Physicians' Academy for Cardiovascular Education

CETP-inhibition: lessons from the halted dal-HEART programme

Literature - Landmesser U, Eur Heart J. 2012 Jun 13

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 [1] and a remaining increased CV risk in patients with low HDL-cholesterol while having a low LDL-cholesterol after statin therapy [2]. HDL-cholesterol can be increased by inhibition of cholesteryl ester transfer protein (CETP) [3].
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 [4], 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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The effects of HDL may vary in different clinical settings. HDL-c is a complex lipoprotein, probably containing more than 1000 different lipid species, all being modifiable. Both the on-treatment vascular effects and the underlying molecular mechanism causing increased HDL-c are important in determining the vascular effects of an HDL-c raising therapy. Easy-to-measure biomarkers that indicate the functionality of HDL are necessary; a post-hoc analysis of the dal-OUTCOMES trial may give a better understanding, also into the lack of positive findings from the dal-VESSEL and the dal-PLAQUE. Such lack of effect in earlier trials should raise concern on efficacy in further clinical development, whereas further imaging development is also useful.


References

1. Besler C, Luscher TF, Landmesser U. Molecular mechanisms of vascular effects of high-density lipoprotein: Alterations in cardiovascular disease. EMBO Mol Med2012;4:251–268.
2. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301–1310.
3. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004;350:1505–1515.
4. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109–2122.
5. Luscher TF, Taddei S, Kaski JC, et al. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-vessel randomized clinical trial. Eur Heart J 2012;33:857–865.
6. Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-plaque): a randomised clinical trial. Lancet 2011;378:1547–1559.

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