Derisking the development programs of CETP inhibitors after
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 : a novel target in prevention ? HDL
Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3% Third Report of the NCEP Expert Panel. NIH Publication No. 01 -3670 2001. http: //hin. nhlbi. nih. gov/ncep_slds/menu. htm
Hazard Ratio Coronary Heart Disease and HDL-C 3. 5 3. 0 2. 5 N = 302, 430 2. 0 1. 5 1. 0 0. 8 30 40 50 60 70 HDL-C (mg/d. L) 80 The Emerging Risk Factors Collaboration. JAMA 2009; 302: 1993 -2000
Reduced HDL is associated with increased CV risk – despite intense statin therapy 10 5 -yr risk of major CV events (%) 9 8 7 6 5 4 3 2 1 0 Q 1 (<37) Q 2 (37 to <42) Q 3 (42 to <47) Q 4 (47 to <55) Quintile of HDL-C level (mg/d. L) Q 4 (≥ 55) Barter P N Engl J Med 2007; 357: 1301 -10
HDL-Raising Therapies on the Horizon CETP Inhibitors Apo. AI Reconstituted upregulation apo. AI/HDL ; HDL delipidation pre-β HDL apo. CIII PPAR agonists HDL hyper. TGemia Omega-3 FAs apo. AII apo. E ABCA 1 induction / LXR agonists s. PLA 2 HL EL LCAT SR-B 1 Apo. AI upregulation Apo. AI mimetics Niacin analogues
Schematic Overview of Lipoprotein Metabolism Courtesy of Brian Brewer
CV Events Lipid Levels 100 80 70 60 50 40 30 20 10 0 -10 -20 -30 without an event (%) % change Torcetrapib in High-risk Patients : ILLUMINATE Study * * 98 Atorvastatin 96 94 92 Atorvastatin + Torcetrapib p=0. 001 90 0 TC HDL * LDL 0 180 360 540 720 Days Barter PJ: NEJM 2008
Arterial diameter (mm) Torcetrapib causes Endothelial Dysfunction independent of CETP inhibition 1. 0 0. 9 0. 8 0. Vehicle Torcetrapib, 30 mg/kg x 4 d Torcetrapib 2 -wk washout 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 BL Post NE 30 15 min Acetylcholine infusions (µg/min for 15 min) post 10 17 Connelly J Cardiovasc Pharmacol 2010 55; 459 -468 56
CETP Inhibition and Endothelial Function Total population Placebo Dalcetrapib 600 mg Dalcetrapib-treated patients by baseline HDLC HDL-C <1. 19 HDL-C >1. 19 mmol/L 4 3 FMD (%) 5 2 1 4 3 2 1 0 BL +2 weeks +4 BL +2 +4 weeks Herman Thrombosis Research 2009 123 460 -465
dal-VESSEL : Study Design Dalcetrapib 600 mg 476 patients randomised Placebo Prerandomisatio n phase 8 weeks 4 weeks 12 weeks ABPMFMD, ABPM Randomisation ; 27: 141 -150 FMD, ABPM 36 weeks FMD, ABPM Double-blind randomised, placebo-controlled, parallel-group multicentre FMD/ABPM study in patients with CHD or CHD-risk equivalent
HDL as a Therapeutic Target q Firm epidemiological link to CV outcome q Exciting therapeutic opportunity q HDL is complex particle with multiple functions q First CETP inhibitor Torcetrapib caused increased mortality q Current trials will define clinical role for HDL elevation
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