1 / 18

PPAR  activation Clinical evidence

PPAR  activation Clinical evidence. Evolution of clinical evidence supporting PPAR  activation. Large observational studies. Ongoing clinical outcomes studies. Surrogate outcomes studies. 2000 2005 and beyond.  Endothelial function  Carotid atherosclerosis  Restenosis.

dalila
Download Presentation

PPAR  activation Clinical evidence

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. PPAR  activationClinical evidence

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

  3. Anticipated results from large multicenter trials in (pre)diabetes NAVIGATOR VADT RECORD ACT-NOW PERISCOPE DREAM CHICAGO ADOPT ACCORDBARI-2DORIGIN APPROACH PROactive 2005 2006 2007 2008 2009 Clinical outcomes Surrogate outcomes

  4. PROactive: Study Design PROspectivepioglitAzoneClinical Trial In macroVascularEvents Randomized, double-blind controlled trial N = 5238 with type 2 diabetes and macrovascular disease Pioglitazone 15 mg qdtitrated to 45 mg qd Placebo 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 Mean follow-up: 34.5 months Dormandy JA et al. Lancet. 2005;366:1279-89.

  5. PROactiveBaseline Characteristics Male (%) Caucasian (%) Age (yrs) BMI (kg/m2) Waist circ. (cm) Current smoker (%) Ex smoker (%) Systolic BP (mm/Hg) Diastolic BP(mm/Hg) PioglitazonePlacebo 66.6 65.6 98.4 98.7 61.9 61.6 30.7 31.0 104.9 105.5 13.1 14.5 46.0 44.0 143.5 143.3 82.8 83.2 Dormandy JA et al. Lancet. 2005;366:1279-89.

  6. PROactiveCV history at baseline % Dormandy JA et al. Lancet. 2005;366:1279-89.

  7. PROactiveCV medications at baseline % Dormandy JA et al. Lancet. 2005;366:1279-89.

  8. 0.25 0.20 0.15 0.10 0.05 0.0 5238 5018 4786 4619 4433 4268 693 (228) 0 6 12 18 24 30 36 Time to primary composite endpoint Kaplan-Meier event rate N events: 3-year estimate: placebo 572 / 2633 23.5% pioglitazone 514 / 2605 21.0% HR 95% CI p value pioglitazone 0.904 0.802 - 1.018 0.0951 vs placebo N at Risk: Time from Randomization (months) Dormandy JA et al., Lancet (2005) 366:1279 - 1289

  9. 0.15 0.10 0.05 0.0 5238 5102 4991 4877 4752 4651 786 (256) 0 6 12 18 24 30 36 Significant reduction in secondary outcome Kaplan-Meier event rate N events: 3-year estimate: placebo 358 / 2633 14.4% pioglitazone 301 / 2605 12.3% HR 95% CI p value pioglitazone 0.841 0.722 - 0.981 0.0273 * vs placebo N at Risk: Time from Randomization (months) Dormandy JA et al., Lancet (2005) 366:1279 - 1289

  10. 0.20 0.15 0.10 0.05 0.0 5238 5080 4947 4816 4684 4564 765 (248) 0 6 12 18 24 30 36 Time to all-cause death, non-fatal MI, stroke or ACS Kaplan-Meier event rate N events: 3-year estimate: placebo 409 / 2633 16.5% pioglitazone 339 / 2605 13.8% HR 95% CI p value pioglitazone 0.828 0.717- 0.956 0.01 * vs placebo N at Risk: Time from Randomization (months) Dormandy JA et al., Lancet (2005) 366:1279 - 1289

  11. Time to permanent insulinuse Kaplan Meier eventrate of progression to permanent insulinuse N events: 0.25 0.20 0.15 0.10 0.05 0.0 3-year estimate: placebo 22,0% 11,1% 362/1737 183/1741 pioglitazone HR p value 95% CI pioglitazonevspalcebo 0.469 0.39-0.56 <0.0001 3478 3346 3198 3075 2955 2824 446 (137) N at risk: 0 6 12 18 24 30 36 Time fromRandomization (months) Dormandy JA et al. Lancet. 2005;366:1279-89.

  12. PROactiveSubgroup analysis – Previous MI n = 2445 with previous MI (≥6 mo) • 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 *Excluding silent MI Adapted from Erdmann E. AHA 2005. www.PROactive-results.com.

  13. PROactiveSubgroup analysis – Previous stroke Fatal and nonfatal stroke with pioglitazone treatment vs placebo in patients with prior history of stroke Wilcox RG. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain.

  14. PROactiveHF hospitalization and mortality * Non-adjudicated Dormandy JA et al. Lancet. 2005;366:1279-89.

  15. 1.0 0.9 0.8 Proportion of patientssurviving Thiazolidinedione (n = 2226) 0.7 13% RRR HR 0.87 (0.80–0.94) 0.6 No insulin sensitizer (n = 12,069) 0 0 50 100 150 200 250 300 350 Follow-up (days) TZDs associated with lower mortality N = 16,417 Medicare patients with diabetes and HF (1998–1999, 2000–2001) Masoudi FA et al. Circulation. 2005;111:583-90.

  16. Summary Pioglitazone treatment compared to placebo in high risk patients with type 2 diabetes: • 10% trend of relative risk reduction in the primary endpoint • 16% significant relative risk reduction in the main secondary endpoint (all-cause death, MI, or stroke) • Significant relative risk reductions of other MACE endpoints: • All-cause death, MI, stroke, or ACS – 17% • CV death, MI, or stroke – 18% • CV death, MI, stroke, or ACS – 20% • Fatal or non-fatal MI – 22%

  17. PROactive in perspective Pioglitazone appears to reduce risk of major adverse cardiovascular events (MACE) in patients with advanced type 2 diabetes • in patients at high risk for cardiovascular events (prior stroke, MI, PCI or CABG) • on top of good standard of care • relatively short-term study PROactive results support use of PPAR modulator in patients with diabetes at high CVD risk May improve CVD outcomes and decrease need to start insulin

  18. CARE HPS Placebo Placebo 30 40 CHD death, MI*, revasc (%) 22% RRR P < 0.0001 25% RRR P = 0.05 30 20 Vascular events (%) 20 Pravastatin Simvastatin 10 10 0 0 0 1 2 3 4 5 0 1 2 3 4 5 6 Years Years Circulation. 1998 Lancet. 2003 MICRO-HOPE PROactive 25 Cardiac death, MI*,coronary revasc, ACS(%) 20 Placebo Placebo 25% RRR P = 0.0004 20 19% RRR P = 0.034 15 15 10 10 Ramipril Pioglitazone 5 5 0 0 0 1 2 3 4 5 0 1 2 3 Years Years Lancet. 2005 Lancet. 2000 * Nonfatal PROactivevs landmark clinical trials: Comparative benefit in patients with diabetes MI, stroke, CV death (%) Lancet 2003;361:2005-2016; Circulation 1998;98:2513-2519; Lancet 2000;355:253-259; Lancet 2005; 366:1279 - 1289

More Related