Effects of Cholesterol Ester Transfer Protein Inhibition on HDL Metabolism

  • Ernst J. Schaefer


Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester from high lipoproteins (HDLs) to triglyceride-rich lipoproteins (TRLs) in exchange for triglyceride. CETP forms a channel or tube between HDL and TRL allowing for this exchange. High levels of HDL cholesterol have been shown to be protective of the development of coronary heart disease (CHD). Patients with CETP deficiency have been reported, who have high levels of HDL cholesterol, and apparently enhanced longevity. Such findings prompted pharmaceutical companies to develop CETP inhibitors, and these agents are very effective in raising HDL cholesterol. Metabolic studies have documented that CETP inhibition in humans delays the fractional catabolism of HDL apolipoproteins (apo) A-I and A-II, while enhancing the fractional catabolism of TRL apoB-100 and apoE. CETP inhibition in humans dramatically increases HDL cholesterol and large HDL particles, while decreasing TRL cholesterol. No significant effects of CETP inhibition of fecal cholesterol excretion were noted. The CETP inhibitor torcetrapib has been tested in clinical trials evaluating carotid intimal medial thickness, coronary atherosclerosis as assessed by intravascular ultrasound, as well clinical endpoints. Excess mortality was observed in a large clinical trial in which torcetrapib and atorvastatin were compared with placebo and atorvastatin in patients with established CHD. Moreover, torcetrapib has been reported to form an unproductive“ complex with HDL and CETP,” as well as increasing aldosterone and blood pressure levels, while decreasing serum potassium concentrations. Other CETP inhibitors, specifically dalcetrapib and ancetrapib, have not been noted to have these latter effects. Clinical trials are going forward with dalcetrapib to determine whether this agent will reduce CHD risk in addition to statin therapy alone in patients with acute coronary syndrome. If clinical trials are positive, then CETP inhibitors will have an important place in the prevention of CHD.


Cholesteryl Ester Coronary Heart Disease Risk Cholesteryl Ester Transfer Protein Cholesteryl Ester Transfer Protein Inhibitor Coronary Heart Disease Risk Reduction 
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  1. 1.
    Qiu X, Mistry A, Ammirati MJ, Chrunyk BA et al (2007) Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat Struct Mol Biol 14:106–113CrossRefPubMedGoogle Scholar
  2. 2.
    Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, Maruhama Y, Mabuchi H, Tall AR (1990) Increased high density lipoprotein levels caused by a common cholesteryl-transfer protein gene mutation. N Engl J Med 323:1234–1238CrossRefPubMedGoogle Scholar
  3. 3.
    Asztalos BF, Horvath KV, Kajinami K, Nartsupha C, Cox CE, Batista M, Schaefer EJ, Inazu A, Mabuchi H (2004) Apolipoprotein composition of HDL in cholesteryl ester transfer protein deficiency. J Lipid Res 45:448–455CrossRefPubMedGoogle Scholar
  4. 4.
    Miwa K, Inazu A, Kawashiri M, Nohara A, Higashikata T, Kobayashi J, Koizumi J, Nakajima K, Nakano T, Niimi M, Mabuchi H, Yamaqishi M (2009) Cholesterol efflux from J774 macrophages and Fu5AH hepatoma cells to serum is preserved in CETP-deficient patients. Clin Chim Acta 402:19–24CrossRefPubMedGoogle Scholar
  5. 5.
    Ordovas JM, Cupples LA, Corella D, Otvos JD, Osgood D, Martinez A, Lahoz C, Coltell O, Wilson PW, Schaefer EJ (2000) Association of cholesteryl ester transfer protein - TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk. The Framingham Study. Arterioscler Thromb Vasc Biol 20:1323–1329PubMedGoogle Scholar
  6. 6.
    Brousseau ME, O’Connor JJ, Ordovas JM, Collins D, Otvos JD, Massov T, McNamara JR, Rubins HB, Robins SJ, Schaefer EJ (2002) Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease endpoints in men with HDL deficiency. Veterans Affairs HDL Cholesterol Intervention Trial. Arterioscler Thromb Vasc Biol 22:1148–1154CrossRefPubMedGoogle Scholar
  7. 7.
    Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR (2003) Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 290:2030–2040CrossRefPubMedGoogle Scholar
  8. 8.
    Hirano K, Yamashita S, Matsuzawa Y (2000) Pros and cons of inhibiting cholesteryl ester transfer protein. Curr Opin Lipidol 11:589–596CrossRefPubMedGoogle Scholar
  9. 9.
    Agerholm-Larsen B, Nordestgaard BG, Steffensen R, Jensen G, Tybjaeg-Hansen A (2000) Elevated HDL cholesterol is a risk factor for ischemic heart disease in white women when caused by a common mutation in the cholesteryl ester transfer protein gene. Circulation 101:1907–1912PubMedGoogle Scholar
  10. 10.
    Regieli JJ, Jukema JW, Grobbee DE, Kastelein JJ, Kuivenhoven JA, Zwinderman AH, van der Graaf Y, Bots ML, Doevendans PA (2008) CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction. Eur Heart J 22:2792–2799CrossRefGoogle Scholar
  11. 11.
    Thompson A, Di Angelantonio E, Sarwar N, Erquo S, Saleheen D, Dullaart RP, Keavney B, Ye Z, Danesh J (2008) Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels and coronary heart disease. JAMA 299:2377–2388CrossRefGoogle Scholar
  12. 12.
    Rittershaus CW, Miller DP, Thomas LJ, Picard MD, Honan CM, Emmett CD et al (2000) Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic atherosclerosis in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol 20:2106–2112PubMedGoogle Scholar
  13. 13.
    Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai A (2000) A cholesteryl ester transfer protein inhibitor attenuated atherosclerosis in rabbits. Nature 406:203–207CrossRefPubMedGoogle Scholar
  14. 14.
    de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, Van Tol A, Kastelein JJ (2002) Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose response study. Circulation 105:2159–2165CrossRefPubMedGoogle Scholar
  15. 15.
    Kuivenhoven JA, de Grooth GJ, Kawamura H, Klerkx AH, Wilhelm F, Trip MD, Kastelein JJ (2005) Effectiveness of of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia. Am J Cardiol 95:1085–1088CrossRefPubMedGoogle Scholar
  16. 16.
    Stein EA, Stroes ES, Steiner G, Buckley BM, Capponoi AM, Burgess T, Niesor EJ, Kallend D, Kastelein JJ (2009) Safety and tolerability of dalcetrapib. Am J Cardiol 104:82–91CrossRefPubMedGoogle Scholar
  17. 17.
    Okamoto H, Miyai A, Sasase T, Furukawa N, Matsushita M, Nakano T, Nakajima K (2006) Cholesteryl ester transfer protein promotes the formation of cholesterol-rich remnant like lipoprotein particles in human plasma. Clin Chim Acta 372:15–21Google Scholar
  18. 18.
    Davidson MH, Ballantyne CM, Chapman MJ (2009) HDL controversy: what have we learned from the clinical trials? Medscape CME June 19Google Scholar
  19. 19.
  20. 20.
    Clark RW, Ruggieri RB, Cunningham D, Bamberger MJ (2006) Description of the torcetrapib series of cholesteryl ester protein inhibitors, including mechanism of action. J Lipid Res 47:537–552CrossRefPubMedGoogle Scholar
  21. 21.
    Brousseau ME, Schaefer EJ, Wolfe ML, Bloedan LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ (2004) Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 350:1505–1515CrossRefPubMedGoogle Scholar
  22. 22.
    Clark RW, Surfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aritey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MF (2004) Raising high-density lipoproteins in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol 24:490–497CrossRefPubMedGoogle Scholar
  23. 23.
    Davidson MH, McKenney JM, Shear CL, Revkin JH (2006) Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below average high density lipoprotein cholesterol levels. J Am Coll Cardiol 48:1782–1790CrossRefPubMedGoogle Scholar
  24. 24.
    Brousseau ME, Diffenderfer MR, Millar JS, Nartsupha C, Asztalos BF, Welty FK, Wolfe ML, Rudling M, Bjorkham I, Angelin B, Mancuso JP, Digenio AG, Rader DJ, Schaefer EJ (2005) Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol 25:1057–1064CrossRefPubMedGoogle Scholar
  25. 25.
    Brousseau ME, Millar JS, Diffenderfer MR, Nartsupha C, Asztalos BF, Wolfe ML, Mancuso JP, Digenio AG, Rader DJ, Schaefer EJ (2009) Effects of cholesteryl ester transfer protein inhibition on apolipoprotein (apo) A-II-containing HDL subspecies and apoA-II metabolism. J Lipid Res 50:1456–1462CrossRefPubMedGoogle Scholar
  26. 26.
    Kee P, Cantazza D, Rye KA, Barrett PH, Morehouse LA, Barter PJ (2006) Effect of inhibiting cholesteryl ester protein on the kinetics of high-density lipoprotein cholesteryl ester transport in plasma. In vivo studies in rabbits. Arterioscler Vasc Thromb Biol 26:884–890CrossRefGoogle Scholar
  27. 27.
    Millar JS, Brousseau ME, Diffenderfer MR, Barrett PH, Welty FK, Faruqi A, Wolfe ML, Nartsupha C, Digenio AG, Mancuso JP, Dolnokowski GG, Schaefer EJ, Rader DJ (2006) Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism. Arterioscler Thromb Vasc Biol 26:1350–1356CrossRefPubMedGoogle Scholar
  28. 28.
    Millar JS, Brousseau ME, Diffenderfer MR, Barrett PH, Welty FK, Cohn JS, Wilson A, Wolfe ME, Schaefer PM, Nartsupha C, Schaefer PM, Digenio AG, Mancuso JP, Dolnikowski GG, Schaefer EJ, Rader DJ (2008) Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism. J Lipid Res 49:543–549CrossRefPubMedGoogle Scholar
  29. 29.
    Guerin M, Le Goff W, Duchene E, Julia Z, Nguyen T, Thuren T, Shear CL, Chapman MJ (2008) Inhibition of CETP by torcetrapib attenuates the atherogenicity of postprandial TG-rich lipoproteins in type IIB hyperlipidemia. Arterioscler Thromb Vasc Biol 28:148–154CrossRefPubMedGoogle Scholar
  30. 30.
    Catalano G, Julia Z, Friedal E, Vedie B, Fiurnier N, Le Goff W, Chapman MJ (2009) Torcetrapib differentially modulates the biological activities of HDL2 and HDL3 particles in the reverse cholesterol transport pathway. Arterioscler Thromb Vasc Biol 29:268–275CrossRefPubMedGoogle Scholar
  31. 31.
    Masson D, Jiang XC, Lagrost L, Tall A (2009) The role of plasma lipid transfer proteins in lipoprotein metabolism and atherogenesis. J Lipid Res 50:S201-S206CrossRefPubMedGoogle Scholar
  32. 32.
    Rader DJ, Alexander ET, Weibel GL, Bilheimer J, Rothblat GH (2009) The role of reverse cholesterol transport in animals and humans in relationship to atherosclerosis. J Lipid Res 50:S189-S194CrossRefPubMedGoogle Scholar
  33. 33.
    Morehouse LA, Sugarman ED, Bourassa PA, Sand TM, Zimetti F, Gao F, Rothblat GH, Milici AJ (2007) Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J Lipid Res 48:1263–1272CrossRefPubMedGoogle Scholar
  34. 34.
    Hu X, Dietz JD, Xia C, Knight DR, Loging WT, Smith AH, Yuan H, Perry DA, Keider J (2009) Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology 150:2211–2219CrossRefPubMedGoogle Scholar
  35. 35.
    Barter PJ, Caulfield M, Erisksson M, Grundy SM, Kastelein JJ, Komajda M et al (2007) Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357:2109–2122CrossRefPubMedGoogle Scholar
  36. 36.
    Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM; ILLUSTRATE Investigators (2007) Effects of torcetrapib on progression of coronary atherosclerosis. N Engl J Med 356:1304–1316Google Scholar
  37. 37.
    Nicholls SJ, Tuzcu EM, Brennan DM, Tardif JC, Nissen SE (2008) Cholesteryl ester transfer protein inhibition, high density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atheroscle­rosis by CETP Inhibition and HDL Elevation). Circulation 118:2506–2514CrossRefPubMedGoogle Scholar
  38. 38.
    Kastelein JJ, van Leuven SI, Burgess L, Evan GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Bots ML; RADIANCE 1 Investigators (2007) Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Eng J Med 356:1620–1630Google Scholar
  39. 39.
    Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, Shear CL, Duggan WT, Vicari RM, Grobbee DE, Kastelein JJ; RADIANCE 2 Investigators (2007) Torcetrapib and carotid intima-media thickness in mixed dyslipidemia (RADIANCE 2 study): a randomized, double-blind trial. Lancet 370:107–108Google Scholar
  40. 40.
    Krishna R, Bergman AJ, Jin B, Garg A, Roadcap B, Chiou R, Dru J, Cote J, Laethem T, Wang RW, Didolkar V, Vets E, Gottesdiener K, Wagner J (2009) Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers. J Clin Pharm 49:80–87CrossRefGoogle Scholar
  41. 41.
    Krishna R, Anderson MS, Bergman AJ, Jin B, Fallon M, Cote J, Rosko K, Chavez-Eng C, Lutz R, Bloomfield DM, Guiterrez M, Doherty J, Biebersdorf F, Chodakewitz J, Gottesdiener KM, Wagner J (2007) Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidemia and on 24-h ambulatory blood pressure in healthy individuals:two double-blinded randomized placebo-controlled phase 1 trials. Lancet 370:1907CrossRefPubMedGoogle Scholar
  42. 42.
    Bloomfield D, Carlson GL, Sapre A, Tribble D, McKenney JM, Littlejohn TW 3rd, Sisk CM, Mitchel Y, Pasternak RC (2009) Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J 157:352–360CrossRefPubMedGoogle Scholar
  43. 43.
    Jenner JL, Seman LJ, Millar JS, Lamon-Fava S, Welty FK, Dolnikowski GG, Marcovina SM, Lichtenstein AH, Barrett PHR, deLuca C, Schaefer EJ (2005) The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein(a) in human beings. Metabolism 54:361–369CrossRefPubMedGoogle Scholar
  44. 44.
    Dumont L, Gauthier T, de Barros JP, Laplanche H, Blache D, Ducuroy P, Fruchart J, Fruchart JC, Gambert P, Masson D, Lagrost L (2005) Molecular mechanism of the blockade of plasma cholesteryl ester protein by its physiologic inhibitor apolipoprotein CI. J Biol Chem 280:38108–38116CrossRefPubMedGoogle Scholar
  45. 45.
    Cheema SK, Agarwal-Mawal A, Murray CM, Tucker S (2005) Lack of stimulation of cholesteryl ester transfer protein by cholesterol in the presence of a high fat diet. J Lipid Res 46:2356–2366CrossRefPubMedGoogle Scholar
  46. 46.
    Asztalos BF, Cupples LA, Demissie S, Horvath K, Cox CE, Batista MC, Schaefer EJ (2004) High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants in the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 24:2181–2187CrossRefPubMedGoogle Scholar
  47. 47.
    Asztalos BF, Collins D, Cupples LA, Demissie S, Horvath KV, Bloomfield HE, Robins SJ, Schaefer EJ (2005) Value of high density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol 25:2185–2191CrossRefPubMedGoogle Scholar
  48. 48.
    Asztalos BF, Batista M, Horvath KV, Cox CE, Dallal GE, Morse JS, Brown GB, Schaefer EJ (2003) Change in alpha 1 HDL concentration predicts progression in coronary artery stenosis. Arterioscler Thromb Vasc Biol 23:847–852CrossRefPubMedGoogle Scholar
  49. 49.
    McNamara JR, Shah PK, Nakajima K, Cupples LA, Wilson PWF, Ordovas JM, Schaefer EJ (2001) Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: results from the Framingham Heart Study. Atherosclerosis 154:229–236CrossRefPubMedGoogle Scholar
  50. 50.
    Zhao L, Jin W, Rader D, Packard C, Feuerstein G (2009) A translational medicine perspective of the development of torcetrapib:does the failure of torcetrapib development cast a shadow on the future development of lipid modifying agents, HDL elevation strategy, or CETP as a viable molecular target for atherosclerosis? A case study of the use of biomarkers and translational medicine in atherosclerosis drug discovery and development. Biochem Pharmacol 78:315–325CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Lipid Metabolism LaboratoryTufts UniversityBostonUSA

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