PPAR  activation
Clinical evidence
Evolution of clinical evidence
supporting PPAR  activation
Surrogate outcomes studies
2000
Endothelial
function
Carotid
atherosclerosis
Restenosis
Large observational
studies
Ongoing clinical
outcomes studies
2005 and beyond
 Onset of
diabetes in
patients with IFG
Mortality in
patients with
diabetes + HF
or AMI
Anticipated results from large
multicenter trials in (pre)diabetes
APPROACH
ACT-NOW
NAVIGATOR
VADT
PERISCOPE
RECORD
2007
2008
DREAM
PROactive
2005
CHICAGO
ADOPT
2006
Clinical outcomes
Surrogate outcomes
ACCORD
BARI-2D
ORIGIN
2009
PROactive: Study Design
PROspective pioglitAzone Clinical Trial In macroVascular Events
Randomized, double-blind controlled trial
N = 5238 with type 2 diabetes and macrovascular disease
Pioglitazone 15 mg qd
titrated to 45 mg qd
Placebo
Primary outcome: Composite of all-cause mortality,
MI (including silent MI), ACS, stroke, revascularization, leg amputation
Secondary outcome: All-cause mortality,
MI (excluding silent MI), stroke
Mean follow-up: 34.5 months
Dormandy JA et al. Lancet. 2005;366:1279-89.
PROactive
Baseline Characteristics
Male (%)
Caucasian (%)
Age (yrs)
BMI (kg/m2)
Waist circ. (cm)
Current smoker (%)
Ex smoker (%)
Systolic BP (mm/Hg)
Diastolic BP (mm/Hg)
Pioglitazone
66.6
98.4
61.9
30.7
104.9
13.1
46.0
143.5
82.8
Placebo
65.6
98.7
61.6
31.0
105.5
14.5
44.0
143.3
83.2
Dormandy JA et al. Lancet. 2005;366:1279-89.
PROactive
CV history at baseline
%
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.
PROactive
CV medications at baseline
%
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
Antiplatelets
85
83
Aspirin
75
72
Statins
43
43
Fibrates
10
11
Dormandy JA et al. Lancet. 2005;366:1279-89.
Time to primary composite endpoint
0.25
Kaplan-Meier event rate
N events:
placebo
0.20
3-year estimate:
572 / 2633
pioglitazone 514 / 2605
23.5%
21.0%
0.15
0.10
0.05
pioglitazone
vs placebo
HR
95% CI
p value
0.904
0.802 - 1.018
0.0951
0.0
N at Risk:
5238
5018
4786
4619
4433
4268
0
6
12
18
24
30
693 (228)
36
Time from Randomization (months)
Dormandy JA et al., Lancet (2005) 366:1279 - 1289
Significant reduction in secondary outcome
0.15
Kaplan-Meier event rate
N events:
placebo
3-year estimate:
358 / 2633
pioglitazone 301 / 2605
14.4%
12.3%
0.10
0.05
pioglitazone
vs placebo
HR
95% CI
p value
0.841
0.722 - 0.981
0.0273 *
0.0
N at Risk:
5238
5102
4991
4877
4752
4651
0
6
12
18
24
30
786 (256)
36
Time from Randomization (months)
Dormandy JA et al., Lancet (2005) 366:1279 - 1289
Time to all-cause death, non-fatal MI,
stroke or ACS
0.20
Kaplan-Meier event rate
N events:
placebo
3-year estimate:
409 / 2633
pioglitazone 339 / 2605
0.15
16.5%
13.8%
0.10
0.05
pioglitazone
vs placebo
HR
95% CI
p value
0.828
0.717- 0.956
0.01 *
0.0
N at Risk:
5238
5080
4947
4816
4684
4564
0
6
12
18
24
30
765 (248)
36
Time from Randomization (months)
Dormandy JA et al., Lancet (2005) 366:1279 - 1289
Time to permanent insulin use
Kaplan Meier event rate of progression to permanent insulin use
N events:
0.25
0.20
3-year estimate:
placebo
362/1737
22,0%
pioglitazone
183/1741
11,1%
0.15
0.10
0.05
HR
pioglitazone vs
palcebo
0.0
N at risk:
3478
0
3346
6
12
3198
18
3075
24 30
2955
95% CI
p value
0.469 0.39-0.56 <0.0001
2824
446 (137)
36
Time from Randomization (months)
Dormandy JA et al. Lancet. 2005;366:1279-89.
PROactive
Subgroup analysis – Previous MI
n = 2445 with previous MI (≥6 mo)
•
Pioglitazone reduced risk of CV events, including:
– Fatal/nonfatal MI* by 28% (P = 0.045)
– ACS by 37% (P = 0.035)
•
Over 3 years, pioglitazone added to medication in 1000
patients could prevent:
– 22 recurrent MIs
– 23 ACS events
•
Future studies are needed to further elucidate the underlying
mechanism(s) of these clinical results
*Excluding silent MI
Adapted from Erdmann E. AHA 2005. www.PROactive-results.com.
PROactive
Subgroup analysis – Previous stroke
Fatal and nonfatal stroke with pioglitazone treatment vs placebo in patients with prior
history of stroke
End point
Pioglitazone
n=486
Placebo
n=498
Hazard ratio
(95% CI)
p
Recurrent
stroke
27
51
0.53
(0.34– 0.94)
0.008
Wilcox RG. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain.
PROactive
HF hospitalization and mortality
Pioglitazone
n (%)
Placebo
n (%)
P
HF leading to hospital
admission*
149 (5.7)
108 (4.1)
0.007
Fatal HF
25 (0.96)
22 (0.84)
NS
* Non-adjudicated
Dormandy JA et al. Lancet. 2005;366:1279-89.
TZDs associated with lower mortality
N = 16,417 Medicare patients with diabetes and HF (1998–1999, 2000–2001)
1.0
0.9
Proportion
of patients
surviving
0.8
Thiazolidinedione (n = 2226)
0.7
13% RRR
HR 0.87 (0.80–0.94)
0.6
No insulin sensitizer (n = 12,069)
0
0
50
100
150
200
250
300
350
Follow-up (days)
Masoudi FA et al. Circulation. 2005;111:583-90.
Summary
Pioglitazone treatment compared to placebo in high risk patients
with type 2 diabetes:
•
•
10% trend of relative risk reduction in the primary endpoint
•
Significant relative risk reductions of other MACE endpoints:
16% significant relative risk reduction in the main secondary
endpoint (all-cause death, MI, or stroke)
–
–
–
–
All-cause death, MI, stroke, or ACS – 17%
CV death, MI, or stroke – 18%
CV death, MI, stroke, or ACS – 20%
Fatal or non-fatal MI – 22%
PROactive in perspective
Pioglitazone appears to reduce risk of major adverse
cardiovascular events (MACE) in patients with advanced
type 2 diabetes
–
in patients at high risk for cardiovascular events
(prior stroke, MI, PCI or CABG)
–
on top of good standard of care
–
relatively short-term study
PROactive results support use of PPAR modulator
in patients with diabetes at high CVD risk
May improve CVD outcomes and decrease need to start insulin
PROactive vs landmark clinical trials:
Comparative benefit in patients with diabetes
HPS
30
Placebo
CHD
30
death,
MI*, 20
revasc (%) 10
22% RRR
P < 0.0001
20
Vascular
events (%) 10
CARE
40
Simvastatin
Placebo
25% RRR
P = 0.05
Pravastatin
0
0
0
1
2
3
Years
4
5
0
6
1
2
3
Years
MICRO-HOPE
Ramipril
Placebo
19% RRR
P = 0.034
Pioglitazone
0
0
1
2
3
4
5
Years
* Nonfatal
PROactive
Cardiac 20
death, MI*,
15
coronary
revasc, ACS 10
(%)
5
Placebo
25% RRR
P = 0.0004
5
Circulation. 1998
Lancet. 2003
25
20
MI, stroke, 15
CV death (%) 10
5
0
4
0
1
2
3
Years
Lancet. 2000
Lancet. 2005
Lancet 2003;361:2005-2016; Circulation 1998;98:2513-2519; Lancet
2000;355:253-259; Lancet 2005; 366:1279 - 1289