| Author | Duriez P. |
| Title | CETP inhibition |
| Full source | Lancet 2007;370:1882-1883 |
| Text |
In today's Lancet, Rajesh Krishna and colleagues report two doubled-blind, placebo-controlled, randomised phase I studies with the cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib, in healthy individuals and in patients with dyslipidaemia.1 The drug increased HDL cholesterol and decreased LDL cholesterol. Importantly, there was no effect on blood pressure. LDL and HDL are independent factors that modulate the risk of cardiovascular disease, and increases in HDL cholesterol might decrease cardiovascular risk.2 CETP inhibitors raise HDL and decrease LDL. Torcetrapib was the first tested in large long-term trials (ILLUMINATE,3 RADIANCE I,4 RADIANCE II,5 and ILLUSTRATE6). On Dec 2, 2006, all torcetrapib clinical trials were stopped in the interests of patients' safety. The data and safety monitoring board on ILLUMINATE recommended termination of the study because there were significantly more major cardiovascular events in the group receiving torcetrapib in combination with atorvastatin than in the group receiving atorvastatin monotherapy.3 In the other trials, torcetrapib failed to reduce the development of atherosclerosis in the common carotid4,5 and coronary arteries,6 but increased blood pressure in every study Torcetrapib induced significant increases in systolic blood pressure (5·4 mmHg) and in serum concentrations of sodium, bicarbonate, and aldosterone, and a significant decrease in serum potassium.3 Increased risk of death was higher when the increase in bicarbonate or decrease in potassium was greater than the median change.8 This off-target effect might have been associated with the increased mortality and morbidity in ILLUMINATE, although further analyses are needed to interpret this relation. Further long-term studies in larger populations will be necessary to confirm the absence of an off-target effect on blood pressure with anacetrapib. This prudence is necessary because torcetrapib and anacetrapib are in the same structural class, and because the effect of torcetrapib on systolic blood pressure was found in large long-term studies;3–6 the effect was lower7 and even not statistically significant8 in phase 2 studies. Furthermore, in ILLUMINATE,3 the standard deviations of log-rank tests for the effects of torcetrapib on systolic blood pressure and for sodium and potassium serum levels were equal to twice the averages, and the alteration in aldosterone level was highly variable, with wide heterogeneity in the susceptibility of patients to these off-target effects of torcetrapib. An important proof of absence of toxic efffects with anacetrapib on blood pressure regulation would involve having data on aldosterone production and the expression of genes coding for mineralocorticoid biosynthesis in the adrenal glands. If anacetrapib truly lacks such off-target effects, this molecule would be a good tool to study whether CETP inhibition decreases or increases cardiovascular risk. The decrease in LDL cholesterol and the large increase in HDL cholesterol induced by anacetrapib would theoretically decrease cardiovascular risk. Nevertheless, there is no proof that decreasing the activity of CETP reduces cardiovascular risk, although there are several potential mechanisms by which HDLs protect against the development of vascular disease. One relates to the unique ability of these lipoproteins to remove cholesterol from the arterial wall and to transport this cholesterol to the liver (reverse cholesterol transport). Furthermore, HDLs help maintain endothelial integrity, inhibit blood-cell adhesion to vascular endothelium, reduce platelet aggregability and coagulation, may favour fibrinolysis, and facilitate vascular relaxation. These functions of HDLs complement their activity in the removal of arterial cholesterol and provide an excellent rationale for inducing chronic elevation of plasma HDL concentration. Long-term increases in HDL cholesterol might favourably influence pathological processes, such as accelerated atherosclerosis, acute coronary syndromes, and restenosis after coronary angioplasty. But it has been suggested that CETP inhibition may generate HDL particles that are non-functional or even proatherogenic.9 However, HDL from torcetrapib-treated patients induced a modestly higher in-vitro efflux of cellular cholesterol than did that from controls.10 That finding indicates that the first step of reverse cholesterol transport could be improved by torcetrapib, but the relevance of this in-vitro test for human disease is unknown. Modified HDL could have deleterious effects via many other mechanisms. For example, HDL increases nitric oxide secretion by increasing the activity of nitric oxide synthase. Under CETP-inhibitor treatment, enlarged matured HDL could be inefficient at fully stimulating nitric oxide synthase. A local deficit in nitric oxide could predispose to acute vascular events through mechanisms such as vasospasm or platelet aggregation. Another possible mechanism is that, under CETP-inhibitor treatment,11 the prolonged lifespan of apo A-I in serum could increase the susceptibility of this apolipoprotein and of HDL to oxidative stress, resulting in alteration in the antiatherogenic properties of HDL. Finally, HDL and oxidised HDL might induce endothelin-1 secretion by endothelial cells. By highly increasing serum levels of HDL cholesterol, CETP inhibition might increase vasospasm and vascular hypertrophy induced by endothelin-1. The short-term safety of anacetrapib, as found by Krishna and colleagues (which needs to be confirmed in the longer term) opens new perspectives in the study of the effect of CETP inhibition on atherogenesis and cardiovascular risk, and may resuscitate the hope that CETP inhibitors could be an important new class of drugs that normalise lipidaemia.
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