Insulin Sensitizers: Surrogate and Clinical Outcomes Studies

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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


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


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


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


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)


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


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

(%)


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


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.

Insulin Sensitizers: Surrogate and Clinical Outcomes Studies

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