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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