1. VBWG Insulin Sensitizers: Surrogate and Clinical Outcomes Studies

2. VBWG Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50. * P = 0.0027 vs placebo Before treatmentAfter treatment 400 300 250 200 150 50 0 350 Metformin 1000 mg (3 months) 3 Increase in forearm blood flow (%) Acetylcholine (  g/min) 100 * Placebo 103031030 * * Metformin improves endothelial function

3. VBWG PPAR  activation improves renal endothelial function and reduces proteinuria N = 19 with type 2 diabetes with/without microalbuminuria Pistrosch F et al. Diabetes. 2005;54:2206-11. 0 20 40 60 80 100 120 140 Placebo 133 Rosiglitazone 120 Nateglinide 119 Rosiglitazone 103 GFR (mL/min) MicroalbuminuriaNo microalbuminuria Treatment with rosiglitazone was followed by 60% reductions in albuminuria and proteinuria in diabetic patients with microalbuminuria. P < 0.05

4. VBWG PPAR  activation normalizes coronary vasomotor abnormalities in insulin resistance Quiñones MJ et al. Ann Intern Med. 2004;140:700-8. N = 16 with insulin resistance; rosiglitazone 8 mg for 3 months * from rest 0 10 20 30 40 50 Pre-TreatmentPost-TreatmentOff-Treatment P < 0.01  MBF* (%) P < 0.01 19.6 (±24.3) 40.3 (±31.3) 8.7 (±18.9)

5. VBWG PPAR  activation: Consistent reduction in carotid atherosclerosis Study (year)Treatments Patients (n) duration  IMT (mm) Minamikawa (1998) Koshiyama (2001) Sidhu (2004) Langenfeld (2005) Troglitazone 400 mg Usual care Type 2 diabetes (n = 135) 6 mos  0.080, troglitazone  0.027, usual care P < 0.001 Pioglitazone 30 mg Usual care Type 2 diabetes (n = 106) 6 mos  0.084, troglitazone  0.022, usual care P < 0.001 Rosiglitazone 8 mg Placebo Stable CAD (n = 92) 12 mos  0.012, rosiglitazone  0.0031, placebo P = 0.03 Pioglitazone 45 mg Glimepiride 2.7 mg Type 2 diabetes (n = 173) 6 mos  0.054, pioglitazone  0.011, glimepiride P < 0.001 Minamikawa J et al. J Clin Endocrinol Metab. 1998;83:1818-20. Koshiyama H et al. J Clin Endocrinol Metab. 2001;86;3452-6. Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24:930-4. Langenfeld MR et al. Circulation. 2005;111:2525-31.

6. VBWG PPAR  activation blunts progression of carotid atherosclerosis in stable CAD Adapted from Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24:930-4. N = 92 without diabetes Placebo Progression rate = 0.031 mm/48 wks Rosiglitazone 8 mg Progression rate = 0.012 mm/48 wks 0.04 0.03 0.02 0.01 –0.01 0 02448 Time (weeks)  Carotid IMT (mm) P = 0.03

7. VBWG 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

8. VBWG Additive effect of statin and PPAR  activation on atherosclerosis Corti R et al. J Am Coll Cardiol. 2004;43:464-73. *L-805645 20 10 0 –10 –20 –30 P = 0.03 P = 0.04 High- cholesterol diet (n = 6) Normal diet (n = 6) Normal diet + PPAR  - agonist* (n = 7) Normal diet + simvastatin (n = 6) Normal diet + simvastatin + PPAR  agonist * (n = 6) Changes in maximal vessel wall thickness †  (%) † † P < 0.05 vs high-cholesterol diet ‡ P < 0.05 vs normal diet ‡ † ‡ Rabbit model P < 0.01 †

9. VBWG PPAR  activation reduces intimal hyperplasia Wang C-H et al. Circulation. 2004;109:1392-400. Control Rosiglitazone 8 mg/kg 0 1 2 3 4 Control Rosiglitazone I/M ratio (%) Balloon injury in mouse model I/M = Intimal area Medial area 3.1 0.98 P < 0.001

10. VBWG PPAR  activation: Consistent  in neointimal proliferation (stented patients with T2D) Study, year (n)Treatments Trial duration Intimal index (%) Takagi, 2000 (n = 52) Takagi, 2002 (n = 55) Takagi, 2003 (n = 44) Diet ± Troglitazone 400 mg 6 mos 27.1, troglitazone 49.0, control P < 0.001 Ins/SU/Acar ± Troglitazone 400 mg 6 mos 39.1, troglitazone 71.5, control P < 0.0001 Ins/SU/Acar ± Pioglitazone 30 mg 6 mos 28%, pioglitazone 48%, control P < 0.0001 Randomization 2 days prior Intimal index = Intimal area Stent area Takagi T et al. J Am Coll Cardiol. 2000;36:1529-35. Takagi T et al. Am J Cardiol. 2002;89;318-22. Takagi T et al. Am Heart J. 2003;146:e5. Osman A et al. Am Heart J. 2004;147:e23. 1 day prior 8 days prior Osman, 2004 (n = 16) Placebo Rosiglitazone 4 mg/ 8 mg 6 mos (first mo at 4 mg) Trend to benefit After stenting

11. VBWG PPAR  activation reduces in-stent restenosis Control (n = 45) Rosiglitazone* (n = 38) 5 10 15 20 25 P = 0.03 Restenosis (% stents) 21 9 Choi D et al. Diabetes Care. 2004;27:2654-60. 0 *8-mg dose before catheterization; 4 mg daily thereafter N = 95 with type 2 diabetes

12. VBWG Preliminary data support reduction in MI with PPAR  activation Koro CE et al. Diabetes. 2004;53(suppl 2):A247. Sulfonylurea Metformin Thiazolidinedione Sulfonylurea + metformin 0.50.751.251 Odds ratio for MI 0.25 Favors oral therapy Favors insulin 0.51 0.62 0.61 0.56

13. VBWG PPAR  activation associated with lower mortality Masoudi FA et al. Circulation. 2005;111:583-90. Time (days) 0.6 0.7 0.8 1.0 0.5 50100300150200250 0.9 0350 13% Relative risk reduction No insulin sensitizer (n = 12,069) Thiazolidinedione (n = 2226) Proportion of patients surviving N = 16,417 with diabetes and HF

14. VBWG Metformin associated with lower mortality Masoudi FA et al. Circulation. 2005;111:583-90. N = 16,417 with diabetes and HF Metformin (n = 1861) No insulin sensitizer (n = 12,069) Time (days) 1.0 0.9 0.8 0.7 0.6 0.5 050150200250300350100 13% Relative risk reduction Proportion of patients surviving

15. VBWG Neutral effect of PPAR  activation and metformin on hospital readmission N = 16,417 with diabetes and HF Masoudi FA et al. Circulation. 2005;111:583-90. All-causeHF TZD1.04 (0.99–1.10)1.06 (1.00–1.12) Metformin0.94 (0.89–1.01)0.92 (0.86–0.99) Hospital readmission TZD = thiazolidinedione

16. VBWG Thiazolidinediones in patients with type 2 diabetes and HF Nesto RW et al. Circulation. 2003;108:2941-8. NYHA class I/II HF: Thiazolidinediones may be used cautiously, with initiation of treatment at the lowest dose and gradual dose escalation –Allow more time than usual to achieve target A1C NYHA class III/IV HF: Thiazolidinediones should not be used at this time AHA/ADA consensus statement summary

17. VBWG Mortality benefit with combined insulin-sensitizing therapy 8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication Inzucchi SE et al. Diabetes Care. 2005;28:1680-9. No insulin sensitizer (n = 6641) Thiazolidinediones (n = 1273) Metformin (n = 819) TZD + MET (n = 139) 48% Relative risk reduction Days from discharge 1.00 0.95 0.90 0.85 0.80 050200250300350100 Proportion of patients surviving 150

18. VBWG Insulin sensitizers vs other glucose-lowering agents following AMI Inzucchi SE et al. Diabetes Care. 2005;28:1680-9. 8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication MetforminTZDBoth Mortality0.92 (0.81–1.06) 0.92 (0.80–1.05) 0.52 (0.34–0.82) Myocardial infarction readmission 1.02 (0.86–1.20) 0.92 (0.77–1.10) 0.88 (0.56–1.37) Heart failure readmission 1.06 (0.95–1.18) 1.17 (1.05–1.30) 1.24 (0.94–1.63) All-cause readmission 1.04 (0.96–1.13) 1.09 (1.00–1.20) 1.06 (0.87–1.30)

19. VBWG UKPDS: Risk reduction with metformin in overweight patients N = 4075 with type 2 diabetes UKPDS Group. Lancet. 1998;352:854-65. Favors metformin or intensive Favors conventional All-cause mortality Metformin Intensive Myocardial infarction Metformin Intensive Stroke Metformin Intensive 0.021 Aggregate endpointsP* 0.1110 *metformin vs intensive therapy Relative risk reduction (95% CI)

20. VBWG 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

21. VBWG Anticipated results from large multicenter trials in diabetes and prediabetes 2005200620072008 2009 PROactive DREAM ADOPT APPROACH CHICAGO ACCORD BARI-2D ORIGIN Clinical outcomes Surrogate outcomes NAVIGATOR NAVIGATORVADT RECORD RECORD ACT-NOW ACT-NOW PERISCOPE

22. VBWG PROactive: Study design Charbonnel B et al. Diabetes Care. 2004;27:1647-53. Dormandy JA et al. Lancet. 2005;366:1279-89. Objective: Assess the effects of pioglitazone on reducing macrovascular events in type 2 diabetes Design: Randomized double-blind, controlled outcome Population: N = 5238 with type 2 diabetes and history of macrovascular disease Treatment: Pioglitazone (up to 45 mg) or placebo Primary outcome: Composite of all-cause mortality, MI, ACS, coronary or peripheral revascularization, amputation, stroke Secondary outcomes: Individual components of primary outcome, CV mortality Follow-up: 4 years

23. VBWG PROactive: Baseline CV history 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 criteria 4749 %

24. VBWG PROactive: CV medications at study entry 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 Antiplatelet8583 Aspirin7572 Statins43 Fibrates1011 %

25. VBWG PROactive: Reduction in primary outcome Dormandy JA et al. Lancet. 2005;366:1279-89. Number at risk Pioglitazone24882373230222182146348 Placebo25302413231722152122345 5 10 15 25 0 6 20 01218243036 Pioglitazone (514 events) 10% Relative risk reduction HR* 0.90 (0.80–1.02) P = 0.095 Placebo (572 events) Time from randomization Proportion of events (%) All-cause mortality, MI, ACS, coronary or peripheral revascularization, amputation, stroke *Unadjusted

26. VBWG PROactive: Reduction in secondary outcome Dormandy JA et al. Lancet. 2005;366:1279-89. Number at risk Pioglitazone25362487243523812336396 Placebo25662504244223712315390 5 10 15 25 0 6 20 01218243036 Pioglitazone (301 events) Placebo (358 events) Time from randomization Proportion of events (%) 16% Relative risk reduction HR* 0.84 (0.72–0.98) P = 0.027 All-cause mortality, MI (excluding silent MI), stroke *Unadjusted

27. VBWG PROactive: Summary Pioglitazone added to standard antidiabetic and CV therapies showed: 10% RRR in primary outcome –Composite all-cause mortality, nonfatal MI (including silent MI), stroke, ACS, leg amputation, coronary or leg revascularization 16% RRR in secondary outcome – All-cause mortality, nonfatal MI (excluding silent MI) or stroke No difference between groups in HF mortality Continued divergence in survival curves –Greater benefit with longer treatment duration hypothesized Dormandy JA et al. Lancet. 2005;366:1279-89. PROactive results support use of PPAR  modulator in patients with diabetes at high CVD risk – May improve CVD outcomes and need to add insulin

28. VBWG DREAM Objective:Assess efficacy of rosiglitazone and ramipril in diabetes prevention Design: N = 5269 with IGT or IFG, randomized (2x2 factorial design) to Treatment: Rosiglitazone 8 mg vs placebo or ramipril 15 mg vs placebo Primary outcomes:New-onset diabetes and all-cause mortality Secondary outcomes:Combined MI, stroke, CV death, PCI/CABG, HF, angina, ventricular arrhythmia Combined microalbuminuria/macroalbuminuria development, 30% decrease in CrCl STARR substudy:Change in carotid atherosclerosis Follow-up:4 years (anticipated) Completion: 2006 Diabetes REduction Assessment with ramipril and rosiglitazone Medication The DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

29. VBWG DREAM: Baseline characteristics Age (years)54.7 Hypertension (%)43.5 Hyperlipidemia (%) 35.5 BP (mm Hg)136/83 BMI (kg/m 2 )30.5 Waist circumference (inches) Men34.3 Women32.6 The DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

30. VBWG ADOPT: Study design Objective:Assess effect on glucose control of rosiglitazone, metformin, or glyburide monotherapy Design:N = ~3600 with type 2 diabetes of  3 years duration, drug-naïve Treatment: Randomized to rosiglitazone 8 mg, metformin 2 g, or glyburide 15 mg Primary outcome:Time to need for combination therapy Secondary outcomes:  -cell function, insulin sensitivity, dyslipidemia, albumin excretion, PAI-1, fibrinogen, CRP Follow-up:4 years Completion: 2007 A Diabetes Outcome Progression Trial Viberti G et al. Diabetes Care. 2002;25:1737-43.