Systematic Review of CETP Inhibitors for Increasing High-Density Lipoprotein Cholesterol: Where Do These Agents Stand in the Approval Process?

The role that low levels of high-density lipoprotein cholesterol (HDL-C) plays in coronary artery disease and ischemic heart disease is well established. As such, therapies targeting low HDL-C levels have been of great therapeutic interest. These therapies include nonpharmacological methods such as exercise, tobacco cessation, weight reduction, moderate alcohol intake, and increasing dietary monounsaturated fatty acids and polyunsaturated fatty acids. Additionally, pharmacological methods of increasing HDL-C have been of great interest, with 2 classes of drugs, fibric acid derivatives and nicotinic acid, and have mixed trial results when used on top of standard lipid therapy. However, a new class of medications, cholesteryl ester transfer protein inhibitors, has shown increases in HDL-C of over 100%. However, early trial results with torcetrapib showed an increase in mortality, although this was attributed to off-target toxicity. Dalcetrapib was found to be safer than torcetrapib, but data released in 2012 showed no additional benefit in patients suffering an acute coronary syndrome event. Two newer agents, anacetrapib and evacetrapib, in early-phase clinical trials have shown to be safer than torcetrapib and significantly more potent than dalcetrapib (both increase HDL-C by a greater amount and both have a significant effect on low-density lipoprotein cholesterol). It remains to be seen whether the use of cholesteryl ester transfer protein inhibitors will result in clinical benefit in large, randomized double-blind trials and whether any agents in this class will ever be approved for clinical use.