CHICAGO – The experimental oral agent anacetrapib increased HDL cholesterol levels by a staggering 138%, compared with placebo, in high-risk patients and did so without the negative side effects that plagued another drug in the same class.
Dr. Suzanne Oparil: "Conceivably this could take over for a statin."
When compared with placebo at 24 weeks, once-daily anacetrapib increased HDL levels from 40 mg/dL to 101 mg/dL and decreased LDL levels by 40% from 81 mg/dL to 45 mg/dL in the double-blind phase III Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial.
"This is a total change in what lipids can be," said senior investigator Dr. Christopher Cannon, who went one step further in a statement describing anacetrapib as having a "knock-your-socks-off effect on HDL and a jaw dropping effect on LDL" among 1,623 patients already taking a cholesterol-lower statin and had LDL levels consistent with recommended guidelines.
Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor designed to fight hypercholesterolemia by raising levels of HDL. The strategy was called into question, however, after the experimental CETP inhibitor torcetrapib was found to have off-target effects in the adrenal glands, leading to increased blood pressure, mortality and cardiovascular events.
Anacetrapib had an acceptable side-effect profile, with no effects on blood pressure electrolytes or aldosterone through 76 weeks of follow-up, Dr. Cannon, with Brigham and Women’s Hospital, Boston, reported at a press briefing at the annual scientific sessions of the American Heart Association.
The prespecified, adjudicated composite end point of death from cardiovascular causes, MI, hospitalization for unstable angina or stroke occurred in 16 anacetrapib-treated patients and in 21 placebo-treated patients.
Although the trial was not designed as an outcome study, a Bayesian analysis indicated a 94% predictive probability that anacetrapib would not increase cardiovascular events by 25% as seen with torcetrapib.
In addition, anacetrapib reduced the need for revascularization by two-thirds, compared with placebo (8 patients vs. 28 patients), a finding that Dr. Cannon said convinced him that the strategy of CETP inhibition works.
Invited discussant Dr. Thomas Luscher, professor and chair of cardiology at University Hospital, Zurich, said anacetrapib results in impressive changes in lipid profiles beyond that achieved by statins and that these changes are likely to provide prognostic benefit. It remains to be shown whether the larger HDL particles generated with CETP inhibition by anacetrapib are biologically normal.
The REVEAL follow-up trial of anacetrapib vs. placebo is being launched in Europe, North America and Asia in 30,000 patients with occlusive arterial disease, with a primary end point of coronary death, MI or coronary revascularization, Dr. Cannon announced during the press conference.
Dr. Mariell Jessup, who moderated the conference, said, "With 30,000 [patients], we’ll learn a lot more, but it’s really exciting news for patients and the potential for lowering morbidity and mortality."
Reporters questioned whether increasing HDL really matters, to which Dr. Jessup remarked that HDL is a potent marker of risk and that older data showed that niacin, which also works by increasing HDL, decreased the need for revascularization. Two trials of niacin are also underway that may provide more contemporary data.
Although niacin, which can be hard for some patients to tolerate, had pronounced effects on LDL and HDL, they "paled in comparison to DEFINE," said Dr. Jessup of the University of Pennsylvania, Philadelphia.
There is some concern that the drug might be too powerful and potentially push levels too low, as 18% of patients had to discontinue treatment after their LDL cholesterol level fell below 25 mg/dL.
"It’s an ongoing question in every lipid trial we do whether it could get too low, and we’ve not seen it yet," Dr. Cannon said, adding that when managing patients on both drugs one could simply reduce the level of statin therapy. He does not foresee front-line monotherapy with anacetrapib, but rather using it as an add-on to statins or as an option in patients unable to tolerate statins.
But Dr. Suzanne Oparil said the question of whether anacetrapib could potentially replace statins as first-line treatment should be an open one. "Potentially, why not?" she remarked in an interview. "They’re being very cautious because statins are mandated for anyone with any hint of cardiovascular disease or risk. But working things out, and particularly if it’s shown that getting the LDL too low – as you can by combining this drug with a statin – is bad, then conceivably this could take over for a statin." Dr. Oparil is professor of medicine, physiology, and biophysics and director of the vascular biology and hypertension program at the University of Alabama, Birmingham