Transcript Dia 1 - pace

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)
Annual
incidence
60
40
New-onset
diabetes
(%)
12.1%
55% RRR
HR 0.45 (0.25–0.83)*
P = 0.009
Placebo
20
5.4%
Troglitazone
400 mg
0
0
* Unadjusted
12
24
36
48
60
Follow-up (months)
Buchanan TA et al. Diabetes. 2002;51:2796-803.
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
Anticipated results from large
multicenter trials in (pre)diabetes
DREAM
CHICAGO
PROactive
2005
APPROACH
ADOPT
2006
Clinical outcomes
2007
ACT-NOW
NAVIGATOR
VADT
PERISCOPE
RECORD
2008
Surrogate outcomes
ACCORD
BARI-2D
ORIGIN
2009
DREAM
Background and study objective
Diabetes REduction Assessment with ramipril and rosiglitazone Medication
• 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.
DREAM
Study design
Randomized, double-blind 2 × 2 factorial design
N = 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
events
Combined MI, stroke, CV
death, revascularization, HF,
angina,
ventricular arrhythmia
Secondary outcomes II:
Renal events
Progression to micro- or
macroalbuminuria,
or 30% CrCl
Secondary outcomes III:
Glycemic
Glucose levels,
regression to
normoglycemia
Follow-up: 3–5 years
DREAM Trial Investigators. Lancet. 2006;368:1096-1105.
DREAM: Rosiglitazone prolongs time to
occurrence of new-onset diabetes or death
0.6
0.5
0.4
Cumulative
hazard rate
Placebo
60% RRR
HR 0.40 (0.35–0.46)
P < 0.0001
0.3
0.2
Rosiglitazone
0.1
0.0
0
No. at risk
Placebo
Rosiglitazone
1
2
3
4
1148
1310
177
217
Follow-up (years)
2634
2635
2470
2538
2150
2414
DREAM Trial Investigators. Lancet. 2006;368:1096-1105.
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
TZDs blunt diabetes progression
Diabetes Prevention Program
15
Cumulative
incidence
of diabetes
(%)
Placebo
Metformin
850 mg bid
10
Lifestyle
Troglitazone
400 mg/d*
5
75% vs
placebo
P < 0.001
0
0
0.5
1.0
1.5
739
237
Years
n=
2343
1568
* Withdrawn from study after 1.5 yr
Knowler WC et al. DPP Research Group. Diabetes 2005;54:1150-6.
Anticipated results from large
multicenter trials in (pre)diabetes
DREAM
CHICAGO
PROactive
2005
APPROACH
ADOPT
2006
Clinical outcomes
2007
ACT-NOW
NAVIGATOR
VADT
PERISCOPE
RECORD
2008
Surrogate outcomes
ACCORD
BARI-2D
ORIGIN
2009
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 pioglitazone vs glimepiride on
CIMT progression in ethnically and racially diverse, urban patients with T2DM
Mazzone T et al. JAMA. 2006.
CHICAGO: Study design
N = 462 with T2DM
Pioglitazone 15–45 mg*
(n = 232)
Double-blind
Comparator-controlled
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
Primary CIMT analysis†: n = 175
Intention-to-treat (ITT) analysis: n = 230
Primary CIMT analysis†: n = 186
ITT 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.
CHICAGO: Baseline risk factors
ITT population
CIMT population
Pioglitazone
(n = 230)
Glimepiride
(n = 228)
Pioglitazone
(n = 175)
Glimepiride
(n = 186)
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
178.6
170.4
NR
NR
A1C (%)
TG (mg/dL)
NR = not reported
Mazzone T et al. JAMA. 2006.
CHICAGO:
Treatment effect on glucose control
0.2
‡
A1C
change
from
baseline
(least
square
means, %)
*
0
†
-0.2
-0.4
-0.6
Baseline
16
Glimepiride
24
32
40
Week
Pioglitazone
48
60
72
*P = 0.04; †P = 0.01; ‡P = 0.002 (treatment-group difference)
Mazzone T et al. JAMA. 2006.
CHICAGO: Treatment effect on
posterior wall mean CIMT
0.016
0.012
Mean change 0.008
from baseline
0.004
(least
squares, mm)
0
P = 0.02
-0.004
-0.008
-0.012
Baseline
Glimepiride
Week 24
Week 48
Week 72
Pioglitazone
CIMT = carotid intima-media thickness
Mazzone T et al. JAMA. 2006.
CHICAGO: Treatment effect on posterior
wall mean CIMT in prespecified subgroups
Parameter
N
Age (years)
≤64
>64
Gender
Male
Female
Systolic BP (mm Hg)
<130
≥130
Duration of type 2 diabetes (months)
≤67
>67
BMI (kg/m2)
≤31.3
>31.3
A1C (%)
<7
≥7
Statins
Yes*
No
Number of patients
Pioglitazone
Glimepiride
175
186
134
41
136
50
111
64
119
67
87
88
108
78
84
91
97
89
86
89
90
96
71
104
70
116
91
84
101
85
Favors
pioglitazone
-0.04
*Within 7 days of 1st study drug dose
-0.03
-0.02
-0.01
Favors
glimepiride
0
0.01
0.02
Treatment-group difference in posterior wall CIMT
(mean change, mm)
Mazzone T et al. JAMA. 2006.
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 welltreated 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
Statins
Fibric acid derivatives
ACE inhibitors
ARBs
β-blockers
CCBs
Diuretics
Metformin
TZDs
Sulfonylureas
Nonsulfonylureas
Secretagogues
Insulin
ASA
Clopidogrel
Ticlopidine
Dyslipidemia
Atherosclerosis
Hypertension
Hyperglycemia
Insulin resistance
Platelet activation
and aggregation
Adapted from Beckman JA et al. JAMA. 2002;287:2570-81.
Summary: Optimizing outcomes in
patients with multiple CVD risks
Traditional
risk factors
Emerging
biomarkers
Multifactorial risk reduction
Improved clinical outcome
Clinical
trials