ORLANDO – The investigational drug evacetrapib produced dramatic lipid effects with no major safety signals when used as monotherapy or in combination with statin therapy in a phase II randomized trial.
Monotherapy with the cholesteryl ester transfer protein (CETP) inhibitor produced a dose-dependent increase in HDL cholesterol that ranged from 53.6% to 128.8%.
LDL cholesterol levels decreased in a similar fashion from 13.6% to 35.9%, Dr. Stephen J. Nicholls reported at the annual scientific sessions of the American Heart Association.
When evacetrapib, at a dosage of 100 mg, was combined with commonly prescribed statins, LDL cholesterol levels fell significantly, by 46% with simvastatin (Zocor) 40 mg, 48% with atorvastatin (Lipitor), and 52% with rosuvastatin (Crestor) 10 mg. At the same doses, HDL cholesterol levels were increased by 87%, 80%, and 94%, respectively, all highly significant differences.
"This translated to an additional lowering of LDL cholesterol by 32% to 42% in addition to statin therapy," he said.
The data are comparable with those recently achieved by two other CETP inhibitors under investigation, anacetrapib and dalcetrapib. Interestingly, evacetrapib at 500 mg had a similar effect as anacetrapib 100 mg on HDL-C (129% vs. 138%) and LDL-C (136% vs. –40%), but appeared to have a greater impact on triglycerides (–17% vs. –7%), observed Dr. Daniel Rader, who was invited to discuss the paper.
The lack of any major safety signal is encouraging for CETP inhibitors as a class given the early problems surrounding torcetrapib, but that data are still needed from clinical outcome trials to determine whether CETP inhibition can reduce cardiovascular risk, said Dr. Rader, chief of translational medicine and human genetics and director of the preventive cardiovascular program at the University of Pennsylvania, Philadelphia.
"This is one of the great experiments currently being carried out in medicine," he said.
Dr. Rader observed that CETP is a complex entity, and that a critical question for the field is whether the relationship between CETP inhibition and cardiovascular risk reduction is linear, although hypothetically it is more likely to be curved. Notably, CETP inhibition reached 50%, 70%, and 90% with evacetrapib at daily doses of 30 mg, 100 mg, and 500 mg, respectively.
In addition to determining the optimal degree of CETP inhibition, researchers will also have to identify which patients are most likely to benefit from therapy. The ongoing REVEAL and dal-OUTCOMES trials will provide some insights, but both trials exclude patients with LDL levels greater than 100 mg/dL and "yet it could be argued that subjects with elevated LDL on high-dose statins are the ones most likely to benefit," Dr. Rader said.
Subgroup analyses revealed greater increases in HDL-C with evacetrapib monotherapy among patients who were younger, had lower levels of HDL at baseline and higher triglycerides at baseline, said Dr. Nicholls, clinical director of the Cleveland Clinic Center for Cardiovascular Diagnostics and Prevention.
Greater reductions in LDL cholesterol were observed in those who were younger and had lower levels of HDL cholesterol at baseline.
"This is one of the great experiments currently being carried out in medicine."
The study randomly assigned 398 with elevated LDL or low HDL to receive placebo, evacetrapib monotherapy at daily doses of 30 mg, 100 mg, or 500 mg or statin therapy as described above with or without evacetrapib 100 mg/day for 12 weeks. The mean baseline HDL level was 55 mg/dL and the mean LDL level 144 mg/dL.
No significant increase in adverse events or serious adverse events were observed with evacetrapib monotherapy or in combination with statin therapy on either systolic or diastolic blood pressure, biochemical parameters related to renal, muscle, or liver toxicity. Furthermore, there were no adverse effects on aldosterone or cortisol levels, which have been previously observed with torcetrapib, Dr. Nicholls said.
The study was simultaneously published in the Nov. 16 issue of the Journal of the American Medical Association (JAMA. 2011;306:2099-2109).
The study was sponsored by Eli Lilly. Dr. Nicholls reported consulting for and receiving research support and honoraria from several pharmaceutical companies including Eli Lilly.