1. Vascular effects of PPAR  activation: Endothelial function

2. Potential vascular benefits of PPAR activation Cariou B et al. Br J Diabetes Vasc Dis. 2005;5(3):126-32. PPAR agonists  Thrombosis  Plaque stability  Cell recruitment and activation  Inflammatory response  Vasoconstriction  Cell migration  Foam cell formation  Cholesterol efflux  Atherogenesis Improved substrate metabolism

3. Evidence on PPAR  activation and favourable effects on endothelial dysfunction PPARs involved in different dimensions of endothelial dysfunction: contractile, thrombotic, permeability and proliferative PPAR  ligands stimulate EC Nitric oxide release PPAR  agonists ameliorate EC activation via inhibition of DAG-PKC- b signalling pathway Clinical trials in diabetic & nondiabetic patients Cariou B et al. Br J Diabetes Vasc Dis. 2005;5:126-32.

4. PPAR activation and endothelial function Campia U et al. Circulation 2006; 113: 867-75

5. Endothelial dysfunction by TNF  -infusion NO dependent vasodilation -20 0 20 40 60 80 100 00,61,86 Dosis serotonin (ng/100mlFAV/min) MC % change Pioglitazone +TNF (10ng/min/2h) Placebo +TNF (10ng/min/2h) Martens FM, Eur Heart J. 2006;27(13):1605-9

6. PPAR  activation blunts progression of carotid atherosclerosis Langenfeld MR et al. Circulation. 2005;111:2525-31. N = 173 with type 2 diabetes 0.08 0.04 0.00 –0.04 –0.08 –0.12 –0.16 P < 0.005 P < 0.001  Carotid IMT (mm) 01224 Pioglitazone 45 mg Glimepiride 2.7 mg ns Weeks

7. TZDs impact carotid IMT Minamikawa J et al. J Clin Endocrinol Metab 1998; Koshiyama H et al. J Clin Endocrinol Metab 2001; Sidhu JS et al. Arterioscler Thromb Vasc Biol 2004;Langenfeld MR et al. Circulation 2005. TRO = troglitazone ROSI = rosiglitazone PIO = pioglitazone GLIM = glimepiride Study (year)Treatment Patients (Duration)  IMT (mm) Minamikawa (1998) TRO 400 mg Usual care DM2 (6 mo)  0.08, TRO  0.03, Usual care P < 0.001 Koshiyama (2001) PIO 30 mg Usual care DM2 (6 mo)  0.08, PIO  0.02, Usual care P < 0.001 Sidhu (2004) ROSI 8 mg Placebo Stable CAD (48 wk)  0.01, ROSI  0.03, Placebo P = 0.03 Langenfeld (2005) PIO 45 mg GLIM 2.7 mg (mean) DM2 (6 mo)  0.05, PIO  0.01, GLIM P < 0.005

8. TZDs consistently reduce restenosis after coronary stenting in patients with diabetes Takagi T et al. J Am Coll Cardiol 2000; Takagi T et al. Am J Cardiol 2002; Takagi T et al. Am Heart J 2003; Choi D et al. Diabetes Care 2004. * vs diet † vs other anti-diabetic therapy TRO = troglitazone ROSI = rosiglitazone PIO = pioglitazone Neointimal area Restenosis Endpoint ††† P < 0.0001 P = 0.03 -43 -60 -50 -40 -30 -20 -10 0 TRO*TROPIOROSI Reduction over 6 months (%) -50 -39 -54

9. Summary of effects of PPAR  agonists on endothelial dysfunction in diabetes Stimulates EC Nitric Oxide Release Ameliorates EC Activation Attenuates the Glucose-DAG-PKCb pathway Clinical studies in diabetic & nondiabetic patients Affects contractile, inflammatory & thrombotic dimensions of endothelial dysfunction