Anacetrapib
Anacetrapib (MK-0859, Merck) is cholesteryl ester transfer protein inhibitor that raises  high-density lipoprotein (HDL) cholesterol and reduces low-density  lipoprotein (LDL) cholesterol.  Cholesteryl ester transfer protein (CETP), also known as plasma lipid  transfer protein, is a plasma protein that amasses triglycerides (TG)  from VLDL cholesterol or LDL cholesterol and actively exchanges them for  cholesteryl esters from HDL cholesterol. CETP inhibition leads to  increase in size of HDL cholesterol particle and apolipoprotein A-I  concentration, which is a major HDL protein.  Development of Torcetrapib, the first CETP inhibitor, was halted during a phase III randomized clinical trial due to a  25% increase in cardiovascular adverse events within the cohort that received the active treatment.  The increase in adverse events was thought to be secondary to "off target" toxicity including elevated aldosterone levels and consequent electrolyte abnormalities and  elevated blood pressure.

# Results of the Phase II DEFINE Study
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## Design of DEFINE
DEFINEwas a Phase II randomized, double-blind, placebo-controlled trial designed to  assess the safety and lipid-lowering efficacy of anacetrapib. Patients in the study had known coronary heart disease or were at an elevated risk for the devlopment of coronary heart disease.       These patients had a LDL cholesterol level <100 and 99.3% were on statin therapy.  Patients (1,623) were randomized to treatment with either 100 mg of anacetrapib or placebo daily for 18 months in a 1:1 fashion.  The primary end point was percent change in LDL cholesterol from baseline at 24 weeks and safety and tolerability at 76 weeks. Percent change in HDL cholesterol from base line was a secondary end point.

## Efficacy Results of DEFINE
The LDL  cholesterol was reduced from 81 mg per deciliter (2.1 mmol  per liter) to 45 mg per deciliter (1.2 mmol per liter) at 24 weeks in the  anacetrapib group versus 82 mg per deciliter  (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) among  placebo treated patients (P<0.001). This represents a 39.8% reduction with anacetrapib realtive to placebo. Anacetrapib increased the HDL cholesterol level from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter  (2.6 mmol per liter) versus placebo which increased HDL from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per  deciliter (1.2 mmol per liter) (P<0.001). This represents a  138.1% increase in HDL associated with anacetrapib treatment versus placebo.
It should be noted that the trial was underpowered to detect a  meaningful difference in clinical events. The composite of death from  cardiovascular causes, hospitalization from unstable angina, myocardial  infarction or stroke occurred in 2% (16) of patients treated with  Anacetrapib and 2.6% (21) in placebo group.  The decrease in total  cardiovascular events and total revascularizations was very impressive  (8 vs. 28, P = 0.001).

## Safety Results of DEFINE
Throughout the 76 weeks of therapy there were no changes in either systolic or diastolic blood pressure or electrolyte or  aldosterone levels with anacetrapib as compared with placebo.  In this modest sized study there were no liver function test abnormalities and no excess of myalgias. It should be noted that a study of this size may not exclude a risk of low frequency events such as Hy's law.

## Limitations of DEFINE
Limitations of the study include the fact that this was a small population and the majority of patients were Caucasians. Further studies are also needed to further evaluate the effects of decreasing LDL cholesterol to extremely low levels.  In the DEFINE study; Anacetrapib was discontinued in those patients with extremely low cholesterol levels. Larger studies are required to ensure the safety and tolerability of this drug. Given the promising results of this study, Merck has already launched the REVEAL HPS-3 TIMI-55 trial in collaboration with researchers at Harvard and Oxford. This study will include 30,000 patients with CHD who are already on statin therapy.

# REFERENCES
1. Barter PJ, Caulfield M, Eriksson M, et al. Effects of Torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.
2. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004;350:1505-15.
3. Cannon CP, Shah S, Dansky HM,  et al. Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. N Engl J Med 2010; DOI: 10.1056/NEJMoa1009744.
4. Cannon CP, Dansky HM, Davidson M, et al. Design of the DEFINE trial: Determining the Efficacy and tolerability of CETP Inhibition with Anacetrapib. Am Heart J 2009;158(4):513.e3-519.e3.
5. Forrest MJ, Bloomfield D, Briscoe RJ, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008;154:1465-73.
6. Gotto AM. High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease. Am Heart J 2002;144:S33-42
7. www.wikipedia.com
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