Low HDL remains a predictor of cardio- vascular risk in statin-treated patients Barter P et al., N Engl J Med 2007; 357:

dal-VESSEL : Study Design Placebo Randomisation FMD, ABPM 36 weeks FMD, ABPM Dalcetrapib 600 mg Pre- randomisation phase 8 weeks 476 patients randomised 4 weeks ABPM 12 weeks FMD, ABPM Double-blind randomised, placebo-controlled, parallel-group multicentre FMD/ABPM study in patients with CHD or CHD-risk equivalent

Conclusions from dal-VESSEL Dalcetrapib did not cause endothelial dysfunction or have an effect on ABPM, providing further reassurance regarding the safety of dalcetrapib – dalcetrapib reduced CETP activity and increased HDL-C levels by 31% without affecting NO-dependent endothelial function – in contrast to torcetrapib, dalcetrapib did not raise blood pressure This trial also demonstrates the feasibility of using FMD to test the influence of novel cardiovascular compounds on the biology of the vessel wall Further testing in dal-OUTCOMES

HDL – a novel target in coronary disease ? HDL The “good“ cholesterol ?

A-I Liver Bile NascentHDL A-I FC CE Endothelial NO Production Anti-apoptotic Effects Anti-inflammatory Effects Endothelial Repair Anti-thrombotic Effects LCAT MatureHDL HDL CETP VLDL/ LDL TG CE CE FC PLTP LDL-R SR-BIMacrophage ABCA1 ABCG1 ? SR-BI? HDL: proposed anti-atherogenic effects 2. Direct HDL-mediated endothelial-protective potential anti-atherogenic effects 1. HDL-mediated promotion of RCT (reverse cholesterol transport) Besler C et al. & Lüscher T, Landmesser U. Curr Pharmacol Des 2010, 16:

 g/ml 50  g/ml100  g/ml HDL Healthy sCAD ACS P<0.025  Endothelial nitric oxide production [in % of buffer-treated cells] HDL –effects on endothelial cell nitric oxide production in patients with CAD Besler C et al. & von Eckardstein, Lüscher T, Landmesser U. J Clin Invest 2011;121(7):

(1) apoA-I (lipid-free) (2)ABCA1 ABCA1 PL FC PL FC Nascent HDL Mature HDL Peripheral tissues (including lipid-laden macrophages) (3) LCAT (5) SR-BI CE TG-rich lipoproteins (e.g. VLDL) PLTP apoB LDLR CE TG VLDL/LDL (4) CETP FC CE Bile BA ABCG1 (2) ABCA1 (1) apoA-I (lipid-free) HDL metabolism – potential targets ? Besler C, Lüscher T, Landmesser U. EMBO Mol Med 2011 (in press)

 Firm epidemiological link to CV outcome  Exciting therapeutic opportunity  HDL is complex particle with multiple functions  First CETP inhibitor Torcetrapib caused increased mortality  Current trials will define clinical role for HDL elevation HDL as a Therapeutic Target