Low HDL remains a predictor of cardio-vascular risk in statin-treated patients

Barter P et al., N Engl J Med 2007; 357: 1301-10

dal-VESSEL : Study Design

Placebo

RandomisationFMD, ABPM

36 weeksFMD, ABPM

Dalcetrapib 600 mg

Pre-randomisation

phase 8 weeks

476 patientsrandomised

4 weeksABPM

12 weeksFMD, 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

Nascent HDL

A-I

FCCE

FC

Endothelial NO Production

Anti-apoptotic Effects

Anti-inflammatoryEffects

Endothelial Repair

Anti-thromboticEffects

LCATMature HDL

HDL

CETPVLDL/ LDL

TGCE

CEFC

PLTPLDL-R

SR-BI Macrophage

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: 1480-93

-20

-10

0

10

20

30

25 m g/ml 50 m g/ml 100 m g/ml

HDL HDL HDL

Healthy

sCAD

ACS

P<0.025

D E

ndo

the

lial n

itric

oxi

de

pro

du

ctio

n[in

% o

f buf

fer-

tre

ate

d ce

lls]

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):2693-708

(1) apoA-I(lipid-free)

(2)ABCA1 ABCA1PLFC

PLFC

Nascent HDL

Mature HDL

Peripheral tissues (including lipid-laden

macrophages)(3) LCAT

(5) SR-BI

CE

TG-rich lipoproteins

(e.g. VLDL) PLTP

apoB

apoB

LDLR

CE

TG

TG

VLDL/LDL

(4) CETP

FC

CEBile

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