1. CV Risk Reduction, Diabetes Prevention, and TZDs

2. UKPDS 34: Intensive glucose control and CV protection n = 1704 overweight, with diabetes; n = 342 metformin group UKPDS Group. Lancet. 1998;352:854-65. Favors metformin or intensive Favors usual care All-cause mortality Metformin Intensive Myocardial infarction Metformin Intensive Stroke Metformin Intensive 0.02 0.12 0.08 Aggregate endpointsP* 012 *Metformin vs other intensive therapy (sulfonylurea or insulin) Relative risk (95% CI)

3. DCCT/EDIC: Lower glucose = lower long-term CV risk DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-53. Primary outcome: Nonfatal MI, stroke, CV death, confirmed angina, revascularization Mean follow-up: 6.5 yr (1983–1993) DCCT Type 1 diabetes, ages 13 to 40 yr N = 1441 EDIC n = 1394 (97%) Follow-up: 11 yr (1994–2005) Intensive diabetes therapy*Conventional diabetes therapy † All patients offered intensive treatment *≥3 insulin injections or pump admin/day † 1–2 injections/day

4. DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-53. DCCT/EDIC: Intensive glucose control reduces long-term CV risk  42% (95% CI 9%–63%) P = 0.02  57% (95% CI 12%–79%) P = 0.02 Cumulative incidence of any first CV event Cumulative CV death, nonfatal MI, stroke Time (years) Conventional 52 events Intensive 31 events Conventional 25 events Intensive 11 events 0 0.12 0.08 0.10 0.06 0.04 0.02 05101520 0 0.12 0.08 0.10 0.06 0.04 0.02 05101520 N = 1441 with type 1 diabetes

5. DCCT/EDIC: Intensive treatment slows renal changes DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-53. Microalbuminuria: albumin excretion rate ≥40 mg/24 hr Albuminuria: albumin excretion rate ≥300 mg/24 hr *P < 0.01, † P < 0.05 vs intensive treatment IntensiveConventional 9 2 0 5 10 15 20 MicroalbuminuriaAlbuminuria Patients (%) Microal- buminuria Albumin- uria 6 * 17 * 5 7 End EDIC year 11DCCT 5 13 * Baseline 0 1 End 0 3 † Baseline N = 1441 with type 1 diabetes

6. Vascular effects of thiazolidinediones (TZDs) Examining the clinical impact of TZDs

7. TZDs impact carotid IMT 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 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 PIO = pioglitazone ROSI = rosiglitazone GLIM = glimepiride

8. TZD impact on restenosis in type 2 diabetes Choi D et al. Diabetes Care. 2004;27:2654-60. *8 mg before catheterization, 4 mg/d thereafter, combined with conventional antidiabetic therapy Change at 6 months (%) P = 0.03 P = 0.004 Restenosis rate at ≥50% stenosis Stent diameter reduction ROSI* (n = 38 w/51 lesions) Control (n = 45 w/55 lesions) N = 95 with DM2 and CAD

9. Neointimal area Restenosis TZDs consistently reduce restenosis after coronary stenting in patients with diabetes Endpoint 1 Takagi T et al. J Am Coll Cardiol 2000. 2 Takagi T et al. Am J Cardiol 2002. 3 Takagi T et al. Am Heart J 2003. 4 Choi D et al. Diabetes Care 2004. *vs diet † vs other anti-diabetes therapy ††† P < 0.0001 P = 0.03 -43 -50 -39 -54

10. 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.

11. Major TZD outcome trials 2005200620072008 2009 PROactive ADOPT CHICAGO DREAM APPROACH ACCORD BARI-2D ORIGIN ACT-NOW VADT PERISCOPE RECORD

12. Major TZD outcome trials 2005200620072008 2009 PROactive ADOPT CHICAGO DREAM APPROACH ACCORD BARI-2D ORIGIN ACT-NOW VADT PERISCOPE RECORD

13. Dormandy JA et al. Lancet. 2005;366:1279-89. 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

14. PROactive: CV history at baseline 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 criteria4749 %

15. PROactive: CV medications at baseline 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 Antiplatelets8583 Aspirin7572 Statins43 Fibrates1011 %

16. PROactive: Nonsignificant reduction in primary outcome Dormandy JA et al. Lancet. 2005;366:1279-89. Events (%) All-cause mortality, nonfatal MI,* ACS, stroke, coronary or peripheral revascularization, leg amputation *Including silent MI Time from randomization (months) 5 10 15 25 0 6 20 01218243036 Pioglitazone 514 events Placebo 572 events 10% RRR HR 0.90 (0.80–1.02) P = 0.095

17. PROactive: Significant reduction in secondary outcome Dormandy JA et al. Lancet. 2005;366:1279-89. Events (%) *Excluding silent MI 0 601218243036 Time from randomization (months) 16% RRR HR 0.84 (0.72–0.98) P = 0.027 5 10 15 25 20 Pioglitazone 301 events Placebo 358 events All-cause mortality, nonfatal MI*, stroke

18. 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 2005. www.PROactive-results.com. *Excluding silent MI n = 2445 with previous MI (≥6 mo)

19. 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) 0.007 NS Dormandy JA et al. Lancet. 2005;366:1279-89. *Non-adjudicated N = 5238

20. 25 20 15 10 5 0 012345 012345 0 20 30 40 PROactive vs landmark clinical trials: Comparative benefit in patients with diabetes *Nonfatal CHD death, MI*, revasc (%) Years Pravastatin Placebo CARE Circulation. 1998;98. 25% RRR P = 0.05 www.proactive-results.com.Lancet. 2000;355. Lancet. 2003;361. MI, stroke, CV death (%) Vascular events (%) Cardiac death, MI*, coronary revasc, ACS (%) Years 0123 0123456 Ramipril Placebo 0 30 20 10 Simvastatin Placebo 0 5 10 20 Pioglitazone Placebo HPS MICRO-HOPEPROactive 22% RRR P < 0.0001 19% RRR P = 0.034 25% RRR P = 0.0004 15

21. PROactive in perspective Significant 16% reduction in secondary outcome (MI, stroke, or death) despite nonsignificant 10% reduction in primary outcome HF hospitalizations increased vs placebo, though HF deaths were similar TZD effect on plaque stability and inflammation might contribute to CV benefits 3-year trial may be too short to definitively evaluate CV treatment effect; event curves did not begin to separate until 18 months Dormandy JA et al. Lancet. 2005;366:1279-89. Fonseca V et al. J Clin Endocrinol Metab. 2006;91:25-7. Meisner F et al. Arterioscler Thromb Vasc Biol. 2006;26:845-50.

22. Fluid retention after TZD use tends to be peripheral n = 99 with diabetes, chronic systolic HF, and fluid retention; 34% NYHA III–IV Tang WHW et al. J Am Coll Cardiol. 2003;41:1394-8. Patients (%) No TZD (n = 80)TZD (n = 19) 63 11 32 0 18 73 80 95 0 20 40 60 80 100 Pulmonary edema Jugular venous distention AscitesPeripheral edema

23. Managing TZD-related fluid retention n = 260 with type 2 diabetes Karalliedde J et al. Diabetes. 2005;54(suppl 1):A20-1. ROSIROSI + furosemide 40 mg/d ROSI + HCTZ 25 mg/d ROSI + spironolactone 50 mg/d Placebo (ROSI discontinued) Hct = hematocrit ROSI = rosiglitazone 4 mg bid 0.50 0.25 0 -0.25 -0.50 -0.75 Change in Hct (%)

24. Collecting duct (CD) PPAR  : Potential mechanism for volume expansion  32.2%  15.5% Zhang H et al. Proc Nat Acad Sci. USA. 2005;102:9406-11. CD-specific PPAR  knockout (KO) mouse model vs control P < 0.001 P = NS  VehicleRosiglitazone 320 mg/kg diet Plasma volume (µL/g body wt)

25. TZDs associated with lower mortality Masoudi FA et al. Circulation. 2005;111:583-90. Follow-up (days) Proportion of patients surviving N = 16,417 Medicare patients with diabetes and HF (1998–1999, 2000–2001) 0.6 0.7 0.8 1.0 0 50100300150200250 0.9 0 350 13% RRR HR 0.87 (0.80–0.94) No insulin sensitizer (n = 12,069) Thiazolidinedione (n = 2226)

26. TZDs in type 2 diabetes and HF Class I–II Use cautiously Initiate treatment at lowest dose Escalate dose gradually Allow more time than usual to achieve A1C target Class III–IV TZDs should not be used at this time Nesto RW et al. Circulation. 2003;108:2941-8. AHA/ADA consensus statement, NYHA HF classification

27. Major TZD outcome trials 2005200620072008 2009 PROactive ADOPT CHICAGO DREAM APPROACH ACCORD BARI-2D ORIGIN ACT-NOW VADT PERISCOPE RECORD

28. DREAM: Background and study objective Previous studies have shown evidence for  new-onset diabetes with RAAS and PPAR agonists Does treatment with ramipril and/or rosiglitazone prevent or delay the development of diabetes in persons with IGT or IFG and no diabetes? DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. Diabetes REduction Assessment with ramipril and rosiglitazone Medication

29. Reduction in new diabetes (%) Adapted from Pepine CJ, Cooper-Dehoff RM. J Am Coll Cardiol 2004. Julius S et al. Lancet 2004. PEACE Trial Investigators. N Engl J Med 2004. RAAS modulation reduces new-onset diabetes Treatment with ACE inhibitors or ARBs SCOPECHARM ANBP2 LIFE HOPE ALLHAT CAPPP STOP-2VALUE PEACE -40 -30 -20 -10 0

30. TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetes TRoglitazone In Prevention Of Diabetes n = 236 Hispanic women with gestational diabetes 60 40 20 0 New-onset diabetes (%) Follow-up (months) 01224364860 Buchanan TA et al. Diabetes. 2002;51:2796-803. Placebo Troglitazone 400 mg 12.1% 5.4% Annual incidence 55% RRR HR 0.45 (0.25–0.83)* P = 0.009 *Unadjusted

31. 0 TZDs blunt diabetes progression DPP Research Group. Diabetes. 2005;54:1150-6. *Withdrawn from study after 1.5 yr Diabetes Prevention Program 10 15 5 1.5 Cumulative incidence of diabetes (%) Years 1.00.50 Placebo Metformin 850 mg bid Lifestyle Troglitazone 400 mg/d* 237 739 1568 2343n =  75% vs placebo P < 0.001

32. Primary outcome: Diabetes or death from any cause DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. DREAM: Study design Secondary outcomes I: CV events Combined MI, stroke, CV death, revascularization, HF, angina, ventricular arrhythmia Secondary outcomes II: Renal events Combined microalbuminuria, macroalbuminuria, or  30% in CrCl Ramipril 15 mg/d + Rosiglitazone 8 mg/d Ramipril 15 mg/d + Placebo Placebo + Placebo Rosiglitazone 8 mg/d + Placebo Randomized, double-blind 2 × 2 factorial design N = 5269 with IFG and/or IGT Follow-up: 3–5 years

33. DREAM: 2 x 2 factorial design DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. RosiglitazonePlacebo Ramipril Ramipril + Rosiglitazone Ramipril + Placebo Placebo Rosiglitazone + Placebo Placebo + Placebo N = 5269 with IFG and/or IGT

34. DREAM: Inclusion criteria Age ≥30 years IFG and/or IGT –Fasting plasma glucose 100–125 mg/dL –2-hour 75 g OGTT 140–199 mg/dL DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. N = 5269

35. DREAM: Key exclusion criteria ACEI/TZD use or contraindication LVEF <40% or other CVD with ACEI indication Diabetes Renal disease, including renal artery stenosis Diseases/medications that affect glucose tolerance Use of steroids/niacin Pregnancy DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

36. DREAM: Baseline characteristics Age (years)54.7 Women (%)58.5 Women with prior gestational diabetes (%)9.3 Hypertension (%)43.5 Hyperlipidemia (%)35.5 BP (mm Hg)136/83 BMI (kg/m 2 )30.5 Waist-hip ratio, men0.96 Waist-hip ratio, women0.87 Waist circumference, men (in)34.3 Waist circumference, women (in)32.6 DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

37. DREAM: Baseline glucose status Isolated IGT 1835 (35%) Isolated IFG* 739 (14%) IGT and IFG* 2692 (51%) FPG (mean) 104 2-hr plasma glucose (mean) 157 DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. *Based on 100 mg/dL threshold n mg/dL

38. DREAM: Beyond diabetes prevention IFG and IGT are strong risk factors for CV disease Does treatment with rosiglitazone and/or ramipril improve IFG, IGT, and glucose control? Positive result for either or both drugs will: –Affirm that links between RAAS, glucose homeostasis, and CV disease are clinically important –Highlight relevance of elevated glucose levels as modifiable risk factors for CV disease DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

39. DREAM: Substudies STARR (STudy of Atherosclerosis with Ramipril and Rosiglitazone) (N = 1427) Carotid atherosclerosis progression DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. EpiDREAM: Epidemiologic follow-up of individuals screened but not randomized for DREAM (N ≈ 20,000) Environmental/genetic determinants of diabetes, obesity, and CV disease Effects of rampiril and rosiglitazone Conversion of IGT to normal glucose tolerance Insulin resistance and  -cell function FPG, 2-hr plasma glucose, A1C

40. ADOPT: Study objective What is the long-term efficacy of monotherapy with rosiglitazone vs metformin or glyburide on glucose control in patients with type 2 diabetes (diagnosed ≤3 years)? A Diabetes Outcome Progression Trial Viberti G et al. Diabetes Care. 2002;25:1737-43.

41. ADOPT: Study design Follow-up: 4 years Viberti G et al. Diabetes Care. 2002;25:1737-43. Glyburide 15 mg/day*Metformin 2 g/day* Secondary outcomes: Changes in A1C, FPG,  -cell function, insulin sensitivity, lipids, BP, albumin excretion, PAI-1, fibrinogen, CRP Primary outcome: Time to monotherapy failure Rosiglitazone 8 mg/day* *Titrated to maximum tolerated dose Randomized, double-blind, parallel group design N ≈ 3600, drug naïve with type 2 diabetes <3 years

42. CHICAGO: Study objective How effective is pioglitazone in controlling the progression of atherosclerosis in patients with type 2 diabetes, as measured by carotid artery thickness? NIH. www.clinicaltrials.gov. Mazzone T. Am J Cardiol. 2004;93(suppl):27C-31C. Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone trial

43. CHICAGO: Study design *Titrated to reach glycemic control NIH. www.clinicaltrials.gov. Mazzone T. Am J Cardiol. 2004;93(suppl):27C-31C. Double-blind, randomized, active control, parallel-efficacy study Type 2 diabetes, asymptomatic for CAD N ≈ 462 Pioglitazone 15, 30, or 45 mg*Glimepiride 1, 2, or 4 mg* Primary outcome: Change in carotid intima-media thickness at 18 months Secondary outcome: Carotid artery calcium score