CETP inhibition unlikely to be responsible for hypertensive effects of torcetrapib
A large-scale collaborative analysis of data from torcetrapib trials and genetic studies adds to evidence suggesting that the hypertensive effects observed with torcetrapib are unlikely to be related to cholesteryl ester transfer protein (CETP) inhibition. These findings, reported in Circulation, will help to reassure the clinical community that chemically dissimilar CETP inhibitors currently in development are unlikely to share this adverse effect.
The study was reviewed by Professor Philip Barter, Heart Research Institute, Sydney, Australia.
Sofat R, Hingorani AD, Smeeth L et al. Separating the mechanism-based on off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation published on-line 21 December 2009. DOI: 10.1161/CIRCULATIONAHA.109.865444
CETP in human plasma promotes the transfer of cholesterol from high density lipoproteins (HDL) to low density lipoproteins (LDL) and triglyceride-rich lipoproteins such as very low density lipoproteins (VLDLs) and chylomicrons. Consequently, inhibition of CETP has the potential to shift the balance of plasma cholesterol in favour of the protective HDL fraction.
Thus, the development of the CETP inhibitors potentially represents a novel class of drug for raising circulating HDL cholesterol levels. However, the first of these agents, torcetrapib, resulted in an excess number of deaths in the ILLUMINATE trial, leading to the premature termination of the clinical development programme for torcetrapib. In this trial and three imaging studies, torcetrapib also raised blood pressure by 3-5 mmHg. However, analysis of the possible relationship between events and changes in blood pressure in ILLUMINATE was confusing (1). Paradoxically, there was an excess of both deaths and major cardiovascular events in the torcetrapib-treated patients who had a change in systolic blood pressure less than the median. Furthermore, patients who had the greatest increase in blood pressure also had the lowest level of blood pressure at baseline, making it difficult to interpret the relationship without further analysis.
Whether the hypertensive effects of torcetrapib resulted from CETP inhibition or an off-target effect of the drug has been the subject of much debate.
In this large-scale collaborative analysis, the authors used an alternative approach to address this issue. The investigation was based on the principle that allelic variants in the CETP gene can be used to model the mechanism-based effect of modifying the same target pharmacologically. The authors hypothesed that common single-nucleotide polymorphisms (SNPs) in the CETP gene (TaqIB and -629C polymorphisms) could help to differentiate mechanism-based from off-target actions of the CETP inhibitors. The analysis was therefore based on the effects of torcetrapib and carriage of common CETP SNPs on lipids, lipoproteins, blood pressure and other markers of cardiovascular risk.
This analysis included data from up to 67,687 individuals from genetic studies and 17,911 individuals from randomized trials of torcetrapib.
Both CETP SNPs and torcetrapib treatment reduced CETP activity, and this had a concordant effect on eight lipid and lipoprotein traits: total, LDL and HDL cholesterol, HDL2, HDL3, apolipoproteins A-I and B, and triglycerides (Table 1). The genetic effect on HDL cholesterol (increase by 0.13 mmol/L, 95% CI 0.11-0.14) was consistent with that expected with a 10 mg dose of torcetrapib.
However, there was discordance between the genetic effects and torcetrapib effects on blood pressure. Whereas torcetrapib 60 mg raised systolic blood pressure by 4.47 mmHg (95% CI 4.10 to 4.84 mmHg) and diastolic blood pressure by 2.08 mmHg (95% CI 1.84 to 2.31 mmHg), genetic effects on blood pressure were effectively null (0.16, 95% CI -0.28 to 0.60 mmHg for systolic and -0.04 mmHg, 95% CI -0.36 to 0.28 mmHg for diastolic blood pressure) and significantly different from that expected for torcetrapib 10 mg. Similarly, the CETP genotype was not associated with serum sodium, potassium, creatinine concentration or with urinary sodium or potassium concentration.
The authors did acknowledge a number of limitations to their study. As the effect of CETP alleles is much smaller than the effect observed with the torcetrapib dose, it is possible that the failure to detect any association between CETP genotype and blood pressure might be due to inadequate statistical power. However, given that blood pressure was widely recorded in the studies in this analysis, and that the effect of CETP genotype on triglycerides was of similar magnitude to that expected for blood pressure if mechanism-based, suggests that the data are not biased.
The authors concluded that their findings support the interpretation that the blood pressure-raising effect of torcetrapib (as well as effects on electrolytes) was not related mechanistically to CETP inhibition. These data were consistent with evidence from studies with other CETP inhibitors (anacetrapib and dalcetrapib) currently in development that have so far failed to demonstrate adverse effects on blood pressure (2-4). Together, the data provide reassurance that the adverse effects of torcetrapib are unlikely to be shared by other CETP inhibitors. Ultimately, however, the results of large outcomes studies are needed to definitively confirm this.
References
1. Barter P, Caulfield M, Eriksson M et al. Effects of Torcetrapib on Morbidity and Mortality in Patients at High Risk for Coronary Events. New Eng J Med 2007;357:2109-22.
2. 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;370:1907-14.
3. Bloomfield D, Carlsson 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;157:332-360.e352.
4. Stein EA, Stroes ES, Steiner G et al. Safety and tolerability of dalcetrapib. Am J Cardiol. 2009;104:82-91.
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