Insulin Sensitizers: Surrogate and Clinical Outcomes Studies

1
Insulin Sensitizers Surrogate and Clinical
Outcomes Studies
2
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
Acetylcholine (?g/min)
Before treatment
After treatment
Mather KJ et al. J Am Coll Cardiol.
2001371344-50.
P 0.0027 vs placebo
3
PPAR? activation improves renal endothelial
function and reduces proteinuria
N 19 with type 2 diabetes with/without
microalbuminuria
P lt 0.05
P lt 0.05
140
133
120
Treatment with rosiglitazone was followed by 60
reductions in albuminuria and proteinuria in
diabetic patients with microalbuminuria.
119
120
103
100
GFR(mL/min)
80
60
40
20
0
Placebo
Rosiglitazone
Nateglinide
Rosiglitazone
Microalbuminuria
No microalbuminuria
Pistrosch F et al. Diabetes. 2005542206-11.
4
PPAR? activation normalizes coronary vasomotor
abnormalities in insulin resistance
N 16 with insulin resistance rosiglitazone 8
mg for 3 months
50
P lt 0.01
P lt 0.01
40
40.3(31.3)
?MBF ()
30
20
19.6(24.3)
10
8.7(18.9)
0
Pre-Treatment
Post-Treatment
Off-Treatment
Quiñones MJ et al. Ann Intern Med. 2004140700-8.
from rest
5
PPAR? activation Consistent reduction in
carotid atherosclerosis
Patients (n)duration
Study (year)
Treatments
? IMT (mm)
?0.080, troglitazone?0.027, usual careP lt 0.001
Type 2 diabetes (n 135)6 mos
Minamikawa(1998)
Troglitazone 400 mgUsual care
Type 2 diabetes(n 106) 6 mos
?0.084, troglitazone?0.022, usual careP lt 0.001
Koshiyama(2001)
Pioglitazone 30 mgUsual care
?0.012, rosiglitazone?0.0031, placeboP 0.03
Stable CAD(n 92)12 mos
Sidhu(2004)
Rosiglitazone 8 mgPlacebo
?0.054, pioglitazone?0.011, glimepirideP lt 0.001
Langenfeld(2005)
Type 2 diabetes(n 173)6 mos
Pioglitazone 45 mgGlimepiride 2.7 mg
Minamikawa J et al. J Clin Endocrinol Metab.
1998831818-20.Koshiyama H et al. J Clin
Endocrinol Metab. 2001863452-6.Sidhu JS et al.
Arterioscler Thromb Vasc Biol. 200424930-4.Lang
enfeld MR et al. Circulation. 20051112525-31.
6
PPAR? activation blunts progression of carotid
atherosclerosis in stable CAD
N 92 without diabetes
0.04
PlaceboProgression rate 0.031 mm/48 wks
0.03
0.02
? Carotid IMT (mm)
Rosiglitazone 8 mgProgression rate 0.012
mm/48 wks
0.01
0
0.01
0
24
48
Time (weeks)
Adapted from Sidhu JS et al. Arterioscler Thromb
Vasc Biol. 200424930-4.
P 0.03
7
PPAR? activation blunts progression of carotid
atherosclerosis
N 173 with type 2 diabetes
0.08
ns
0.04
0.00
?CarotidIMT (mm)
P lt 0.001
0.04
0.08
0.12
P lt 0.005
0.16
0
12
24
Weeks
Glimepiride 2.7 mg
Pioglitazone 45 mg
Langenfeld MR et al. Circulation.
20051112525-31.
8
Additive effect of statin and PPAR? activation
on atherosclerosis
Rabbit model
Changes in maximal vessel wall thickness
High- cholesterol diet (n 6)
20
Normal diet simvastatin PPAR? agonist (n
6)
Normal diet PPAR?-agonist (n 7)
Normal diet simvastatin (n 6)
10
Normal diet(n 6)
0
? ()
P lt 0.01

10



20
30
P 0.04
P 0.03
L-805645
P lt 0.05 vs high-cholesterol diet
Corti R et al. J Am Coll Cardiol. 200443464-73.
P lt 0.05 vs normal diet
9
PPAR? activation reduces intimal hyperplasia
Balloon injury in mouse model
Rosiglitazone 8 mg/kg
Control
4
3.1
3
I/M ratio()
2
P lt 0.001
0.98
1
0
Intimal area Medial area
Control
Rosiglitazone
I/M
Wang C-H et al. Circulation. 20041091392-400.
10
PPAR? activation Consistent ? in neointimal
proliferation (stented patients with T2D)
Intimal index ()
Trialduration
Study, year (n)
Treatments
Randomization
6 mos
2 days prior
Diet Troglitazone 400 mg
27.1, troglitazone49.0, controlP lt 0.001
Takagi,2000(n 52)
Ins/SU/Acar Troglitazone400 mg
6 mos
39.1, troglitazone71.5, controlP lt 0.0001
1 day prior
Takagi,2002(n 55)
6 mos
Takagi,2003(n 44)
28, pioglitazone48, controlP lt 0.0001
8 days prior
Ins/SU/Acar Pioglitazone 30 mg
Trend to benefit
Placebo Rosiglitazone4 mg/ 8 mg
After stenting
Osman,2004(n 16)
6 mos(first mo at 4 mg)
Takagi T et al. J Am Coll Cardiol.
2000361529-35.Takagi T et al. Am J Cardiol.
200289318-22.Takagi T et al. Am Heart J.
2003146e5. Osman A et al. Am Heart J.
2004147e23.
Intimal area
Intimal index
Stent area
11
PPAR? activation reduces in-stent restenosis
N 95 with type 2 diabetes
25
P 0.03
21
20
15
Restenosis ( stents)
9
10
5
0
Control(n 45)
Rosiglitazone(n 38)
8-mg dose before catheterization 4 mg daily
thereafter
Choi D et al. Diabetes Care. 2004272654-60.
12
Preliminary data support reduction in MIwith
PPAR? activation
Favors oral therapy
Favors insulin
0.62
Sulfonylurea
0.61
Metformin
Sulfonylurea metformin
0.56
0.51
Thiazolidinedione
0.5
0.75
1.25
1
0.25
Odds ratio for MI
Koro CE et al. Diabetes. 200453(suppl 2)A247.
13
PPAR? activation associated with lower mortality
N 16,417 with diabetes and HF
1.0
0.9
0.8
Proportion of patientssurviving
Thiazolidinedione (n 2226)
0.7
13 Relative risk reduction
0.6
No insulin sensitizer (n 12,069)
0.5
50
100
300
150
200
250
0
350
Time (days)
Masoudi FA et al. Circulation. 2005111583-90.
14
Metformin associated with lower mortality
N 16,417 with diabetes and HF
1.0
0.9
0.8
Metformin (n 1861)
Proportion of patientssurviving
0.7
13 Relativerisk reduction
No insulin sensitizer (n 12,069)
0.6
0.5
0
50
150
200
250
300
350
100
Time (days)
Masoudi FA et al. Circulation. 2005111583-90.
15
Neutral effect of PPAR? activationand metformin
on hospital readmission
N 16,417 with diabetes and HF
Hospital readmission

• All-cause HF
• TZD 1.04 (0.991.10) 1.06 (1.001.12)
• Metformin 0.94 (0.891.01) 0.92 (0.860.99)

TZD thiazolidinedione
Masoudi FA et al. Circulation. 2005111583-90.
16
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. 20031082941-8.
17
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)Thiazolidinedione
s (n 1273) Metformin (n 819) TZD MET (n
139)
1.00
0.95
Proportion of patientssurviving
0.90
48 Relativerisk reduction
0.85
0.80
0
50
200
250
300
350
100
150
Days from discharge
Inzucchi SE et al. Diabetes Care. 2005281680-9.
18
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 (0.811.06)
0.92 (0.801.05)
0.52 (0.340.82)
Myocardial infarction readmission
1.02 (0.861.20)
0.92 (0.771.10)
0.88 (0.561.37)
Heart failurereadmission
1.06 (0.951.18)
1.17 (1.051.30)
1.24 (0.941.63)
All-cause readmission
1.04 (0.961.13)
1.09 (1.001.20)
1.06 (0.871.30)
Inzucchi SE et al. Diabetes Care. 2005281680-9.
19
UKPDS Risk reduction with metformin in
overweight patients
N 4075 with type 2 diabetes
Aggregate endpoints
P
Favors metforminor intensive
Favors conventional
All-cause mortality Metformin Intensive Myocardia
l infarction Metformin Intensive Stroke Metformin
Intensive
0.021 0.021 0.021
0.1
1
10
Relative risk reduction(95 CI)
UKPDS Group. Lancet. 1998352854-65.
metformin vs intensive therapy
20
Evolution of clinical evidence supporting PPAR?
activation
Surrogate outcomes studies
Ongoing clinical outcomes studies
Large observational studies
2000 2005 and beyond
?Mortality in patients with diabetes HF or AMI
?Endothelialfunction ?Carotid atherosclerosis ?Re
stenosis
21
Anticipated results from large multicenter trials
in diabetes and prediabetes
NAVIGATOR VADT RECORD
ACT-NOW PERISCOPE
ADOPTAPPROACH CHICAGO
ACCORDBARI-2DORIGIN
DREAM
PROactive
2005 2006 2007 2008 2009
Clinical outcomes
Surrogate outcomes
22
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 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
Charbonnel B et al. Diabetes Care.
2004271647-53. Dormandy JA et al. Lancet.
20053661279-89.
23
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
gt2 macrovascular disease criteria 47 49
Dormandy JA et al. Lancet. 20053661279-89.
24
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. 20053661279-89.
25
PROactive Reduction in primary outcome
All-cause mortality, MI, ACS, coronary or
peripheral revascularization, amputation, stroke
25
10 Relative risk reduction HR 0.90
(0.801.02)P 0.095
Placebo(572 events)
20
Pioglitazone(514 events)
15
Proportionof events()
10
5
0
6
0
12
18
24
30
36
Time from randomization
Number at risk
Pioglitazone
2488
2373
2302
2218
2146
348
Placebo
2530
2413
2317
2215
2122
345
Dormandy JA et al. Lancet. 20053661279-89.
Unadjusted
26
PROactive Reduction in secondary outcome
All-cause mortality, MI (excluding silent MI),
stroke
25
20
Placebo(358 events)
16 Relative risk reduction HR 0.84
(0.720.98)P 0.027
15
Proportionof events()
10
Pioglitazone(301 events)
5
0
6
0
12
18
24
30
36
Time from randomization
Number at risk
Pioglitazone
2536
2487
2435
2381
2336
396
Placebo
2566
2504
2442
2371
2315
390
Dormandy JA et al. Lancet. 20053661279-89.
Unadjusted
27
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. 20053661279-89.
28
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 Foll
ow-up 4 years (anticipated) Completion 2006
The DREAM Trial Investigators. Diabetologia.
2004471519-27.
29
DREAM Baseline characteristics
Age (years) 54.7 Hypertension () 43.5 Hyperlipi
demia () 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.
2004471519-27.
30
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. 2002251737-43.