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Insulin Sensitizers: Surrogate and Clinical Outcomes Studies. Metformin improves endothelial function. Metformin 1000 mg ( 3 months). Placebo. 400. 350. *. 300. 250. Increase in forearm blood flow (%). 200. *. 150. 100. *. 50. 0. 3. 10. 30. 3. 10. 30. - PowerPoint PPT Presentation
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Insulin Sensitizers: Surrogate and Clinical
Outcomes Studies
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Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50. * P = 0.0027 vs placebo
Before treatment After treatment
400
300
250
200
150
50
0
350
Metformin 1000 mg (3 months)
3
Increase in forearm blood
flow (%)
Acetylcholine (g/min)
100
*
Placebo
10 30 3 10 30
*
*
Metformin improves endothelial function
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PPAR activation improves renal endothelial function and reduces proteinuria N = 19 with type 2 diabetes with/without microalbuminuria
Pistrosch F et al. Diabetes. 2005;54:2206-11.
0
20
40
60
80
100
120
140
Placebo
133
Rosiglitazone
120
Nateglinide
119
Rosiglitazone
103
GFR(mL/min)
Microalbuminuria No microalbuminuria
Treatment with rosiglitazone was followed by 60%
reductions in albuminuria and proteinuria in
diabetic patients with microalbuminuria.
P < 0.05P < 0.05
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PPAR activation normalizes coronary vasomotor abnormalities in insulin resistance
Quiñones MJ et al. Ann Intern Med. 2004;140:700-8.
N = 16 with insulin resistance; rosiglitazone 8 mg for 3 months
* from rest
0
10
20
30
40
50
Pre-Treatment Post-Treatment Off-Treatment
P < 0.01
MBF*(%)
P < 0.01
19.6(±24.3)
40.3(±31.3)
8.7(±18.9)
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PPAR activation: Consistent reduction in carotid atherosclerosis
Study (year) TreatmentsPatients (n)
duration IMT (mm)
Minamikawa(1998)
Koshiyama(2001)
Sidhu(2004)
Langenfeld(2005)
Troglitazone 400 mgUsual care
Type 2 diabetes (n = 135)6 mos
0.080, troglitazone0.027, usual careP < 0.001
Pioglitazone 30 mgUsual care
Type 2 diabetes(n = 106)6 mos
0.084, troglitazone0.022, usual careP < 0.001
Rosiglitazone 8 mgPlacebo
Stable CAD(n = 92)12 mos
0.012, rosiglitazone0.0031, placeboP = 0.03
Pioglitazone 45 mgGlimepiride 2.7 mg
Type 2 diabetes(n = 173)6 mos
0.054, pioglitazone0.011, glimepirideP < 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.
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PPAR activation blunts progression of carotid atherosclerosis in stable CAD
Adapted from Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24:930-4.
N = 92 without diabetes
PlaceboProgression rate = 0.031 mm/48 wks
Rosiglitazone 8 mgProgression rate = 0.012 mm/48 wks
0.04
0.03
0.02
0.01
–0.01
0
0 24 48
Time (weeks)
Carotid
IMT(mm)
P = 0.03
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PPAR activation blunts progression of carotid atherosclerosis
Langenfeld MR et al. Circulation. 2005;111:2525-31.
N = 173 with type 2 diabetes0.08
0.04
0.00
–0.04
–0.08
–0.12
–0.16
P < 0.005
P < 0.001
CarotidIMT (mm)
0 12 24
Pioglitazone 45 mg Glimepiride 2.7 mg
ns
Weeks
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Additive effect of statin and PPAR activation on atherosclerosis
Corti R et al. J Am Coll Cardiol. 2004;43:464-73.
*L-805645
20
10
0
–10
–20
–30
P = 0.03
P = 0.04
High- cholesterol
diet (n = 6)
Normal diet(n = 6)
Normal diet + PPAR-agonist* (n = 7)
Normal diet +simvastatin
(n = 6)
Normal diet +simvastatin
+ PPAR agonist * (n = 6)
Changes in maximal vessel wall thickness
†
(%)
†
†P < 0.05 vs high-cholesterol diet‡P < 0.05 vs normal diet
‡
†‡
Rabbit model
P < 0.01
†
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PPAR activation reduces intimal hyperplasia
Wang C-H et al. Circulation. 2004;109:1392-400.
Control Rosiglitazone 8 mg/kg
0
1
2
3
4
Control Rosiglitazone
I/M ratio(%)
Balloon injury in mouse model
I/M =Intimal area
Medial area
3.1
0.98
P < 0.001
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PPAR activation: Consistent in neointimal proliferation (stented patients with T2D)
Study, year (n) TreatmentsTrial
duration
Intimal index (%)
Takagi,2000(n = 52)
Takagi,2002(n = 55)
Takagi,2003(n = 44)
Diet ±Troglitazone 400 mg
6 mos 27.1, troglitazone49.0, controlP < 0.001
Ins/SU/Acar ± Troglitazone400 mg
6 mos 39.1, troglitazone71.5, controlP < 0.0001
Ins/SU/Acar ± Pioglitazone 30 mg
6 mos 28%, pioglitazone48%, controlP < 0.0001
Randomization
2 days prior
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.
1 day prior
8 days prior
Osman,2004(n = 16)
Placebo Rosiglitazone4 mg/ 8 mg
6 mos(first mo at 4 mg)
Trend to benefitAfter stenting
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PPAR activation reduces in-stent restenosis
Control(n = 45)
Rosiglitazone*(n = 38)
5
10
15
20
25P = 0.03
Restenosis(% stents)
21
9
Choi D et al. Diabetes Care. 2004;27:2654-60.
0
*8-mg dose before catheterization; 4 mg daily thereafter
N = 95 with type 2 diabetes
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Preliminary data support reduction in MIwith PPAR activation
Koro CE et al. Diabetes. 2004;53(suppl 2):A247.
Sulfonylurea
Metformin
Thiazolidinedione
Sulfonylurea + metformin
0.5 0.75 1.251
Odds ratio for MI0.25
Favors oral therapy Favors insulin
0.51
0.62
0.61
0.56
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PPAR activation associated with lower mortality
Masoudi FA et al. Circulation. 2005;111:583-90.
Time (days)
0.6
0.7
0.8
1.0
0.5
50 100 300150 200 250
0.9
0 350
13% Relative risk reduction
No insulin sensitizer (n = 12,069)
Thiazolidinedione (n = 2226) Proportionof patientssurviving
N = 16,417 with diabetes and HF
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Metformin associated with lower mortality
Masoudi FA et al. Circulation. 2005;111:583-90.
N = 16,417 with diabetes and HF
Metformin (n = 1861)
No insulin sensitizer (n = 12,069)
Time (days)
1.0
0.9
0.8
0.7
0.6
0.50 50 150 200 250 300 350100
13% Relativerisk reduction
Proportionof patientssurviving
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Neutral effect of PPAR activationand metformin on hospital readmissionN = 16,417 with diabetes and HF
Masoudi FA et al. Circulation. 2005;111:583-90.
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)
Hospital readmission
TZD = thiazolidinedione
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Thiazolidinediones in patients with type 2 diabetes and HF
Nesto RW et al. Circulation. 2003;108:2941-8.
• 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
AHA/ADA consensus statement summary
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Mortality benefit with combined insulin-sensitizing therapy8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication
Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.
No insulin sensitizer (n = 6641)Thiazolidinediones (n = 1273)Metformin (n = 819)TZD + MET (n = 139)
48% Relativerisk reduction
Days from discharge
1.00
0.95
0.90
0.85
0.800 50 200 250 300 350100
Proportionof patientssurviving
150
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Insulin sensitizers vs other glucose-lowering agents following AMI
Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.
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 failurereadmission
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)
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UKPDS: Risk reduction with metformin in overweight patientsN = 4075 with type 2 diabetes
UKPDS Group. Lancet. 1998;352:854-65.
Favors metforminor intensive
Favors conventionalAll-cause mortality
MetforminIntensive
Myocardial infarctionMetforminIntensive
StrokeMetforminIntensive
0.021
0.021
0.021
Aggregate endpoints P*
0.1 1 10
*metformin vs intensive therapy
Relative risk reduction(95% CI)
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Evolution of clinical evidence supporting PPAR activation
20002000 2005 and beyond2005 and beyond
Surrogate outcomes
studies
Large observational
studies
Ongoing clinical outcomes
studies
Endothelialfunction
Carotid atherosclerosis
Restenosis
Mortality in patients with diabetes + HF or AMI
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Anticipated results from large multicenter trials in diabetes and prediabetes
20052005 20062006 20072007 20082008 2009 2009
PROactivePROactive DREAMDREAM
ADOPTADOPTAPPROACHAPPROACH CHICAGO CHICAGO
ACCORDACCORDBARI-2DBARI-2DORIGINORIGIN
Clinical outcomesClinical outcomes Surrogate outcomesSurrogate outcomes
NAVIGATORNAVIGATOR
VADTVADT
RECORDRECORD
ACT-NOWACT-NOW
PERISCOPEPERISCOPE
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PROactive: Study design
Charbonnel B et al. Diabetes Care. 2004;27:1647-53.Dormandy JA et al. Lancet. 2005;366:1279-89.
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: Composite of all-cause mortality, MI, ACS, coronary or peripheral revascularization, amputation, stroke
Secondary outcomes: Individual components of primary outcome, CV mortality
Follow-up: 4 years
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PROactive: Baseline CV history
Dormandy JA et al. Lancet. 2005;366:1279-89.
Pioglitazonen = 2605
Placebon = 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
%
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PROactive: CV medications at study entry
Dormandy JA et al. Lancet. 2005;366:1279-89.
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
%
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PROactive: Reduction in primary outcome
Dormandy JA et al. Lancet. 2005;366:1279-89.
Number at risk
Pioglitazone 2488 2373 2302 2218 2146 348Placebo 2530 2413 2317 2215 2122 345
5
10
15
25
06
20
0 12 18 24 30 36
Pioglitazone(514 events)
10% Relative risk reduction
HR* 0.90 (0.80–1.02)P = 0.095
Placebo(572 events)
Time from randomization
Proportionof events
(%)
All-cause mortality, MI, ACS, coronary or peripheral revascularization, amputation, stroke
*Unadjusted
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PROactive: Reduction in secondary outcome
Dormandy JA et al. Lancet. 2005;366:1279-89.
Number at risk
Pioglitazone 2536 2487 2435 2381 2336 396
Placebo 2566 2504 2442 2371 2315 390
5
10
15
25
06
20
0 12 18 24 30 36
Pioglitazone(301 events)
Placebo(358 events)
Time from randomization
Proportionof events
(%)
16% Relative risk reduction
HR* 0.84 (0.72–0.98)P = 0.027
All-cause mortality, MI (excluding silent MI), stroke
*Unadjusted
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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
Dormandy JA et al. Lancet. 2005;366:1279-89.
PROactive results support use of PPAR modulator in patients with diabetes at high CVD risk
– May improve CVD outcomes and need to add insulin
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DREAM
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
Diabetes REduction Assessment with ramipril and rosiglitazone Medication
The DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
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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.
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ADOPT: Study design
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
A Diabetes Outcome Progression Trial
Viberti G et al. Diabetes Care. 2002;25:1737-43.