Anacetrapib: “knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL”

Following the failure of torcetrapib in 2006 the future of CETP inhibitors appeared quite troubled. Now, with the results of  DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib), presented at the AHA in Chicago and published online simultaneously in the New England Journal of Medicine, the future for this novel class of drugs appears much brighter, but the final decision about anacetrapib will have to wait for a larger clinical trial.

DEFINE was designed to assess the side-effect and overall safety profile of anaceptrapib, as well as its effects on lipids. The trial randomized 1623 patients already taking statins or other lipid-lowering agents to either anacetrapib or placebo for 18 months.

The primary endpohnts of the study were the percent change in LDL at 24 weeks and the side-effect profile at 76 weeks. Compared to its effect on placebo, anacetrapib reduced LDL by 40% and raised raised HDL by 138%:

LDL at baseline and 24 weeks:

  • Anacetrapib: 81 mg/dl- 45 mg/dl
  • Placebo: 82 mg/dl -77 mg/dl

HDL at baseline and 24 weeks:

  • Anacetrapib: 41 mg/dl- 101 mg/dl
  • Placebo: 40 mg/dl -46 mg/dl

There were no differences between the groups in blood pressure, electrolytes, or aldosterone levels associated with anaceptrapib.

There were 16 (2%) adjudicated cardiovascular events in the anaceptrapib group versus 21 (2.6%) events in the placebo group. There were 8 revascularizations in the anaceptrapib group versus 28 in the placebo group.

“Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL,” said Chris Cannon in an AHA press release.

Here is the AHA press release:

New drug significantly raises good cholesterol, cuts bad nearly in half

Study Highlights:

  • An experimental cholesterol drug significantly raises good cholesterol while reducing bad cholesterol by almost half.
  • The new drug did not appear to have the blood pressure-raising effects of another agent in the same class that was linked to increased deaths.
  • If borne out by larger studies, the research could provide a new class of cholesterol-modifying drugs.

CHICAGO, Nov. 17, 2010 — An experimental drug more than doubles the level of good cholesterol and cuts the bad kind 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 milligrams (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 low-density lipoprotein (LDL) cholesterol.

The study’s primary endpoints were the percent change in LDL, known as the “bad” cholesterol associated with the development of clogged arteries, 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 milligrams per deciliter (mg/dL) to 49 mg/dL. It also more than doubled the level of high-density lipoprotein cholesterol (HDL) that helps clear lipids from the bloodstream — 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 the good HDL to the bad 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.



  1. Though I want to congratulate Pharma on its repeated
    trial to raise HDL dramaticaly(also lower the LDL).I cannot ignor the fact that the increase of HDL by 138%
    is out of line for nature.
    Even in pregnancy when conditions must be optimal for the sake of the fetus,HDL peaks at 67 mg/dl,and
    LDL hoovers around 240 mgm/dl,(everybody is happy).
    To reach HDL levels of 100 mgm/dl means a “none
    physiologic”status,or at least formation of HDL3 which
    is not cardioprotective.
    Like anybody else,I hope for sucess in the studies of
    Anacepibib,Still looking back on the other-pevious four preparations,I fear for its lack of sucess.I know why.


  1. […] some respects, the results of this randomized, placebo-controlled large trial are knock-your-socks-off impressive: patients on the drug had, an average, a more-than doubling of their serum HDL levels, […]

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