Anacetrapib Finds (Modest) Success Where All Other CETP Inhibitors Failed

BARCELONA, Spain—The fourth time appears to be the charm when it comes to a beleaguered drug class designed to raise HDL cholesterol levels.

In a study presented today at the European Society of Cardiology Congress 2017,the REVEAL investigators report that treating high-risk patients with anacetrapib (Merck), a cholesteryl ester transfer protein (CETP), lowered the risk of a first major coronary event by 9% when compared with placebo.

“There have been a number of previous trials of other CETP inhibitors, which have typically been stopped at 2 years of follow-up—either due to unexpected hazard, as was the case with torcetrapib, which had a substantial effect on blood pressure and an adverse effect on cardiovascular mortality, or an apparent lack of efficacy, as in the case of dalcetrapib and evacetrapib,” Martin Landry, MBChB, PhD (University of Oxford, England), a co-principal investigator of REVEAL, said during a press conference announcing the results.

Anacetrapib, therefore, was the last CETP inhibitor standing, and while there was a significant reduction in cardiovascular events, investigators believe the benefit is largely attributable to lowering LDL cholesterol levels and not the effect on HDL cholesterol.

“This trial result could be seen not only as a demonstration of the benefits of anacetrapib, but actually a further demonstration, along with the data from the PCSK9 inhibitors, that lowering LDL cholesterol well below the current recommendations continues to yield benefit,” said Landry. “It seems unlikely that the increase in HDL cholesterol—the doubling of HDL cholesterol—has played a major role in this particular result.”

Louise Bowman, MD (University of Oxford), a co-principal investigator of REVEAL, told TCTMD that it is difficult to say “categorically” that the benefit observed with anacetrapib is solely the result of lowering LDL cholesterol. However, “what we’ve seen is consistent with the LDL hypothesis and our results don’t fit with there being additional benefit from raising HDL cholesterol,” she said. 

The study was published simultaneously in the New England Journal of Medicine.

A Long, Strange Trip It’s Been

The CETP inhibitors generated a lot of excitement in the early days, particularly since many believed that raising HDL cholesterol levels would help reduce the residual risk of cardiovascular events among patients with well-treated LDL cholesterol levels.

Bad news first emerged, though, way back in 2006 when Pfizer announced they were halting development of torcetrapib after a large study showed the drug increased the risk of death and cardiovascular events. Studies testing the other CETP inhibitors were less disastrous—neither agent appeared to kill patients—but dalcetrapib was stopped due to lack of clinical efficacy and the evacetrapib clinical outcomes study revealed no benefit.

In the REVEAL trial, which included 30,449 adults with atherosclerotic vascular disease who were treated with intensive lipid-lowering therapy, HDL cholesterol levels more than doubled from 40 mg/dL at baseline to 85 mg/dL at the study midpoint with anacetrapib. In contrast, LDL cholesterol was reduced from 61 mg/dL to 38 mg/dL and non-HDL cholesterol from 92 mg/dL to 79 mg/dL. 

Overall, the primary endpoint, a composite of coronary death, MI, or coronary revascularization, occurred in 10.8% of patients who received anacetrapib and in 11.8% of those treated with placebo (RR 0.91; 95% CI 0.85-0.97), a benefit that did not emerge for the first 2 years. Regarding individual outcomes, there was a 13% lower risk of MI and a 10% lower risk of coronary revascularization. The reduction in coronary death was not statistically significant.   

The investigators point out that while HDL increased, the difference in achieved non-HDL cholesterol between the anacetrapib- and placebo-treated patients (17 mg/dL) would translate into a 10% reduction in the risk of MI and coronary death, a reduction that is line with what they observed.

Gregg Stone, MD (Columbia University Medical Center, New York, NY), who was not involved in REVEAL, noted that while the study was positive, the effect size is small. With an absolute difference of 1% between treatment arms, there is just a 0.25% difference in events per year over the study’s 4-year duration.

“It’s almost exactly what would have been predicted from the reduction in LDL cholesterol,” Stone told TCTMD. “It’s also very similar to what was seen with ezetimibe in the IMPROVE-IT trial. The good news was there were no substantial side effects. . . . It seems like raising the HDL didn’t do any harm, but it also didn’t do any good.”

Stone views anacetrapib as a modest LDL-lowering agent, pointing out that even if it was approved by regulatory agencies, there are other less expensive ways to lower LDL cholesterol. Still, “the drug did what it was supposed to do—patients did do better who were on this drug and the side effect profile was favorable,” he said.

Overall, blood pressure increased 0.7 mm Hg with treatment and the risk of new-onset diabetes was lower with the CETP inhibitor. Stone said anacetrapib is a compound similar to evacetrapib, and suggested one of the possible reasons that drug failed to show a clinical benefit is that the ACCELERATE trial was simply too short at 26 months. 

Speaking with the media, Landray said there is a clinical role for anacetrapib, noting that one in 10 patients treated with placebo, despite aggressive treatment with high-intensity statins, had a clinical event during the study. “I think, as a clinician, it’s an interesting and important result,” he said. Bowman agreed, also likening anacetrapib to ezetimibe, saying it is a “potentially useful therapy” for high-risk patients in need to additional LDL lowering.