Transcript Document

VBWG
Insulin Sensitizers:
Surrogate and Clinical
Outcomes Studies
VBWG
Metformin improves endothelial function
Metformin
1000 mg
(3 months)
400
350
*
300
Increase in
forearm
blood
flow (%)
Placebo
250
200
*
150
100
*
50
0
3
10
30
3
10
30
Acetylcholine (g/min)
Before treatment
* P = 0.0027 vs placebo
After treatment
Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50.
VBWG
PPAR activation improves renal endothelial
function and reduces proteinuria
N = 19 with type 2 diabetes with/without microalbuminuria
P < 0.05
140
P < 0.05
133
120
120
119
103
100
GFR
80
(mL/min)
60
40
20
Treatment with
rosiglitazone was
followed by 60%
reductions in albuminuria
and proteinuria in
diabetic patients with
microalbuminuria.
0
Placebo
Rosiglitazone
Microalbuminuria
Nateglinide Rosiglitazone
No microalbuminuria
Pistrosch F et al. Diabetes. 2005;54:2206-11.
VBWG
PPAR activation normalizes coronary
vasomotor abnormalities in insulin resistance
N = 16 with insulin resistance; rosiglitazone 8 mg for 3 months
50
P < 0.01
40

MBF*
(%)
P < 0.01
40.3
(±31.3)
30
20
19.6
(±24.3)
10
8.7
(±18.9)
0
Pre-Treatment
* from rest
Post-Treatment
Off-Treatment
Quiñones MJ et al. Ann Intern Med. 2004;140:700-8.
VBWG
PPAR activation: Consistent reduction
in carotid atherosclerosis
Study (year)
Treatments
Patients (n)
duration
 IMT (mm)
Minamikawa
(1998)
Troglitazone 400 mg
Usual care
Type 2 diabetes
(n = 135)
6 mos
0.080, troglitazone
0.027, usual care
P < 0.001
Koshiyama
(2001)
Pioglitazone 30 mg
Usual care
Type 2 diabetes
(n = 106)
6 mos
0.084, troglitazone
0.022, usual care
P < 0.001
Sidhu
(2004)
Rosiglitazone 8 mg
Placebo
Stable CAD
(n = 92)
12 mos
0.012, rosiglitazone
0.0031, placebo
P = 0.03
Langenfeld
(2005)
Pioglitazone 45 mg
Glimepiride 2.7 mg
Type 2 diabetes
(n = 173)
6 mos
0.054, pioglitazone
0.011, glimepiride
P < 0.001
Minamikawa J et al. J Clin Endocrinol Metab. 1998;83:1818-20.
Koshiyama H et al. J Clin Endocrinol Metab. 2001;86;3452-6.
Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24:930-4.
Langenfeld MR et al. Circulation. 2005;111:2525-31.
VBWG
PPAR activation blunts progression of
carotid atherosclerosis in stable CAD
N = 92 without diabetes
0.04
Placebo
0.03

0.02
Carotid
IMT
(mm)
0.01
Progression rate =
0.031 mm/48 wks
Rosiglitazone 8 mg
Progression rate =
0.012 mm/48 wks
0
–0.01
0
24
48
Time (weeks)
P = 0.03
Adapted from Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24:930-4.
VBWG
PPAR activation blunts progression
of carotid atherosclerosis
N = 173 with type 2 diabetes
0.08
ns
0.04

0.00
P < 0.001
Carotid –0.04
IMT (mm)
–0.08
–0.12
P < 0.005
–0.16
0
12
24
Weeks
Pioglitazone 45 mg
Glimepiride 2.7 mg
Langenfeld MR et al. Circulation. 2005;111:2525-31.
VBWG
Additive effect of statin and PPAR
activation on atherosclerosis
Rabbit model
Changes in maximal vessel wall thickness
20
Highcholesterol
diet
(n = 6)
10

0
P < 0.01
(%) –10
–20
Normal diet
(n = 6)
Normal diet
+ PPARagonist*
(n = 7)
†
†
Normal diet +
simvastatin
Normal diet +
simvastatin + PPAR agonist *
(n = 6)
(n = 6)
†‡
†‡
–30
P = 0.04
P = 0.03
*L-805645
†P < 0.05 vs high-cholesterol diet
‡P < 0.05 vs normal diet
Corti R et al. J Am Coll Cardiol. 2004;43:464-73.
VBWG
PPAR activation reduces intimal hyperplasia
Balloon injury in mouse model
Rosiglitazone 8 mg/kg
Control
4
3.1
3
I/M ratio 2
(%)
1
I/M =
Intimal area
Medial area
0
P < 0.001
0.98
Control
Rosiglitazone
Wang C-H et al. Circulation. 2004;109:1392-400.
VBWG
PPAR activation: Consistent  in neointimal
proliferation (stented patients with T2D)
Intimal
index (%)
Treatments
Randomization
Trial
duration
Takagi,
2000
(n = 52)
Diet ±
Troglitazone
400 mg
2 days prior
6 mos
27.1, troglitazone
49.0, control
P < 0.001
Takagi,
2002
(n = 55)
Ins/SU/Acar ±
Troglitazone
400 mg
1 day prior
6 mos
39.1, troglitazone
71.5, control
P < 0.0001
Takagi,
2003
(n = 44)
Ins/SU/Acar ±
Pioglitazone
30 mg
8 days prior
6 mos
28%, pioglitazone
48%, control
P < 0.0001
Osman,
2004
(n = 16)
Placebo
Rosiglitazone
4 mg/ 8 mg
After stenting
6 mos
(first mo
at 4 mg)
Trend to benefit
Study, year (n)
Intimal index =
Intimal area
Stent area
Takagi T et al. J Am Coll Cardiol. 2000;36:1529-35.
Takagi T et al. Am J Cardiol. 2002;89;318-22.
Takagi T et al. Am Heart J. 2003;146:e5.
Osman A et al. Am Heart J. 2004;147:e23.
VBWG
PPAR activation reduces in-stent restenosis
N = 95 with type 2 diabetes
25
21
P = 0.03
20
Restenosis
(% stents)
15
9
10
5
0
Control
(n = 45)
*8-mg dose before catheterization;
4 mg daily thereafter
Rosiglitazone*
(n = 38)
Choi D et al. Diabetes Care. 2004;27:2654-60.
VBWG
Preliminary data support reduction in MI
with PPAR activation
Favors oral therapy
Favors insulin
0.62
Sulfonylurea
0.61
Metformin
Sulfonylurea
+ metformin
0.56
0.51
Thiazolidinedione
0.25
0.5
0.75
1
1.25
Odds ratio for MI
Koro CE et al. Diabetes. 2004;53(suppl 2):A247.
VBWG
PPAR activation associated with
lower mortality
N = 16,417 with diabetes and HF
1.0
0.9
Proportion 0.8
of patients
surviving 0.7
Thiazolidinedione (n = 2226)
13% Relative
risk reduction
0.6
No insulin sensitizer (n = 12,069)
0.5
0
50
100
150
200
250
300
350
Time (days)
Masoudi FA et al. Circulation. 2005;111:583-90.
VBWG
Metformin associated with lower mortality
N = 16,417 with diabetes and HF
1.0
0.9
Proportion
of patients
surviving
0.8
Metformin (n = 1861)
0.7
13% Relative
risk reduction
No insulin sensitizer (n = 12,069)
0.6
0.5
0
50
100
150
200
Time (days)
250
300
350
Masoudi FA et al. Circulation. 2005;111:583-90.
VBWG
Neutral effect of PPAR activation
and metformin on hospital readmission
N = 16,417 with diabetes and HF
Hospital readmission
All-cause
HF
TZD
1.04 (0.99–1.10)
1.06 (1.00–1.12)
Metformin
0.94 (0.89–1.01)
0.92 (0.86–0.99)
TZD = thiazolidinedione
Masoudi FA et al. Circulation. 2005;111:583-90.
VBWG
Thiazolidinediones in patients with
type 2 diabetes and HF
AHA/ADA consensus statement summary
• NYHA class I/II HF: Thiazolidinediones may be used
cautiously, with initiation of treatment at the lowest dose
and gradual dose escalation
– Allow more time than usual to achieve target A1C
• NYHA class III/IV HF: Thiazolidinediones should not be
used at this time
Nesto RW et al. Circulation. 2003;108:2941-8.
VBWG
Mortality benefit with combined
insulin-sensitizing therapy
8872 acute MI patients, mean age 76.4 years, discharged
on glucose-lowering medication
No insulin sensitizer (n = 6641)
Thiazolidinediones (n = 1273)
Metformin (n = 819)
TZD + MET (n = 139)
1.00
0.95
Proportion
of patients
surviving
0.90
48% Relative
risk reduction
0.85
0.80
0
50
100 150
200
250
Days from discharge
300
350
Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.
VBWG
Insulin sensitizers vs other glucose-lowering
agents following AMI
8872 acute MI patients, mean age 76.4 years, discharged
on glucose-lowering medication
Metformin
TZD
Both
Mortality
0.92
(0.81–1.06)
0.92
(0.80–1.05)
0.52
(0.34–0.82)
Myocardial
infarction
readmission
1.02
(0.86–1.20)
0.92
(0.77–1.10)
0.88
(0.56–1.37)
Heart failure
readmission
1.06
(0.95–1.18)
1.17
(1.05–1.30)
1.24
(0.94–1.63)
All-cause
readmission
1.04
(0.96–1.13)
1.09
(1.00–1.20)
1.06
(0.87–1.30)
Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.
VBWG
UKPDS: Risk reduction with metformin
in overweight patients
N = 4075 with type 2 diabetes
Aggregate endpoints
All-cause mortality
P*
Favors metformin
or intensive
Favors
conventional
0.021
Metformin
Intensive
Myocardial infarction
0.021
Metformin
Intensive
Stroke
0.021
Metformin
Intensive
0.1
1
10
Relative risk reduction
(95% CI)
*metformin vs intensive therapy
UKPDS Group. Lancet. 1998;352:854-65.
VBWG
Evolution of clinical evidence supporting
PPAR activation
Surrogate
outcomes
studies
2000
Large
observational
studies
Ongoing clinical
outcomes
studies
2005 and beyond
Endothelial
function
Carotid
atherosclerosis
Restenosis
Mortality in
patients with
diabetes + HF
or AMI
VBWG
Anticipated results from large multicenter
trials in diabetes and prediabetes
PROactive
2005
DREAM
ADOPT
APPROACH
CHICAGO
ACT-NOW
NAVIGATOR
VADT
PERISCOPE
RECORD
ACCORD
BARI-2D
ORIGIN
2006
2007
2008
2009
Clinical outcomes
Surrogate outcomes
VBWG
PROactive: Study design
Objective:
Assess the effects of pioglitazone on reducing
macrovascular events in type 2 diabetes
Design:
Randomized double-blind, controlled outcome
Population:
N = 5238 with type 2 diabetes and history of
macrovascular disease
Treatment:
Pioglitazone (up to 45 mg) or placebo
Primary
outcome:
Secondary
outcomes:
Follow-up:
Composite of all-cause mortality, MI, ACS,
coronary or peripheral revascularization,
amputation, stroke
Individual components of primary outcome,
CV mortality
4 years
Charbonnel B et al. Diabetes Care. 2004;27:1647-53.
Dormandy JA et al. Lancet. 2005;366:1279-89.
VBWG
PROactive: Baseline CV history
%
Pioglitazone
n = 2605
Placebo
n = 2633
MI
47
46
Stroke
19
19
PCI or CABG
31
31
Acute coronary syndromes
14
14
Coronary artery disease
48
48
Peripheral arterial disease
19
20
History of hypertension
75
76
>2 macrovascular disease
criteria
47
49
Dormandy JA et al. Lancet. 2005;366:1279-89.
VBWG
PROactive: CV medications at study entry
%
Pioglitazone
n = 2605
Placebo
n = 2633
-Blockers
55
54
ACEIs
63
63
ARBs
7
7
CCBs
34
37
Nitrates
39
40
Thiazide diuretics
15
16
Antiplatelet
85
83
Aspirin
75
72
Statins
43
43
Fibrates
10
11
Dormandy JA et al. Lancet. 2005;366:1279-89.
VBWG
PROactive: Reduction in primary outcome
All-cause mortality, MI, ACS, coronary or peripheral revascularization,
amputation, stroke
25
10% Relative
risk reduction
20
HR* 0.90 (0.80–1.02)
P = 0.095
Placebo
(572 events)
Pioglitazone
(514 events)
15
Proportion
of events 10
(%)
5
0
0
6
Number at risk
Pioglitazone
Placebo
*Unadjusted
2488
2530
12
18
24
Time from randomization
2373
2413
2302
2317
2218
2215
30
36
2146
2122
348
345
Dormandy JA et al. Lancet. 2005;366:1279-89.
VBWG
PROactive: Reduction in secondary outcome
All-cause mortality, MI (excluding silent MI), stroke
25
20
Placebo
(358 events)
16% Relative
risk reduction
15
Proportion
of events 10
(%)
HR* 0.84 (0.72–0.98)
P = 0.027
Pioglitazone
(301 events)
5
0
0
6
Number at risk
12
18
24
Time from randomization
30
36
Pioglitazone
2536
2487
2435
2381
2336
396
Placebo
2566
2504
2442
2371
2315
390
*Unadjusted
Dormandy JA et al. Lancet. 2005;366:1279-89.
VBWG
PROactive: Summary
Pioglitazone added to standard antidiabetic and CV therapies showed:
• 10% RRR in primary outcome
– Composite all-cause mortality, nonfatal MI (including silent MI),
stroke, ACS, leg amputation, coronary or leg revascularization
• 16% RRR in secondary outcome
– All-cause mortality, nonfatal MI (excluding silent MI) or stroke
• No difference between groups in HF mortality
• Continued divergence in survival curves
– Greater benefit with longer treatment duration hypothesized
PROactive results support use of PPAR modulator in patients with
diabetes at high CVD risk
– May improve CVD outcomes and need to add insulin
Dormandy JA et al. Lancet. 2005;366:1279-89.
VBWG
DREAM
Diabetes REduction Assessment with ramipril and rosiglitazone Medication
Objective:
Assess efficacy of rosiglitazone and ramipril in
diabetes prevention
Design:
N = 5269 with IGT or IFG, randomized (2x2 factorial design) to
Treatment:
Rosiglitazone 8 mg vs placebo
or ramipril 15 mg vs placebo
Primary outcomes:
New-onset diabetes and all-cause mortality
Secondary outcomes:
Combined MI, stroke, CV death, PCI/CABG, HF,
angina, ventricular arrhythmia
Combined microalbuminuria/macroalbuminuria
development, 30% decrease in CrCl
STARR substudy:
Change in carotid atherosclerosis
Follow-up:
4 years (anticipated)
Completion:
2006
The DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
VBWG
DREAM: Baseline characteristics
Age (years)
54.7
Hypertension (%)
43.5
Hyperlipidemia (%)
35.5
BP (mm Hg)
136/83
BMI (kg/m2)
30.5
Waist circumference (inches)
Men
34.3
Women
32.6
The DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
VBWG
ADOPT: Study design
A Diabetes Outcome Progression Trial
Objective:
Assess effect on glucose control of rosiglitazone,
metformin, or glyburide monotherapy
Design:
N = ~3600 with type 2 diabetes of 3 years duration,
drug-naïve
Treatment:
Randomized to rosiglitazone 8 mg, metformin 2 g,
or glyburide 15 mg
Primary outcome:
Time to need for combination therapy
Secondary outcomes: -cell function, insulin sensitivity, dyslipidemia,
albumin excretion, PAI-1, fibrinogen, CRP
Follow-up:
4 years
Completion:
2007
Viberti G et al. Diabetes Care. 2002;25:1737-43.