CETP-inhibition: lessons from the halted dal-HEART programme
Increasing high-density lipoprotein cholesterol by cholesteryl ester transfer protein-inhibition: a rocky road and lessons learned? The early demise of the dal-HEART programme
Landmesser U, von Eckardstein A, Kastelein J, Deanfield J, Lüscher TF.
Eur Heart J. 2012 Jun 13. [Epub ahead of print]
Cardiovascular risk might be reduced by raising HDL-cholesterol, which was supported by studies showing the anti-atherogenic properties of HDL  and a remaining increased CV risk in patients with low HDL-cholesterol while having a low LDL-cholesterol after statin therapy . HDL-cholesterol can be increased by inhibition of cholesteryl ester transfer protein (CETP) .
The CETP-inhibitor torcetrapib was evaluated in the ILLUMINATE trial, which had to be stopped due to increased mortality and morbidity in the treatment group , attributed to off-target toxicity.
The CETP-inhibitor dalcetrapib was studied in the dal-HEART programme. However, the dal-OUTCOMES trial was stopped recently due to a lack of clinically meaningful efficacy. While the two preceding safety studies (dal-VESSEL and dal-PLAQUE) did not show adverse vascular effects of dalcetrapib on endothelial function or on vascular structure, a convincing positive effect on these parameters was shown neither. [5,6].
A more potent CETP inhibitor, anacetrapib, is currently tested in a large phase 3 clinical programme. Another CETP-inhibitor in clinical development is evacetrapib. These 2 CETP inhibitors, besides increasing HDL-c more potently, also markedly reduce LDL-c, small dense LDL, lipoprotein (a), non-HDL-c and apoB, also on top of statin treatment (table).
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