Counterpoint: Cholesteryl Ester Transfer Protein Antagonism by Drugs—A Poor Choice

The recent failure to prevent coronary disease with torcetrapib, a major inhibitor of the cholesteryl ester transfer protein (CETP)2 system, indicated that this therapeutic approach is disputable. Evaluation of prior knowledge confirms that the rationale of CETP inhibition appears to be based on incorrect physiological assumptions and that the interpretation of the torcetrapib trials may be flawed because of overinterpretation or some ancillary findings, as well as a lack of consideration of some potentially very negative clinical observations. In the present report we consider the major genetic and clinical aspects of the CETP system, as well as the reasons why CETP inhibition has not proved to be a winning strategy. Reverse cholesterol transport, a classic function of HDL in humans and higher species, is handled by a transfer/exchange system regulated by CETP, which was first described 30 years ago. The major function of CETP (molecular weight 74 kDa) is the exchange of cholesterol esters with triglycerides present, particularly in VLDLs,leading to a triglyceride-enriched HDL. Triglyceride catabolism in the newly formed HDL then leads back to a “small, cholesterol ester poor HDL” capable of effective cholesterol removal (1). CETP mutations may cause a reduced effectiveness of the transfer/exchange process, eventually leading to large amounts of cholesterol esters in HDL (2). Clinical evaluation of individuals with inactivating mutations and extremely increased HDL cholesterol (HDL-C) concentrations has led to conflicting findings. Major support came from genetic studies of Japanese communities, in which a large number of citizens displayed dramatically increased HDL-C concentrations but an apparently reduced incidence of coronary heart disease (2). A more detailed examination, however, showed a paradoxically enhanced risk in many individuals with the more marked increases (3). In the Western world, epidemiologic data appear to indicate ineffective protection against cardiovascular disease by HDL-C increases due to CETP …