PPAR activation Clinical evidence

Evolution of clinical evidence supporting PPAR activation

2000 2005 and beyond

Surrogate outcomes studies Large observational studies

Ongoing clinical outcomes studies

Endothelialfunction

Carotid atherosclerosis

Restenosis

Mortality in patients with diabetes + HF

or AMI

Onset of diabetes in

patients with IFG

Anticipated results from large multicenter trials in (pre)diabetes

2005 2006 2007 2008 2009

PROactive

DREAMCHICAGO

ADOPT APPROACH

ACCORDBARI-2DORIGIN

Clinical outcomes Surrogate outcomes

NAVIGATOR

VADT

RECORD

ACT-NOW

PERISCOPE

Dormandy JA et al. Lancet. 2005;366:1279-89.

PROactive: Study Design

Pioglitazone 15 mg qdtitrated to 45 mg qd

Randomized, double-blind controlled trial N = 5238 with type 2 diabetes and macrovascular disease

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

PROspective pioglitAzone Clinical Trial In macroVascular Events

Mean follow-up: 34.5 months

Placebo

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 Placebo 66.6 65.6

98.4 98.7

61.9 61.6

30.7 31.0

104.9 105.5

13.1 14.5

46.0 44.0

143.5 143.3

82.8 83.2

Dormandy JA et al. Lancet. 2005;366:1279-89.

PROactive CV history at baseline

Dormandy JA et al. Lancet. 2005;366:1279-89.

Pioglitazonen = 2605

Placebon = 2633

MI 47 46Stroke 19 19PCI or CABG 31 31Acute coronary syndromes 14 14Coronary artery disease 48 48Peripheral arterial disease 19 20History of hypertension 75 76≥2 macrovascular disease criteria 47 49

%

PROactive CV medications at baseline

Dormandy JA et al. Lancet. 2005;366:1279-89.

Pioglitazonen = 2605

Placebon = 2633

-blockers 55 54ACEIs 63 63ARBs 7 7CCBs 34 37Nitrates 39 40Thiazide diuretics 15 16Antiplatelets 85 83Aspirin 75 72Statins 43 43Fibrates 10 11

%

Time from Randomization (months)

N at Risk:

HR 95% CI p value

pioglitazone vs placebo 0.904 0.802 - 1.018 0.0951

N events: 3-year estimate:

placebo 572 / 2633 23.5%

pioglitazone 514 / 2605 21.0%

Time to primary composite endpointKaplan-Meier event rate

0 6 12 18 24 30 36

5238 5018 4786 4619 4433 4268 693 (228)

0.0

0.05

0.10

0.25

0.15

0.20

Dormandy JA et al., Lancet (2005) 366:1279 - 1289

Time from Randomization (months)

N at Risk:

HR 95% CI p value

pioglitazone vs placebo 0.841 0.722 - 0.981 0.0273 *

N events: 3-year estimate:

placebo 358 / 2633 14.4%

pioglitazone 301 / 2605 12.3%

Significant reduction in secondary outcomeKaplan-Meier event rate

0 6 12 18 24 30 36

5238 5102 4991 4877 4752 4651 786 (256)

0.0

0.05

0.10

0.15

Dormandy JA et al., Lancet (2005) 366:1279 - 1289

Time from Randomization (months)

N at Risk:

HR 95% CI p value

pioglitazone vs placebo 0.828 0.717- 0.956 0.01 *

N events: 3-year estimate:

placebo 409 / 2633 16.5%

pioglitazone 339 / 2605 13.8%

Time to all-cause death, non-fatal MI, stroke or ACS

Kaplan-Meier event rate

0 6 12 18 24 30 36

5238 5080 4947 4816 4684 4564 765 (248)

0.0

0.05

0.10

0.20

0.15

Dormandy JA et al., Lancet (2005) 366:1279 - 1289

placebo

pioglitazone

N events: 3-year estimate:

362/1737

183/1741

22,0%

11,1%

Kaplan Meier event rate of progression to permanent insulin use

HR 95% CI p value

pioglitazone vs palcebo 0.469 0.39-0.56 <0.0001

Time from Randomization (months)

N at risk:

0.25

0.20

0.15

0.10

0.05

0.0

0 6 12 18 24 30 36

3478 3346 3198 3075 2955 2824 446 (137)

Time to permanent insulin use

Dormandy JA et al. Lancet. 2005;366:1279-89.

PROactive Subgroup analysis – Previous MI

• 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

Adapted from Erdmann E. AHA 2005. www.PROactive-results.com.

*Excluding silent MI

n = 2445 with previous MI (≥6 mo)

PROactive Subgroup analysis – Previous stroke

Wilcox RG. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain.

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

Fatal and nonfatal stroke with pioglitazone treatment vs placebo in patients with prior history of stroke

PROactiveHF hospitalization and mortality

Pioglitazonen (%)

Placebon (%) P

HF leading to hospital admission* Fatal HF

149 (5.7)

25 (0.96)

108 (4.1)

22 (0.84)

0.007

NS

Dormandy JA et al. Lancet. 2005;366:1279-89.

* Non-adjudicated

TZDs associated with lower mortality

Masoudi FA et al. Circulation. 2005;111:583-90.

N = 16,417 Medicare patients with diabetes and HF (1998–1999, 2000–2001)

Follow-up (days)

Proportionof patientssurviving

0.6

0.7

0.8

1.0

050 100 300150 200 250

0.9

0 350

13% RRRHR 0.87 (0.80–0.94)

No insulin sensitizer (n = 12,069)

Thiazolidinedione (n = 2226)

SummaryPioglitazone treatment compared to placebo in high risk patientswith type 2 diabetes:• 10% trend of relative risk reduction in the primary endpoint• 16% significant relative risk reduction in the main secondary

endpoint (all-cause death, MI, or stroke)• Significant relative risk reductions of other MACE endpoints:

– 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

MI, stroke, CV death (%)

25201510

50

0 1 2 3 4 5

0 1 2 3 4 50

10203040

* Nonfatal

CHD death,

MI*, revasc (%)

Years

Pravastatin

PlaceboCARE

Circulation. 1998

25% RRRP = 0.05

Lancet. 2005Lancet. 2000

Lancet. 2003

Vascular events (%)

Cardiac death, MI*,

coronary revasc, ACS

(%)

Years0 1 2 3

Years

0 1 2 3 4 5 6Years

Ramipril

Placebo

0

30

20

10 Simvastatin

Placebo

0

5

10

20

Pioglitazone

Placebo

HPS

MICRO-HOPE PROactive

22% RRR P < 0.0001

19% RRRP = 0.034

25% RRRP = 0.0004 15

Lancet 2003;361:2005-2016; Circulation 1998;98:2513-2519; Lancet 2000;355:253-259; Lancet 2005; 366:1279 - 1289