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 Kaplan NM. Hypertension. 2005;46:257-8.

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

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 Buchanan TA et al. Diabetes. 2002;51: TRIPOD = Troglitazone in Prevention of Diabetes PIPOD = Pioglitazone in Prevention of Diabetes

Anticipated results from large multicenter trials in (pre)diabetes PROactive DREAM CHICAGO ADOPT APPROACH ACCORD BARI-2D ORIGIN Clinical outcomes Surrogate outcomes NAVIGATOR VADT RECORD ACT-NOW PERISCOPE

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: Diabetes REduction Assessment with ramipril and rosiglitazone Medication

DREAM Study design Primary outcome: Diabetes or death from any cause Secondary outcomes I: CV events Combined MI, stroke, CV death, revascularization, HF, angina, ventricular arrhythmia Secondary outcomes II: Renal events Progression to micro- or macroalbuminuria, or  30% CrCl Ramipril 15 mg/d vs placebo AND Rosiglitazone 8 mg/d vs placebo Randomized, double-blind 2 × 2 factorial design N = 5269 with IFG and/or IGT, free from CV disease Follow-up: 3–5 years Secondary outcomes III: Glycemic Glucose levels, regression to normoglycemia DREAM Trial Investigators. Lancet. 2006;368:

DREAM: Rosiglitazone prolongs time to occurrence of new-onset diabetes or death DREAM Trial Investigators. Lancet. 2006;368: No. at risk Placebo Rosiglitazone Follow-up (years) Rosiglitazone Placebo 60% RRR HR 0.40 (0.35–0.46) P < Cumulative hazard rate

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 < ) 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) DREAM Trial Investigators. Lancet. 2006;368: *FPG < 110 mg/dL and 2-h glucose < 141 mg/dL

0 TZDs blunt diabetes progression Knowler WC et al. DPP Research Group. Diabetes 2005;54: * Withdrawn from study after 1.5 yr Diabetes Prevention Program Cumulative incidence of diabetes (%) Years Placebo Metformin 850 mg bid Lifestyle Troglitazone 400 mg/d* n =  75% vs placebo P < 0.001

Anticipated results from large multicenter trials in (pre)diabetes PROactive DREAM CHICAGO ADOPT APPROACH ACCORD BARI-2D ORIGIN Clinical outcomes Surrogate outcomes NAVIGATOR VADT RECORD ACT-NOW PERISCOPE

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 Mazzone T et al. JAMA CHICAGO compared the long-term effects of pioglitazone vs glimepiride on CIMT progression in ethnically and racially diverse, urban patients with T2DM

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

CHICAGO: Baseline risk factors ITT populationCIMT population Pioglitazone (n = 230) Glimepiride (n = 228) Pioglitazone (n = 175) Glimepiride (n = 186) A1C (%) FPG (mg/dL) BMI (kg/m 2 ) BP (mm Hg)130.1/ / / /77.0 LDL-C (mg/dL) NR HDL-C (mg/dL) NR TG (mg/dL) NR Mazzone T et al. JAMA NR = not reported

CHICAGO: Treatment effect on glucose control Mazzone T et al. JAMA *P = 0.04; † P = 0.01; ‡ P = (treatment-group difference) GlimepiridePioglitazone Baseline A 1C change from baseline (least square means, %) Week * † ‡

CHICAGO: Treatment effect on posterior wall mean CIMT Mazzone T et al. JAMA P = 0.02 Week 72Week 48Week 24Baseline Mean change from baseline (least squares, mm) GlimepiridePioglitazone CIMT = carotid intima-media thickness

CHICAGO: Treatment effect on posterior wall mean CIMT in prespecified subgroups Mazzone T et al. JAMA Statins Yes* No A1C (%) <7 ≥ BMI (kg/m 2 ) ≤31.3 > Duration of type 2 diabetes (months) ≤67 > Systolic BP (mm Hg) <130 ≥ Gender Male Female Age (years) ≤64 > N GlimepiridePioglitazoneParameter Number of patients Treatment-group difference in posterior wall CIMT (mean change, mm) Favors pioglitazone Favors glimepiride *Within 7 days of 1 st study drug dose

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, HbA 1C, 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 Bernard S et al. Diabetes Care. 2005;28:

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 mg/dL (pioglitazone) and 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 Dormandy JA et al. Lancet. 2005;366: Langenfeld et al. Circulation 2005;111:

Aggressive medical therapy in diabetes Adapted from Beckman JA et al. JAMA. 2002;287: Atherosclerosis Platelet activation and aggregation Dyslipidemia Hyperglycemia Insulin resistance Hypertension Metformin TZDs Sulfonylureas Nonsulfonylureas Secretagogues Insulin Statins Fibric acid derivatives ACE inhibitors ARBs β-blockers CCBs Diuretics ASA Clopidogrel Ticlopidine

Summary: Optimizing outcomes in patients with multiple CVD risks Improved clinical outcome Multifactorial risk reduction Traditional risk factors Emerging biomarkers Clinical trials