Role of CETP inhibitors in the treatment of dyslipidemia.
OBJECTIVE
This review summarizes novel human data on cholesteryl ester-transfer protein (CETP) and atherosclerosis and the possible use of CETP inhibitors in the treatment of dyslipidemia. In addition, it will underline that therapeutic targeting of the high-density lipoprotein (HDL) metabolism entails more than simply observing changes in cholesterol levels of this lipoprotein.


RESULTS
Two pharmacological small-molecule inhibitors of CETP, JTT-705 and torcetrapib, have recently been shown to effectively raise HDL cholesterol in humans without serious side effects when either used as a monotherapy or combined with statins that lower low-density lipoprotein cholesterol. Importantly, prospective data from the Epic-Norfolk study furthermore indicate that elevated CETP concentration in conjunction with elevated triglyceride levels are associated with increased odds for cardiovascular events. Data from the Diabetic Atherosclerosis Intervention Study furthermore show that elevated CETP concentration is associated with increased progression of coronary atherosclerosis in patients with type 2 diabetes who use fenofibrate.


CONCLUSIONS
Long-term studies will have to show whether CETP inhibition decreases the risk of atherosclerotic disease in dyslipidemic patients. Increased CETP activity might be detrimental under hypertriglyceridemic conditions which is of importance when considering that a large proportion of patients at increased risk from coronary artery disease exhibit elevated triglyceride levels. Studies into the effects of CETP inhibition in hypertriglyceridemic patients therefore seem warranted. Awaiting the first data on the effect of CETP inhibition on surrogate endpoints for atherosclerosis, this review furthermore outlines that the complexity of HDL metabolism will necessitate a wide variety of studies on many aspects of this intriguing lipoprotein.
van der Steeg
W A
WA
Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands.
Kuivenhoven
J A
JA
Klerkx
A H
AH
Boekholdt
S M
SM
Hovingh
G K
GK
Kastelein
J J P
JJ
D000577:Amides; D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000037:antagonists & inhibitors; D004952:Esters; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*
D000577:Amides; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D006023:Glycoproteins; D000960:Hypolipidemic Agents; D011804:Quinolines; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; C483909:torcetrapib