Clinical Evaluation and Nonlipid Clinical Evaluation and Nonlipid

Treatment of Coronary Artery Treatment of Coronary Artery

Disease in the Diabetic PatientDisease in the Diabetic Patient

Richard Nesto, MDRichard Nesto, MD

Prevalence of Asymptomatic CAD in Prevalence of Asymptomatic CAD in Diabetes MellitusDiabetes MellitusKoistinen MJ. BMJ 1990;301:92-95.

Type 2 Type 1 Controls

Naka M et al. Am Heart J 1992;123:46-53.

Type 2 Controls

MiSAD Group. Am J Cardiol 1997;79:134-139.

Type 2

Rutter MK et al. Am J Cardiol 1999;83:27-31.

Type 2 w microalb Type 2 w/o microalb

Le A et al. Am J Kidney Dis 1994;24:65-71.

Type 1 Renal Transplant

Holley JL et al. Am J Med 1991;90:563-570.

Type 1 & 2 Renal Transplant

n = 64 n = 72 n = 80

n = 142 n = 149

n = 925

n = 43 n = 43

Positive Positive ETTETT

Positive Positive AngiographyAngiography

(thal201)

36% 24% 9%

31% 30%

12.1%

65% 40%

58%

55%

9% 11% 9%

12.1% 5.3%

6.4%

— —

35%

43%

Indications for Cardiac Testing in Indications for Cardiac Testing in Diabetic PatientsDiabetic Patients Typical or atypical cardiac symptoms

Resting ECG suggestive of ischemia or infarction

Peripheral or carotid occlusive arterial disease

Sedentary lifestyle or plan to begin a vigorous exercise program

Two or more of the risk factors listed below

- Total cholesterol >240 mg/dL, LDL cholesterol >160 mg/dL, or HDL cholesterol <35 mg/dL

- Blood pressure >140/90 mmHg

- Smoking

- Family history of premature CAD

- Positive micro/macroalbuminuria

Factors Limiting Accuracy of Noninvasive Factors Limiting Accuracy of Noninvasive "Stress" Tests for CAD"Stress" Tests for CAD

Hypertensive Cardiomyopathy

Diabetic Cardiomyopathy

Autonomic Cardiomyopathy

Renal Insufficiency

Microvascular Dysfunction

Benefits of Early Detection of CADBenefits of Early Detection of CAD

Implement more aggressive CHD prevention regimen

Initiate anti-ischemic medications

Identify patients who would benefit from revascularization

Educate patients to recognize coronary symptoms

0

20

40

60

80

100

120

140

160

180

Kannel WB et al. Am Heart J 1991;121:1268-1273.

Blood Pressure and CVD: Blood Pressure and CVD: Framingham Heart StudyFramingham Heart StudyA

ge-a

dju

sted C

V E

vent

Rate

/1,0

00

Systolic BP (mmHg)

105 135 165 1950

20

40

60

80

100

120

140

160

180

Systolic BP (mmHg)

105 135 165 195A

ge-a

dju

sted C

V E

vent

Rate

/1,0

00

24

5038

77

59

119

90

174

15

3123

4836

74

56

113

No Glucose Intolerance

Glucose Intolerance

No Glucose Intolerance

Glucose Intolerance

MENMEN WOMENWOMEN

UKPDS Group. Lancet 1998;352:837-853.

Effect of Glycemic Control in the UK Effect of Glycemic Control in the UK Prospective Diabetes Study (UKPDS)Prospective Diabetes Study (UKPDS)

Any diabetes related*

MI

Stroke

PVD

Microvascular

40.9

14.7

5.6

1.1

8.6

46

17.4

5

1.6

11.4

0.029

0.052

0.52

0.15

0.0099

11

16

–

–

25

(rate/1000 pt yrs)

* Combined microvascular and macrovascular events

Intensive

%Decreas

e

(rate/1000 pt yrs) P

Conventional

Endpoints

Reasons for Death in UKPDS Intensive Reasons for Death in UKPDS Intensive Treatment Arm: Treatment Arm: 10-Year Follow-up10-Year Follow-up

UKPDS Group. Lancet 1998;352:837-853.

Fatal MI or SD

Cancer

Other

Fatal Stroke

Renal Disease

Accidents

PVD

Hypo- or Hyperglycemia

231

120

74

43

16

5

2

1

(8.4%)

(4.4%)

(2.9%)

(1.6%)

(0.6%)

(0.2%)

(0.07%)

(0.04%)

(%)N =

2729

47%47%

8.7%8.7%

24%24%

15%15%

3.3%3.3% 2.5%2.5%

MI or SDMI or SD

CancerCancer

StrokeStroke

OtherOther

RenalRenal

Accidents, PVD, Hypo-Accidents, PVD, Hypo-& Hyperglycemia& Hyperglycemia

UKPDS Group. BMJ 1998;317:703-713.

Effect of Blood Pressure Control in the UKPDSEffect of Blood Pressure Control in the UKPDSTight vs. Less Tight ControlTight vs. Less Tight Control

Any diabetes-related endpoint

Diabetes-related deaths

Heart failure

Stroke

Myocardial infarction

Microvascular disease

Tight Control

1,148 Type 2 patients

Average BP lowered to 144/82 mmHg (controls: 154/87);9-year follow-up

24

32

56

44

21

37

Risk Reduction (%) P value

0.0046

0.019

0.0043

0.013

NS

0.0092

UKPDS: ACE Inhibitor vs. Beta-blocker for HTNUKPDS: ACE Inhibitor vs. Beta-blocker for HTNAggregate Clinical EndpointsAggregate Clinical Endpoints

0.50.5 11 22

Relative Risk & 95% CIRelative Risk & 95% CI

Any diabetes-related endpoint

Diabetes-related deaths

All-cause mortality

Myocardial infarction

Stroke

Microvascular

1.10

1.27

1.14

1.20

1.12

1.29

0.43

0.28

0.44

0.35

0.74

0.30

ppRRRR

UKPDS Group. BMJ 1998;317:713-720.

FavorsFavorsACE inhibitorACE inhibitor

FavorsFavorsBeta blockerBeta blocker

0

10

20

30

40

50

60

70

Placebo

Events

/ 1

000 P

t-Years

Systolic Hypertension in Europe (Syst-Eur) Trial: Systolic Hypertension in Europe (Syst-Eur) Trial: Effect of Systolic BP Control on All Cardiovascular Events Effect of Systolic BP Control on All Cardiovascular Events at 2 Yearsat 2 Years

Tuomilehto J et al. NEJM 1999;340: 677-684.

N=492; N=492; PP=0.002=0.002

Active Rx

57.657.6

22.022.0

62%62%RiskRisk

ReductionReduction

N=4,203; N=4,203; PP=0.02=0.02

31.431.423.523.5

Placebo Active Rx

25%25%RiskRisk

ReductionReduction

Diabetic Patients Nondiabetic Patients

0

5

10

15

20

25

30

Major CV Events MI

Events

/ 1

000 P

t-Years

Major Outcomes of the Hypertension Optimal Major Outcomes of the Hypertension Optimal Treatment (HOT) Trial: Treatment (HOT) Trial: Diabetes SubgroupDiabetes Subgroup

Hansson L et al. Lancet 1998;351: 1755-1762.

CV Mortality

<90 mmHg (N=501)

<85 mmHg (N=501)

<80 mmHg (N=499)

Diastolic Target

p<0.045p<0.016

p<0.005

0

5

10

15

20

25

30

<90

Events

/ 1

000 P

t-Years

HOT Trial:Cardiovascular Events in Diabetics and HOT Trial:Cardiovascular Events in Diabetics and Nondiabetics—Nondiabetics—Effect of Diastolic Target at 4 YearsEffect of Diastolic Target at 4 Years

Hansson L et al. Lancet 1998;351: 1755-1762.

DiabeticDiabetic Patients Patientsn=1,501; p=0.016n=1,501; p=0.016

<85 <80 <90 <85 <80

NondiabeticNondiabetic Patients Patientsn=18,790; p=NSn=18,790; p=NS

24.424.4

18.618.6

11.911.99.99.9 10.010.0 9.39.3

48%48%RiskRisk

ReductionReduction

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in DiabetesAntihypertensive Agents in Diabetes

SHEP = Systolic Hypertension in the Elderly Program; GISSI = Grupo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico; Syst-Eur = Systolic Hypertension in Europe; HOT = Hypertension Optimal Treatment; CAPPP = Captopril Prevention Project

Curb JD et al. JAMA 1996;276:1886-1892; Zuanetti G et al. Circulation 1997;96:4239-4245; Staessen JA et al. Am J Cardiol 1998;82:20R-22R; Hansson L et al. Lancet 1998;351:1755-1762;UK Prospective Diabetes Study Group. BMJ 1998;317:703-713; Hansson L et al. Lancet 1999;353:611-616.

SHEP

GISSI-3

Syst-Eur

HOT

UKPDS

CAPPP

Results on CVDResults on CVDDiabetic/TotalDiabetic/TotalTrialTrial

583/4736

2790/18,131

492/4695

1501/18,790

1148

572/10,985

Beneficial

Beneficial

Beneficial

Beneficial

Beneficial

Beneficial

Heart Outcomes Prevention Evaluation (HOPE) StudyHeart Outcomes Prevention Evaluation (HOPE) StudyEffect of Ramipril on Cardiovascular Events (Myocardial Effect of Ramipril on Cardiovascular Events (Myocardial Infarction, Stroke, or CVD Death) ~ 4.5 Yrs Infarction, Stroke, or CVD Death) ~ 4.5 Yrs

Hope Study Investigators. NEJM 2000;342:145-153.

0

5

10

15

20

25

Placebo

% o

f Pati

ents

Ramipril

19.819.8

15.015.0

24%24%RiskRisk

ReductionReduction16.416.4

13.013.0

Placebo Ramipril

21%21%RiskRisk

ReductionReduction

Diabetic Patients Nondiabetic PatientsN=3,578, N=3,578, PP=<0.001=<0.001 N=5,719, N=5,719, PP=<0.001=<0.001

Diabetes Increases Risk of Coronary PlaqueDiabetes Increases Risk of Coronary PlaqueDisruption and ThrombosisDisruption and Thrombosis Cause of Myocardial InfarctionCause of Myocardial Infarction

PlaquePlaqueFormationFormation

F VIIF VII

F VIIIF VIII

Coronary ArteryCoronary Artery

Sympathetic ToneSympathetic Tone

PAI-1PAI-1

TPATPA

PGIPGI22

Platelet AggregationPlatelet Aggregation

FibrinogenFibrinogen

vWFvWF

ThrombusThrombus

PlaquePlaqueDisruptionDisruption

Impact of Serum Fibrinogen and Total Cholesterol Impact of Serum Fibrinogen and Total Cholesterol Levels on Risk of Coronary Events in ECATLevels on Risk of Coronary Events in ECAT

Thompson SG. N Engl J Med 1995;332:635-641.

0

1

2

3

4

5

6

7

Fibrinogen

LowerMiddle

Higher

Higher

Middle

Lower

Total CholesterolRisk of

Coronary Events

(%)4/306

9/261 10/282

5/311

3/247 10/281 11/266

16/304

21/305

Effect of Aspirin on Mortality in Type 2 Patients with Effect of Aspirin on Mortality in Type 2 Patients with CHD: CHD: Bezafibrate Infarction Prevention StudyBezafibrate Infarction Prevention Study

Harpaz D et al. Am J Med 1998;105:494-499.

70

80

90

100

Surv

ival (%

) Nodiabetes

Type 2diabetes

Time (Years)

0 1 2 3 4 5 6

No aspirin

Aspirin

OR=0.8 (0.7-0.9)

OR=0.7 (0.6-0.8)

Antiplatelet Agents Reduce CVD Events in Antiplatelet Agents Reduce CVD Events in Patients with Diabetes: Patients with Diabetes: Antiplatelet Antiplatelet Trialists’ CollaborationTrialists’ Collaboration

Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106.

0

5

10

15

20

25

CV

D E

vents

(%

)

Diabetes

Antiplatelet Therapy

Control

No Diabetes

P<0.002

P<0.00001

Diabetes Mellitus Insulin Glucose Infusion in Acute Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Benefit of Tight Glycemic Control in No Insulin – Low Risk CohortControl in No Insulin – Low Risk Cohort

Malmberg K et al. BMJ 1997;314:1512-1515.

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Mort

alit

y

Mort

alit

y

Total Cohort No Insulin – Low Risk

Years in Study Years in Study

Control

Insulin-glucoseInfusion

0 1 2 3 4 5 0 1 2 3 4 5

Insulin-glucoseInfusion

Control

p = .0111 p = .004

n=133

n=139

n=314

n=306

0.0

0.1

0.2

0.3

0.4

0.5

Effect of Trandolapril on Post-MI CHF Progression: Effect of Trandolapril on Post-MI CHF Progression: Trandolapril Cardiac Evaluation (TRACE)Trandolapril Cardiac Evaluation (TRACE)

Years

Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.

Diabetics (n=237)Diabetics (n=237)

0 1 2 3 4

Even

t R

ate

0.0

0.1

0.2

0.3

0.4

0.5

Years

Nondiabetics (n=1512)Nondiabetics (n=1512)

0 1 2 3 4

Even

t R

ate

Relative risk, 0.38P<0.001

Relative risk, 0.81P = 0.1

Placebo

Trandolapril

Placebo

Trandolapril

Cardiovascular death

Sudden death

Reinfarction

Progression in CHF

DiabeticsDiabetics

RR (95% CI) PRR (95% CI) PEnd PointEnd Point

Effect of Trandolapril on Secondary Effect of Trandolapril on Secondary Endpoints in TRACEEndpoints in TRACE

0.56 (0.37-0.85)

0.46 (0.25-0.85)

0.55 (0.29-1.07)

0.38 (0.21-0.67)

0.79 (0.66-0.96)

0.84 (0.63-1.12)

0.93 (0.69-1.26)

0.81 (0.63-1.04)

0.17

0.09

0.15

0.03

NondiabeticsNondiabetics

RR (95% CI) PRR (95% CI) P

InteractionInteraction

PP

CI = confidence interval; RR = relative risk.

Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.

0.01

0.01

0.08

<0.001

0.02

0.23

0.65

0.10

Woodfield SL et al. J Am Coll Cardiol 1996;28:1661-1669.

Effect of Diabetes on 30-Day Mortality: Effect of Diabetes on 30-Day Mortality: Global Utilization of Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I)Coronary Arteries (GUSTO-I)

2.7

2.1

2.4

2.0

0 1 2 3 4 5Odds Ratio for 30-Day Mortality

Diabetes vs no diabetes(unadjusted)

Adjusted for clinical variables

Adjusted for angiographicvariables

Adjusted for clinical &angiographic variables

Overall 5-Year Mortality in the Bypass Angioplasty Overall 5-Year Mortality in the Bypass Angioplasty Revascularization Investigation (BARI-1)Revascularization Investigation (BARI-1)

Detre KM et al. N Engl J Med 2000;342:989-997.

0.0

0.2

0.4

0.6

0.8

1.0

0

Mort

alit

y

DM-PTCA

DM-CABG

Non DM-CABG

Non DM-PTCA

Follow-up (years)

0.250.180.080.07

1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

0.0

0.2

0.4

0.6

0.8

1.0

Impact of PTCA vs. CABG on Mortality Impact of PTCA vs. CABG on Mortality in BARI-1in BARI-1

Mort

alit

y

Follow-up (years) Years after Q-MI

DM-PTCA

DM-CABG

Non DM-CABG

Non DM-PTCA

Mort

alit

y

Mortality in PatientsMortality in Patientswithout Q-MIwithout Q-MI

Mortality in PatientsMortality in PatientsAfter Q-MIAfter Q-MI

0 1 2 3 4 5 0 1 2 3 4 5

0.220.220.160.160.070.070.060.06

0.790.79

0.290.290.270.27

0.170.17

Detre KM et al. N Engl J Med 2000;342:989-997.

0

20

40

60

80

100

Impact of Diabetes on 7-year Survival in BARIImpact of Diabetes on 7-year Survival in BARI

BARI Investigators. J Am Coll Cardiol 2000;35:1122-1129.

% S

urv

ival

0 1 3 4 5 72 6Years

Patients without Treated DiabetesPatients without Treated Diabetes

0

20

40

60

80

100

% S

urv

ival

0 1 3 4 5 72 6

All PatientsAll Patients

0

20

40

60

80

100

% S

urv

ival

0 1 3 4 5 72 6

Patients with Treated DiabetesPatients with Treated Diabetes

p = 0.0425

p = 0.7155p = 0.0011

CABG (n=914)

PTCA (n=915)

CABG (n=180)

PTCA (n=173)

CABG (n=734)

PTCA (n=742)

84.480.9

76.4

55.7

86.8

86.4

0

20

40

60

80

100

Eight-Year Mortality in Emory Angioplasty vs Surgery Eight-Year Mortality in Emory Angioplasty vs Surgery Trial (EAST)Trial (EAST)

King SB III et al. J Am Coll Cardiol 2000;35:1116-1121.

% S

urv

ival

Years after Randomization

Patients without DiabetesPatients without Diabetes

0

20

40

60

80

100

% S

urv

ival

All EAST PatientsAll EAST Patients

0

20

40

60

80

100

% S

urv

ival

Treated Diabetic PatientsTreated Diabetic Patients

p = 0.40

p = 0.71p = 0.23

CABG (n=194)

PTCA (n=198)

CABG (n=30)

PTCA (n=29)

CABG (n=164)

PTCA (n=169)

0 1 3 4 5 82 76

0 1 3 4 5 82 76 0 1 3 4 5 82 76

82.779.3

0

25

50

75

100

0

25

50

75

100

6-Month Angiographic Outcome after PTCA 6-Month Angiographic Outcome after PTCA in Diabetes in Diabetes (377 Patients with 476 Lesions)(377 Patients with 476 Lesions)

Van Belle E et al. J Am Coll Cardiol 1999;34:476-485.

Lesi

ons

(%)

Angiographic FU = 6 months

62%

PTCA Site(s)1 Site 2 Sites 3 Sites

Overall Restenosis RateOverall Restenosis Rate Total OcclusionTotal Occlusion

49%49%

13%13%

Restenosis(n = 237)

Total Occlusion(n = 60)

Pati

ents

(%

)

11%

25%

37%

Impact of Restenosis and Total Occlusion Impact of Restenosis and Total Occlusion on LV Function in Diabeteson LV Function in Diabetes

Van Belle E et al. J Am Coll Cardiol 1999;34:476-485.

-20

-15

-10

-5

0

5

10

15

in

EF

(%)

p = ns p = ns p = 0.0001

(n = 297) (n = 237) (n = 60)

Restenosis (–)Total Occlusion (–)

Restenosis (+)Total Occlusion (–)

Total Occlusion (+)

-1.5+9.5 +0.5+9.9

-6.2+9.9

Effect of Stents on Target Vessel Effect of Stents on Target Vessel Revascularization (TVR) after PTCA in DiabetesRevascularization (TVR) after PTCA in Diabetes

1.00

0.95

0.90

0.85

0.80

0.75

0.70

0

Pro

port

ion F

ree o

f TV

R p = 0.021df = 3, Log-rank Test

Rankin JM et al. Circulation 1998;98:I-79.

Months Post PTCA

0 2 4 6 8 10 12

Year

1994

1995

1996

1997

1997

1996

1995

1994

N

305

425

480

288

% Stent

17.4

24.9

41.0

55.5

Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT): Trial (EPISTENT): Benefit of Abciximab and Stenting in Benefit of Abciximab and Stenting in Diabetes on Reducing TVRDiabetes on Reducing TVR

Lincoff AM et al. N Engl J Med 1999;341:319-327.

Days after Randomization

0

5

10

15

20Stent + PlaceboStent + AbciximabAngioplasty + Abciximab

Patients with DiabetesPatients with Diabetes(n = 491)(n = 491)

0 30 90 120 18060 150

Inci

dence

of

repeate

d T

VR

at

6 m

os.

(%

)

Days after Randomization

0

5

10

15

20

Patients without Patients without DiabetesDiabetes

(n = 1908)(n = 1908)

0 30 90 120 18060 150In

cidence

of

repeate

d T

VR

at

6 m

os.

(%

)

18.4%

16.6%

8.1%

14.6%

Stent + PlaceboStent + AbciximabAngioplasty + Abciximab

9.0%

8.8%

0

5

10

15

% o

f Pati

ents

Days

EPISTENT: EPISTENT: Optimization of PTCA/Stent Optimization of PTCA/Stent Outcomes with Platelet IIb/IIIa InhibitionOutcomes with Platelet IIb/IIIa Inhibition

Marso SP et al. Circulation 1999;100:2477-2484.

12.7%

7.8%6.2%

0 30 90 120 18060 150

6-Month Death, MI for Diabetics6-Month Death, MI for Diabetics

Stent + PlaceboStent + AbciximabPTCA + Abciximab

p = 0.029

ConclusionsConclusions

identify diabetic patients with particularly high risk for CAD and perform appropriate screening

aggressively identify and modify coronary risk factors

explore and implement treatment to protect the left ventricle from ischemic injury

maintain tight but judicious glycemic control in acute coronary syndromes

use medications proven to dramatically improve outcomes in acute MI (beta blockers, ACE inhibitors, aspirin, IIb/IIIa platelet inhibitors, statins)

In patients with diabetes mellitus, there are numerous opportunities In patients with diabetes mellitus, there are numerous opportunities to reduce morbidity and mortality from CAD:to reduce morbidity and mortality from CAD:

Future DirectionsFuture Directions

Additional clinical trials are needed to evaluate cardiovascular therapeutic interventions in diabetic patients, because certain therapies may produce different results in the presence of diabetes