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Anacetrapib (USAN,[1] pINN; codenamed MK-0859, Merck) is a CETP inhibitor being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease.[2]

Clinical trials[edit]

At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New York, Oct 4-7, 2007), Merck reported on a Phase IIb study. The eight-week study reported dosage correlated reduction in LDL-C and increases in HDL-C levels with no corresponding increases in blood pressure in any cohort. The increase in HDL was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133 percent at doses of 10 mg, 40 mg, 150 mg and 300 mg.

Merck performed a dose-ranging study of anacetrapib,[3] with the results presented in 2009.[4]

A 2013 study of 407 Japanese patients found anacetrapib reduced LDL and raised HDL alone or with atorvastatin.[5]

A concern raised in October 2013 is related to the time that the drug remains in people's bodies after they stop taking it. The report shows that even after 4 years the levels of the medicine were still detectable.[6]

A 2014 study found HDL and drug levels remained elevated 2 to 4 years after discontinuation.[7]

Phase III trial (DEFINE)[edit]

Merck started a Phase III trial to assess the drug's effects on LDL, HDL, clinically measurable cardiovascular events, and safety;[8] It was code-named DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib), and was described as a medium-sized safety and efficacy trial.[9]

Early results from the DEFINE trial were presented on November 17 at AHA2010, a meeting of the American Heart Association. At 100 mg dosage, LDL decreased by 36%, lipoprotein(a) decreased by 36.4%, while HDL increased by 138%. Systolic blood pressure showed no increase, and there was no association with increased CVD death or events.[10] In 2012 the results were updated to 39.8% of LDL decrease.[11]

Cardiologist Steve Nissen (in 2010) described DEFINE as a medium-sized safety trial intended to find out "whether anacetrapib would show the same increase in adverse cardiovascular events that was seen with torcetrapib." Fortunately, anacetrapib did not. In his opinion the DEFINE study was too small to show a clear benefit, but the trends in the major adverse cardiovascular events were going in the right direction.[12]

A two-year follow up is due to complete by December 2012.[needs update]

As of March 2016 the trial is due to complete in November 2017.[8]

Phase III trial (REVEAL)[edit]

The REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification) will assess whether there is clinical benefit associated with anacetrapib. REVEAL recruited 30,000 participants[13] for a randomized, double-blinded, placebo-controlled trial.

The study will compare patients with a history of vascular disease (such as heart disease, cerebrovascular disease, and peripheral vascular disease) on 100 mg of anacetrapib daily to those on placebo, to determine if the addition of anacetrapib reduces the risk of major coronary events (defined as the composite of coronary death, myocardial infarction, and coronary revascularization).[14]

On June 27, 2017, Merck announced that anacetrapib met its primary endpoint of significantly reducing major coronary events in patients who were already receiving an effective LDL-C lowering regimen. At the end of August, the full results of the trial will be presented at the European Society of Cardiology 2017 Congress in Barcelona, Spain.[15]

See also[edit]

Other CETP inhibitors:


  1. ^ "Statement on a nonproprietary name adopted by the USAN Council: Anacetrapib" (PDF). American Medical Association. 2007. Retrieved 2008-01-19. 
  2. ^ Gutstein DE, Krishna R, Johns D, et al. (2012). "Anacetrapib, a Novel CETP Inhibitor: Pursuing a New Approach to Cardiovascular Risk Reduction". Clinical Pharmacology & Therapeutics. 91 (1): 109–122. doi:10.1038/clpt.2011.271. 
  3. ^ "MK0859 Dose-Ranging Study". 
  4. ^ Bloomfield D, Carlson GL, Sapre A, et al. (October 2009). "Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and co-administered with atorvastatin in dyslipidemic patients". Am. Heart J. 157 (2): 352–360. PMID 19185645. doi:10.1016/j.ahj.2008.09.022. 
  5. ^ "Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with dyslipidemia.". Atherosclerosis. 230: 52–60. Sep 2013. PMID 23958252. doi:10.1016/j.atherosclerosis.2013.05.012. 
  6. ^ Matthew Herper (October 22, 2013). "Merck heart drug runs into a new worry". 
  7. ^ "Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease.". The American Journal of Cardiology. 113: 76–83. 2014-01-01. PMID 24188894. doi:10.1016/j.amjcard.2013.08.041. 
  8. ^ a b "Phase III Study to Assess the Tolerability and Efficacy of Anacetrapib in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease (DEFINE)". U.S. NIH. 
  9. ^ Cannon CP, Dansky HM, Davidson M, et al. (October 2009). "Design of the DEFINE trial: determining the Efficacy and tolerability of CETP Inhibition with AnacEtrapib". Am. Heart J. 158 (4): 513–519.e3. PMID 19781408. doi:10.1016/j.ahj.2009.07.028. 
  10. ^ Cannon, Christopher; S. Shah; et al. (November 17, 2010). "Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease". The New England Journal of Medicine. 363 (25): 2406–2415. doi:10.1056/NEJMoa1009744. 
  11. ^ Antonio M Gotto Jr.; Jennifer E Moon (August 2012). "Safety of Inhibition of Cholesteryl Ester Transfer Protein With AnacetrapibThe DEFINE Study". Expert Rev Cardiovasc Ther. 
  12. ^ O'Riordan, Michael (November 17, 2010). "DEFINE: Large effects on LDL and HDL cholesterol with CETP inhibitor anacetrapib". 
  13. ^ "HPS3/TIMI55 – REVEAL trial of Anacetrapib in high-risk vascular patients recruits the target of 30,000 participants" (PDF). University of Oxford Clinical Trial Service Unit & Epidemiological Studies Unit. September 2, 2013. Archived from the original (PDF) on December 3, 2013. 
  14. ^ National Institute of Health (January 30, 2012). "REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification". 
  15. ^ "Merck Provides Update on REVEAL Outcomes Study of Anacetrapib". June 27, 2017. 

Further reading[edit]