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)
60
40
20
0
New-onset diabetes (%)
Follow-up (months)
0 12 24 36 48 60
Buchanan TA et al. Diabetes. 2002;51:2796-803.
Placebo
Troglitazone 400 mg
12.1%
5.4%
Annual incidence
55% RRRHR 0.45 (0.25–0.83)*
P = 0.009
* 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;51:2796-803
TRIPOD = Troglitazone in Prevention of DiabetesPIPOD = Pioglitazone in Prevention of Diabetes
Anticipated results from large multicenter trials in (pre)diabetes
2005 2006 2007 2008 2009
PROactive
DREAMCHICAGOADOPT
APPROACHACCORDBARI-2DORIGIN
Clinical outcomes Surrogate outcomes
NAVIGATOR
VADT
RECORD
ACT-NOW
PERISCOPE
DREAMBackground 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
DREAMStudy 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 placeboAND
Rosiglitazone 8 mg/d vs placebo
Randomized, double-blind 2 × 2 factorial designN = 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;368:1096-1105.
DREAM: Rosiglitazone prolongs time to occurrence of new-onset diabetes or death
DREAM Trial Investigators. Lancet. 2006;368:1096-1105.
No. at riskPlaceboRosiglitazone
26342635
24702538
21502414
11481310
177217
0.6
0.5
0 1 2 3 4
Follow-up (years)
0.4
0.3
0.2
0.1
0.0
Rosiglitazone
Placebo60% RRR HR 0.40 (0.35–0.46) P < 0.0001
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 < 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)
DREAM Trial Investigators. Lancet. 2006;368:1096-1105
*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;54:1150-6.
* Withdrawn from study after 1.5 yr
Diabetes Prevention Program
10
15
5
1.5
Cumulativeincidence
of diabetes(%)
Years
1.00.50
Placebo
Metformin850 mg bid
Lifestyle
Troglitazone400 mg/d*
23773915682343n =
75% vs placebo
P < 0.001
Anticipated results from large multicenter trials in (pre)diabetes
2005 2006 2007 2008 2009
PROactive
DREAMCHICAGOADOPT
APPROACHACCORDBARI-2DORIGIN
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. 2006.
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. 2006.
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 = 175Intention-to-treat (ITT) analysis: n = 230
Primary CIMT analysis†: n = 186ITT analysis: n = 228
Double-blindComparator-controlled
CHICAGO: Baseline risk factors
ITT population CIMT population
Pioglitazone(n = 230)
Glimepiride(n = 228)
Pioglitazone(n = 175)
Glimepiride(n = 186)
A1C (%) 7.43 7.40 7.44 7.36
FPG (mg/dL) 151.7 149.6 149.2 148.2
BMI (kg/m2) 32.0 31.9 32.2 32.0
BP (mm Hg) 130.1/78.3 128.7/77.1 130.0/78.5 128.3/77.0
LDL-C (mg/dL) 113.8 111.3 NR NR
HDL-C (mg/dL) 47.1 47.6 NR NR
TG (mg/dL) 178.6 170.4 NR NR
Mazzone T et al. JAMA. 2006.
NR = not reported
CHICAGO: Treatment effect on glucose control
Mazzone T et al. JAMA. 2006.
*P = 0.04; †P = 0.01; ‡P = 0.002 (treatment-group difference)
Glimepiride Pioglitazone
724824Baseline-0.6
-0.4
-0.2
0
0.2
A1C change
from baseline
(least square
means, %)
60403216Week
* †
‡
CHICAGO: Treatment effect on posterior wall mean CIMT
Mazzone T et al. JAMA. 2006.
P = 0.02
Week 72Week 48Week 24Baseline-0.012
-0.008
-0.004
0
0.004
0.008
0.012
0.016
Mean change from baseline
(least squares, mm)
Glimepiride Pioglitazone
CIMT = carotid intima-media thickness
CHICAGO: Treatment effect on posterior wall mean CIMT in prespecified subgroups
Mazzone T et al. JAMA. 2006.
10185
9184
Statins Yes* No
70116
71104
A1C (%) <7 ≥7
9096
8689
BMI (kg/m2) ≤31.3 >31.3
9789
8491
Duration of type 2 diabetes (months) ≤67 >67
10878
8788
Systolic BP (mm Hg) <130 ≥130
11967
11164
Gender Male Female
13650
13441
Age (years) ≤64 >64
186175NGlimepiridePioglitazoneParameter
Number of patients
Treatment-group difference in posterior wall CIMT(mean change, mm)
-0.04 -0.03 -0.02 -0.01 0 0.01 0.02
Favorspioglitazone
Favorsglimepiride
*Within 7 days of 1st 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, 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.
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.
Aggressive medical therapy in diabetes
Adapted from Beckman JA et al. JAMA. 2002;287:2570-81.
Atherosclerosis
Platelet activationand aggregation
Dyslipidemia
HyperglycemiaInsulin resistance
Hypertension
MetforminTZDs
SulfonylureasNonsulfonylureas
SecretagoguesInsulin
StatinsFibric acid derivatives
ACE inhibitorsARBs
β-blockersCCBs
Diuretics
ASAClopidogrelTiclopidine
Summary: Optimizing outcomes inpatients with multiple CVD risks
Improved clinical outcome
Multifactorial risk reduction
Traditional risk factors
Emergingbiomarkers
Clinicaltrials