Lindsay and Choudhury, Nature Reviews: Drug Discovery 2008, 7: Imaging the vessel wall in atherosclerosis

@12 Months Vessel wall area Aorta decrease ~ 8% Carotid decrease ~ 15% Lumen Area Aorta unchanged Carotid unchanged Max Thickness Aorta decrease ~ 9% Carotid decrease ~ 11% Corti R et al. Circulation, 2001;104: Atherosclerosis regression on statins – wall imaging with MRI

Underhill et al. AHJ, 2008;155:584:e1-8 T1W ToF PDW T2W t = 0 t = 2y ~40 patients with US-defined carotid artery stenosis. Randomised to rosuvastatin 5mg vs mg / day No change in overall plaque burden BUT In patients (n=16) with lipid rich core – regression of core over 24 months Plaque composition analysis

SCREENING INDIVIDUAL PARTICIPATION COMPLETED Established atherosclerosis and HDL-c < 1mmol/L All treated with statins Randomised to placebo or Niaspan 375mg for 1wk > 500mg for 1 wk > 750mg for 1 wk > 1000mg for 4 wks > 1500mg 4 wks > 2000mg maintenance Primary end point = change in carotid wall area at 12 months 6 MONTH REVIEW MRI FASTING BLOODS 12 MONTH REVIEW MRI FASTING BLOODS Week 7 LFTs, CK Week 15 LFTs, CK BASELINE MRI FASTING BLOODS Effect of nicotinic acid on atherosclerosis progression when added to statin therapy

Placebo Nicotinic acid Change in carotid wall area (mm 2 ) * * p=0.03 (mixed effect model adjusted for baseline covariates) estimated treatment difference [95% CI] = −1.64 mm 2 [−3.12, −0.16] Lee JMS et al; J Am Coll Cardiol, 2009;54: Effect of nicotinic acid on atherosclerosis progression

TBR >1.6- inflammation present by a central core lab A double-blind, randomized, placebo (S.O.C.)- controlled, parallel group, multi-center (11 sites) study in 130 patients with CHD or CHD equivalent Fayad ZA et al. Am Heart J Treated (1:1 allocation)189 patients screened Recruitment n=189 subjects screened Double-blind treatment period Subjects allocated to dalcetrapib 600 mg/day (n=64) or placebo (n=66) for 24 months 24-month MRI* 6-month MRI 3-month PET/CT Baseline PET/CT at screening *Primary Endpoints 24 months -3 months First patient screened Feb 2008 Last patient randomised Nov 2008 Change in arterial wall 18F-FDG uptake (target to background ratio) within the index vessel (left/right carotid or ascending aorta) after 6 months Structural changes in the arterial wall (total vessel area, wall area, wall thickness, normalised wall index) based on the average of the right and left carotids after 24 months* 6-month PET/CT* Baseline MRI 2 wk before randomisation 0 months 6 months randomisation 12-month MRI 12 months Dal-PLAQUE: design

“Failure of Torcetrapib”

Variable Placebo (N=65) Dalcetrapib (N=63) Absolute change vs placebo (90% CI) P value No-harm boundary* * MRI, mean* (SE) † Total vessel area, mm (1.45)1.71 (1.43) (-7.23, -0.80) Wall area, mm (1.05)0.49 (1.04) (-4.54, 0.13) Wall thickness, mm0.05 (0.03)0.02 (0.03) (-0.11, 0.04) Normalized wall index, % (0.80)0.30 (0.80) 0.60 (-1.20, 2.50) PET/CT, mean* (SE) ‡ Most diseased segment mean of maximum TBR (0.08)-0.19 (0.08) 0.07 (-0.11, 0.25) SE = standard error *After adjustment for baseline and centre † Total number of patients with MRI vessel parameter measurements was 56 for placebo and 58 for dalcetrapib ‡ Total number of patients with target-to-background ratio measurements was 56 for placebo and 56 for dalcetrapib. **For upper limit of 90% CI for placebo-corrected change from baseline Nominal P-values Dal-PLAQUE: MRI (24 months) and PET (6 months) outcomes