1. Vascular effects of PPAR  activation: Inflammation

2. Campia U et al. Circulation. 2006;113:867-75. Pioglitazone improves endothelial vasodilation and decreases inflammation Forearm blood flow (%  from baseline) after 16 wks N = 80 with hypertension or hypercholesterolemia and no diabetes Pioglitazone 45 mg/d Placebo 100 200 400 600 500 400 300 0 Bradykinin (ng/min) All subjects Insulin resistant Insulin sensitive CRP (mg/L) 7 5 3 1 0 6 4 2 P = 0.0001 P = 0.38 P = 0.0008 P = 0.01 0 P = 0.41 P = 0.02

3. PPAR  agonists impact inflammatory markers and adiponectin N = 54 adults with metabolic syndrome and no diabetes Samaha FF et al. Arterioscler Thromb Vasc Biol. 2006;26:624-30. *P = 0.002; † P = 0.027; ‡ P < 0.001 Change from baseline after 12 weeks (%) * † ‡ PlaceboRosiglitazone 8 mg/d IL-6CRP Adiponectin -40 -20 0 20 40 0 50 100 150 200

4. Surrogate outcome results driving major TZD trials TZDs are associated with reductions in atherosclerotic progression and restenosis TZDs reduce inflammatory markers (CRP, TNF  ) independent of glycemic control Reducing CV risk factors with TZDs may also reduce CV morbidity and mortality Dormandy JA et al. Lancet. 2005;366:1279-89.