November 17th, 2010

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 cholesteryl ester transfer protein (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 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 anacetrapib, 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 endpoints 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 HDL by 138%:

LDL at baseline and 24 weeks:

  • Anacetrapib: 81 mg/dL and 45 mg/dL
  • Placebo: 82 mg/dL and 77 mg/dL

HDL at baseline and 24 weeks:

  • Anacetrapib: 41 mg/dL and 101 mg/dL
  • Placebo: 40 mg/dL and 46 mg/dL

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

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

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

8 Responses to “Anacetrapib: “Knock-Your-Socks-Off Effect on HDL and a Jaw-Dropping Effect on LDL””

  1. The drug clearly shows promise – and I like that Merck is now going to do a large trial and test whether the drug can safely reduce risk.
    I wrote a blog that expresses my thoughts for the Forbes web site…
    if you are interested see

  2. I would hold on to my legs (sans socks) and my head (jaw up) while sliding down the slippery slope of biomarkers!
    Outcomes, hard outcomes, nothing but the cold hard outcomes!

  3. Leon Hyman, Ms M.D. says:

    Will it safely alter the incidence of MI, CVA’s and development of angina? Pricing will also be a strong consideration,especially comparing it to the statins. By the time this could reach the market, there will be a generic lipitor available.

    Competing interests pertaining specifically to this post, comment, or both:

  4. Dramatic reduction in LDL and monumental increase in HDL but no difference in combined outcomes. Had they not included 4 MIs in the post treatment placebo group, it would have faired much worse.

    I fail to see how rendering HDL cholesterol ineffective is going to improve outcomes. I can only hope that I am wrong.

  5. I viewed Harlan’s Forbes website and agree that Merck deserves credit for moving Anacetrapib to the next study to get “the cold hard outcomes” that the leg-holding, jaw thrusting Sanjay requests.

  6. By cold hard outcomes, I mean death, MI or stroke. Revascularization does not belong to that echelon as it is driven by individual, institutional, local, and national practice patterns. Even ischemia-driven revascularization is somewhat arbitrary because the threshold of clinical importance has not been clearly delineated (10% or 20% ischemic LV?). The problem with such a primary composite endpoint is that the pomelo (revasc) will undeniably dominate the kumquats (death, MI)!

  7. My take is that
    1)Anecetrapib does not raise BP unlike Torcetrapib
    2)Massive changes in lipids but no drop in CRP is worrisome and all cause mortality a bit higher also somewhat worrisome but study clearly underpowered for events
    3) Event based trial is the only way out and Merck is doing the right thing although at a potentially considerable risk
    4) Dalcetrapib trial is fully recruited and results will likely be available before Anecatrapib events trial is completed
    CETP inhibition remains a dicey target but we are at an equipoise at this time

    Competing interests pertaining specifically to this post, comment, or both:
    I am on the steering Committee of DalOutcome Trial

  8. The differential effect on LDL (36% reduction) and apoB (18% reduction) with anacetrapib is similar to what was observed with torcetrapib in Illuminate (20% LDL vs 10% apoB reduction) but quite different from the niacin effect observed in HATS trial (42 % LDL vs 40% apoB reduction). This might imply a phenotypic change in LDL with both anacetrapib and torcetrapib.

    The fact that BP and aldosterone did not change with anacetrapib can only be viewed as ‘reassuring’ if one is convinced that these variables contributed largely to adverse cardiovascular events in Illuminate (note stroke events were not different, and noncardiovascular deaths due to cancer and infection were numerically higher with torcetrapib). One has to remain open to the possibility that these factors may not be causal and that other unforeseen causal factors might emerge.

    The Bayesian analysis in DEFINE (using a noninformative prior) reported a 94% probability of ruling out a 25% excess CV risk with anacetrapib. If one were to use prior information from illuminate (1.25, 95% CI 1.09, 1.44), the probability of ruling out 25% excess risk would be 61%, which is hardly reassuring.

    Bottom line, although the data appear encouraging at first look, we must remain prudently skeptical. The proof of the pudding is in the eating, let us not ‘overegg’ it!