1. PPAR  activation & lipid metabolism

2. Diabetic dyslipidaemia Lipid profiles and hyperinsulinaemia in newly diagnosed type 2 diabetic patients Niskanen L et al. Diabetes Care 1998;21:1861-9 Type 2 diabetesControlp HDL-C (mmol/L)1.071.34<0.05 Triglycerides (mmol/L)2.411.60<0.05 LDL-C (mmol/L)4.494.17NS Total-C (mmol/L)6.436.7NS Fasting insulin (mU/L)24.815.40.003

3. Effects of pioglitazone vs gliclazide addition to metformin on dyslipidaemia % change from baseline after 2 yrs Triglycerides HDL cholesterol LDL cholesterol TC / HDL ratio -23 22 2 -7 7 -6 -10 -30.00 -20.00 -10.00 0.00 10.00 20.00 30.00 p<0.001 -17 Pioglitazone + Metformin Gliclazide + Metformin Betteridge DJ, Verges B. Diabetologia 2005; 48: 2477-81

4. Changes in dyslipidaemic profile with TZDs *p<0.05 vs baseline; † p<0.001 between treatment groups Goldberg RB et al. Diabetes Care 2005; 28: 1547–1554 Goldberg RB et al. Circulation 2005; 111: 1727–1728 * † * Change from baseline to endpoint (%) after 24 weeks † * Mean baseline mmol/L Mean endpoint mmol/L 2.92.7 2.32.8 1.0 1.15 1.08 4.0 4.14.6 * * TriglyceridesHDL-CNon-HDL-C

5. Sulfonylurea + TZD or metformin: Comparison of lipid and renal effects Hanefeld M et al. Diabetes Care. 2004;27:141-7. N = 639 with poorly controlled DM2 * † ‡ † † *P = 0.008, † P < 0.001, ‡ P = NS Pioglitazone 15–45 mg + sulfonylurea Metformin 850–2550 mg + sulfonylurea Change after 52 wks (%)

6. TZDs and metformin reduce risk of MI Case-control study of insulin-sensitizing therapy and first MI in patients with type 2 diabetes *Adjusted for age, sex, BMI, ACE inhibitor use, history of hypertension or hypercholesterolemia Sauer WH et al. Am J Cardiol. 2006; 97:651-4. Monotherapy Metformin TZD TZD + sulfonylurea Metformin + sulfonylurea Insulin-sensitizing drugs Sulfonylurea monotherapy P 0.01 0.03 0.04 0.19 Odds ratio for MI (95% CI)* Combination therapy PatientsControls 3887 719 718 4062 00.20.40.60.81.01.2 n