1. PPAR  activation Clinical evidence

2. Evolution of clinical evidence supporting PPAR  activation 20002005 and beyond Surrogate outcomes studies Large observational studies Ongoing clinical outcomes studies  Endothelial function  Carotid atherosclerosis  Restenosis  Mortality in patients with diabetes + HF or AMI  Onset of diabetes in patients with IFG

3. Anticipated results from large multicenter trials in (pre)diabetes 2005200620072008 2009 PROactive DREAM CHICAGO ADOPT APPROACH ACCORD BARI-2D ORIGIN Clinical outcomes Surrogate outcomes NAVIGATOR VADT RECORD ACT-NOW PERISCOPE

4. Dormandy JA et al. Lancet. 2005;366:1279-89. PROactive: Study Design Pioglitazone 15 mg qd titrated to 45 mg qd Randomized, double-blind controlled trial N = 5238 with type 2 diabetes and macrovascular disease Primary outcome: Composite of all-cause mortality, MI (including silent MI), ACS, stroke, revascularization, leg amputation Secondary outcome: All-cause mortality, MI (excluding silent MI), stroke PROspective pioglitAzone Clinical Trial In macroVascular Events Mean follow-up: 34.5 months Placebo

5. PROactive Baseline Characteristics Male (%) Caucasian (%) Age (yrs) BMI (kg/m 2 ) Waist circ. (cm) Current smoker (%) Ex smoker (%) Systolic BP (mm/Hg) Diastolic BP (mm/Hg) Pioglitazone Placebo 66.6 65.6 98.4 98.7 61.9 61.6 30.7 31.0 104.9 105.5 13.1 14.5 46.0 44.0 143.5 143.3 82.8 83.2 Dormandy JA et al. Lancet. 2005;366:1279-89.

6. PROactive CV history at baseline Dormandy JA et al. Lancet. 2005;366:1279-89. Pioglitazone n = 2605 Placebo n = 2633 MI4746 Stroke19 PCI or CABG31 Acute coronary syndromes14 Coronary artery disease48 Peripheral arterial disease1920 History of hypertension7576 ≥2 macrovascular disease criteria4749 %

7. PROactive CV medications at baseline Dormandy JA et al. Lancet. 2005;366:1279-89. Pioglitazone n = 2605 Placebo n = 2633  -blockers 5554 ACEIs63 ARBs 7 7 CCBs3437 Nitrates3940 Thiazide diuretics1516 Antiplatelets8583 Aspirin7572 Statins43 Fibrates1011 %

8. Time from Randomization (months) N at Risk: HR95% CIp value pioglitazone vs placebo 0.9040.802 - 1.018 0.0951 N events: 3-year estimate: placebo 572 / 263323.5% pioglitazone 514 / 260521.0% Time to primary composite endpoint Kaplan-Meier event rate 061218243036 523850184786461944334268693(228) 0.0 0.05 0.10 0.25 0.15 0.20 Dormandy JA et al., Lancet (2005) 366:1279 - 1289

9. Time from Randomization (months) N at Risk: HR95% CIp value pioglitazone vs placebo 0.8410.722 - 0.981 0.0273 * N events: 3-year estimate: placebo 358 / 263314.4% pioglitazone 301 / 260512.3% Significant reduction in secondary outcome Kaplan-Meier event rate 061218243036 523851024991487747524651786(256) 0.0 0.05 0.10 0.15 Dormandy JA et al., Lancet (2005) 366:1279 - 1289

10. Time from Randomization (months) N at Risk: HR95% CIp value pioglitazone vs placebo 0.8280.717- 0.956 0.01 * N events: 3-year estimate: placebo 409 / 263316.5% pioglitazone 339 / 260513.8% Time to all-cause death, non-fatal MI, stroke or ACS Kaplan-Meier event rate 061218243036 523850804947481646844564765(248) 0.0 0.05 0.10 0.20 0.15 Dormandy JA et al., Lancet (2005) 366:1279 - 1289

11. placebo pioglitazone N events: 3-year estimate: 362/1737 183/1741 22,0% 11,1% Kaplan Meier event rate of progression to permanent insulin use HR 95% CI p value pioglitazone vs palcebo 0.469 0.39-0.56 <0.0001 Time from Randomization (months) N at risk: 0.25 0.20 0.15 0.10 0.05 0.0 0 6 12 18 24 30 36 3478 33463198307529552824446(137) Time to permanent insulin use Dormandy JA et al. Lancet. 2005;366:1279-89.

12. PROactive Subgroup analysis – Previous MI Pioglitazone reduced risk of CV events, including: – Fatal/nonfatal MI* by 28% (P = 0.045) – ACS by 37% (P = 0.035) Over 3 years, pioglitazone added to medication in 1000 patients could prevent: – 22 recurrent MIs – 23 ACS events Future studies are needed to further elucidate the underlying mechanism(s) of these clinical results Adapted from Erdmann E. AHA 2005. www.PROactive-results.com. *Excluding silent MI n = 2445 with previous MI (≥6 mo)

13. PROactive Subgroup analysis – Previous stroke Wilcox RG. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. End pointPioglitazone n=486 Placebo n=498 Hazard ratio (95% CI) p Recurrent stroke 27510.53 (0.34 – 0.94) 0.008 Fatal and nonfatal stroke with pioglitazone treatment vs placebo in patients with prior history of stroke

14. PROactive HF hospitalization and mortality Pioglitazone n (%) Placebo n (%)P HF leading to hospital admission* Fatal HF 149 (5.7) 25 (0.96) 108 (4.1) 22 (0.84) 0.007 NS Dormandy JA et al. Lancet. 2005;366:1279-89. * Non-adjudicated

15. TZDs associated with lower mortality Masoudi FA et al. Circulation. 2005;111:583-90. N = 16,417 Medicare patients with diabetes and HF (1998–1999, 2000–2001) Follow-up (days) Proportion of patients surviving 0.6 0.7 0.8 1.0 0 50100300150200250 0.9 0 350 13% RRR HR 0.87 (0.80–0.94) No insulin sensitizer (n = 12,069) Thiazolidinedione (n = 2226)

16. Summary Pioglitazone treatment compared to placebo in high risk patients with type 2 diabetes: 10% trend of relative risk reduction in the primary endpoint 16% significant relative risk reduction in the main secondary endpoint (all-cause death, MI, or stroke) Significant relative risk reductions of other MACE endpoints: – All-cause death, MI, stroke, or ACS – 17% – CV death, MI, or stroke – 18% – CV death, MI, stroke, or ACS – 20% – Fatal or non-fatal MI – 22%

17. PROactive in perspective Pioglitazone appears to reduce risk of major adverse cardiovascular events (MACE) in patients with advanced type 2 diabetes – in patients at high risk for cardiovascular events (prior stroke, MI, PCI or CABG) – on top of good standard of care – relatively short-term study PROactive results support use of PPAR  modulator in patients with diabetes at high CVD risk May improve CVD outcomes and decrease need to start insulin

18. PROactive vs landmark clinical trials: Comparative benefit in patients with diabetes MI, stroke, CV death (%) Lancet 2003;361:2005-2016; Circulation 1998;98:2513-2519; Lancet 2000;355:253-259; Lancet 2005; 366:1279 - 1289