Anacetrapib: The Next Best Thing Since Statins?

Statins have had a dramatic impact on preventing and treating coronary heart disease (CHD). They lower low density lipoprotein (LDL) cholesterol by as much as 50 percent and significantly reduce the number of heart attacks and strokes. But while statins lower the "bad" LDL cholesterol, they only raise the "good" high density lipoprotein (HDL) cholesterol by 6 to 8 percent. Now there's promise that a new drug, known as a CETP inhibitor, will dramatically raise HDL cholesterol and even lower LDL cholesterol significantly. 

Previous efforts unsuccessful

Population studies have uniformly shown that low levels of HDL cholesterol increase, and high levels of HDL cholesterol decrease, the risk of CHD. Efforts to develop a drug to raise HDL cholesterol levels substantially, however, have been relatively unsuccessful. The most effective drug, niacin, can increase HDL cholesterol by 20 to 30 percent, but its use is associated with troublesome side effects.

Development of CEPT inhibitors

Animal studies found that blocking the action of a protein which normally carries cholesterol esters from HDL to LDL--cholesterol ester transfer protein (CETP)--could raise HDL cholesterol levels considerably.

Based on these results, Pfizer started a large trial (ILLUMINATE) of the CETP-inhibiting drug torcetrapib. Although the drug increased HDL cholesterol by 72 percent, unfortunately during the 12 months of the trial major cardiovascular events and overall mortality were higher in those taking the drug compared to participants on placebo. Further studies on torcetrapib were then discontinued in 2007 and these results were viewed as the possible death knell of CETP inhibitors.

However, CETP inhibitors appear rejuvenated with the exciting results of the DEFINE trial published recently in the New England Journal of Medicine. The 1,623 participants who either had or were at high risk for CHD and already had their LDL cholesterol lowered to the range of 50 to 100 mg/dL with a statin. They were randomized to either a placebo or another CETP inhibitor, anacetrapib, which raised HDL cholesterol by 138 percent and lowered LDL cholesterol by an additional 56 percent. Particularly important was the absence of any increase in cardiovascular events in the treated patients compared with the placebo group.

Will anacetrapib diminish the number of cardiovascular events?

These findings suggest that anacetrapib may be the most important breakthrough since the statins for the management of blood lipid disorders and the prevention of cardiovascular events and deaths.  Still, the bottom line of a drug’s worth cannot be judged by its effects on HDL and LDL cholesterol. There remains the need to determine whether anacetrapib diminishes the number of cardiovascular events and deaths. 

To answer these questions, Merck plans to start the REVEAL trial in approximately 30,000 patients. The company has stated that it will not ask the FDA to approve the drug before 2015 when results of REVEAL are revealed. Nonetheless, keep an eye on this drug--promising findings in the trial may lead to its early termination and a sooner request for FDA approval of anacetrapib.