Posts Tagged ‘Anacetrapib’

Curator: Aviva Lev-Ari, PhD, RN


UPDATED on 7/29/2018


HDL-C: Is It Time to Stop Calling It the ‘Good’ Cholesterol? – Medscape – Jul 27, 2018.


In Eli Lilly’s Pipeline: DISCONTINUING Evacetrapib, a CETP inhibitor that’s meant to boost HDL

Reporter: Aviva Lev-Ari, PhD, RN



On April 3, 2012 we published

Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

ACP-501, a recombinant human lecithin-cholesterol acyltransferase (LCAT) enzyme.

LCAT, an enzyme in the bloodstream, is a key component in the reverse cholesterol transport (RCT) system, which is thought to play a major role in driving the removal of cholesterol from the body and may be critical in the management of high-density lipoprotein (HDL) cholesterol levels.  The LCAT enzyme could also play a role in a rare, hereditary disorder called familial LCAT deficiency (FLD) in which the LCAT enzyme is absent.


On April 4, 2013, the next day, a new study was published on a novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects was published on Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953).

Writer’s VIEWS:

    • AstraZeneca acquisition of AlphaCore represents its market entry into the CETP inhibitor segment via an acquisition where the company did not have presence or inhouse research. The results of the second study will position Merck at a superior position upon completion of Phase III Clinical Trials for Anacetrapib
    • If Biologics will help increase HDL in wide market penetration, the market share of Statins will be negatively impacted. Patent expiration and generic market availability of Statin erode future profits
    • Anacetrapib in in Phase III clinical Trial, if successfully completed — will be the FIRST biologics to use CETP inhibition biology of lipid metabolism in the quest to fight atherosclerosis by improving CVD outcomes
    • A connection between this two events and cites in Disclosure, AstraZeneca, Merck, supporting the research of Christopher P Cannon on the study on Anacetrapib.
    • Full Article PDF file was published in Research Reports in Clinical Cardiology, one of the Journals on Beall’s list publisher, where scientists pay to have the article been published, Dove Press, on its Web site says, “There are no limits on the number or size of the papers we can publish.” See reference for Beall’s list publishers http://www.nytimes.com/2013/04/08/health/for-scientists-an-exploding-world-of-pseudo-academia.html?pagewanted=1&_r=0&emc=eta1

Study Goals:

  • testing the hypothesis that CETP inhibition may reduce atherosclerotic outcomes. 
  • answer important questions regarding the role of CETP in the biology of lipid metabolism and atherosclerosis.

Research Reports in Clinical Cardiology, 4 April 2013 Volume 2013:4 Pages 39 – 53

Dylan L Steen,1 Amit V Khera,2 Christopher P Cannon1

1TIMI Study Group, Cardiovascular Division, 2Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA


Dr Cannon is a member of the advisory boards of and has received grant support from Alnylam, Bristol-Myers Squibb, Pfizer, and CSL Behring; has received grant support from Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda; and is a clinical advisor to Automated Medical Systems. All other authors have reported that they have no relationships relevant to the contents of this paper.

Abstract: Despite major advances in cardiovascular care in recent decades, atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Statins have been shown to reduce cardiovascular events by 25%–40% in a dose-dependent fashion; yet additional therapies are needed to reduce vascular disease progression and acute thrombotic events. In addition to low-density lipoprotein cholesterol (LDL-C) reduction, other lipid risk factors, such as low high-density lipoprotein cholesterol (HDL-C), have created interest as therapeutic targets to lower cardiovascular risk. However, the absence of compelling data for incremental benefit of non-LDL-centric therapies in the statin era has limited their clinical use. A novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects. While in vitro and animal data for CETP inhibition have been encouraging, the initial enthusiasm for the class has been tempered by the failure of two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III trials to reduce cardiovascular outcomes. Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953).

Keywords: anacetrapib, cholesteryl ester transfer protein, cholesteryl ester transfer protein inhibitor, atherosclerosis

  • Niacin, which augments HDL-C by 20%–25%, recently failed to lower atherosclerotic events in both the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH)6 and Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials.7,8
  • Lp(a) lowering has not yet been evaluated in randomized controlled trials, but observational and genetic (including Mendelian randomization) analyses have demonstrated an independent association of increased Lp(a) levels with increased CV events, suggesting Lp(a) lowering may confer benefit.9
  • surprising failure of the first two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III outcomes trials has somewhat tempered this initial excitement and forced a re-evaluation of the complex effects of CETP inhibition on lipid metabolism and vascular biology.
  • Anacetrapib results in near-complete CETP inhibition with more pronounced lipid effects than its predecessors and is currently in a Phase III study for secondary prevention of coronary events. If successful it is likely that anacetrapib will also be considered for statin-intolerant patients and for primary prevention in patients who require LDL-C lowering beyond statin monotherapy
  • Human CETP is a 476-residue, 74 kDa, hydrophobic glycoprotein primarily secreted by the liver and adipose tissue.13 CETP was first cloned in 1987.14 The structure of CETP allows formation of a tunnel with the opening on one end interacting with HDL and the other with a very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), or LDL particle. The hydrophobic central cavity of this tunnel is large enough to allow transfer of neutral lipids (eg, cholesteryl esters [CEs], triglycerides [TGs]) from donor to acceptor particles, but conformational changes may occur to accommodate larger lipoprotein particles. The concave surface of CETP matches the curvature of the HDL particles to which it is primarily bound in the bloodstream.15,16
  • The overall effect of CETP is a net transfer of CE from HDL to these apolipoprotein B (apoB)-containing particles and TG to HDL and LDL
  • An important driver of the transfer of CE from HDL to apoB-containing particles is the production of CE from free cholesterol within HDL by lecithin acetyltransferase (LCAT).17

    The role of CETP in reverse cholesterol transport.

    Beginning in the peripheral tissues, free cholesterol is predominantly taken up by small “immature” HDL particles (eg, pre-β-HDL) via the ABCA1 transporter. Alternatively, it can be taken up by larger “mature” HDL particles (eg, HDL2) via the ABCG1 transporter. LCAT converts free cholesterol into cholesteryl ester, which is then shuttled to apoB-lipoproteins (eg, LDL, VLDL) in exchange for triglycerides. Only a minority of cholesteryl ester is delivered directly to the liver by HDL via the SR-BI; the majority is delivered indirectly to the liver by apoB-lipoproteins via the LDL recepter.

    Abbreviations: CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; LCAT, lecithin acetyltransferase; apoB, apolipoprotein B; LDL, low-density lipoprotein; VLDL, very low density lipoprotein; SR-BI, scavenger receptor-BI; FC, free cholesterol; CE, cholesteryl ester.

  • One of the interesting questions in CETP deficiency is whether the HDL particles produced by potent CETP inhibition are functional. Regardless of whether reverse cholesterol transport is increased, the initial steps of cholesterol efflux from foam cells may be one of the key anti-atherogenic functions of HDL.5
  • This increased efflux is related to the very high content of LCAT and apoE in these large HDL particles, presumably driving net cholesterol efflux by promoting cholesterol esterification.36
  • effect of CETP deficiency on liver uptake of cholesteryl ester, an important downstream step in a reverse cholesterol transport. These studies suggest that there may be increased CE uptake via SR-BI as well as through a high affinity of large apoE-rich HDL for LDL receptors.20
  • meta-analysis established that three CETP genotypes were not only associated with decreased CETP activity and increased HDL but also with a lower risk of myocardial infarction (MI). For example, for each allele inherited, individuals with the TaqIB polymorphism had lower mean CETP activity (−8.6%), higher mean HDL-C (4.5%), higher mean apoA-I (2.4%), and an odds ratio for coronary disease of 0.95 (95% confidence intervals [CI], 0.92, 0.99). Similar associations were found for the other two CETP genotypes.40
  • Subsequent studies have confirmed that genetic variants leading to reduced CETP activity and its corresponding anti-atherogenic lipid profile are associated with reduced atherosclerotic outcomes.41–43
  • In ILLUSTRATE, an inverse association between HDL-C achieved and the primary endpoint of atheroma volume (r = −0.17, P , 0.001) was found. In addition, the highest quartile of HDL-C achieved (.86 mg/dL) demonstrated atheroma regression, suggesting that there may be a “threshold effect” to HDL-C elevation.68
  • Other CETP inhibitors:

was developed by Hoffmann–La Roche until May 2012. It did not raise blood pressure and did raise HDL, but it showed no clinically meaningful efficacy.


is under development by Eli Lilly & Company.
was developed by Pfizer until December 2006 but caused unacceptable increases in blood pressure and had net cardiovascular detriment.
Anacetrapib At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New York, Oct 4-7, 2007), Merck reported on a Phase IIb study. The eight week study reported dosage correlated reduction in LDL-C and increases in HDL-C levels with no corresponding increases in blood pressure in any cohort. The increase in HDL was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133 percent at doses of 10 mg, 40 mg, 150 mg and 300 mg. Merck performed a dose-ranging study of anacetrapib, with the results presented in 2009.


Anacetrapib is a 3,5-bis-trifluoromethyl-benzene derivative with similar binding properties to CETP as torcetrapib. The compound was developed when it was found that a substitution modification of the oxazolidinone ring increased its potency for CETP inhibition in a transgenic mouse model.85 In terms of its pharmacokinetics and pharmacodynamics, anacetrapib is rapidly absorbed with a time-to-peak plasma concentration of about 4 hours. The oral bioavailability of anacetrapib is poor, with only about 20% being absorbed; however at this exposure, LDL-C is reduced up to 40% and HDL-C increased up to 140%. It is recommended that anacetrapib be taken with food (ie, low-fat diet) to increase drug exposure (and efficacy) as well as compliance.86

Anacetrapib is highly protein bound (eg, CETP) in the plasma (.99.5%). It is cleared by oxidative metabolism via Cytochrome P450 3A4 (CYP3A4) with excretion of the metabolites via the biliary/fecal route. Only a trace amount is eliminated by urinary excretion.87 Importantly, while anacetrapib is a sensitive CYP3A4 substrate, anacetrapib neither inhibits nor induces CYP3A4 activity. No meaningful interactions have been found between anacetrapib and simvastatin, digoxin, or warfarin.86 Anacetrapib in part to its redistribution to adipose tissue has a long terminal half-life.88

In terms of safety endpoints, anacetrapib demonstrated no increase in side effects (including myalgia), drug-related adverse effects, adverse events leading to drug discontinuation, or other important safety endpoints, such as BP, electrolyte, aldosterone, creatinine kinase, or transaminase levels. A very small increase in C-reactive protein of undetermined significance was seen with anacetrapib, which notably was also reported with torcetrapib and dalcetrapib in their Phase III studies. It is unknown whether this is a class effect as the small sample size in the evacetrapib Phase II study limits evaluation of small C-reactive protein changes.

It is expected that the REVEAL (the Phase III) population will also have lower starting LDL-C levels, both because statin-intolerant subjects will not be enrolled and because of more stringent lipid entry criteria. The final major difference is that the primary endpoint in REVEAL is focused on coronary events, while ACCELERATE has a broader primary endpoint. A broader primary endpoint along with a slightly higher risk population will allow for a shorter follow-up duration and much smaller sample size in ACCELERATE.


  • CETP remains a valid target and that the lipid changes resulting from its inhibition may be protective. The biology of CETP inhibition is complex, and questions remain regarding which lipid changes (eg, reductions in LDL and Lp(a), increases in HDL) are most likely to be important and whether there are still unknown effects that may negate any overall clinical benefit.
  • if potent CETP inhibition is found to be beneficial, it is still unclear whether this effect will be homogeneous or vary based on individual metabolism.
  • anacetrapib-induced HDL (especially the apoE-rich HDL2 particles) may have an enhanced ability for reverse cholesterol transport without any known adverse effects. Importantly, if a threshold effect for HDL-C augmentation exists, the vast majority of patients taking anacetrapib would be expected to cross it.
  • Despite a difficult beginning for the class of CETP inhibitors, anacetrapib and evacetrapib hold promise as future therapies for patients with atherosclerosis

1. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, 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. 2010;376(9753):1670–1681.

2. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–1504.

3. Steinberg D. The rationale for initiating treatment of hypercholesterolemia in young adulthood. Curr Atheroscler Rep. 2013;15(1):296.

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):707–714.

5. Vergeer M, Holleboom AG, Kastelein JJ, Kuivenhoven JA. The HDL hypothesis: Does high-density lipoprotein protect from atherosclerosis? J Lipid Res. 2010;51(8):2058–2073.

6. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–2267

7. Armitage J, Baigent C, Chen Z, Landray M. Treatment of HDL to reduce the incidence of vascular events HPS2-THRIVE. Available from: http://clinicaltrials.gov/ct2/show/NCT00461630. Updated 2010. Accessed February 1, 2012.

8. Merck announces HPS2-THRIVE study of TREDAPTIVE (extended-release Niacin/Laropriprant) did not achieve primary endpoint. Available from: http://www.mercknewsroom.com/press-release/prescription-medicine-news/merck-announces-hps2-thrive-study-tredaptive-extended-relea. Updated 2012. Accessed December 31, 2012.

9. Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: A rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol. 2012;60(8):716–721.

10. Brown ML, Inazu A, Hesler CB, et al. Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins. Nature. 1989;342(6248):448–451.

11. 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):1234–1238.

12. Ohtani R, Inazu A, Noji Y, et al. Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects. Clin Chim Acta. 2012;413(5–6):537–543.

13. Chapman MJ, Le Goff W, Guerin M, Kontush A. Cholesteryl ester transfer protein: At the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. Eur Heart J. 2010;31(2):149–164.

14. Drayna D, Jarnagin AS, McLean J, et al. Cloning and sequencing of human cholesteryl ester transfer protein cDNA. Nature. 1987;327(6123): 632–634.

15. Qiu X, Mistry A, Ammirati MJ, et al. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat Struct Mol Biol. 2007;14(2):106–113.

16. Zhang L, Yan F, Zhang S, et al. Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein. Nat Chem Biol. 2012;8(4):342–349.

17. Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: A novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23(2):160–167.

18. Niesor EJ. Different effects of compounds decreasing cholesteryl ester transfer protein activity on lipoprotein metabolism. Curr Opin Lipidol. 2011;22(4):288–295.

19. Arai T, Tsukada T, Murase T, Matsumoto K. Particle size analysis of high density lipoproteins in patients with genetic cholesteryl ester transfer protein deficiency. Clin Chim Acta. 2000;301(1–2):103–117.

20. Yamashita S, Sprecher DL, Sakai N, Matsuzawa Y, Tarui S, Hui DY. Accumulation of apolipoprotein E-rich high density lipoproteins in hyperalphalipoproteinemic human subjects with plasma cholesteryl ester transfer protein deficiency. J Clin Invest. 1990;86(3):688–695.

21. Ikewaki K, Nishiwaki M, Sakamoto T, et al. Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency. J Clin Invest. 1995;96(3):1573–1581.

22. Millar JS, Brousseau ME, Diffenderfer MR, et al. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipo­protein B100 metabolism in humans. Arterioscler Thromb Vasc Biol. 2006;26(6):1350–1356.

23. Rosenson RS, Brewer HB Jr, Davidson WS, et al. Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport. Circulation. 2012;125(15):1905–1919.

24. Foger B, Chase M, Amar MJ, et al. Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J Biol Chem. 1999;274(52):36912–36920.

25. Hayek T, Masucci–Magoulas L, Jiang X, et al. Decreased early athero­sclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. J Clin Invest. 1995;96(4):2071–2074.

26. MacLean PS, Bower JF, Vadlamudi S, et al. Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice. Arterioscler Thromb Vasc Biol. 2003;23(8):1412–1415.

27. Marotti KR, Castle CK, Boyle TP, Lin AH, Murray RW, Melchior GW. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature. 1993;364(6432):73–75.

28. Plump AS, Masucci–Magoulas L, Bruce C, Bisgaier CL, Breslow JL, Tall AR. Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler Thromb Vasc Biol. 1999;19(4):1105–1110.

29. Westerterp M, van der Hoogt CC, de Haan W, et al. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggra­vates atherosclerosis in APOE*3-leiden mice. Arterioscler Thromb Vasc Biol. 2006;26(11):2552–2559.

30. Tanigawa H, Billheimer JT, Tohyama J, Zhang Y, Rothblat G, Rader DJ. Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport. Circulation. 2007;116(11): 1267–1273.

31. Schwartz CC, VandenBroek JM, Cooper PS. Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J Lipid Res. 2004;45(9):1594–1607.

32. Khera AV, Wolfe ML, Cannon CP, Qin J, Rader DJ. On-statin choles­teryl ester transfer protein mass and risk of recurrent coronary events (from the pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 [PROVE IT-TIMI 22] study). Am J Cardiol. 2010;106(4):451–456.

33. Evans GF, Bensch WR, Apelgren LD, et al. Inhibition of cholesteryl ester transfer protein in normocholesterolemic and hypercholester­olemic hamsters: Effects on HDL subspecies, quantity, and apolipo­protein distribution. J Lipid Res. 1994;35(9):1634–1645.

34. Rittershaus CW, Miller DP, Thomas LJ, 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):2106–2112.

35. Sugano M, Makino N, Sawada S, et al. Effect of antisense oligonucle­otides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits. J Biol Chem. 1998;273(9): 5033–5036.

36. Matsuura F, Wang N, Chen W, Jiang XC, Tall AR. HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway. J Clin Invest. 2006;116(5):1435–1442.

37. Curb JD, Abbott RD, Rodriguez BL, 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(5): 948–953.

38. Moriyama Y, Okamura T, Inazu A, et al. A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev Med. 1998;27(5 Pt 1): 659–667.

39. Zhong S, Sharp DS, Grove JS, 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(12): 2917–2923.

40. Thompson A, Di Angelantonio E, Sarwar N, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activ­ity, lipid levels, and coronary risk. JAMA. 2008;299(23):2777–2788.

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.

42. Voight BF, Peloso GM, Orho–Melander M, et al. Plasma HDL cho­lesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet. 2012;380(9841):572–580.

43. 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):2041–2048.

submit your manuscript | http://www.dovepress.com Dovepress Dovepress 51 Anacetrapib for coronary heart disease Research Reports in Clinical Cardiology 2013:4

44. Clark RW, Ruggeri RB, Cunningham D, Bamberger MJ. Descrip­tion of the torcetrapib series of cholesteryl ester transfer pro­tein inhibitors, including mechanism of action. J Lipid Res. 2006;47(3):537–552.

45. Ranalletta M, Bierilo KK, Chen Y, et al. Biochemical characterization of cholesteryl ester transfer protein inhibitors. J Lipid Res. 2010;51(9): 2739–2752.

46. 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):1505–1515.

47. 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):490–497.

48. McKenney JM, Davidson MH, Shear CL, Revkin JH. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin. J Am Coll Cardiol. 2006;48(9): 1782–1790.

49. 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): 1263–1272.

50. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21): 2109–2122.

51. Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007;356(16):1620–1630.

52. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADI­ANCE 2 study): A randomised, double-blind trial. Lancet. 2007;370(9582):153–160.

53. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356(13): 1304–1316.

54. Hu X, Dietz JD, Xia C, 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):2211–2219.

55. Forrest MJ, Bloomfield D, Briscoe RJ, 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):1465–1473.

56. DePasquale M, Cadelina G, Knight D, et al. Mechanistic studies of blood pressure in rats treated with a series of cholesteryl ester transfer protein inhibitors. Drug Develop Res. 2009;70(10.1002/ddr.20282):35.

57. Clerc RG, Stauffer A, Weibel F, 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): 1676–1686.

58. Sofat R, Hingorani AD, Smeeth L, et al. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation. 2010;121(1): 52–62.

59. Blasi E, Bamberger M, Knight D, et al. Effects of CP-532,623 and torcetrapib, cholesteryl ester transfer protein inhibitors, on arterial blood pressure. J Cardiovasc Pharmacol. 2009;53(6):507–516.

60. Connelly MA, Parry TJ, Giardino EC, et al. Torcetrapib produces endothelial dysfunction independent of cholesteryl ester transfer protein inhibition. J Cardiovasc Pharmacol. 2010;55(5):459–468.

61. Simic B, Hermann M, Shaw SG, et al. Torcetrapib impairs endothelial function in hypertension. Eur Heart J. 2012;33(13):1615–1624.

62. Westerterp M, Koetsveld J, Tall AR. Cholesteryl ester transfer protein inhibition: A dysfunctional endothelium. J Cardiovasc Pharmacol. 2010;55(5):456–458.

63. Guerin M, Le Goff W, Duchene E, et al. Inhibition of CETP by torce­trapib attenuates the atherogenicity of postprandial TG-rich lipoproteins in type IIB hyperlipidemia. Arterioscler Thromb Vasc Biol. 2008;28(1): 148–154.

64. Yvan–Charvet L, Matsuura F, Wang N, et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol. 2007;27(5): 1132–1138.

65. Tall AR. The effects of cholesterol ester transfer protein inhibition on cholesterol efflux. Am J Cardiol. 2009;104(Suppl 10):39E–45E.

66. Tchoua U, D’Souza W, Mukhamedova N, et al. The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse choles­terol transport. Cardiovasc Res. 2008;77(4):732–739.

67. Briand F, Thieblemont Q, Andre A, Ouguerram K, Sulpice T. CETP inhibitor torcetrapib promotes reverse cholesterol transport in obese insulin-resistant CETP-ApoB100 transgenic mice. Clin Transl Sci. 2011;4(6):414–420.

68. 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):2506–2514.

69. Fryirs MA, Barter PJ, Appavoo M, et al. Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion. Arterioscler Thromb Vasc Biol. 2010;30(8):1642–1648.

70. Barter PJ, Rye KA, Tardif JC, 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):555–562.

71. Funder JW. Aldosterone, hypertension and heart failure: Insights from clinical trials. Hypertens Res. 2010;33(9):872–875.

72. Kuivenhoven JA, de Grooth GJ, Kawamura H, et al. Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combina­tion with pravastatin in type II dyslipidemia. Am J Cardiol. 2005;95(9): 1085–1088.

73. 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):203–207.

74. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, 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):2159–2165.

75. Niesor EJ, Magg C, Ogawa N, et al. Modulating cholesteryl ester transfer protein activity maintains efficient pre-beta-HDL formation and increases reverse cholesterol transport. J Lipid Res. 2010;51(12): 3443–3454.

76. Derks M, Anzures–Cabrera J, Turnbull L, Phelan M. Safety, tolerability and pharmacokinetics of dalcetrapib following single and multiple ascending doses in healthy subjects: A randomized, double-blind, placebo-controlled, phase I study. Clin Drug Investig. 2011;31(5):325–335.

77. Stein EA, Roth EM, Rhyne JM, Burgess T, Kallend D, Robinson JG. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): Results from a 48-week trial. Eur Heart J. 2010;31(4):480–488.

78. Fayad ZA, Mani V, Woodward M, 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):1547–1559.

79. Luscher TF. Effects of dalcetrapib on vascular function: Results of phase IIb dal-VESSEL study. Available from: http://www.escardio.org/about/press/press-releases/esc11-paris/Pages/HL1-dal-VESSEL.aspx. Updated 2011. Accessed February 1, 2012.

80. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: Efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J. 2009;158(6):896–901. e3.

81. Miller R. Roche stops dalcetrapib trial for lack of benefit. Available from: http://www.theheart.org/article/1395141.do. Updated 2012. Accessed June 21, 2012.

82. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–2099.

83. Nicholls SJ, Brewer HB, Kastelein JJ et al. Effects of the CETP Inhibitor evacetrapib administered as monotherpay or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306(19):2099-2109.

84. Eli Lilly and Company. A study of evacetrapib in high-risk vascular disease (ACCELERATE); NCT01687998. Available from: http://www.clinicaltrials.gov/ct2/show/study/NCT01687998?term=evacetrapib&rank=3. Updated 2012. Accessed November 17, 2012.

85. Smith CJ, Ali A, Hammond ML, et al. Biphenyl-substituted oxazolidinones as cholesteryl ester transfer protein inhibitors: Modifica­tions of the oxazolidinone ring leading to the discovery of anacetrapib. J Med Chem. 2011;54(13):4880–4895.

86. Gutstein DE, Krishna R, Johns D, et al. Anacetrapib, a novel CETP inhibitor: Pursuing a new approach to cardiovascular risk reduction. Clin Pharmacol Ther. 2012;91(1):109–122.

87. Kumar S, Tan EY, Hartmann G, et al. Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans. Drug Metab Dispos. 2010;38(3):474–483.

88. Dansky HM, Bloomfield D, Gibbons P, et al. Efficacy and safety after cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859) in patients with primary hypercholesterolemia or mixed hyperlipidemia. Am Heart J. 2011;162(4): 708–716.

89. Bloomfield D, Carlson GL, Sapre A, 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.

90. Krishna R, Anderson MS, Bergman AJ, 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(9603):1907–1914.

91. Krauss RM, Wojnooski K, Orr J, et al. Changes in lipoprotein subfrac­tion concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib. J Lipid Res. 2012;53(3): 540–547.

92. Krishna R, Bergman AJ, Green M, Dockendorf MF, Wagner JA, Dykstra K. Model-based development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor. AAPS J. 2011;13(2): 179–190.

93. Yvan–Charvet L, Kling J, Pagler T, et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol. 2010;30(7):1430–1438.

94. Castro–Perez J, Briand F, Gagen K, et al. Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters. J Lipid Res. 2011;52(11):1965–1973.

95. Cannon CP, Dansky HM, Davidson M, et al. Design of the DEFINE trial: Determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib. Am Heart J. 2009;158(4):513–519. e3.

96. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363(25):2406–2415.

97. Davidson M, Liu SX, Barter P, et al. Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib. J Lipid Res. 2013;54(2):467–472.

98. Brinton E, Liu S, Stepanavage M, et al. Lipid-modifying effects of anacetrapib in patients with lower versus higher baseline levels of HDL-C, LDL-C, and TG: Pre-specified subgroup analyses of the DEFINE (determining the efficacy and tolerability of CETP INhibition with AnacEtrapib) trial. Circulation. 2011;124:A9649.

99. Gotto A, Cannon C, Shah S, et al. Lipid modifying effects of anacetrapib: Pre-specified subgroup analyses. Circulation. 2011;124: A15035.

100. Bowman L. REVEAL: Randomized EValuation of the effects of anacetrapib through lipid-modification. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01252953?term=anacetrapib&rank=4. Updated 2011. Accessed June 25, 2012.

101. Cannon CP. High-density lipoprotein cholesterol as the Holy Grail. JAMA. 2011;306(19):2153–2155 Research Reports in Clinical Cardiology 2013:4

Read Full Post »

%d bloggers like this: