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 Third Report of the NCEP Expert Panel. NIH Publication No % decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3%

The Emerging Risk Factors Collaboration. JAMA 2009;302: Coronary Heart Disease and HDL-C Hazard Ratio HDL-C (mg/dL) N = 302,

Reduced HDL is associated with increased CV risk – despite intense statin therapy Barter P N Engl J Med 2007; 357: Quintile of HDL-C level (mg/dL) Q1 (<37) Q2 (37 to <42) Q3 (42 to <47) Q4 (47 to <55) Q4 (≥55) yr risk of major CV events (%)

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

Schematic Overview of Lipoprotein Metabolism Courtesy of Brian Brewer

Torcetrapib in High-risk Patients : ILLUMINATE Study Barter PJ: NEJM TC HDL LDL * * * % change Atorvastatin Atorvastatin + Torcetrapib p=0.001 Days without an event (%) CV Events Lipid Levels

Torcetrapib causes Endothelial Dysfunction independent of CETP inhibition Connelly J Cardiovasc Pharmacol ; Arterial diameter (mm) BLBL Post NE min post Acetylcholine infusions (µg/min for 15 min) Vehicle Torcetrapib, 30 mg/kg x 4d Torcetrapib 2-wk washout

CETP Inhibition and Endothelial Function FMD (%) HDL-C <1.19 mmol/L HDL-C >1.19 mmol/L Dalcetrapib 600 mg Placebo Total population Dalcetrapib-treated patients by baseline HDL- C BL weeks BL weeks FMD (%) Herman Thrombosis Research

dal-VESSEL : Study Design ; 27: Placebo Randomisation FMD, ABPM 36 weeks FMD, ABPM Dalcetrapib 600 mg Pre- randomisatio n phase 8 weeks 476 patients randomised 4 weeks ABPM 12 weeks FMD, ABPM Double-blind randomised, placebo-controlled, parallel-group multicentre FMD/ABPM study in patients with CHD or CHD-risk equivalent

 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