Correspondence

Torcetrapib and Coronary Events

N Engl J Med 2008; 358:1862-1864April 24, 2008

Article

To the Editor:

Barter et al. (Nov. 22 issue)1 report the findings in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial of torcetrapib for the prevention of cardiovascular events. Was the result really as unexpected and its explanation as enigmatic as Rader suggests in his accompanying editorial?2 Taking into account our knowledge about the function of cholesteryl ester transfer protein (CETP) and the fact that a heterozygous genetic CETP deficiency is associated with an increased prevalence of cardiovascular disease despite increased high-density lipoprotein (HDL) cholesterol,3 the answer is clearly no. Can the off-target effect of torcetrapib on blood pressure and the renin–angiotensin–aldosterone system really explain its failure? Apparently, these effects of torcetrapib were not considered to be relevant when the ILLUMINATE trial was launched. Furthermore, it is disappointing that Barter et al. did not analyze whether a history of diabetes, which almost half their patients had, or hypertriglyceridemia influenced the outcome. It would not be surprising if the rate of excess cardiovascular events with torcetrapib was changed among patients who had diabetes, hypertriglyceridemia, or both. In contrast to serum potassium and bicarbonate levels, this information would further our knowledge about the role of CETP.

Karl J. Lackner, M.D.
Johannes Gutenberg University Mainz, D 55101 Mainz, Germany
lackner@zentrallabor.klinik.uni-mainz.de

3 References

1
Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-2122
Full Text | Web of Science | Medline

2
Rader DJ. Illuminating HDL -- is it still a viable therapeutic target? N Engl J Med 2007;357:2180-2183
Full Text | Web of Science | Medline

3
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;97:2917-2923
CrossRef | Web of Science | Medline

To the Editor:

In all the discussion about the failure of torcetrapib to reduce clinical end points, a central aspect of the study has been ignored. For marketing reasons, the drug was studied only in combination with atorvastatin. Since the cause of the adverse effects is unknown, could not an interaction with atorvastatin explain the poor results of the trial?

Lawrence J. Cohn, M.D.
Lenox Hill Hospital, New York, NY 10021

To the Editor:

Barter et al. report that the CETP inhibitor torcetrapib increases cardiovascular risk, despite increasing the level of HDL cholesterol. Torcetrapib administration is associated with a rise in blood pressure, electrolyte changes, and an increase in the serum aldosterone concentration, which suggest off-target effects.1 Notably, aldosterone regulation could be affected by CETP, since systolic blood pressure is reduced in Dahl salt-sensitive hypertensive rats in response to human CETP expression.2 We determined whether serum aldosterone was associated with plasma CETP (measured with the use of an immunoassay3) in subjects who did not have hypertension or cardiovascular disease. As shown in Table 1Table 1Serum Aldosterone and Potassium Levels and Clinical Factors in 87 Subjects without Hypertension and Cardiovascular Disease, According to Sex-Stratified Cholesteryl Ester Transfer Protein (CETP) Quartile., serum aldosterone levels were higher in subjects with plasma CETP levels in the lowest quartile (quartile I) than in subjects with higher CETP levels (quartiles II to IV). Multiple linear regression analysis showed that aldosterone was negatively related to CETP (P=0.006) after adjustment for age, sex, body-mass index, and serum potassium level. Our preliminary data raise the possibility that a low CETP level may itself affect aldosterone regulation, contributing to hyperaldosteronemia in susceptible persons.

Robin P. Dullaart, M.D., Ph.D.
Anneke C. Muller Kobold, Ph.D.
Arie van Tol, Ph.D.
University of Groningen, 9700 RB Groningen, the Netherlands
r.p.f.dullaart@int.umcg.nl

3 References

1
Tall AR, Yvan-Charvet L, Wang N. The failure of torcetrapib: was it the molecule or the mechanism? Arterioscler Thromb Vasc Biol 2007;27:257-260
CrossRef | Web of Science | Medline

2
Herrera VLM, Makrides SC, Xie HX, et al. Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein. Nat Med 1999;5:1383-1389
CrossRef | Web of Science | Medline

3
Niemeijer-Kanters SDJM, Dallinga-Thie GM, Ruijter-Heijstek FC, et al. Effect of intensive lipid-lowering strategy on low-density lipoprotein particle size in patients with type 2 diabetes mellitus. Atherosclerosis 2001;156:209-216
CrossRef | Web of Science | Medline

Author/Editor Response

Lackner is not alone in his retrospective questioning of the unexpected results of the ILLUMINATE trial. The subgroup analyses that he and many others suggest are currently in progress. Although it is easy to be wise after the fact, we continue to believe that a comprehensive review of the evidence provided more than sufficient justification to conduct the ILLUMINATE trial. This evidence included the epidemiologic basis,1 as well as torcetrapib's antiatherosclerotic action in rabbits2 and increased cholesterol efflux from macrophages.3 Lackner's statement, in reference to the Honolulu Heart Study, that “a heterozygous genetic CETP deficiency is associated with an increased prevalence of cardiovascular disease despite increased HDL cholesterol” is at odds with a later analysis of the Honolulu Heart Study data by the same authors, in which a trend toward a lower incidence of events in subjects with CETP deficiency was observed.4 Similar results that are consistent with a protective effect of CETP deficiency were also found in a large cohort of Japanese subjects with high levels of HDL cholesterol associated with a genetic CETP deficiency.5 It is thus difficult to implicate CETP deficiency itself as a cause of increased cardiovascular disease. Lackner's suggestion that we ignored the blood-pressure effect of torcetrapib is quite simply wrong. Before starting the ILLUMINATE trial, the sponsor had investigated torcetrapib in a stepwise manner that included full characterization of the blood-pressure effect. This effect was easily monitored and controlled. Studies investigating the mechanism of off-target actions of the drug are ongoing.

Cohn's assertion that torcetrapib was studied with atorvastatin for marketing reasons is incorrect. Rather, the program was designed to provide the greatest medical benefit to patients with a high residual risk despite aggressive statin therapy. There is no evidence from the development program suggesting that an atorvastatin–torcetrapib interaction was responsible for the ILLUMINATE results.

The association between CETP mass (activity is not reported) and aldosterone presented by Dullaart et al. is interesting, although the study is very small and provides no mechanistic insights, and the findings are inconsistent with other information. Data presented by DePasquale et al. and by Forrest et al. in two posters at Late Breaking Science Session 12 of the American Heart Association Scientific Sessions, in Orlando, Florida, on November 5, 2007, showed not only that aldosterone release is induced by torcetrapib in experimental models that lack CETP but also that it is specific to torcetrapib and is not induced by other CETP inhibitors.

Philip Barter, M.D., Ph.D.
Heart Research Institute, Sydney, NSW 2050, Australia
barterp@hri.org.au

Charles L. Shear, Dr.P.H.
James H. Revkin, M.D.
Pfizer, New London, CT 06320

5 References

1
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;23:160-167
CrossRef | Web of Science | Medline

2
Morehouse LA, Sugarman ED, Bourassa P-A, et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand white rabbits. J Lipid Res 2007;48:1263-1272
CrossRef | Web of Science | Medline

3
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;27:1132-1138
CrossRef | Web of Science | Medline

4
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;97:2917-2923
CrossRef | Web of Science | Medline

5
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;27:659-667
CrossRef | Web of Science | Medline

Author/Editor Response

Lackner suggests that the results of the ILLUMINATE trial could have been predicted on the basis of data regarding the genetics of CETP in humans and the relationship to cardiovascular disease. However, the relationship of CETP deficiency or polymorphisms to the risk of cardiovascular disease remains an unresolved issue. The 1996 article on the Honolulu Heart Study that he cites1 was followed in 2004 by a report on a longitudinal study of the same cohort, which showed no significant difference in the risk of cardiovascular disease among CETP heterozygotes.2 The risk of cardiovascular disease among CETP homozygotes remains a contentious unresolved issue. Association studies of common single-nucleotide polymorphisms in the human CETP gene show consistent associations with HDL cholesterol levels but inconsistent and contradictory associations with cardiovascular disease.3 The concept that CETP promotes reverse cholesterol transport despite lowering HDL cholesterol levels remains a largely theoretical construct.4 Thus, the field was, and importantly still is, in equipoise regarding the effect of CETP inhibition on cardiovascular risk. This question will be definitively answered only with another clinical-outcome trial with a clean CETP inhibitor devoid of off-target effects.

Daniel J. Rader, M.D.
University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160

4 References

1
Zhong S, Sharp DS, Grove JS, et al. Increased coronary heart disease in Japanese-American men with mutations in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest 1996;97:2917-2923
CrossRef | Web of Science | Medline

2
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;45:948-953
CrossRef | Web of Science | Medline

3
Boekholdt SM, Thompson JF. Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J Lipid Res 2003;44:1080-1093
CrossRef | Web of Science | Medline

4
Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest 2006;116:3090-3100
CrossRef | Web of Science | Medline

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