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De-risking the development programs of CETP inhibitors after the torcetrapib failure: Endothelial function & blood

De-risking the development programs of CETP inhibitors after the torcetrapib failure: Endothelial function & blood pressure. Prof. John Deanfield University College London United Kingdom. HDL. HDL : a novel target in prevention ?.

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De-risking the development programs of CETP inhibitors after the torcetrapib failure: Endothelial function & blood

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  1. De-risking the development programs of CETP inhibitors after the torcetrapib failure: Endothelial function & blood pressure Prof. John Deanfield University College London United Kingdom

  2. HDL HDL : a noveltarget in prevention ?

  3. Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% decreasein LDL-C reduces CHD risk by1% 1% increasein HDL-C reduces CHD risk by3% Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

  4. Coronary Heart Disease and HDL-C 3.5 3.0 2.5 N = 302,430 Hazard Ratio 2.0 1.5 1.0 0.8 30 40 50 60 70 80 HDL-C (mg/dL) The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000

  5. Reduced HDL is associated with increased CV risk – despite intense statin therapy 10 9 8 7 6 5-yr risk of majorCV events (%) 5 4 3 2 1 0 Q1(<37) Q2(37 to <42) Q3(42 to <47) Q4(47 to <55) Q4(≥55) Quintile of HDL-C level (mg/dL) Barter P N Engl J Med 2007; 357: 1301-10

  6. HDL-RaisingTherapies on the Horizon Reconstituted apoAI/HDL ; HDL delipidation pre-β HDL ApoAI upregulation CETP Inhibitors HDL hyperTGemia Omega-3 FAs ApoAI upregulation apoCIII ABCA1 induction / LXR agonists PPAR agonists ApoAI mimetics apoAII apoE sPLA2 HL EL LCAT SR-B1 Niacin analogues

  7. Schematic Overview of Lipoprotein Metabolism Courtesy of Brian Brewer

  8. Torcetrapib in High-risk Patients : ILLUMINATE Study CV Events Lipid Levels 100 80 * 98 Atorvastatin 70 without an event (%) 60 96 50 94 40 30 % change 92 20 * Atorvastatin + Torcetrapib p=0.001 10 90 0 -10 -20 0 0 180 360 540 720 -30 * TC LDL HDL Days Barter PJ: NEJM 2008

  9. 1.0 Torcetrapib causes Endothelial Dysfunction independent of CETP inhibition Vehicle Torcetrapib, 30 mg/kg x 4d Torcetrapib 2-wk washout 0.9 0.8 0.7 0.6 Arterial diameter (mm) 0.5 0.4 0.3 0.2 0.1 0.0 30 15 min post BL 10 17 Post NE 56 Acetylcholine infusions (µg/min for 15 min) Connelly J CardiovascPharmacol 2010 55; 459-468

  10. Total population Dalcetrapib-treated patients by baseline HDL-C CETP Inhibition and Endothelial Function Placebo Dalcetrapib 600 mg HDL-C >1.19 mmol/L HDL-C <1.19 mmol/L 4 5 3 4 FMD (%) FMD (%) 2 3 2 1 1 0 0 BL +2 +4 BL +2 +4 BL +2 +4 BL +2 +4 weeks weeks weeks weeks Herman Thrombosis Research 2009 123 460-465

  11. dal-VESSEL: Study Design Dalcetrapib 600 mg 476 patientsrandomised Placebo Pre-randomisation phase8 weeks 4 weeksABPM 12 weeksFMD, ABPM 36 weeksFMD, ABPM RandomisationFMD, ABPM ; 27:141-150 Double-blind randomised, placebo-controlled, parallel-group multicentre FMD/ABPM study in patients with CHD or CHD-risk equivalent

  12. 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

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