dal-OUTCOMES: Wrestling With Why the CETP Inhibitor Failed to Reduce Outcomes

November 05, 2012

LOS ANGELES — Final results of the dal-OUTCOMES study, a phase 3 clinical trial testing the efficacy of the investigational cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib (Hoffman-La Roche, Ltd), were presented today at the American Heart Association 2012 Scientific Sessions and published simultaneously in the New England Journal of Medicine, leaving investigators to wrestle with reasons that the drug failed to have an impact on clinical outcomes. Some experts believe the modest but clinically significant increase in blood pressure might have doomed the drug.

As reported previously by heartwire , dal-OUTCOMES was stopped after an interim analysis of the study showed the HDL-cholesterol–boosting drug was not significantly reducing cardiovascular adverse events despite increases in HDL cholesterol of approximately 30%. Dalcetrapib is the second CETP inhibitor to fall by the wayside, despite initial excitement that raising HDL-cholesterol levels would translate into a reduction in clinical events. In 2005, Pfizer halted the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) of torcetrapib when it was revealed the drug increased the risk of cardiovascular morbidity and mortality.

Two other CETP inhibitors, evacetrapib (Lilly, Indianapolis, IN) and anacetrapib (Merck, Whitehouse Station, NJ) are currently being tested in large phase 3 morbidity and mortality trials. Dr Alan Tall (Columbia University, New York), who commented on the dal-OUTCOMES trial and CETP inhibition as a whole, said he does not believe the stopping of dal-OUTCOMES is a harbinger of more negative news to come about the drug class.

"I wouldn't make that conclusion," Tall told the media during a formal presentation Sunday morning. "There is a concern the tiny blood-pressure signal could be a class effect, but in pretty big studies already done with anacetrapib and evacetrapib, there is no trace of that. It's important to note that the two remaining players in the field are really quite different. They lower LDL quite extensively, they lower vLDL cholesterol, and they really raise HDL cholesterol quite a lot, a lot more than dalcetrapib."

In the DEFINE study, anacetrapib reduced LDL-cholesterol levels 36% and increased HDL-cholesterol levels by 138% in patients with coronary artery disease currently taking a statin. Evacetrapib was shown to have similar potency, reducing LDL cholesterol by as much as 52% when added to statin therapy and increasing HDL cholesterol by 129%.

Understanding why dalcetrapib failed

Dr Gregory Schwartz (University of Colorado School of Medicine, Denver), the lead investigator of dal-OUTCOMES, noted that there was no effect on LDL-cholesterol levels in the 15 871-patient trial. He added that the findings of the dal-OUTCOMES study highlight the importance of conducting large, phase 3 studies in order to detect small but clinically important safety signals. In the phase 2 studies with dalcetrapib, there was no evidence of an increase in blood pressure, but dal-OUTCOMES showed that blood pressure was increased 0.6 mm Hg with the CETP inhibitor. "The fact that anacetrapib and evacetrapib, in studies of about 1000 or 1500 patients, have not shown adverse effects on blood pressure doesn't mean that phase 3 trials might not end up showing something that we have seen here," said Schwartz.

In addition to the adverse effect on blood pressure, Tall said that the modest 30% increase in HDL cholesterol might have been insufficient in patients optimally treated with statins and other cardioprotective medications. This hypothesis is supported by the AIM-HIGH study, where a small 15% increase in HDL cholesterol with niacin did not translate into a reduction in the clinical end point. Equally important, it's possible that CETP inhibition might produce a form of HDL cholesterol that is dysfunctional and incapable of reverse cholesterol transport.

"It may be that when other risk factors are controlled as well as we currently can using many, if not all, of our evidence-based treatments, including statins, dual antiplatelet therapies, beta blockers, etc, that the risk that's modifiable by altering HDL-cholesterol levels may not be significant," said Schwartz. He pointed out that even among patients in dal-OUTCOMES who achieved the highest HDL-cholesterol levels, approximately 70 mg/dL in about 10% of patients, there was no apparent decrease in risk compared with other patients in the trial.

Full results of the morbidity and mortality trials with anacetrapib and evacetrapib are not expected for a few years.