An experimental drug more than doubles the level of high-density lipoprotein cholesterol (HDL) and cuts low-density lipoprotein (LDL) cholesterol nearly in half without the blood pressure increase linked to another agent in its class, according to late-breaking clinical trial results presented 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 who took either 100 mg of the cholesterylester transfer protein (CETP) inhibitor anacetrapib, or a placebo for 18 months at 153 centers in 20 countries. The patients were already being treated with a statin and/or other lipid-lowering medicine and had achieved their goal level of LDL cholesterol.

The study's primary endpoints were the percent change in LDL and safety as measured by a number of clinical and laboratory measures as well as cardiovascular (CV) events.

Anacetrapib reduced LDL by 40 percent - from 81 mg/dL to 49 mg/dL. It also more than doubled the level of HDL from 40 mg/dL to 101 mg/dL without raising blood pressure.

"Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL," said Christopher P. Cannon, M.D., senior investigator of the TIMI Study Group in the cardiovascular division of Brigham and Women's Hospital in Boston, Mass. "These changes are striking because virtually all the patients in the study were already taking cholesterol-lowering drugs and achieved previously unattainable levels of good and bad cholesterol."

The experimental drug is one of a new class that blocks the ability of the CETP enzyme to transfer cholesterol particles from HDL to LDL.

Elevated LDL and low levels of HDL are both risk factors for cardiovascular disease. Statins reduce LDL and lessen cardiovascular risk. Despite statin therapy, many patients still have a high risk of cardiovascular disease.

High natural levels of HDL are associated with lower cardiovascular risk, which is why researchers have been looking for ways to increase HDL levels, said Cannon, an associate professor of medicine at Harvard Medical School.

"No treatments raise HDL levels as substantially as seen here (more than doubling of the levels)," said Cannon.

Patients in DEFINE were 62.5 years old on average; 23 percent were women; 17 percent were Asian, black or multiracial and 15 percent 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.

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.

Although the study was not designed or powered to assess the effects of anacetrapib on cardiovascular events, fewer cardiovascular events occurred in the anacetrapib group than in the statin-only group. The full efficacy and safety of anacetrapib will be evaluated in a larger Phase III trial, Cannon said.

"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," he 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."

Co-authors are Sukrut Shah, R.Ph., Ph.D.; Hayes M. Dansky, M.D.; Michael Davidson, M.D.; Eliot A. Brinton, M.D.; Antonio M. Gotto Jr., M.D., D.Phil.; Michael Stepanavage, M.S.; Sherry Xueyu Liu, M.S.; Patrice Gibbons, M.S.; Tanya B. Ashraf, B.A.; Jennifer Zafarino, M.S.; Yale Mitchel, M.D. and Philip Barter, M.D., Ph.D. Author disclosures are on the abstract.

Merck Research Laboratories, Rahway, N.J., funded the study.