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

The dal-VESSEL study on dalcetrapib's effects in statin-treated patients reveals its HDL-C increase without blood pressure elevation and lack of endothelial dysfunction. The study highlights HDL's cardioprotective potential and implications for novel cardiovascular therapies.

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

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  1. Low HDL remains a predictorofcardio-vascularrisk in statin-treatedpatients Barter P et al., N Engl J Med 2007; 357: 1301-10

  2. dal-VESSEL: Study Design Dalcetrapib 600 mg 476 patientsrandomised Placebo Pre-randomisation phase8 weeks 4 weeksABPM 12 weeksFMD, ABPM 36 weeksFMD, ABPM RandomisationFMD, ABPM Double-blind randomised, placebo-controlled, parallel-group multicentre FMD/ABPM study in patients with CHD or CHD-risk equivalent

  3. 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

  4. HDL – a noveltarget in coronarydisease ? HDL The “good“ cholesterol ?

  5. HDL: proposed anti-atherogeniceffects SR-BI? ABCG1 SR-BI LDL-R 1. HDL-mediatedpromotionof RCT (reversecholesteroltransport) VLDL/ LDL CE CETP TG A-I A-I FC PLTP CE FC LCAT Nascent HDL Mature HDL CE ABCA1 FC Bile HDL Macrophage Liver 2. Direct HDL-mediatedendothelial-protective potential anti-atherogeniceffects Anti-apoptotic Effects Endothelial Repair Endothelial NO Production Anti-inflammatory Effects Anti-thrombotic Effects Besler C et al. & Lüscher T, Landmesser U. CurrPharmacol Des 2010, 16: 1480-93

  6. Healthy P<0.025 sCAD 30 ACS 20 10 production Endothelial nitric oxide [in % of buffer-treated cells] 0 -10 -20 D g/ml 25 m 50 m g/ml 100 m g/ml HDL HDL HDL HDL –effects on endothelialcellnitricoxideproductionin patientswith CAD Besler C et al. & von Eckardstein, Lüscher T, Landmesser U. J ClinInvest2011;121(7):2693-708

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

  8. HDL as a Therapeutic Target • 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

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