Anacetrapib, DEFINE TRIAL

'DEFINE optimism: Now that we have a safe cholesteryl ester transfer protein inhibitor—could it be effective?'

Our previous experience with Torcetrapib has instilled cautious optimism regarding pharmaceutical approaches to reducing LDL cholesterol and raising HDL cholesterol utilizing cholesteryl ester transfer protein (CETP) inhibitors. The safety profile of Anacetrapib, another CETP inhibitor has revived our interest in this direction with its remarkable safety profile as described in the recently published Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial.

Despite our best modern antihyperlipidemic treatment approach, residual coronary atherosclerotic disease activity remains present in some individuals. t the present time, our approach involves using combinations of drug classes that aim to lower the LDL cholesterol to specified targets depending on individual patient risk. While the risk of low HDL cholesterol is recognized, pharmacologic .approaches to raise HDL cholesterol as a secondary goal to lipid management has been generally unsuccessful.

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.

Further development of Torcetrapib, the first CETP inhibitor, was dramatically halted during phase III randomized clinical trials due to a 25% increase in cardiovascular adverse events within the cohort that received the active treatment. Torcetrapib was also associated with elevated aldosterone levels leading to electrolyte abnormalities and elevated blood pressures.

Anacetrapib is a CETP inhibitor that reduces the LDL cholesterol levels and increases HDL cholesterol level. Designed as a safety, efficacy and tolerability trial, the DEFINE trial was a 76-week prospective, randomized, double blind placebo control, Phase III trial. A total of 2757 patients from 20 countries were screened between April 1, 2008 and January 15, 2009. About 1623 patients, ages 18-80, with a history of CHD or CHD risk equivalent entered the study. These patients had a LDL cholesterol level <100 and 99.3% were on statin therapy. Patients were randomized 1:1 to placebo (n= 812) or 100 mg Anacetrapib daily (n=811). 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.

At 24 weeks, LDL cholesterol levels differences in the treatment arms were highly significant with a decrease from 81 to 45 mg/dL (~40% reduction) in patients taking Anacetrapib as compared to 82 to 77 mg/dL (~6% reduction) for those on placebo. Similarly, there was a 138.1% increase in HDL cholesterol in patients taking Anacetrapib. Although not designed for this purpose, in the DEFINE study there were impressive differences noted in atherosclerotic outcomes or revascularization rates for those that were taking Anacetrapib compared to those with placebo (8 vs. 28 patients respectively, P = 0.001).

The safety of Anacetrapib as demonstrated in the results of DEFINE trial have revived significant interest (and optimism) in future use of CETP inhibition. The DEFINE trial observed no difference in adverse cardiovascular events in the cohort that received Anacetrapib versus those that received placebo. There was no significant treatment differences observed in composite of death from cardiovascular causes, hospitalization from unstable angina, myocardial infarction or stroke in either cohort. Furthermore, there were no observable differences in serum aldosterone levels, electrolyte parameters and blood pressure between treatment arms in this study.

Limitations of the study include a small population size with the majority involving Caucasians. Further studies are also needed to evaluate the effects of decreasing LDL cholesterol to extremely low levels as there have been no studies on this case. In DEFINE study; Anacetrapib was discontinued in 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, the developers of Anacetrapib have launched a definitive randomized clinical trial of 30,000 patients over a 4-year period with CHD who are already on statin therapy to receive Anacetrapib or placebo with mortality and morbidity as the primary outcome. As one reflects on DEFINE study, it appears that CETP inhibitors are effective in lowering LDL cholesterol, as well as increasing HDL cholesterol. Furthermore, this study suggests that lowering LDL cholesterol and increasing HDL cholesterol levels lead to significant reduction in revascularizations and cardiovascular events. However, one might wonder if HDL cholesterol generated by CETP inhibitor retains its atheroprotective function? Consequently, does lowering of LDL cholesterol to extremely low levels be beneficial? In vitro studies have shown that HDL cholesterol particles isolated from patients being treated with CETP inhibitors have an enhanced functionality at a high HDL cholesterol concentration. A more extensive analysis of potential benefits of extremely low LDL cholesterol may be an area of future interest. We have come a long way in our search for combined pharmacologic therapies in patients with high risk cardiovascular disease and to say the least, the findings of the DEFINE study are not only a relief—they are indeed breathtaking.

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