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PPAR  activation Impact on pathways of clinical care

PPAR  activation Impact on pathways of clinical care. New paradigm of multiple risk factormanagement. The future of drug therapy belongs to prevention, which is just now being addressed, and to intensive management of all cardiovascular risk factors.

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PPAR  activation Impact on pathways of clinical care

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  1. PPAR  activationImpact on pathways of clinical care

  2. New paradigm of multiple risk factormanagement The future of drug therapy belongs to prevention, which is just now being addressed, and to intensive management of all cardiovascular risk factors Kaplan NM. Hypertension. 2005;46:257-8.

  3. TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetes 12.1% 5.4% TRoglitazoneIn Prevention Of Diabetes(n = 236 Hispanic women with gestational diabetes) Annual incidence 60 55% RRR HR 0.45 (0.25–0.83)*P = 0.009 40 New-onset diabetes (%) Placebo 20 Troglitazone 400 mg 0 0 12 24 36 48 60 Follow-up (months) * Unadjusted Buchanan TA et al. Diabetes. 2002;51:2796-803.

  4. TRIPOD & PIPOD: Evidence that insulin resistance causes -cell failure • PPAR  activation: 55% relative risk reduction for new-onset diabetes (HR 0.45; 0.25–0.83) • Effect was most prominent in women with initial increase in insulin sensitivity and accompanying large reduction in insulin output • Protection persisted 8 months after cessation of active treatment • PPAR activation associated with preserved -cell function • TRIPOD and PIPOD studies demonstrate that prevention of type 2 diabetes is possible through ß-cell rest TRIPOD = Troglitazone in Prevention of Diabetes PIPOD = Pioglitazone in Prevention of Diabetes Buchanan TA et al. Diabetes. 2002;51:2796-803

  5. 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

  6. DREAMBackground and study objective Diabetes REductionAssessment with ramipril and rosiglitazoneMedication • 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.

  7. DREAMStudy design Randomized, double-blind 2 × 2 factorial designN = 5269 with IFG and/or IGT, free from CV disease Ramipril 15 mg/d vs placebo AND Rosiglitazone 8 mg/d vs placebo Primary outcome:Diabetes or death from any cause Secondary outcomes I: CV eventsCombined MI, stroke, CV death, revascularization, HF, angina, ventricular arrhythmia Secondary outcomesII: Renal eventsProgression to micro- or macroalbuminuria, or 30% CrCl Secondary outcomesIII: GlycemicGlucose levels,regression to normoglycemia Follow-up: 3–5 years DREAM Trial Investigators. Lancet. 2006;368:1096-1105.

  8. DREAM: Rosiglitazone prolongs time to occurrence of new-onset diabetes or death 0.6 Placebo 60% RRR HR 0.40 (0.35–0.46) P < 0.0001 0.5 0.4 Cumulative hazard rate 0.3 0.2 Rosiglitazone 0.1 0.0 0 1 2 3 4 Follow-up (years) No. at riskPlaceboRosiglitazone 26342635 24702538 21502414 11481310 177217 DREAM Trial Investigators. Lancet. 2006;368:1096-1105.

  9. DREAM results: Summary Rosiglitazone • 60% RRR in new-onset diabetes or death (P < 0.001) NNT = 7 • Benefit observed regardless of ethnicity, gender, age, weight, and fat distribution • Increased regression to normoglycemia* vs placebo (50.5% vs 30.3%)(HR 1.71, P < 0.0001) Ramipril • 9% RRR in new-onset diabetes or death (non significant) • Increased regression to normoglycemia* vs placebo (42.5% vs 38.2%)(HR 1.16, P = 0.001) *FPG < 110 mg/dL and 2-h glucose < 141 mg/dL DREAM Trial Investigators. Lancet. 2006;368:1096-1105

  10. TZDs blunt diabetes progression Diabetes Prevention Program 15 Placebo Metformin 850 mg bid Cumulative incidence of diabetes (%) 10 Lifestyle 75% vs placeboP < 0.001 Troglitazone400 mg/d* 5 0 0 0.5 1.0 1.5 Years 1568 n = 2343 237 739 * Withdrawn from study after 1.5 yr Knowler WC et al. DPP Research Group. Diabetes 2005;54:1150-6.

  11. 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

  12. CHICAGO: Background and rationale • Even in the presence of optimal cardiovascular (CV) risk factor control (LDL-C and BP), individuals with T2DM remain at high risk for CV events • Thiazolidinediones have shown favorable effects on systemic inflammation, coagulation, lipids, and endothelial function • Carotid intima-media thickness (CIMT) is a highly validated surrogate endpoint to detect future CV disease risk CHICAGO compared the long-term effects of pioglitazonevsglimepiride on CIMT progression in ethnically and racially diverse, urban patients with T2DM Mazzone T et al. JAMA. 2006.

  13. CHICAGO: Study design N = 462 with T2DM Pioglitazone 15–45 mg*(n = 232) Glimepiride 1–4 mg*(n = 230) Double-blindComparator-controlled Primary endpoint:Change in mean posterior-wall CIMT in right and left common carotid arteries Follow-up: 18 months Primary CIMT analysis†: n = 175Intention-to-treat (ITT) analysis: n = 230 Primary CIMT analysis†: n = 186ITT analysis: n = 228 *Initial dose based on sulfonylurea use and titrated to achieve fasting plasma glucose (FPG) ≤140 mg/dL†Baseline + 1 qualifying CIMT image Mazzone T et al. JAMA. 2006.

  14. CHICAGO: Baseline risk factors NR = not reported Mazzone T et al. JAMA. 2006.

  15. 0.2 ‡ † * 0 A1C change from baseline (least square means, %) -0.2 -0.4 -0.6 Baseline 16 24 32 40 48 60 72 Week Glimepiride Pioglitazone CHICAGO: Treatment effect on glucose control *P = 0.04; †P = 0.01; ‡P = 0.002 (treatment-group difference) Mazzone T et al. JAMA. 2006.

  16. CHICAGO: Treatment effect on posterior wall mean CIMT 0.016 0.012 Mean change from baseline (least squares, mm) 0.008 P = 0.02 0.004 0 -0.004 -0.008 -0.012 Baseline Week 24 Week 48 Week 72 Glimepiride Pioglitazone CIMT = carotid intima-media thickness Mazzone T et al. JAMA. 2006.

  17. Number of patients Favorspioglitazone Favorsglimepiride Parameter Pioglitazone Glimepiride N 175 186 Age (years) ≤64 >64 134 41 136 50 Gender Male Female 111 64 119 67 Systolic BP (mm Hg) <130 ≥130 87 88 108 78 Duration of type 2 diabetes (months) ≤67 >67 84 91 97 89 BMI (kg/m2) ≤31.3 >31.3 86 89 90 96 A1C (%) <7 ≥7 71 104 70 116 Statins Yes* No 91 84 101 85 -0.04 -0.03 -0.02 -0.01 0 0.01 0.02 Treatment-group difference in posterior wall CIMT(mean change, mm) *Within 7 days of 1st study drug dose CHICAGO: Treatment effect on posterior wall mean CIMT in prespecified subgroups Mazzone T et al. JAMA. 2006.

  18. CHICAGO: Summary • In an ethnically and racially diverse patient population with T2DM, treatment with pioglitazone demonstrated clinical benefits: • Progression of carotid atherosclerosis was retarded vs sulfonylurea (P = 0.02) • Benefits observed across all prespecified subgroups: age, gender, SBP, diabetes duration, BMI, HbA1C, statin use • Edema and weight gain were higher in TZD group • CIMT may be preferred for assessing treatment-related changes in carotid atherosclerosis Mazzone T et al. JAMA. 2006. Bernard S et al. Diabetes Care. 2005;28:1158-62.

  19. CHICAGO: Implications • Compared with previous trial cohorts, patients in CHICAGO were well-treated at baseline and had near-optimal risk factor control: • Mean LDL-C 113.8 mg/dL (pioglitazone) and 111.3 mg/dL (glimepiride) • 130.1/78.3 mm Hg (pioglitazone) and 128.7/77.1 mm Hg (glimepiride) • Slowed atherosclerosis progression is consistent with clinical endpoint data reported in PROactive • Results are similar to those by Langenfeld et al., who also showed pioglitazone was associated with a greater reduction in carotid IMT at 24 weeks compared with glimepiride in diabetic patients • Additional data will contribute to the overall understanding and clinical significance of CHICAGO results Mazzone T et al. JAMA. 2006.Dormandy JA et al. Lancet. 2005;366:1279-89. Langenfeld et al. Circulation 2005;111:2525-31.

  20. Aggressive medical therapy in diabetes StatinsFibric acid derivatives Dyslipidemia Atherosclerosis ACE inhibitorsARBs β-blockersCCBsDiuretics Hypertension MetforminTZDsSulfonylureasNonsulfonylureasSecretagogues Insulin Hyperglycemia Insulin resistance Platelet activationand aggregation ASAClopidogrelTiclopidine Adapted from Beckman JA et al. JAMA. 2002;287:2570-81.

  21. Traditional risk factors Emergingbiomarkers Clinicaltrials Summary: Optimizing outcomes in patients with multiple CVD risks Multifactorial risk reduction Improved clinical outcome

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