CETP Inhibitors: Will They Live up to Their Promise?
- PDF / 161,901 Bytes
- 8 Pages / 595.276 x 790.866 pts Page_size
- 92 Downloads / 168 Views
LIPIDS (JM ORDOVAS, SECTION EDITOR)
CETP Inhibitors: Will They Live up to Their Promise? Valerie Cheung & Robert A. Hegele
Published online: 15 October 2011 # Springer Science+Business Media, LLC 2011
Abstract Cholesterol ester transfer protein (CETP) exchanges lipids between circulating plasma lipoproteins and has been considered as an excellent drug target for raising plasma levels of high-density lipoprotein (HDL) cholesterol. However, HDL displays considerably more complexity than low-density lipoprotein (LDL) in terms of structure, proteomics, and several physiologic functions. After the discouraging results from clinical trials of torcetrapib (an early inhibitor of CETP that dramatically raised HDL cholesterol levels), there is renewed hope that dalcetrapib and anacetrapib are sufficiently different structurally and functionally to justify large-scale clinical end point studies. In fact, such trials are already underway in the case of dalcetrapib and are imminent in the case of anacetrapib. These end point trials will show whether CETP inhibition will live up to its promise for atheroprotection. Keywords Atherosclerosis . Cardiovascular risk . Cholesterol ester transfer protein . High-density lipoprotein . Reverse cholesterol transport
Introduction Cardiovascular disease (CVD) is the leading cause of death globally [1]. Statins reduce low-density lipoprotein (LDL) cholesterol (C): for every 1-mmol/L (38.7 mg/dL) decrease V. Cheung : R. A. Hegele Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8
in LDL-C, major CVD events decrease by 21% and total mortality decreases by 12% [2]. Despite the efficacy of statin therapy, there remains a high residual risk of CVD events. Reduced levels of high-density lipoprotein (HDL)C may contribute to this residual risk [3]. According to the Framingham study, HDL-C is the strongest lipid risk factor for CHD when compared with fasting plasma triglyceride (TG), LDL-C, and total cholesterol levels. Higher levels of HDL-C correlate inversely with coronary heart disease (CHD) [4]. An increase in 1 mg/dL (0.26 mmol/L) of HDLC is associated with a 2% to 3% decrease in CVD risk [5]. Nonpharmacologic measures that raise HDL-C include weight loss, prudent diet, smoking cessation, aerobic exercise, and moderate alcohol intake. In addition, pharmacologic therapies that raise HDL-C levels include niacin, fibrates, and newer agents such as inhibitors or modulators of cholesterol ester transfer protein (CETP). CETP is involved in the reverse cholesterol transport (RCT) pathway [3] and exchanges lipids between circulating plasma lipoproteins. Among CETP inhibitors, torcetrapib reached later-stage clinical trials. However, torcetrapib was paradoxically found to increase total mortality and adverse CVD outcomes [6], so its development was terminated in 2006. Two other agents from the same general class of CETP inhibitors, namely dalcetrapib and anacetrapib, are currently being evaluated in clinical trials. This article reviews the mechan
Data Loading...
