1

Issues in the Management of Diabetic

Patients with Cardiovascular Disease

Elliot Rapaport, MD

December 13, 2008

2

Hyperglycemia and Acute Coronary Syndromes

3

Effect of Hyperglycemia in STEMI

Impairs microvascular perfusion

Increases endothelial dysfunction

Decreases NO production

Increases oxidative stress

Promotes a pro-thrombotic state

Abolishes ischemic reconditioning experimentally

Increases inflammatory markers

Increases free fatty acid concentration

4

Kosiborod et al Circulation 2008;117:1018

Reference Mean BG 100-<110

No diabetes

Diabetes

All

< 3.5 5.0 7.5 10.0 12.5 15.0

Mean Blood Glucose (mM / l)

No Diabetes

Diabetes

All

Kosiborod et al Circulation 2008;117:1018

(90 mg/dl) (270 mg/dl)

Association between Mean Blood Glucose and In-

Hospital Mortality.

5

Copyright ©2005 American College of Cardiology Foundation. Restrictions may apply.

Pinto, D. S. et al. J Am Coll Cardiol 2005;46:178-180

Relationship of blood glucose level (BGL) and death at 30 days stratified by Thrombolysis In Myocardial Infarction (TIMI) risk score (TRS)

6

Stress hyperglycemia in AMI: Association with mortality

risk in patients without known diabetes

ReferenceReference

Hyperglycemia Hyperglycemia

definition definition

(mg/dL)(mg/dL)

00 1313

Unadjusted RR of in-hospital mortality after MI*

Capes SE et al. Capes SE et al. Lancet.Lancet. 2000;355:7732000;355:773--8.8.*vs patients with normoglycemia

O’Sullivan 19911991 >144>144

Lewandowicz 19791979 ≥≥121121

Soler 1981 1981 ≥≥110110

Oswald 19861986 ≥≥144144

Bellodi 19891989 >121>121

Ravid 19751975 >121>121

Sewdarsen 19891989 ≥≥144144

PooledPooled

11 22 33 44 55 66 77 88 99 1010 1111 1212

(3.9-fold higher risk )

7

*Multivariate analysis

∆∆∆∆Glucose (24 hr vs baseline)

≥30 mg/dL decrease No change to <30 mg/dL decrease Increase

Admission glucose and glucose change within 24

hours predict mortality risk

Goyal A et al. Eur Heart J. 2006;27:1289-97.

N = 1469 with AMI (n = 1219 without DM)

0

2

4

6

8

10

12

30-day

mortality

(%)

Baseline glucose (mg/dL)

<125 125–<140 140–<170 ≥170

0

↓↓↓↓9% in 30-day mortality per

↓↓↓↓11 mg/dL glucose in first

24 hr (P = 0.002)*

8

Potential beneficial effects of insulin

Dandona P et al. Am J Cardiol.

2007;99(suppl):15B-26.

Mechanistic

benefits

of insulin

Vasodilatory +

Platelet inhibitory↑↑↑↑NO release ↑↑↑↑cAMP

↑↑↑↑eNOS

Antithrombotic↓↓↓↓TF

↓↓↓↓PAI-1

Glucose

lowering

Anti-inflammatory↓↓↓↓NF-κB

↓↓↓↓MCP-1

↓↓↓↓ICAM-1

↓↓↓↓CRP

↑↑↑↑IκB

Anti-oxidative↓↓↓↓ROS

Cardioprotective

Neuroprotective

Antiapoptotic

9

Early impact of insulin on mortality for hyperglycaemic patients

without known diabetes with ACS

• 2003–5 Registry in 201 UK hospitals

• 38,864 ACS patients with no hx diabetes

– 3835 with glucose > 11 mmol/l (198 mg/dl)

– 31% received insulin

Mortality 7 days 30 days

Received insulin 11.6% 15.8%

No insulin 16.5% 22.1%

HR (95% CI) 1.56 (1.22 – 2.0) 1.51 (1.22 - 1.86)

p < O.OO1 < O.OO1

Weston et al Heart 2007;93:1542

10

CREATE-ECLA: Effect of GIK on mortality, glucose

CREATE-ECLA Trial Group Investigators. JAMA. 2005;293:437-46.

Mean

glucose

(mg/dL)

Mortality,

cumulative

events

(%)

*Usual care only†6 hours after randomization

Days

0 5 10 15 20 25 30

0

12.0

GIK infusion

Control*

2.0

4.0

6.0

8.0

10.0

Baseline

(both

groups)

GIK

group

Control*

148†

162

187†200

150

100

50

0

N = 20,201

11

Insulin infusion to normalize BG recommended for

patients with STEMI + complicated courses

During acute management of STEMI in patients with

hyperglycemia, it is reasonable to administer insulin

infusion to normalize BG, even in those with an

uncomplicated course

After acute phase of STEMI, individualize diabetes

treatment; select combinations of agents that achieve

optimal glycemic control and are well tolerated

ACC/AHA STEMI guidelines:

Strict glucose control

Antman EM et al. J Am Coll Cardiol. 2004;44:671-719.

II IIaIIa IIbIIb IIIIII

BBBB

BBBB

CCCC

Class and level of evidence

12

SWEET ACS trial SWEET ACS Trial

13

General Management of the Diabetic

Undergoing an ACS or STEMI

14

Diabetes and FibrinolysisDiabetes and Fibrinolysis

Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group Lancet 1994;343:311-22

10.710.7

17.317.3

8.78.7

13.613.6

00

55

1010

1515

Placebo/Control

Fibrinolysis

Non-Diabetic

3030--35 Day Mortality35 Day Mortality

2020

Diabetic

% of Patients

Lives Saved per 1000

Patients Treated17 35

15

16

Meta-Analysislsis:: Stenting vs Balloon for STEMI(13RCT’s; n=6921) 12-month MORTALITY

STENTING BALLOON n/N (%) n/N (%) OR (fixed) 95% CI Weight% OR 95% CI P value STUDY

WITHOUT ABCIXIMAB I II

CADILLAC 17/512 (3.3%) 28/518 (5.4%) 16.47 0.60 [0.32, 1.11] 1.0

FRESCO 1/75 (1.3%) 4/75 (5.3%) 2.42 0.24 [0.03, 2.20] 0.36

Jacksch et al 5/231 (2.2%) 7/231 (3.0%) 4.19 0.71 [0.22, 2.26] 0.56

PAMI 26/452 (5.8%) 14/448 (3.1%) 8.11 1.89 [0.97, 3.67] 0.056

PASTA 3/67 (4.5%) 6/69 (8.7%) 3.46 0.49 [0.12, 2.05] 0.49

PSAAMI 4/44 (9.1%) 8/44 (18.2%) 4.45 0.45 [0.12, 1.62] 0.35

STENTIM-2 3/101 (3.0%) 2/110 (1.8%) 1.14 1.65 [0.27, 10.1] 0.58

ZWOLLE-5 3/112 (2.7%) 4/115 (3.5%) 2.35 0.76 [0.17, 3.49] 1.0

ZWOLLE-6 47/785 (6.0%) 45/763 (5.9%) 26.26 1.02 [0.67, 1.55] 0.94

WITHI ABCIXIMAB II

STOPAMI-3 25/305 (8.2%) 28/306 (9.2%) 15.71 0.89 [0.50, 1.56] 0.67

STOPAMI-4 7/90 (7.8%) 11/91 (12.1%) 6.21 0.61 [0.23, 1.66] 0.33

CADILLAC 28/524 (5.3%) 16/528 (3.0%) 9.23 1.81 [0.97, 3.38] 0.061

ABCIXIMAB 60/919 (6.5%) 55/925 (5.9%) 31.25 1.10 [0.76, 1.61] 0.6

CONTROL 109/2379 (4.6%) 118/2373 (5.0%) 68.75 0.92 [0.70, 1.20] 0.5

TOTAL (95% CI) 169/3298 (5.1%) 173/3298 (5.2%) 100.00 0.97 [0.78, 1.21] 0.81

De Luca, , Suryapranatarrt et al. JACC 2006t l. 0.1 0.2 0.5 1 2 5 10

I STENT BETTER BALLOON BETTER

De Luca, Suryapranatarrt et al. JACC 2006t l.

STENT BETTER BALLOON BETTER

17

Diabetes Remains a Major Risk Factor for Mortality after AMI for

Patients Managed by an Invasive Strategy

Norhammer et al J Am Coll Cardiol 2004;43:585

Independent Predictors

FRISC 2

18

Outcomes in Patients with UA/NSTEMIInvasive vs Noninvasive Strategy

Death or MI

Norhammer et al J Am Coll Cardiol 2004;43:585FRISC 2

19

36.136.1

10.210.24.54.5

14.814.8

2.12.1

57.557.5

23.123.1

12.512.5

35.235.2

33

67.167.1

33.833.8

10.110.1

43.543.5

1.31.300

2020

4040

6060

8080

ACS IACS I ACS IIACS II

NonNon--diabeticdiabetic

ACS I DMACS I DM

ACS IACS I ACS IIACS II ACS IACS I ACS IIACS II ACS IACS I ACS IIACS II ACS IACS I ACS IIACS II

n=757 n=757 532 532 1424 1424

Underutilization of an Invasive ManagementUnderutilization of an Invasive Management

Strategy in Canadian NonStrategy in Canadian Non--STST↑↑↑↑↑↑↑↑ ACS Diabetic Patients:ACS Diabetic Patients:

The Problem Still RemainsThe Problem Still Remains

Yan R et al Circulation 2005;112(Suppl II):694.Yan R et al Circulation 2005;112(Suppl II):694.

DeathDeathAny Any RevascRevasc..CABGCABGPCIPCIAngiographyAngiography

% of Patients% of Patients

pp≤≤≤≤≤≤≤≤0.0010.001

pp≤≤≤≤≤≤≤≤0.0010.001

pp≤≤≤≤≤≤≤≤0.0010.001

pp≤≤≤≤≤≤≤≤0.0010.001

p<0.02p<0.02

ACS I (1999ACS I (1999--2001) Diabetes 25.9% 2001) Diabetes 25.9%

ACS II (2002ACS II (2002--2004) Diabetes 27.2% 2004) Diabetes 27.2%

ACS II DMACS II DM

20

GP GP IIb/IIIaIIb/IIIa Inhibition for NonInhibition for Non--STST--Elevation ACSElevation ACS

3030--Day Death or Nonfatal MIDay Death or Nonfatal MI

Risk Ratio & 95% CIRisk Ratio & 95% CI

Placebo BetterPlacebo BetterGP GP IIb/IIIaIIb/IIIa BetterBetter

TrialTrial

PooledPooled11.5%11.5%

PlaceboPlacebo GP GP IIb/IIIaIIb/IIIa

10.7%10.7%29,85529,855

nn

0.92 (0.86, 0.995)0.92 (0.86, 0.995)p = 0.037p = 0.037

PRISM PLUSPRISM PLUS 11.9%11.9% 10.2%10.2%1,9151,915

PURSUITPURSUIT 15.7%15.7% 14.2%14.2%9,4619,461

PARAGON APARAGON A 11.7%11.7% 11.3%11.3%2,2822,282

7.1%7.1%PRISMPRISM 5.8%5.8%3,2323,232

0.50.5 1.01.0 1.51.5

PARAGON BPARAGON B 11.4%11.4% 10.5%10.5%5,1655,165

GUSTOGUSTO--IV IV ACSACS

8.0%8.0% 8.7%8.7%7,8007,800

Boersma, Lancet 2002BoersmaBoersma, Lancet 2002, Lancet 2002

21

IIIIbb/III/IIIa a BetterBetter Placebo BetterPlacebo Better00 11 22

0.74 (0.59, 0.92) p=0.0070.74 (0.59, 0.92) p=0.007

Odds Ratio & 95% CI PlaceboPlacebo IIIIbb/III/IIIa a NN

NonNon--STST↑↑↑↑↑↑↑↑ACS GP ACS GP IIb/IIIaIIb/IIIa AgentsAgents

PRISMPRISM 687687 4.2%4.2% 1.8%1.8%

PARAGON APARAGON A 412412 6.2%6.2% 4.6%4.6%

PARAGON BPARAGON B 1,1571,157 4.8%4.8% 4.9%4.9%

GUSTO IVGUSTO IV 1,6771,677 7.8%7.8% 5.0%5.0%

PRISMPRISM--PLUSPLUS 362362 6.7%6.7% 3.6%3.6%

6.1%6.1% 5.1%5.1%PURSUITPURSUIT 2,1632,163

30 Day Death 30 Day Death –– Diabetic PatientsDiabetic Patients

Trial

PooledPooled 6,4586,458 6.2%6.2% 4.6%4.6%

Roffi et al Circulation 2000;104:2767-71

p=0.33p=0.33

p=0.07p=0.07

p=0.17p=0.17

p=0.022p=0.022

p=0.51p=0.51

p=0.93p=0.93

Note: Pooled mortality

for Non-diabetics was

3.0% in both groups

22

NAPLES (Novel Approaches for

Preventing or Limiting Event Study)• DESIGN: Prospective, randomized, double-arm,

single-center clinical study

Diabetic Patients

Elective PCI

Biomarker negative

UFH + Tirofiban Bivalirudin alone

ASA

Clopidogrel

(loading dose 300 mg

the day before procedure)

Elective PCI

30 day endpoints

Death, MI, IUR, ACUITY major bleeding

(net clinical outcome)

N = 168 N = 167

23

12.5

10.2

7.7

1.8

20.8

12.0

0

5

10

15

20

25

30

%

Non Q-wave

MI

Bleeding Composite

End Point

P = 0.038

P = 0.035

P = 0.606

UFH plus tirofiban(n = 168)

Bivalirudin(n = 167)

OR, 0.517

95% CI, 0.284-0.940

OR, 0.793

95% CI, 0.402-1.564

OR, 0.218

95% CI, 0.061-0.780

24

Adjunctive Pharmacologic Management of the

Diabetic Patient Undergoing an ACS

25

TNT: Intensive Atorvastatin Treatment

Reduces Cardiovascular Events in Patients

With CHD and DiabetesLDL-C 98.6 mg/dl

LDL-C 76.7 mg/dl

26

STUDY DESIGNSTUDY DESIGN

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL

60 mg LD/ 10 mg MD

CLOPIDOGREL

300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke

2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch

CV death, MI, UTVR

Stent Thrombosis

Key Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

27

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81

(0.73-0.90)

P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32

(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.8

2.4

138

events

35

events

Balance of Balance of

Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major

NonCABG Bleeds

NNT = 46

NNH = 167

28

CV Death, Non-fatal MI and Non-fatal Stroke and Major

Bleeds among Diabetic Subjects in TRITON-TIMI 38

Diabetics Non-diabetics( n = 3,148 ) ( n = 10,462 )

Primary End Point

Prasugrel

Clopidogrel

RR Reduction

Major Bleeds

Prasugrel

Clopidogrel

RR Increase

12.2%

17.0%

30.0%

2.5%

2.6%

+6.0%

9.2%

10.6%

14.0%

2.4%

1.6%

+43.0%

29

PROactive: Ti me to Pri mar y

Composite End Point

(all-cause death, nonfatal MI [including silent MI], stroke, ACS,

leg amputation, coronary revascularization, leg revascularization)

30

PROactive: Ti me to Death, MI (Excluding Silent), or Stro ke

( maim secondary endpoint )

31

Cardiovascular Impact of Pioglitazone

Therapy: A Meta-analysis

Lincoff AM et al. JAMA. 2007;298(10):1180-1188.

Endpoint

Pioglitazone

(n=8,554)

(%)

Control

(n=7,836)

(%)

Hazard Ratio

(95% CI) P

Death, myocardial

infarction, stroke4.4 5.7

0.82

(0.72-0.94)0.005

Death 2.4 2.90.92

(0.76-1.11)0.38

Myocardial

infarction1.5 2.0

0.81

(0.64-1.02)0.08

Stroke 1.2 1.70.80

(0.62-1.04)0.09

Serious heart

failure2.3 1.8

1.41

(1.14-1.76)0.002

32

TM

© 1999 Professional Postgraduate Services®

DAIS: Final Results in CAD Patients WithType 2 Diabetes (200 mg/d Fenofibrate v plac.)

CAD

• Treatment with fenofibrate resulted in 40% reduction in rate

of progression of localized CAD (by prior angiography) versus

placebo

• 23% reduction in combined coronary events following

fenofibrate treatment (P=NS*)

Lipids

• Average reductions with fenofibrate: TC, 10%; LDL-C, 6%;

TG, 29%; average increase in HDL-C, 6%

Safety

• Very few serious adverse events; no significant differences in

tolerability between fenofibrate and placebo treatments;

95% compliance *Researchers report that results suggest benefit to patients.

Steiner G. XIIth International Symposium on Atherosclerosis;

June 27, 2000; Stockholm, Sweden.N = 418

33

CABG or PCI in Diabetics with Multivessel CAD

34

BARI I: Poorer Outcome with Revascularization

in Diabetics

BARI I: BARI I: Poorer Outcome with Revascularization Poorer Outcome with Revascularization

in Diabeticsin Diabetics

0

20

40

60

80

100

0 1 2 3 4 5 6 7

Pe

rce

nt

Su

rviv

al

Years

Non Diabetic PTCA 86.8%

Non Diabetic CABG 86.4%

Diabetic CABG 76.4%

Diabetic PTCA 55.7%

Treatment Comparisons

Non-diabetics: p=0.72

Diabetics: p=0.0011

35

510 patients recruited between

Jan 2002 and May 2007

ESC Congress Munich Sep1, 2008

Coronary Revascularization in Diabetes Trial Design

36

Death, Non-fatal MI, Non-fatal Stroke

37

38

39

40

41

42

Note: Propensity score matching based on 67 patient, procedural and hospital variables

43

44

Long Term Therapy Following DES Use in AMI Patients with Diabetics

� High dose HMG Co-A Reductase Inhibitors with

LDL-C target < 70 mg/dl

� ACE Inhibitors or Angiotensin-Receptor Blockers

� Beta-Receptor Blockers

� Eplerenone if LV failure at onset and LVEF <40

� Low dose aspirin

� Extended Thienopyridine Therapy

� Diabetes Control