The ACCELERATE results reaffirm the lack of accuracy for high-density lipoprotein cholesterol as a surrogate biomarker for therapeutic interventions. We’re beginning to learn that HDL cholesterol is not such a good cholesterol; it’s a difficult lipoprotein.
The results also raise questions about low-density lipoprotein cholesterol. We had believed that it was good for patients to lower their LDL cholesterol level regardless of how that was accomplished. The 37% lowering we saw in ACCELERATE should have translated into about a 15% drop in cardiovascular disease events. One possible reason why this reduction wasn’t seen is that the HDL-cholesterol increase was not neutral in its effect but harmful.
Other potentially harmful effects from evacetrapib might explain its lack of incremental clinical benefit despite lowering LDL cholesterol. Patients who received the drug had on average about a 1-mm Hg increase in their systolic blood pressure, which suggests a potentially meaningful difference in blood pressure among at least some patients on the drug. Evacetrapib treatment also raised serum levels of C-reactive protein by an average of almost 5%, suggesting that the drug might be proinflammatory.
Evacetrapib led to a lipidologist’s dream effect on plasma lipids without producing clinical benefit. I think this finding, following the failures with dalcetrapib and torcetrapib, is the last nail into the coffin of the cholesterol ester transfer protein inhibitor drug class. A pivotal trial is ongoing for a fourth drug in this class, anacetrapib, but I will be surprised if those results show a clinical benefit.
Dr. Prediman K. Shah, professor of medicine and director of the Atherosclerosis Prevention and Management Center at Cedars-Sinai Medical Center in Los Angeles, made these comments as a designated discussant of ACCELERATE. He has received research support from Aegerion, Amgen, Sanofi, and Cardiovax.
