PPAR  activation Clinical evidence

Evolution of clinical evidence supporting PPAR  activation 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

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

Dormandy JA et al. Lancet. 2005;366: 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

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 Dormandy JA et al. Lancet. 2005;366:

PROactive CV history at baseline Dormandy JA et al. Lancet. 2005;366: 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 %

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

Time from Randomization (months) N at Risk: HR95% CIp value pioglitazone vs placebo N events: 3-year estimate: placebo 572 / % pioglitazone 514 / % Time to primary composite endpoint Kaplan-Meier event rate (228) Dormandy JA et al., Lancet (2005) 366:

Time from Randomization (months) N at Risk: HR95% CIp value pioglitazone vs placebo * N events: 3-year estimate: placebo 358 / % pioglitazone 301 / % Significant reduction in secondary outcome Kaplan-Meier event rate (256) Dormandy JA et al., Lancet (2005) 366:

Time from Randomization (months) N at Risk: HR95% CIp value pioglitazone vs placebo * N events: 3-year estimate: placebo 409 / % pioglitazone 339 / % Time to all-cause death, non-fatal MI, stroke or ACS Kaplan-Meier event rate (248) Dormandy JA et al., Lancet (2005) 366:

placebo pioglitazone N events: 3-year estimate: 362/ / ,0% 11,1% Kaplan Meier event rate of progression to permanent insulin use HR 95% CI p value pioglitazone vs palcebo < Time from Randomization (months) N at risk: (137) Time to permanent insulin use Dormandy JA et al. Lancet. 2005;366:

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 *Excluding silent MI n = 2445 with previous MI (≥6 mo)

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 (0.34 – 0.94) Fatal and nonfatal stroke with pioglitazone treatment vs placebo in patients with prior history of stroke

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) NS Dormandy JA et al. Lancet. 2005;366: * Non-adjudicated

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

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%

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

PROactive vs landmark clinical trials: Comparative benefit in patients with diabetes MI, stroke, CV death (%) Lancet 2003;361: ; Circulation 1998;98: ; Lancet 2000;355: ; Lancet 2005; 366: