New torcetrapib data rejuvenate interest in other CETP inhibitors

November 05, 2007

Orlando, FL - New data from the ILLUMINATE and ILLUSTRATE trials with the HDL-increasing drug torcetrapib (Pfizer) have shown that the drug stimulates aldosterone, which possibly accounts for its adverse outcomes. In addition, both studies showed that patients with the largest HDL increases showed benefits with the drug. Although torcetrapib itself is firmly dead and buried, these findings are expected to rejuvenate interest in the development of other cholesteryl ester transfer protein (CETP) inhibitors.

ILLUMINATE now published

Final results of the ILLUMINATE trial were presented today at the American Heart Association (AHA) 2007 Scientific Sessions and published simultaneously online in the New England Journal of Medicine[1]. The study was stopped prematurely last December because of a higher rate of deaths and cardiovascular events in the torcetrapib group. These findings put a damper on the whole class of CETP inhibitors, but it now appears that the toxicity associated with torcetrapib might have been caused by mechanisms separate from CETP inhibition, which might not be shared by other drugs in this class.

Dr Philip Barter

Presenting the ILLUMINATE data, Dr Philip Barter (Heart Research Institute, Sydney, Australia) commented: "There have been concerns voiced that the HDL produced by CETP inhibitors may be dysfunctional in some way. But our results, along with new data from the ILLUSTRATE study, are not consistent with that idea. Rather, they are supportive of other in vitro studies that suggest the HDL formed by these drugs is functional." He added that "the observation that torcetrapib increases aldosterone levels is very exciting. If this off-target toxicity was not there, the clinical outcome results may have been very different. Several other CETP inhibitors in early development do not appear to have this effect on aldosterone, which gives us hope that this class of drugs may still be successful."

These new findings were greeted with much interest at the AHA meeting. Dr Steven Nissen (Cleveland Clinic, OH), who was also involved in trials with torcetrapib, agreed with Barter that the new data justified continued development of other drugs in this class. "Further study of other CETP inhibitors without adrenal toxicity seems warranted. We should not give up on the class just because of the failure of torcetrapib," he commented to heart wire .

But others were more underwhelmed with the findings. Dr Raymond Gibbons (Mayo Clinic, Rochester, MN) told heart wire , "I've heard all this hype about these findings over the past few days, but now that I've heard the presentation and read the paper, I don't understand what the fuss is about. I can't see the good news here. These new data have not ruled out CETP inhibition as the cause of the adverse outcomes with torcetrapib. A lot of this is still speculation. I would still be very cautious about other drugs in this class."

But Barter's enthusiasm would not be denied. "This class of drug has the potential to save so many lives. The increased events in ILLUMINATE were a huge disappointment, but these latest findings suggesting that the HDL produced by CETP inhibition was not dysfunctional are enormously reassuring. And with other new data suggesting that the adverse effect of torcetrapib on blood pressure and aldosterone is not mediated by CETP inhibition, the door is now wide open for other compounds in this class."

Rat study suggests adverse effects independent of CETP

The data suggesting that the adverse effects of torcetrapib on blood pressure and aldosterone are not mediated by CETP came from a preclinical study, also presented at the AHA meeting this week by Merck scientists. It showed that blood pressure and aldosterone levels were increased with torcetrapib but not with the Merck CETP inhibitor anacetrapib in rats. Barter explained to heart wire that because rats do not have CETP, these effects of torcetrapib cannot be mediated by CETP inhibition.

ILLUMINATE results

The ILLUMINATE trial randomized 15 067 patients at high cardiovascular risk to either torcetrapib plus atorvastatin or atorvastatin alone. After an average 12 months of follow-up, the torcetrapib patients showed an increase of 72.1% in HDL and a decrease of 24.9% in LDL, compared with baseline. Torcetrapib was also associated with an increase of 5.4 mm Hg in systolic blood pressure, an increase in cardiovascular events of 25%, and an increase in all-cause death of almost 60%.

ILLUMINATE: Major results

End point Atorvastatin (n=7534), n Atorvastatin + torcetrapib (n=7533), n Hazard ratio (95% CI) p
Major CV events 373 464 1.25 (1.09-1.44) 0.001
Deaths 59 93 1.58 (1.14-2.19) 0.006

Torcetrapib was also associated with a decrease in serum potassium and increases in serum sodium, bicarbonate, and aldosterone. Post hoc analyses showed an increased risk of death in torcetrapib-treated patients whose reduction in potassium or increase in bicarbonate was greater than the median change, Barter reported.

Further analysis on the causes of death showed more fatal stroke with torcetrapib (six vs zero) and more deaths due to cancer (24 vs 14) and infection (nine vs zero). But new cases of cancer or infection were not increased with the CETP inhibitor. Barter commented that "this suggests that the drug is not actually causing infection or cancer but may make people with infection or cancer more susceptible to death."

He suggested that as well as increasing aldosterone levels, the drug stimulates cortisol, which can compromise the immune system. "The same cells that make aldosterone also make cortisol and, if cortisol is also increased, this would go a long way to explaining our observations," he said. But he stressed that he had not had time to verify this hypothesis, so it remained speculation at this point.

HDL produced not dysfunctional?

The data suggesting that the HDL produced by torcetrapib has protective properties comes from a post hoc exploratory analysis of the ILLUMINATE trial. This showed that rates of CHD death/MI were lowest in torcetrapib-treated patients with the biggest increases in HDL levels.

Hazard ratio for CHD death/MI according to HDL level (adjusted or baseline HDL level)

HDL level (mg/dL) at month 3 on torcetrapib Hazard ratio for CHD death/MI
<60 1.00
60-70 0.67
71-80 0.47
81-93 0.57
>93 0.43

Similar data were also presented from the ILLUSTRATE IVUS study, which showed that increasing levels of HDL from torcetrapib treatment were associated with a beneficial impact on atherosclerotic plaque progression. Reporting the results, Dr Steven Nicholls (Cleveland Clinic) said, "At the highest level of HDL, there was a clear regression of plaque. This was very clear-cut. We also found that in patients with reduced potassium levels, we no longer saw this benefit of high HDL, suggesting that stimulation of aldosterone is mitigating the benefit of raising HDL."

Conclusion cautious

But the conclusion of the ILLUMINATE paper is cautious. The researchers write: "Our study neither validates nor invalidates the hypothesis that raising levels of HDL cholesterol by the inhibition of CETP may be cardioprotective. Thus, the possibility that the inhibition of CETP may be beneficial will remain hypothetical until it is put to the test in a trial with a CETP inhibitor that does not share the off-target pharmacologic effects of torcetrapib."

In an accompanying editorial[2], Dr Daniel Rader (University of Pennsylvania School of Medicine, Philadelphia) says that the "off-target" effects of torcetrapib probably contributed in important ways to the increased rate of cardiovascular events and death in the ILLUMINATE trial, but he adds that it is much harder to explain the increased rate of death from noncardiovascular causes by either CETP inhibition or off-target effects of torcetrapib.

He writes: "CETP inhibition increases the size and alters the lipid and protein composition of HDL particles. Could these changes in composition alter the immune or inflammatory function of HDL in such a way as to increase the risk of death from cancer or infection? Alternatively, off-target effects of torcetrapib could potentially account for the excessive rate of death from noncardiovascular causes through an unknown mechanism." Although Rader does not speculate about which of these mechanisms is true, he agrees it is premature to announce the death of CETP inhibitors on the basis of the torcetrapib experience alone.

Califf: Reform needed in drug development

The discussant of the ILLUMINATE study at the late-breaking clinical-trial session, Dr Robert Califf (Duke University, Durham, NC), said that the trial should serve as a major warning that reform is needed in drug development, both for better early screening for off-target pharmacology and for better systems to evaluate the results of large trials as close to real time as possible. Noting that he has low HDL and therefore a vested interest in the field, Califf said he would have liked to have seen these data sooner, given that the trial was stopped last December. Noting that all drugs have off-target effects that may influence clinical outcomes, Califf said this study emphasized the importance of outcome trials and not a reliance on surrogate end points.

Rader reports receiving consulting fees from Pfizer, Merck, and Roche and lecture fees and grant support from Pfizer and Merck. No other potential conflict of interest relevant to this article was reported.

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