 High density lipoproteins (HDL) protect against cardiovascular disease  A novel mechanism for raising HDL levels is to inhibit a protein known as CETP. This protein transfers cholesterol from the protective HDL fraction to the harmful LDL fraction. Thus, inhibiting CETP retains cholesterol in the protective HDL.  Torcetrapib is a drug that inhibits CETP and had been shown in humans to raise the level of HDL cholesterol and lower that of LDL cholesterol.  Studies in rabbits have shown that inhibiting CETP with torcetrapib protects against atherosclerosis.  The ILLUMINATE trial was designed to test the hypothesis that inhibiting CETP with torcetrapib would also protect against cardiovascular disease in humans. Rationale Torcetrapib – Final Results of the ILLUMINATE Trial Philip Barter, The Heart Research Institute, Sydney, Australia for the ILLUMINATE Steering Committee and Investigators

Torcetrapib + titrated atorvastatin dose Titrated atorvastatin dose Planned 4.5 years of treatment Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events Patient Population Subjects Primary End Point Men or postmenopausal women Men or postmenopausal women Statin eligible Statin eligible Any HDL-C level Any HDL-C level CHD or risk equivalent (type 2 DM) CHD or risk equivalent (type 2 DM) 15,000 15,000 7 countries 7 countries Major cardiovascular events Major cardiovascular events Atorvastatin run-in to LDL <100 mg/dL (2.6 mmol/L) 4-10 weeks ILLUMINATE: Long-term Outcomes in Patients With CHD or CHD Risk Equivalence

Atorvastatin Group=A (n=7534) Torcetrapib/Atorvastatin Group=T/A (n=7533) Compared to A, T/A increased HDL-C by 72% and reduced LDL-C by 25% A T/A Major cardiovascular events (p=0.001) Deaths59 93 (p=0.006) Cardiovascular events and mortality in the ILLUMINATE trial at termination of the trial on Dec 02, 2006

Causes Of Death Fatal stroke 4 4 Reason unknown 34Trauma/suicide/homicide 4 2 Other non-cardiovascular 9 0 Infection Cancer Any non-cardiovascular 3 2 Other vascular death/procedure related MI 2 1 Fatal heart failure 4 1 Other cardiac death Fatal MI - not procedure related Sudden cardiac death 4935 Any cardiovascular death Torcetrapib/ Atorvastatin (n=93) Atorvastatin (n=59 )

Investigator-reported SAEs of neoplasms Atorvastatin Group136 Torcetrapib/atorvastatin Group128 Investigator-reported SAEs of infections/infestations Atorvastatin Group177 Torcetrapib/atorvastatin Group182

In patients receiving torcetrapib/atorvastatin (but not in those receiving atorvastatin alone) there was a significant: Increase in blood pressure Increase in blood pressure Reduction in serum potassium Reduction in serum potassium Increase in serum bicarbonate Increase in serum bicarbonate Increase in serum sodium Increase in serum sodium Increase in serum aldosterone Increase in serum aldosterone These changes are consistent with activation of the renin-angiotensin- aldosterone system The adverse clinical outcome associated with use of torcetrapib may have been the consequence of an off-target pharmacology but the possibility of an adverse effect of CETP inhibition cannot be excluded by the results of this randomized trial. Off-target pharmacological effects of torcetrapib unrelated to CETP inhibition

Cox proportional hazard model adjusted for age, gender and baseline HDL-C. Excludes 265 patients with missing month 3 HDL-C. Preliminary analysis initiated and authorised by P Barter and conducted by Pfizer Hazard ratios for CHD Death or Non-Fatal MI by quintile of on-trial HDL-C (referent group is HDL-C < 60 mg/dL stratum) CHD Death or Non-Fatal MI (Hazard Ratio) < >93 Quintiles of HDL-C (mg/dL) at Month 3 *P<0.05 * * * Post-hoc Exploratory Analyses in the Torcetrapib/Atorvastatin Group