AHA 2010: CETP-inhibitor Anacetrapib has Dramatic Effects on HDL, LDL

Study shows that cholesteryl ester transfer protein (CETP) inhibitor anacetrapib reduced LDL by 40% and doubled HDL in patients with coronary disease.

Trial results show that the experimental cholesterol drug anacetrapib reduced LDL by 40% and more than doubled HDL without raising blood pressure, according to data presented Wednesday at the American Heart Association’s Scientific Sessions 2010.

Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE) is a randomized, double-blind trial of 1,623 patients at 153 centers in 20 countries with known coronary disease or at very high risk who took either 100 mg of the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib or a placebo for 18 months. The patients were already being treated with a statin and/or other lipid-lowering medicine and had achieved their goal LDL level. Anacetrapib reduced LDL from 81 mg/dL to 49 mg/dL. It also increased HDL 138% to 101 mg/dL. The findings were released at the American Heart Association’s Scientific Sessions 2010.

Cardiovascular events were not elevated with anacetrapib (2.0% versus 2.6% in the placebo arm) unlike what was observed in trials involving its predecessor, torcetrapib, which were halted in 2006 when the drug showed high levels of cardiovascular events and mortality. Need for revascularization was reduced by about two-thirds, a highly significant finding. “This is a total change in what lipids can be achieved,” said Christopher P. Cannon, MD, of Brigham and Women's Hospital in Boston.

“The very exciting thing is that we’re entering an era where we have medications that could raise HDL. No treatments raise HDL levels as substantially as seen here. It’s been a very difficult lipid parameter to impact,” Cannon said, noting that niacin is the only other drug proven to raise HDL.

The goal of this trial was to do a robust-sized safety study given the prior problems of torcetrapib. Patients in DEFINE were 62.5 years old on average; 23% were women; 17% were Asian, black or multiracial; and 15% were Hispanic. The study included interim safety analyses at six and 12 months, and researchers found no change in blood pressure or electrolytes among participants.

“We’re very encouraged by this. It’s a moderate-size safety study so we have reassurance that we can now move forward and really test this,” Cannon said. He announced that the next step is a worldwide study of 30,000 patients with heart disease to study anacetrapib on the background of statin therapy, with a scheduled four-year follow-up period.

The experimental drug is one of a new class that blocks the ability of the CETP enzyme to transfer cholesterol particles from the good HDL to the bad LDL. In the trial, patients’ levels of aldosterone, a hormone produced in the adrenal gland that affects kidney function and blood pressure, didn’t change. The researchers also found no increase in muscle problems or liver function abnormalities between groups -- a side effect occasionally associated with statins.

“This agent provides us a very strong add-on treatment to statins that dramatically increases the good cholesterol and dramatically further decreases the bad cholesterol,” Cannon said. “If the cardiovascular effects are borne out by future research, it would be a very promising approach to reducing cardiovascular events in patients with or prone to atherosclerosis.”