Cleveland, OH and Amsterdam, the Netherlands - Two new studies published this week help shed light on the off-target toxicity of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib, although researchers come to different conclusions about the atheroprotective functionality of the HDL cholesterol resulting from the drug.

In the first study [1], a pooled analysis of data from the Rating Atherosclerotic Disease Change by Imaging with a New Cholesteryl-Ester-Transfer Protein Inhibitor (RADIANCE) 1 and 2 trials, researchers showed that patients treated with torcetrapib had higher systolic blood pressure and large electrolyte changes, such as higher plasma sodium and bicarbonate levels and lower potassium levels.

The group, led Dr Menno Vergeer (University of Amsterdam, the Netherlands), reports that no inverse relation was observed between HDL-cholesterol levels and carotid intima-media thickness (CIMT), suggesting that a "torcetrapib-induced HDL-cholesterol increase does not mediate atheroprotection."

An analysis of data from the Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE) study also showed that torcetrapib raised serum sodium and lowered potassium levels, consistent with effects mediated by aldosterone [2]. In contrast with the RADIANCE analysis, however, there was slowed progression of coronary atherosclerosis, as measured by intravascular ultrasound (IVUS), among patients with the highest HDL-cholesterol levels achieved in the trial.

"We were surprised by the relationship between the degree of HDL-cholesterol elevation and the degree of slowing disease progression," senior investigator Dr Steven Nissen (Cleveland Clinic, OH) told heartwire. "The overall group didn't show any slowed progression, but the more HDL cholesterol these patients got, the better they did. This suggests that if somebody can develop a CETP inhibitor that doesn't affect the adrenal glands, the way torcetrapib did, then it has a pretty good chance of succeeding."

Speaking with heartwire, Vergeer emphasized the similarities, rather than the differences, in the two groups' conclusions. "The conclusion is that . . . torcetrapib's failure is based on the drug's off-target toxicity," he said. "I think that's the most important conclusion we both arrive at."

In December 2006, data from a 15 000-patient morbidity and mortality trial ended all hopes for Pfizer's torcetrapib, because the drug was shown to increase the risk of death and cardiovascular events. While the morbidity and mortality trial was ongoing, investigators conducted three imaging studies to clarify the specific effects of torcetrapib (these results have been reported by heartwire and published previously). Overall, the imaging studies were neutral, leaving unanswered questions about what went wrong with the CETP inhibitor.

In this latest analysis of the RADIANCE data, Vergeer and colleagues, including senior investigator Dr John Kastelein (University of Amsterdam), report that torcetrapib induced electrolyte changes, such as reduced potassium, increased sodium levels, increased blood pressure, and increased CIMT progression. Individuals who had the largest reduction in LDL-cholesterol levels showed the smallest progression in CIMT, whereas subjects with the highest increase in blood pressure had the largest progression of CIMT. There was no relation between increased HDL cholesterol and decreased CIMT progression.

Vergeer said the focus with torcetrapib has been on its HDL-cholesterol-raising ability, but the drug also significantly lowers LDL cholesterol. In the RADIANCE analysis, 904 patients had familial hypercholesterolemia and, among these patients, elevated LDL cholesterol is the most important risk factor. The altered electrolytes observed in this analysis also support the ILLUMINATE findings showing increases in aldosterone levels, he added.

"This business with torcetrapib having some off-target drug toxicity is now pretty well established, with the paper by John Kastelein giving further details," said Nissen. "We've known that torcetrapib was upregulating something in the adrenals that was increasing blood pressure and altering electrolytes. Many believe that these off-target effects led to the excess mortality in ILLUMINATE, the large outcomes trial."

In his analysis of the 910 patients in the ILLUSTRATE trial, however, Nissen and colleagues, one of whom was Dr Stephen Nicholls (Cleveland Clinic, OH), wanted to determine whether those who had the greatest increases in HDL cholesterol had slower progression, which would mean that the HDL-cholesterol increase with torcetrapib is functional. Patients in the highest on-treatment HDL-cholesterol quartile (>86 mg/dL) showed significant regression in percent atheroma volume (PAV), compared with those in the lowest quartile. In addition, those who had the most changes in HDL cholesterol during treatment showed the least progression in PAV.

In contrast with the Dutch researchers, Nissen said CETP inhibitors lacking the off-target toxicity of torcetrapib might have a future. Currently, two other CETP inhibitors, anacetrapib (Merck) and dalcetrapib (Roche Pharmaceuticals), are in development.

Dr Michael Davidson (Radiant Research, Chicago, IL), who was not part of either study, said the off-target toxicity data are reassuring. The new ILLUSTRATE analysis is also in line with a post hoc analysis of the ILLUMINATE data, which showed a trend toward fewer cardiovascular events among patients with HDL-cholesterol levels above the median. This suggests that a different drug capable of safely increasing HDL cholesterol and lowering LDL cholesterol still has clinical potential, said Davidson. Dalcetrapib is currently in an ongoing outcomes study, with data still about one year away, while anacetrapib is being studied in a large phase 3 safety and efficacy study.

Asked about the disparate findings and conclusions reached by the research teams, Nissen said the two imaging modalities and the relations observed with HDL cholesterol complicate the picture a little. However, as a proponent of IVUS, he believes it is better able to assess coronary atherosclerosis than the noninvasive CIMT. The validity of CIMT has also recently been questioned as a surrogate marker of atherosclerosis in light of data from the ENHANCE trial.

Speaking with heartwire, Davidson said the results and conclusions are not entirely inconsistent when the patient populations are analyzed. RADIANCE 1 and 2, for example, included patients with familial hypercholesterolemia and mixed dyslipidemia. Compared with the coronary atherosclerosis patients in the ILLUSTRATE trial, a patient population that had large amounts of lipid-rich plaque, the RADIANCE patients had less plaque to alter, which might explain the lack of effect on the common CIMT end point and the lack of relation to HDL cholesterol.

As pointed out by Vergeer, however, the potential efficacy of CETP inhibitors remains unknown. The new data, although intriguing, are based on a post hoc analysis and "should be taken with a grain of salt." Nissen agreed, adding that researchers will still look at the data very closely "because everybody wants to know if we can develop CETP inhibitors after torcetrapib's failure."