Insulin Sensitizers: Surrogate and Clinical Outcomes Studies

1. Insulin Sensitizers: Surrogate and Clinical Outcomes Studies

2. Metformin improves endothelial function Metformin 1000 mg (3 months) Placebo 400 350 * 300 250 Increase in forearm blood flow (%) 200 * 150 100 * 50 0 3 10 30 3 10 30 Acetylcholine (g/min) Before treatment After treatment Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50. * P = 0.0027 vs placebo

3. PPAR activation improves renal endothelial function and reduces proteinuria N = 19 with type 2 diabetes with/without microalbuminuria P < 0.05 P < 0.05 140 133 120 Treatment with rosiglitazone was followed by 60% reductions in albuminuria and proteinuria in diabetic patients with microalbuminuria. 119 120 103 100 GFR(mL/min) 80 60 40 20 0 Placebo Rosiglitazone Nateglinide Rosiglitazone Microalbuminuria No microalbuminuria Pistrosch F et al. Diabetes. 2005;54:2206-11.

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

5. PPAR activation: Consistent reduction in carotid atherosclerosis Patients (n)duration Study (year) Treatments  IMT (mm) 0.080, troglitazone0.027, usual careP < 0.001 Type 2 diabetes (n = 135)6 mos Minamikawa(1998) Troglitazone 400 mgUsual care Type 2 diabetes(n = 106) 6 mos 0.084, troglitazone0.022, usual careP < 0.001 Koshiyama(2001) Pioglitazone 30 mgUsual care 0.012, rosiglitazone0.0031, placeboP = 0.03 Stable CAD(n = 92)12 mos Sidhu(2004) Rosiglitazone 8 mgPlacebo 0.054, pioglitazone0.011, glimepirideP < 0.001 Langenfeld(2005) Type 2 diabetes(n = 173)6 mos Pioglitazone 45 mgGlimepiride 2.7 mg 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. PPAR activation blunts progression of carotid atherosclerosis in stable CAD N = 92 without diabetes 0.04 PlaceboProgression rate = 0.031 mm/48 wks 0.03 0.02  Carotid IMT (mm) Rosiglitazone 8 mgProgression rate = 0.012 mm/48 wks 0.01 0 –0.01 0 24 48 Time (weeks) Adapted from Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24:930-4. P = 0.03

7. PPAR activation blunts progression of carotid atherosclerosis N = 173 with type 2 diabetes 0.08 ns 0.04 0.00 CarotidIMT (mm) P < 0.001 –0.04 –0.08 –0.12 P < 0.005 –0.16 0 12 24 Weeks Glimepiride 2.7 mg Pioglitazone 45 mg Langenfeld MR et al. Circulation. 2005;111:2525-31.

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

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

10. PPAR activation: Consistent  in neointimal proliferation (stented patients with T2D) Intimal index (%) Trialduration Study, year (n) Treatments Randomization 2 days prior 6 mos Diet ± Troglitazone 400 mg 27.1, troglitazone49.0, controlP < 0.001 Takagi,2000(n = 52) Ins/SU/Acar ±Troglitazone400 mg 6 mos 1 day prior 39.1, troglitazone71.5, controlP < 0.0001 Takagi,2002(n = 55) 6 mos Takagi,2003(n = 44) 8 days prior 28%, pioglitazone48%, controlP < 0.0001 Ins/SU/Acar ±Pioglitazone 30 mg Trend to benefit Placebo Rosiglitazone4 mg/ 8 mg After stenting Osman,2004(n = 16) 6 mos(first mo at 4 mg) 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. Intimal area Intimal index = Stent area

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

12. Preliminary data support reduction in MIwith PPAR activation Favors oral therapy Favors insulin 0.62 Sulfonylurea 0.61 Metformin Sulfonylurea + metformin 0.56 0.51 Thiazolidinedione 0.5 0.75 1 1.25 0.25 Odds ratio for MI Koro CE et al. Diabetes. 2004;53(suppl 2):A247.

13. PPAR activation associated with lower mortality N = 16,417 with diabetes and HF 1.0 0.9 0.8 Proportion of patientssurviving Thiazolidinedione (n = 2226) 0.7 13% Relative risk reduction 0.6 No insulin sensitizer (n = 12,069) 0.5 0 50 100 150 200 250 300 350 Time (days) Masoudi FA et al. Circulation. 2005;111:583-90.

14. Metformin associated with lower mortality N = 16,417 with diabetes and HF 1.0 0.9 0.8 Proportion of patientssurviving Metformin (n = 1861) 0.7 13% Relativerisk reduction No insulin sensitizer (n = 12,069) 0.6 0.5 0 50 100 150 200 250 300 350 Time (days) Masoudi FA et al. Circulation. 2005;111:583-90.

15. Neutral effect of PPAR activationand metformin on hospital readmission N = 16,417 with diabetes and HF All-cause HF TZD 1.04 (0.99–1.10) 1.06 (1.00–1.12) Metformin 0.94 (0.89–1.01) 0.92 (0.86–0.99) Hospital readmission TZD = thiazolidinedione Masoudi FA et al. Circulation. 2005;111:583-90.

16. Thiazolidinediones in patients with type 2 diabetes and HF AHA/ADA consensus statement summary • 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 Nesto RW et al. Circulation. 2003;108:2941-8.

17. Mortality benefit with combined insulin-sensitizing therapy 8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication No insulin sensitizer (n = 6641)Thiazolidinediones (n = 1273) Metformin (n = 819) TZD + MET (n = 139) 1.00 0.95 Proportion of patientssurviving 0.90 48% Relativerisk reduction 0.85 0.80 0 50 100 150 200 250 300 350 Days from discharge Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.

18. Insulin sensitizers vs other glucose-lowering agents following AMI 8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication Metformin TZD Both Mortality 0.92 (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 failurereadmission 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) Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.

19. UKPDS: Risk reduction with metformin in overweight patients N = 4075 with type 2 diabetes Aggregate endpoints P* Favors metforminor intensive Favors conventional All-cause mortality Metformin Intensive Myocardial infarction Metformin Intensive Stroke Metformin Intensive 0.021 0.021 0.021 0.1 1 10 Relative risk reduction(95% CI) *metformin vs intensive therapy UKPDS Group. Lancet. 1998;352:854-65.

20. Evolution of clinical evidence supporting PPAR activation Surrogate outcomes studies Ongoing clinical outcomes studies Large observational studies 2000 2005 and beyond Mortality in patients with diabetes + HF or AMI Endothelialfunction Carotid atherosclerosis Restenosis

21. Anticipated results from large multicenter trials in diabetes and prediabetes NAVIGATOR VADT RECORD ACT-NOW PERISCOPE ADOPTAPPROACH CHICAGO ACCORDBARI-2DORIGIN DREAM PROactive 2005 2006 2007 2008 2009 Clinical outcomes Surrogate outcomes

22. PROactive: Study design 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 Charbonnel B et al. Diabetes Care. 2004;27:1647-53. Dormandy JA et al. Lancet. 2005;366:1279-89.

23. PROactive: Baseline CV history % Dormandy JA et al. Lancet. 2005;366:1279-89.

24. PROactive: CV medications at study entry % Dormandy JA et al. Lancet. 2005;366:1279-89.

25. PROactive: Reduction in primary outcome All-cause mortality, MI, ACS, coronary or peripheral revascularization, amputation, stroke 25 10% Relative risk reduction HR* 0.90 (0.80–1.02)P = 0.095 Placebo(572 events) 20 Pioglitazone(514 events) 15 Proportionof events(%) 10 5 0 0 6 12 18 24 30 36 Time from randomization Number at risk Pioglitazone 2488 2373 2302 2218 2146 348 Placebo 2530 2413 2317 2215 2122 345 *Unadjusted Dormandy JA et al. Lancet. 2005;366:1279-89.

26. PROactive: Reduction in secondary outcome All-cause mortality, MI (excluding silent MI), stroke 25 20 Placebo(358 events) 16% Relative risk reduction HR* 0.84 (0.72–0.98)P = 0.027 15 Proportionof events(%) 10 Pioglitazone(301 events) 5 0 0 6 12 18 24 30 36 Time from randomization Number at risk Pioglitazone 2536 2487 2435 2381 2336 396 Placebo 2566 2504 2442 2371 2315 390 *Unadjusted Dormandy JA et al. Lancet. 2005;366:1279-89.

27. 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 PROactive results support use of PPAR modulator in patients with diabetes at high CVD risk – May improve CVD outcomes and need to add insulin Dormandy JA et al. Lancet. 2005;366:1279-89.

28. DREAM Diabetes REduction Assessment with ramipril and rosiglitazone Medication 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 The DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

29. DREAM: Baseline characteristics Age (years) 54.7 Hypertension (%) 43.5 Hyperlipidemia (%) 35.5 BP (mm Hg) 136/83 BMI (kg/m2) 30.5 Waist circumference (inches) Men 34.3 Women 32.6 The DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

30. ADOPT: Study design ADiabetes Outcome Progression Trial 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 Viberti G et al. Diabetes Care. 2002;25:1737-43.