. 47.
    Barter PJ, Cochran BJ, Rye KA. CETP inhibition, statins and diabetes. Atherosclerosis. 2018;278:143–6.CrossRefGoogle Scholar
  48. 48.
    von Eckardstein A, Widmann C. High-density lipoprotein, beta cells, and diabetes. Cardiovasc Res. 2014;103(3):384–94.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.South Australian Health and Medical Research InstituteAdelaideAustralia
  2. 2.Monash Cardiovascular Research CentreMonash UniversityMelbourneAustralia

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