epidemiología de la resistencia a la insulina, diabetes mellitus y enfermedad coronaria

Slide SourceLipidsOnline

www.lipidsonline.org

Epidemiology of Insulin Resistance, Epidemiology of Insulin Resistance,

Diabetes Mellitus, and Coronary Diabetes Mellitus, and Coronary

Heart DiseaseHeart Disease

Steven Haffner, MDSteven Haffner, MD



Adapted from World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Geneva: World Health Organization:1999:52.

Criteria for the Diagnosis of Diabetes Criteria for the Diagnosis of Diabetes Mellitus and HyperglycemiaMellitus and HyperglycemiaPlasma Glucose ConcentrationPlasma Glucose Concentration

>7.0 (>126)

>6.1 (>110) to <7.0 (<126)

2-Hour Post2-Hour PostGlucose LoadGlucose Load

FastingFastingGlucoseGlucose

Diabetes Mellitus

Impaired Glucose Tolerance

Impaired Fasting Glucose

>11.1 (>200)

>7.8 (>140) to<11.1 (<200)

Values are mmol/L (mg/dl)



0

1

2

3

4

5

6

7

8

9

Developed Developing

Perc

ent

King H et al. Diabetes Care 1998;21:1414-1431.

World

1995

Prevalence of Diabetes in Adult PopulationPrevalence of Diabetes in Adult Population(Aged (Aged >>20 years) by Year and Region20 years) by Year and Region

2000 2025



Hospitalization Costs for Chronic Hospitalization Costs for Chronic Complications of Diabetes in the USComplications of Diabetes in the US

American Diabetes Association. Economic Consequences of Diabetes Mellitusin the US in 1997. Alexandria, VA: American Diabetes Association, 1998:1-14.

Total costs 12 billion US $

CVD accounts for 64% of total costs

OthersOphthalmic disease

Cardiovasculardisease

Renal disease

Neurologic disease

Peripheral vascular disease



0

2

4

6

8

10

12

14

16

18

Annual

CH

D D

eath

s per

1000 P

erso

ns

Kannel WB, McGee DL. JAMA 1979;241:2035-2038.

Framingham Study: DM and CHD MortalityFramingham Study: DM and CHD Mortality20-Year Follow-up20-Year Follow-up

1717

88

1717

44

MenMen WomenWomen

DMDM

Non-DMNon-DM



0

10

20

30

40

50

Ischemicheart

disease

% o

f D

eath

s

Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11.

Mortality in People with DiabetesMortality in People with DiabetesCauses of DeathCauses of Death

Otherheart

disease

Diabetes Cancer Stroke Infection Other



0

5

10

15

20

25

30

35

Mort

ality

per

1000

per

son-y

ears

*

*Age-adjustedAdapted from Gu K et al. Diabetes Care 1998;21:1138-1145.

Mortality Due to Heart Disease in Men and Mortality Due to Heart Disease in Men and Women with or without Diabetes (US)Women with or without Diabetes (US)

29.9

19.2

Men Women

DiabetesDiabetes

No DiabetesNo Diabetes

All heart disease Ischemic heart diseaseMen Women

11.5

6.3

23.0

7.1

11.0

3.6



NondiabetesNondiabetesDiabetesDiabetes

0

5

10

15

20

*Defined in 1971-1975, followed up through 1982-1984.**Defined in 1982-1984, followed up through 1992-1993.Gu K et al. JAMA 1999;281:1291-1297.

Trends in Mortality Rates for Ischemic Heart Trends in Mortality Rates for Ischemic Heart Disease in NHANES Subjects with and without Disease in NHANES Subjects with and without Diabetes*Diabetes*

17.0

6.8

-16.6%-16.6% +10.7%+10.7%

Men, cohort 1*Men, cohort 1*Men, cohort 2**Men, cohort 2**Women, cohort 1*Women, cohort 1*Women, cohort 2**Women, cohort 2**

-43.8%-43.8% -20.4%-20.4%

14.2

7.6 7.4

4.22.4 1.9

(P=0.46) (P=0.76) (P<0.001) (P=0.12)

Rat

e per

1000 p

erso

n-y

ears



WOMENWOMENMENMEN

Survival Post-MI in Diabetic and Nondiabetic Survival Post-MI in Diabetic and Nondiabetic Men and Women: Men and Women: Minnesota Heart SurveyMinnesota Heart Survey

Adapted from Sprafka JM et al. Diabetes Care 1991;14:537-543.

100

80

60

40

0

Surv

ival

(%

)

Months Post-MI

No diabetes

n=228

n=1628

Months Post-MI

Surv

ival

(%

)0 20 40 60

Diabetes

100

80

60

40

080 0 20 40 60 80

Diabetes

No diabetes

n=156

n=568



WOMENWOMENMENMEN

0

10

20

30

40

50

60

Cardiovascular Mortality in People Cardiovascular Mortality in People with Diabeteswith Diabetes

% o

f D

eath

s (C

rude

Rat

e)

Adapted from Miettinen H et al. Diabetes Care. 1998;21:69-75.

Diabetes No Diabetes

28.628.622.122.1

10.910.9 11.911.9

Diabetes No Diabetes

15.415.4

9.69.622.722.7

9.09.0

9.19.1

4.24.2 11.111.1

2.82.8

28 d – 1 y

Hospitalization – 28 d

Out of Hospital



Influence of Multiple Risk Factors* on CVD Influence of Multiple Risk Factors* on CVD Death Rates in Diabetic and Nondiabetic Men: Death Rates in Diabetic and Nondiabetic Men: MRFIT ScreeneesMRFIT Screenees

0

20

40

60

80

100

120

140

None One onlyAge-

adju

sted

CVD

dea

th r

ate

per

10,0

00 p

erso

n-y

ears

*Serum cholesterol >200 mg/dl, smoking, SBP >120 mmHgStamler J et al. Diabetes Care 1993;16:434-444

All three

No diabetes Diabetes

Two only



Putative Mechanism for Increased Putative Mechanism for Increased Atherosclerosis in Type 2 DiabetesAtherosclerosis in Type 2 Diabetes

BLACK BOX Dyslipidemia

Hypertension

Hyperinsulinemia/insulin resistance

Hemostatic abnormalities

Hyperglycemia

AGE proteins

Oxidative stress

AGE = advanced glycation end productsAdapted from Bierman EL. Arterioscler Thromb 1992;12:647-656.



+ = moderately increased compared with nondiabetic population++ = markedly increased compared with nondiabetic population – = not different compared with nondiabetic population

Prevalence of Cardiovascular Risk Factors in Prevalence of Cardiovascular Risk Factors in Diabetic Subjects Relative to NondiabeticsDiabetic Subjects Relative to Nondiabetics

Type 1Type 1Dyslipidemia Hypertriglyceridemia Low HDL Small, dense LDL Increased apo BHypertensionHyperinsulinemia/insulin resistanceCentral obesityFamily history of atherosclerosisCigarette smoking

Adapted from Chait A, Bierman EL. In: Joslin’s Diabetes Mellitus. Philadelphia: Lea & Febiger, 1994:648-664.

Type 2Type 2Risk FactorRisk Factor

+–––+––––

+++++++++++++++–



Differences in HDL Cholesterol and LDL Size Differences in HDL Cholesterol and LDL Size by Diabetic Status in Women and Menby Diabetic Status in Women and Men

Howard BV et al. Diabetes Care 1998; 21:1258-1265.

0

-2

-4

-6

-8

Diffe

rence

s bet

wee

n p

artici

pan

ts

with a

nd w

ithout

dia

bet

es

HDL CholesterolHDL Cholesterol LDL SizeLDL SizeÅ0

-2

-4

-6

-8

mg/dL

WomenWomen

MenMen

WomenWomen

MenMen



Strategies for Reduction of Diabetic Strategies for Reduction of Diabetic ComplicationsComplications

Microvascular complications- Aggressive screening- Improved metabolic control

Macrovascular complications- Improved glycemic control (positive but minor)- Prevention of type 2 diabetes- Aggressive treatment of established CVRF in diabetic and possibly prediabetic subjects- Diabetic agents that improve cardiovascular risk



0

10

20

30

40

50

Incidence Rates of MI and Microvascular Incidence Rates of MI and Microvascular Endpoints by Mean Systolic Blood Pressure: Endpoints by Mean Systolic Blood Pressure: UKPDSUKPDS

110 120 130 140 150 160 170

Inci

den

ce p

er 1

000 P

erso

n

Yea

rs (

%)

Adler AI et al. BMJ 2000;321:412-419.

Updated Mean Systolic Blood Pressure (mmHg)Adjusted for age, sex, and ethnic group

Myocardial Infarction

Microvascular Endpoints



0

20

40

60

80

Incidence Rates of MI and Microvascular Incidence Rates of MI and Microvascular Endpoints by Mean HemoglobinEndpoints by Mean Hemoglobin AA1c1c: : UKPDSUKPDS

5 6 7 8 9 10 11

Inci

den

ce p

er 1

000 P

erso

n

Yea

rs (

%)

Stratton IM et al. BMJ 2000;321:405-412.

Updated Mean Hemoglobin A1c Concentration (%)Adjusted for age, sex, and ethnic group

Myocardial Infarction

Microvascular Endpoints



Plasma Insulin and Triglycerides Predict Plasma Insulin and Triglycerides Predict Ischemic Heart Disease: Ischemic Heart Disease: Quebec Quebec Cardiovascular StudyCardiovascular Study

Despres JP et al. N Engl J Med 1996;334:952-957.

0.0

2.0

4.0

6.0

8.0

Odds

Rat

io

<12 12-15 >15F-Insulin (µU/ml)

4.6

p=0.005

>150 mg/dl

<150 mg/dl

Triglycerides

1.0

1.5 5.3

p=0.001

P<0.001

6.75.4

P=0.002



Plasma Insulin and Apolipoprotein B Plasma Insulin and Apolipoprotein B Predict Ischemic Heart Disease: Predict Ischemic Heart Disease: Quebec Quebec Cardiovascular StudyCardiovascular Study

Despres JP et al. N Engl J Med 1996;334:952-957.

0.0

2.0

4.0

6.0

8.0

10.0

12.0

Odds

Rat

io

<12 12-15 >15F-Insulin (µU/ml)

3.0p=0.04

>119 mg/dl

<119 mg/dl

Apolipoprotein B

1.0

1.5 3.2

p<0.001

11.09.7

P<0.001

p=0.04



0

1

2

3

4

5

6

LDL Particle Size and Apolipoprotein B Predict LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Ischemic Heart Disease: Quebec Cardiovascular Quebec Cardiovascular StudyStudy

Lamarche B et al. Circulation 1997;95:69-75.

>25.64 <25.64LDL Peak Particle Diameter (nm)

1.01.0

6.2

(p<0.001)

Apo B

>120 mg/dl

2.0

<120 mg/dl



Baseline Anthropometric Variables and Cardiovascular Risk Baseline Anthropometric Variables and Cardiovascular Risk Factors in Subjects with Factors in Subjects with NormalNormal Glucose Tolerance at Glucose Tolerance at Baseline According to Conversion Status at 8-Year Follow-Baseline According to Conversion Status at 8-Year Follow-up:up: San Antonio Heart Study San Antonio Heart Study

BMI (kg/m2)

Centrality*

TG (mmol)

HDLC (mmol)

SBP (mmHg)

Fasting glucose (mmol)

Fasting insulin (pmol)

Haffner SM et al. JAMA 1990;263:2893-2898.

28.2 + 1.1

1.38 + 0.09

1.83 + 0.12

1.14 + 0.07

116.8 + 3.0

5.28 + 0.1

157 + 27

27.2 + 0.2

1.16 + 0.2

1.26 + 0.10

1.28 + 0.02

108.8 + 0.8

5.00 + 0.02

81 + 5

.472

.472

.006

.045

.004

.032

.006

Conversion Status at Follow-up

Diabetes (n=18)Diabetes (n=18) Normal (n=490)Normal (n=490) PP

* Ratio of subscapular to triceps skinfolds



““Ticking Clock” HypothesisTicking Clock” Hypothesis

WHO. Diabetologia 1985;28:615-640; Haffner SM et al. JAMA 1990;263:2893-2898.

ForFor

Microvascular Microvascular complicationscomplications

Macrovascular Macrovascular complicationscomplications

The “clock starts ticking”The “clock starts ticking”

At onset of hyperglycemiaAt onset of hyperglycemia

Before the diagnosis of Before the diagnosis of hyperglycemiahyperglycemia



Hemoglobin AHemoglobin A11Fasting GlucoseFasting Glucose

The 7-Year Age-Adjusted Incidence of CHD The 7-Year Age-Adjusted Incidence of CHD Mortality and All CHD Events: Mortality and All CHD Events: East-West StudyEast-West Study

Lehto S et al. Diabetes 1997;46:1354-1359.

40

30

20

10

0

% I

nci

den

ce

P-glucose (mmol/L)<9.6 9.6-13.4 >13.4

40

30

20

10

0%

Inci

den

ce

CHD Mortality

All CHD Events

CHD Mortality

All CHD Events

HbA1 (%)<8.9 8.9-10.7 >10.7



Stepwise Selection of Risk Factors* in 2693 White Stepwise Selection of Risk Factors* in 2693 White Patients with Type 2 Diabetes with Dependent Patients with Type 2 Diabetes with Dependent Variable as Time to First Event: Variable as Time to First Event: UKPDSUKPDS

VariableVariable

Low-Density Lipoprotein Cholesterol

High-Density Lipoprotein Cholesterol

Hemoglobin A1c

Systolic Blood Pressure

Smoking

P ValueP Value

<0.0001

0.0001

0.0022

0.0065

0.056

Coronary Artery Disease (n=280)

Position in ModelPosition in Model

First

Second

Third

Fourth

Fifth

*Adjusted for age and sex.Turner RC et al. BMJ 1998;316:823-828.



Criteria for Accepting Cardiovascular Risk Criteria for Accepting Cardiovascular Risk Factor Management as Similar in Diabetic Factor Management as Similar in Diabetic and CHD Subjectsand CHD Subjects

The risk of vascular disease is similar in diabetic subjects without pre-existing vascular disease as in nondiabetic subjects with vascular disease

Glycemia alone will not completely eliminate the excess of CHD risk in diabetic subjects

Lipid interventions to reduce CHD can be equally effective in diabetic and nondiabetic subjects



Incidence of Fatal or Nonfatal MI During a 7-Year Incidence of Fatal or Nonfatal MI During a 7-Year Follow-up in Relation to History of MI in Follow-up in Relation to History of MI in Nondiabetic vs Diabetic Subjects: Nondiabetic vs Diabetic Subjects: East-West StudyEast-West Study

0

10

20

30

40

50

Inci

den

ce D

uri

ng

Follo

w-u

p (

%)

(n=69)

Nondiabetics with prior MI

Nondiabetics with no prior MI

Diabetics with prior MI

Diabetics with no prior MI

18.8

Haffner SM et al. N Engl J Med 1998;339:229-234.

(n=1304) (n=169) (n=890)3.0 0.5 7.8 3.2

3.5

45.0

20.2

Events per100 person-yr:

P<0.001

p<0.001



Incidence of Fatal or Nonfatal Stroke During a Incidence of Fatal or Nonfatal Stroke During a 7-Year Follow-up in Relation to History of MI in 7-Year Follow-up in Relation to History of MI in Nondiabetic vs Diabetic Subjects: Nondiabetic vs Diabetic Subjects: East-West StudyEast-West Study

0

5

10

15

20

25

Inci

den

ce D

uri

ng

Follo

w-u

p (

%)

(n=69)

Nondiabetics with prior MI

Nondiabetics with no prior MI

Diabetics with prior MI

Diabetics with no prior MI

7.2

Haffner SM et al. N Engl J Med 1998;339:229-234.

(n=1304) (n=169) (n=890)1.2 0.3 3.4 1.6

1.9

19.5

10.3

Events per100 person-yr:

P=0.01

p<0.001



ConclusionsConclusions

Epidemiological data suggest that the risk of CHD in type 2 diabetes is equivalent to that in people with prevalent CHD.

Although hyperglycemia is significantly related to CHD, the magnitude of association is unlikely to explain the entire excess risk of cardiovascular disease.

Within type 2 diabetics, increased blood pressure and LDL-C and low HDL-C also predict the risk of future myocardial infarction.



Clinical Trials and Guidelines for Clinical Trials and Guidelines for

Lipid Management in the Diabetic Lipid Management in the Diabetic

PatientPatient




UKPDS DesignUKPDS Design

AimAim

To determine whether intensified blood glucose control, with either sulphonylurea or insulin, reduces the risk of macrovascular or microvascular complications in type 2 diabetes

PatientsPatients

3867 newly diagnosed type 2 diabetic patients who were asymptomatic after 3 months of diet; fasting glucose 6.1-15 mmol/L (110-270 mg/dl); treat for 10 years

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; Turner R et al. Ann Intern Med 1996;124:136-145.


www.lipidsonline.orgUKPDS Group. Lancet 1998;352:837-853.

UKPDS 10-Year Follow-up Results:UKPDS 10-Year Follow-up Results:Glycemic Control, Weight, and Plasma InsulinGlycemic Control, Weight, and Plasma Insulin

Years from Randomization

0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12

Years from Randomization

Conventional

Conventional

Intensive

IntensiveConventional

Intensive

Intensive

Conventional

Fasting plasma glucose

Med

ian (

mm

ol/

L) Hemoglobin A1c

Weight Plasma insulin

11

10

9

8

7

60

Med

ian (

%)

9

8

7

60

7.5

5

2.5

0

-2.5

Baseline = 75 kgMea

n C

han

ge

(kg)

40

30

20

10

0

-10

-20Med

ian C

han

ge (

pm

ol/

L)Baseline = 89 pmol/L



UKPDS: Proportion of Patients Taking Different UKPDS: Proportion of Patients Taking Different Therapies in the Conventional-Therapy GroupTherapies in the Conventional-Therapy Group

Courtesy of Dr. Amanda Adler

% o

f pat

ients

100

80

60

40

20Diet aloneDiet alone

1 3 5 7 9 11Years from randomization

AdditionalAdditionalpharmacologicpharmacologic

therapytherapy



UKPDS: Causes of Death by Glucose UKPDS: Causes of Death by Glucose Treatment GroupTreatment Group

Rate/1000Rate/1000patient-yearspatient-years

MIStrokeSudden deathPVD

All macrovascular

Renal disease

CancerOther specifiedUnknown

Total

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

%%Rate/1000Rate/1000

patient-yearspatient-years %%

7.61.60.90.1

10.2

0.3

4.42.40.5

17.8

CauseCause

43951

58

2

25133

100

8.01.31.60.3

11.2

0.2

4.42.70.2

18.7

43782

60

1

24141

100

ConventionalConventionalIntensiveIntensive



UKPDS: Endpoints by Glucose UKPDS: Endpoints by Glucose Treatment GroupTreatment Group

Rate/1000Rate/1000Patient-YearsPatient-Years

Any diabetes-related*

MI

Stroke

PVD**

Microvascular


Rate/1000Rate/1000Patient-YearsPatient-Years PPCauseCause

40.9

14.7

5.6

1.1

8.6

*Combined microvascular and macrovascular events**Amputation or death from PVD

% Risk% RiskReductionReduction

46.0

17.4

5.0

1.6

11.4

0.029

0.052

0.52

0.15

0.0099

12

16

–

–

25

ConventionalConventionalIntensiveIntensive



UKPDS: Impact of Glucose-Lowering UKPDS: Impact of Glucose-Lowering Agents on MI and StrokeAgents on MI and Stroke

Sulphonylurea or exogenous insulin (n=2729)

MI 16% reduction (P = 0.052)

Stroke 11% increase (P = 0.52)

Metformin in overweight subjects (n = 342)

MI 39% reduction (P = 0.01)

Stroke 41% reduction (P = 0.13)

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-865.



UKPDS Results: Intensive Blood Pressure UKPDS Results: Intensive Blood Pressure ControlControl

Any diabetes-related endpoint

Deaths related to diabetes

Myocardial infarction

Stroke

Microvascular disease

Intensive BloodIntensive BloodPressure ControlPressure Control

24

32

21

44

37

0.0046

0.019

NS

0.013

0.092

Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:703-713.

ReductionReduction(%)(%) P ValueP Value



Comparison of Captopril vs. Atenolol Comparison of Captopril vs. Atenolol in UKPDSin UKPDS

Primary


Death related to diabetes

All-cause mortality Secondary


Stroke

Peripheral vascular disease


Clinical EndpointClinical Endpoint

Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:713-720.

RR forRR forCaptoprilCaptopril P ValueP Value

1.10 (0.86–1.41)

1.27 (0.82–1.97)

1.14 (0.81–1.61)

1.20 (0.82–1.76)

1.12 (0.59–2.12)

1.48 (0.35–6.19)

1.29 (0.80–2.10)

0.43

0.28

0.44

0.35

0.74

0.59

0.30



Comparison of Glucose Lowering and Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDSBlood Pressure Lowering in UKPDS



Stroke


12

16

11↑

25

Reduction Reduction %%

↑ = Increase in risk

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; UK Prospective Diabetes Study Group. BMJ 1998;317:703-713.

PPValueValue

Reduction Reduction %%

PPValueValue

Intensive BloodIntensive BloodGlucose Control (n=2729)Glucose Control (n=2729)

Intensive BloodIntensive BloodPressure Control (n=758)Pressure Control (n=758)

0.029

0.052

NS

0.0099

24

21

44

37

0.0046

NS

0.013

0.092



Treatment Strategies for Diabetic Treatment Strategies for Diabetic DyslipidemiaDyslipidemia

Primary Strategy

- Lower LDL cholesterol Secondary Strategy

- Raise HDL cholesterol

- Lower triglycerides Other Approaches

- Non-HDL cholesterol

- ApoB

- RemnantsAdapted from American Diabetes Association. Diabetes Care. 2000;23(suppl 1):S57-S60; Chait A, Brunzell JD. Diabetes Mellitus. A Fundamental and Clinical Text. Philadelphia: Lippincott Raven, 1996;772-779; European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730.



CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects: Diabetic Subjects: Subgroup AnalysesSubgroup Analyses

Primary Prevention

AFCAPS/TexCAPS

Secondary Prevention

CARE

4S

LIPID

BaselineBaselineLDL-C,LDL-C,mg/dlmg/dl

(mmol/L)(mmol/L)

*Values for overall group

Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Pyörälä K et al. Diabetes Care 1997;20:614-620; Haffner SM et al. Arch Intern Med 1999;159:2661-2667; The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357.

DrugDrug No.No.LDL-CLDL-C

LoweringLowering

Lovastatin

Pravastatin

Simvastatin

Pravastatin

25%

28%

36%

25%*

150 (3.9)

136 (3.6)

186 (4.8)

150* (3.9)

239

586

202

782

StudyStudy



CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects: Diabetic Subjects: Subgroup Analyses Subgroup Analyses (cont’d)(cont’d)

Primary Prevention

AFCAPS/TexCAPS


CARE

4S

LIPID

4S-Extended

CHD RiskCHD RiskReductionReduction(overall)(overall)DrugDrug No.No.

Lovastatin

Pravastatin

Simvastatin

Pravastatin

Simvastatin

43%

25% (p=0.05)

55% (p=0.002)

19%

42% (p=0.001)

37%

23%

32%

25%

32%

239

586

202

782

483

CHD RiskCHD RiskReductionReduction(diabetes)(diabetes)StudyStudy

Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Pyörälä K et al. Diabetes Care 1997;20:614-620; The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357; Haffner SM et al. Arch Intern Med 1999;159:2661-2667.


www.lipidsonline.orgAdapted from Pyörälä et al. Diabetes Care 1997;20:614-620.

Diabetic vs. Nondiabetic Patients in 4SDiabetic vs. Nondiabetic Patients in 4S

0 0.2 0.4 0.8 1.4Relative Risk with 95% Confidence Intervals

Total mortality

0.6 1.0 1.2

Reduced Increased

CHD mortality

Simvastatin BetterPlacebo Better

Major CHD event

Cerebrovascular event

Any atherosclerotic event

P=0.001P=0.087

P<0.0001P=0.242

P<0.0001P=0.002

P=0.097P=0.071

P<0.0001P=0.018

No diabetesDiabetes



1.0

0.9

0.8

0.7

0.6

0.5

0

Proport

ion w

ithout

Maj

or

CH

D E

vent

Years Since Randomization0 1 2 3 4 5 6

Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620.

Diabetes by Hx, simvastatinDiabetes by Hx, placebo

No diabetes by Hx, simvastatinNo diabetes by Hx, placebo

P=0.002

P=0.0001

Major Coronary Events in 4S Patients with Major Coronary Events in 4S Patients with or without Diabetes by History (n=202)or without Diabetes by History (n=202)


www.lipidsonline.orgAdapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667

4S: Extended Diabetic Subgroup Analysis: 4S: Extended Diabetic Subgroup Analysis: Diabetes (n=483; 251 on Simvastatin) — Fasting Diabetes (n=483; 251 on Simvastatin) — Fasting Glucose Glucose >>7 mmol/L (126 mg/dl)7 mmol/L (126 mg/dl)

0.0 0.2 0.4 0.8 1.4Relative Risk

CHD mortality (P=0.26)

Total mortality (P=0.34)

Revascularizations (P=0.005)

Major coronary events (P=0.001)

0.6 1.0 1.2

0.72

0.79

0.52

0.58


www.lipidsonline.orgAdapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667

4S: Extended Diabetic Subgroup Analysis:4S: Extended Diabetic Subgroup Analysis:Impaired Fasting Glucose (n=678; 343 on Simvastatin) — Impaired Fasting Glucose (n=678; 343 on Simvastatin) — Fasting Glucose 6.0-6.9 mmol/L (110-125 mg/dl)Fasting Glucose 6.0-6.9 mmol/L (110-125 mg/dl)

0.0 0.2 0.4 0.8 1.4Relative Risk

CHD mortality (P=0.007)

Total mortality (P=0.02)

Revascularizations (P=0.01)

Major coronary events (P=0.003)

0.6 1.0 1.2

0.45

0.57

0.57

0.62



0

200

400

600

800

1000

1200

Simvastatin

Normal fastingglucose

Bed

Day

s (p

er 1

00 P

ts)

4S: 4S: Effect of Statin Therapy on Hospital StayEffect of Statin Therapy on Hospital Stay

Adapted from Herman WH et al. Diabetes Care 1999;22:1771-1778.

↓55%(p<0.001)

Placebo Simvastatin

Impaired fastingglucose

Placebo Simvastatin Placebo

Diabetesmellitus

↓38%(p=0.005)

↓28%(p<0.001)



CARE: Major Coronary Events in CARE: Major Coronary Events in Diabetic SubgroupsDiabetic Subgroups

Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519.

45

35

30

25

20

15

10

5

0

Per

cent

with E

vent

No Diabetes by HistoryNo Diabetes by History Diabetes by HistoryDiabetes by History

Follow-up Time (years)

Perc

ent

with E

vent

45

35

30

25

20

15

10

5

0

Follow-up Time (years)0 1 2 3 4 65 0 1 2 3 4 65

Placebo

Pravastatin

Pravastatin

Placebo

Relative risk = 0.75P=0.05

Relative risk = 0.77P<0.001



-70

-60

-50

-40

-30

-20

-10

0

% R

isk

Red

uct

ion

AFCAPS/TexCAPS: Subgroup AnalysisAFCAPS/TexCAPS: Subgroup Analysis

Downs JR et al. JAMA 1998;279:1615-1622.

Men Women Older Smokers HTN Diabetes

-37

-46

-31

-58

-38-42

Lovastatin Reduced the Risk of Acute MCELovastatin Reduced the Risk of Acute MCE



CARE: Major Coronary Events in CARE: Major Coronary Events in Diabetic SubgroupsDiabetic Subgroups

Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519.

454035302520151050

Per

cent

with E

vent

No Diabetes by HistoryNo Diabetes by History Diabetes by HistoryDiabetes by History

Follow-up Time (years)

Perc

ent

with E

vent

Follow-up Time (years)0 1 2 3 4 65 0 1 2 3 4 65

Placebo

Pravastatin

Pravastatin

Placebo

Relative risk = 0.75P=0.05

Relative risk = 0.77P<0.001

454035302520151050



0

10

20

30

40

50

Per-

Patien

t %

of G

raft

sPOST-CABG: Effect of Aggressive Lipid POST-CABG: Effect of Aggressive Lipid Lowering on Progression in a Diabetic Lowering on Progression in a Diabetic Subgroup Subgroup

Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294.

AggressiveRx

ModerateRx

AggressiveRx

ModerateRx

Diabetes (n=116) No Diabetes (n=1235)

99% CI99% CI(0.20-1.19)(0.20-1.19)

99% CI99% CI(0.46-0.79)(0.46-0.79)

51% 51% 40% 40%



CHD Prevention Trials with Fibrates in CHD Prevention Trials with Fibrates in Diabetic Subjects: Diabetic Subjects: Subgroup AnalysesSubgroup Analyses

Primary Prevention

HelsinkiHeart Study


VA-HIT

BaselineBaselineLDL-C,LDL-C,mg/dlmg/dl

(mmol/L)(mmol/L)No.No.LDL-CLDL-C

LoweringLowering

Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825; Rubins HB et al. N Engl J Med 1999;341:410-418.

DrugDrugDoseDoseStudyStudy

CHDCHDReductionReduction

Gemfibrozil(1200 mg/d)

Gemfibrozil(1200 mg/d)

135

627

203(5.2)

112(2.9)

68%NS

24%p=0.05

6%

–



Primary CHD* Prevention in Type 2 Diabetic Primary CHD* Prevention in Type 2 Diabetic Patients: Patients: The Helsinki Heart StudyThe Helsinki Heart Study

0

5

10

15

5-Y

ear

Inci

den

ce o

f CH

D (

%)

Type 2(n=135)

*Myocardial infarction or cardiac deathAdapted from Koskinen P et al. Diabetes Care 1992;15:820-825.

Others(n=3946)

Type 2 on Placebo(n=76)

Type 2 onGemfibrozil

(n=59)

P<0.02

7.4

3.3

10.5

3.4

P=0.19



0

5

10

15

20

25

1 2 3 4 5 6Year

Cum

ula

tive

Inci

den

ce (

%)

VA-HIT: VA-HIT: Incidence of Death from CHDIncidence of Death from CHD and Nonfatal MIand Nonfatal MI

Placebo

Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418.

Gemfibrozil



VA-HIT: VA-HIT: Death Due to CHD, Nonfatal MI, Death Due to CHD, Nonfatal MI, and Confirmed Stroke in Diabetic Patientsand Confirmed Stroke in Diabetic Patients

Diabetes

No diabetes

Placebo*Placebo*

*Values are numbers with events/total numbers (%)

Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418.

RiskRiskReductionReductionGemfibrozil*Gemfibrozil* P ValueP Value

116/318

(36)

214/949

(23)

88/309

(28)

170/955

(18)

24%

24%

0.05

0.009



Future DirectionsFuture DirectionsOngoing Trials withOngoing Trials withLipid-Lowering FocusLipid-Lowering Focus DrugDrug

Simvastatin

Atorvastatin

Atorvastatin

Cerivastatin +fenofibrate micronized

Fenofibrate micronized

Fenofibrate micronized

HPS = Heart Protection Study; ASPEN = Atorvastatin Study in Preventing Endpoints in NIDDM; CARDS = Collaborative Atorvastatin Diabetes Study; LDS = Lipids in Diabetes Study; DAIS = Diabetes Atherosclerosis Intervention Study; FIELD = Fenofibrate Intervention and Event Lowering in Diabetes

HPS

ASPEN

CARDS

LDS

DAIS

FIELD



Heart Protection StudyHeart Protection Study Primary prevention with risk factors

(hypertension, diabetes, and CVA)

2x2 factorial design simvastatin 40 mg/day, antioxidant cocktail (600 mg vitamin E, 250 mg vitamin C, 20 mg beta carotene)

N = 20,000; subgroups include: Women (n ~ 5,000) Elderly (>65, n ~ 10,000) Diabetics (n ~ 6,000) Stroke (n ~ 3,000) Hypertension (n ~ 8,000) Noncoronary vascular disease (n ~ 7,000) Low to average blood cholesterol (n ~ 8,000)

FPI – 1996, fully enrolled, results 2001 Medical Research Council. August 1994



Endpoint Studies: Treating to New Targets Endpoint Studies: Treating to New Targets (TNT):(TNT): Study DesignStudy Design

Site SelectionSite SelectionNovember 1997November 1997

InvestigatorInvestigatorMeetingMeeting

March 1998March 1998

RecruitmentRecruitmentCompleteCompleteJune 1999June 1999

Study EndStudy EndDec 2004Dec 2004

AtorvastatinAtorvastatin10 mg10 mg

LDLLDL75 mg/dL75 mg/dL

LDLLDL100 mg/dL100 mg/dL

5 Years5 Years

AtorvastatinAtorvastatin80 mg80 mg

10,000 CAD Patients10,000 CAD Patients



Study of the Effectiveness of Additional Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine Reductions in Cholesterol and Homocysteine with Simvastatin and Folic Acid/Vitamin Bwith Simvastatin and Folic Acid/Vitamin B1212 (SEARCH): (SEARCH): Study DesignStudy Design

Primary objective: To determine whether the greater cholesterol reductions achieved with simvastatin 80 mg produce greater CHD reductions in post-MI patients than achieved with simvastatin 20 mg

Secondary prevention

2x2 factorial design:simvastatin 20 or 80 mg; 2 mg folic acid/1 mg Vitamin B12

N = 12,000

FPI – 12/97, results 2003



Cerivastatin ArmCerivastatin ArmFe

nofibra

te A

rmFe

nofibra

te A

rm

CerivastatinCerivastatinFenofibrateFenofibrate(n=1,250)(n=1,250)

PlaceboPlaceboFenofibrateFenofibrate(n=1,250)(n=1,250)

CerivastatinCerivastatinPlaceboPlacebo

(n=1,250)(n=1,250)

PlaceboPlaceboPlaceboPlacebo

(n=1,250)(n=1,250)

2,5002,500activeactive

fenofibratefenofibrate

2,5002,500placeboplacebo

fenofibratefenofibrate

n=2,500 activen=2,500 activecerivastatincerivastatin

n=2,500 placebon=2,500 placebocerivastatincerivastatin

5,000 pts5,000 ptsin totalin total

Lipids in Diabetes Study (LDS):Lipids in Diabetes Study (LDS): Two-by-Two Factorial RandomizationTwo-by-Two Factorial Randomization




CHD risk is extremely high in diabetic subjects

Benefits of risk-factor modification in intervention trials also apply to subgroups with diabetes

Results of strict glycemic control on macrovascular disease are inconclusive



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

Type 1 Renal TransplantHolley 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 StudyAge-

adju

sted

CV E

vent

Rat

e/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 195Age-

adju

sted

CV E

vent

Rat

e/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


www.lipidsonline.orgUKPDS 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%

Decrease(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


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


www.lipidsonline.orgUKPDS 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


Diabetes-related deaths

Heart failure

Stroke



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


Diabetes-related deaths

All-cause mortality


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

Eve

nts

/ 1

000 P

t-Yea

rsSystolic 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

Eve

nts

/ 1

000 P

t-Yea

rsMajor 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

Eve

nts

/ 1

000 P

t-Yea

rsHOT 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 Pa

tien

ts

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

CVD

Eve

nts

(%

)

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

ality

Mort

ality

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

Eve

nt

Rat

e

0.0

0.1

0.2

0.3

0.4

0.5

Years

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

0 1 2 3 4

Eve

nt

Rat

eRelative risk, 0.38

P<0.001Relative risk, 0.81

P = 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


www.lipidsonline.orgWoodfield 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

ality

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

ality

Follow-up (years) Years after Q-MI

DM-PTCA

DM-CABG

Non DM-CABG

Non DM-PTCA

Mort

ality

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)

Patien

ts (

%)

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 E

F (%

)

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

Proport

ion F

ree

of TVR p = 0.021

df = 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

den

ce o

f re

pea

ted T

VR

at 6

mos.

(%

)

Days after Randomization

0

5

10

15

20

Patients without DiabetesPatients without Diabetes(n = 1908)(n = 1908)

0 30 90 120 18060 150In

ciden

ce o

f re

pea

ted T

VR

at 6

mos.

(%

)

18.4%

16.6%

8.1%

14.6%

Stent + PlaceboStent + AbciximabAngioplasty + Abciximab

9.0%

8.8%



0

5

10

15

% o

f Pa

tien

ts

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




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



Diabetic Dyslipidemia and Diabetic Dyslipidemia and

AtherosclerosisAtherosclerosis

Henry Ginsberg, MDHenry Ginsberg, MD



Interrelation Between Atherosclerosis Interrelation Between Atherosclerosis and Insulin Resistanceand Insulin Resistance

HypertensionHypertension

ObesityObesity

HyperinsulinemiaHyperinsulinemia

DiabetesDiabetes

HypertriglyceridemiaHypertriglyceridemia

Small, dense LDLSmall, dense LDL

Low HDLLow HDL

HypercoagulabilityHypercoagulability

InsulinInsulinResistanceResistance

InsulinInsulinResistanceResistance AtherosclerosisAtherosclerosisAtherosclerosisAtherosclerosis



Abdominal obesity

TG + HDL-C

Glucose intolerance

Hypertension

Atherosclerosis

Ethnicity

Insulin Resistance and Hyperinsulinemia: Insulin Resistance and Hyperinsulinemia: Clinical CluesClinical Clues



Elevated total TG

Reduced HDL-C

Small, dense LDL-C

Dyslipidemia in the Insulin Resistance Dyslipidemia in the Insulin Resistance SyndromeSyndrome



Dyslipidemias in Adults with DiabetesDyslipidemias in Adults with DiabetesFramingham Heart StudyFramingham Heart Study

Increased cholesterol

Increased LDL

Decreased HDL

Increased triglycerides

NormalNormal DMDM NormalNormal DMDM

14%

11%

12%

9%

13%

9%

21%

19%

MENMEN WOMENWOMEN

21%

16%

10%

8%

24%

15%

25%

17%

Garg A et al. Diabetes Care 1990;13:153-169.



Mean Plasma Lipids at Diagnosis of Mean Plasma Lipids at Diagnosis of Type 2 Diabetes - Type 2 Diabetes - UKPDSUKPDS

Number of Pts

TC (mg/dl)

LDL-C (mg/dl)

HDL-C (mg/dl)

TG (mg/dl)

Type 2Type 2 ControlControlMENMEN

UKPDS Group. Diabetes Care 1997;20:1683-1687.

* P<0.001, ** P<0.02 comparing type 2 vs. controll

2139

213

139

39**

159*

52

205

132

43

103

Type 2Type 2 ControlControlWOMENWOMEN

1574

224

151*

43*

159*

143

217

135

55

95



Relation Between Insulin Resistance and Relation Between Insulin Resistance and HypertriglyceridemiaHypertriglyceridemia

Olefsky JM et al. Am J Med. 1974;57:551-560.* Total area under 3-hour response curve (mean of 2 tests).

625

500

400

300

200

100

100 200 300 400 500 600Insulin Response to Oral Glucose*

Pla

sma

TG

(m

g/d

L)

r = 0.73P < 0.0001



Association Between Hyperinsulinemia Association Between Hyperinsulinemia and Low HDL-Cand Low HDL-C

20

30

40

50

60

HD

L-C (

mg/d

L)

Reaven GM. In: LeRoith D et al., eds. Diabetes Mellitus. Philadelphia: Lippincott-Raven,1996:509-519.

Nonobese

Hyperinsulinemic

Normoinsulinemic

Obese

P<0.005

P<0.005



Mechanisms Relating Insulin Resistance Mechanisms Relating Insulin Resistance and Dyslipidemiaand Dyslipidemia

Fat CellsFat Cells LiverLiver

InsulinInsulin

IRIR XX

FFAFFA





InsulinInsulin

IRIR XX

TGTG Apo BApo B VLDLVLDL

VLDLVLDL

FFAFFA



(hepatic(hepaticlipase)lipase)



KidneyKidneyInsulinInsulin

IRIR XX

(CETP)(CETP)

CECE


VLDLVLDL HDLHDL

TGTGApo A-1Apo A-1

FFAFFA



(hepatic(hepaticlipase)lipase)



KidneyKidneyInsulinInsulin

IRIR XX

(CETP)(CETP)

CECE


(CETP)(CETP)

VLDLVLDL HDLHDL

(lipoprotein or hepatic lipase)(lipoprotein or hepatic lipase)

SDSDLDLLDL

LDLLDL

TGTGApo A-1Apo A-1

TGTGCECE

FFAFFA



IncreasedIncreased

Dyslipidemia in DiabetesDyslipidemia in Diabetes

DecreasedDecreased

Triglycerides

VLDL

LDL and small dense LDL

Apo B

HDL

Apo A-I



LDL Subclass Phenotypes in LDL Subclass Phenotypes in Diabetes MellitusDiabetes Mellitus

Men*Men* Diabetic Nondiabetic

Women**Women** Diabetic Nondiabetic

** Selby JV et al. Circulation 1993; 88:381-387.

IntInt BB

* Feingold KR et al. Arterioscler Thromb 1992; 12:1496-1502.

2987

54543

2847

3485

2129

309

5124

366

LDL SubclassLDL Subclass

nn AA

PercentPercent



Increased susceptibility to oxidation

Increased vascular permeability

Conformational change in apo B

Decreased affinity for LDL receptor

Association with insulin resistance syndrome

Association with high TG and low HDL

Small Dense LDL and CHD: Small Dense LDL and CHD: Potential Atherogenic MechanismsPotential Atherogenic Mechanisms

Austin MA et al. Curr Opin Lipidol 1996;7:167-171.



Accumulation of chylomicron remnants

Accumulation of VLDL remnants

Generation of small, dense LDL-C

Association with low HDL-C

Increased coagulability

- plasminogen activator inhibitor (PAI-1)

- factor VIIc

- Activation of prothrombin to thrombin

Hypertriglyceridemia and CHD Risk: Hypertriglyceridemia and CHD Risk: Associated AbnormalitiesAssociated Abnormalities



TG Metabolism in CHD: TG Metabolism in CHD: Studies in theStudies in the Postprandial StatePostprandial State

400

300

200

100

0

TG

(m

g/d

L)

UncorrectedUncorrectedCorrected for Fasting Corrected for Fasting

TG Level*TG Level*

Hours after Test Meal

300

200

100

0

Patsch JR et al. Arterioscler Thromb 1992;12:1336-1345.

0 2 4 6 8 0 2 4 6 8

CHD Cases

Controls

Controls

Error bars = SEM

CHD Cases



Increased plasma fibrinogen

Increased plasminogen activator inhibitor 1

Increased platelet aggregability

Factors Promoting Thromboembolic Factors Promoting Thromboembolic Disease in DiabetesDisease in Diabetes

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



Predisposition to thrombosisPredisposition to thrombosis

- Platelet hyperaggregability

- Elevated concentrations of procoagulants

- Decreased concentration and activity of antithrombotic factors

Predisposition to attenuation of fibrinolysisPredisposition to attenuation of fibrinolysis

- Decreased t-PA activity

- Increased PAI-1

- Decreased concentrations of α2-antiplasmin

Adverse Effects on Balance Between Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Subjects Thrombosis and Fibrinolysis in Subjects with Diabeteswith Diabetes

Sobel BE. Circulation 1996;93:1613-1615.



PAI-1 Activity in Blood in Patients with PAI-1 Activity in Blood in Patients with Type 2 DiabetesType 2 Diabetes

0

5

10

15

20

PAI-

1 A

ctiv

ity

(AU

/mL)

McGill JB et al. Diabetes. 1994;43:104-109.

Lean

No Diabetes

Diabetes

Obese

PAI-1 = plasminogen activator inhibitor type 1



Elevation of PAI-1 Induced by Elevation of PAI-1 Induced by Hyperinsulinemia, Hyperglycemia, and Hyperinsulinemia, Hyperglycemia, and Increased FFA in Blood of Normal SubjectsIncreased FFA in Blood of Normal Subjects

Calles-Escandon J et al. Diabetes. 1998;47:290-293.*P<0.05 vs saline infusions in same subjects

Values are mean + SD

0

3

6

9

12

15

18

21

PAI-

I (m

g/m

L)

0 2 4 6 8 12Time (h)

10

*Infusion of glucose Infusion of glucose

and intralipidand intralipid



First-line agentsFirst-line agents

HMG CoA reductase inhibitorHMG CoA reductase inhibitor

Fibric acid derivativeFibric acid derivative

Second-line agentsSecond-line agents

Bile acid binding resinsBile acid binding resins

Nicotinic acidNicotinic acid

Pharmacologic Agents for Treatment of Pharmacologic Agents for Treatment of DyslipidemiaDyslipidemia

American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.

In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred.

Effect on lipoprotein

LDL HDL Triglyceride



LDL cholesterol lowering*LDL cholesterol lowering* - First choice: HMG CoA reductase inhibitor (statin)

- Second choice: Bile acid binding resin or fenofibrate

HDL cholesterol raisingHDL cholesterol raising - Behavior interventions such as weight loss, increased physical activity and

smoking cessation

- Glycemic control

- Difficult except with nicotinic acid, which is relatively contraindicated, or fibrates

Triglyceride loweringTriglyceride lowering - Glycemic control first priority

- Fibric acid derivative (gemfibrozil, fenofibrate)

- Statins are moderately effective at high dose in hypertriglyceridemic subjects who also have high LDL cholesterol

* Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data indicating safety as well as efficacy of the available agents.

Order of Priorities for Treatment of Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults*Diabetic Dyslipidemia in Adults*

Adapted from American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.



Update on the Metabolic SyndromeUpdate on the Metabolic Syndrome




Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Metabolic Syndrome Increases Risk for CHD Metabolic Syndrome Increases Risk for CHD and Type 2 Diabetesand Type 2 Diabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome



Atdischarge

3 molater

Atdischarge

High Risk of Impaired Glucose Tolerance and Type 2 High Risk of Impaired Glucose Tolerance and Type 2 Diabetes by OGTT in Post-MI Patients without Known Diabetes by OGTT in Post-MI Patients without Known DiabetesDiabetes

IGTIGT

% o

f Pat

ients

3 molater

New DMNew DM

35%35% 40%40%31%31% 25%25%

n = 181n = 181

Norhammar A et al. Lancet 2002;359:2140-2144.

0

20

40

60

80

100



Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kg/m2) 28.2 ± 1.1 27.2 ± 0.2 .472

Centrality* 1.38 ± 0.09 1.16 ± 0.2 .472

TG (mmol) 1.83 ± 0.12 1.26 ± 0.10 .006

HDL-C (mmol) 1.14 ± 0.07 1.28 ± 0.02 .045

SBP (mm Hg) 116.8 ± 3.0 108.8 ± 0.8 .004

Fasting glucose (mmol) 5.28 ± 0.1 5.00 ± 0.02 .032

Fasting insulin (pmol) 157 ± 27 81 ± 5 .006

Increased Metabolic Syndrome in Prediabetic Subjects: Baseline Increased Metabolic Syndrome in Prediabetic Subjects: Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status at Baseline according to Conversion Status at 8-Year Follow-up:8-Year Follow-up: San Antonio Heart Study San Antonio Heart Study

Haffner SM et al. JAMA 1990;263:2893-2898.

* Ratio of subscapular to triceps skinfolds



Nondiabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Diagnosis of Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes: Type 2 Diabetes: Nurses’ Health StudyNurses’ Health Study

Copyright © 2002 American Diabetes AssociationFrom Diabetes Care, Vol. 25, 2002; 1129-1134Reprinted with permission from The American Diabetes Association.

Rel

ative

Ris

k

11

2.822.82

3.713.71

5.025.02

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6



Risk of Major CHD Event Associated with Insulin Risk of Major CHD Event Associated with Insulin Quintiles in Nondiabetic Subjects: Quintiles in Nondiabetic Subjects: Helsinki Helsinki Policemen StudyPolicemen Study

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Years5 10 200 15 25

Pyörälä M et al. Circulation 1998;98:398-404.

Log rank:Overall P = .001Q5 vs. Q1 P < .001

Q1

Q2

Q3Q4Q5Pr

oport

ion w

ithout

Maj

or

CH

D E

vent

0



HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mg/dl) 51.7 49.3 47.8 45.0 41.2

LDL-C (mg/dl) 115.7 119.3 125.0 128.1 124.8

Cholesterol (mg/dl) 188.0 191.6 197.9 200.8 199.0

Triglyceride (mg/dl) 105.7 116.6 129.7 145.4 187.2

Systolic BP (mm Hg) 114.9 116.5 118.3 119.3 123.0

Diastolic BP (mm Hg) 69.0 70.4 71.9 73.1 75.4

CVD Risk Factors across HOMA-IR Quintiles: CVD Risk Factors across HOMA-IR Quintiles: San Antonio Heart Study (Phase II)San Antonio Heart Study (Phase II)

All p(trend) < 0.0001; quintile cutpoints: 1.0, 1.6, 2.5, 4.8

Adjusted for age, sex, ethnicity

Copyright © 2002 American Diabetes AssociationFrom Diabetes Care, Vol. 25, 2002; 1177-1184Reprinted with permission from The American Diabetes Association.



Definitions of the Metabolic SyndromeDefinitions of the Metabolic Syndrome

According to clinical outcomes

According to underlying causes

According to metabolic components

According to clinical criteria



Definition of Metabolic Syndrome:Definition of Metabolic Syndrome:According to Underlying CausesAccording to Underlying Causes

Insulin resistance (1999 WHO)

Insulin resistance syndrome

Lifestyle: especially obesity (NCEP ATP III)

Metabolic syndrome

Subclinical inflammation

WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. | Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.



Therapeutic Implications: Therapeutic Implications: According to According to Underlying CausesUnderlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle: especially obesity

Prevent and treat obesity

Subclinical inflammation

Treat obesity

Statins, TZDs, etc.



Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

TG ≥150 mg/dl

HDL-C

MenWomen

<40 mg/dl<50 mg/dl

Blood pressure ≥130/≥85 mm Hg

Fasting glucose ≥110 mg/dl

ATP III: The Metabolic SyndromeATP III: The Metabolic SyndromeDiagnosis is established when Diagnosis is established when ≥≥3 of these risk factors are 3 of these risk factors are presentpresent

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.



40–49

Prevalence of the NCEP Metabolic Syndrome: Prevalence of the NCEP Metabolic Syndrome: NNHANES III by AgeHANES III by Age

Ford ES et al. JAMA 2002;287:356-359.

Prev

alen

ce,

%

2020–70+70+Age, years

20–29 3030–3939 50–59 6060–6969 ≥70

Men

Women

24%24%23%23%

8%8%6%6%

44%44%44%44%

0%

10%

20%

30%

40%

50%



0%

10%

20%

30%

40%

Prevalence of the NCEP Metabolic Syndrome: Prevalence of the NCEP Metabolic Syndrome: NHANES III by Sex and Race/EthnicityNHANES III by Sex and Race/Ethnicity

Prev

alen

ce,

%

MenFord ES et al. JAMA 2002;287:356-359.

Women

WhiteAfrican AmericanMexican AmericanOther

25%25%

16%16%

28%28%

21%21%23%23%

26%26%

36%36%

20%20%



Prevalence of CHD by the Metabolic Syndrome and Prevalence of CHD by the Metabolic Syndrome and Diabetes in the NHANES Population Age 50+Diabetes in the NHANES Population Age 50+

CH

D P

reva

lence

% of Population =

No MS/No DMNo MS/No DM54.2%54.2%

MS/No DMMS/No DM28.7%28.7%

DM/No MSDM/No MS2.3%2.3%

DM/MSDM/MS14.8%14.8%

8.7%

13.9%

7.5%

19.2%

0%

5%

10%

15%

20%

25%

Alexander CM et al. Diabetes 2003;52:1210-1214..



ATP III Metabolic Syndrome:ATP III Metabolic Syndrome:Therapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore, prevent development of obesity in the general population

Also, treat obesity in the clinical setting (NHLBI/NIDDK Obesity Education Initiative)



VariableOddsRatio

Lower 95%Limit

Upper 95%Limit

Waist circumference 1.13 0.85 1.51

Triglycerides 1.12 0.71 1.77

HDL cholesterol* 1.74 1.18 2.58

Blood pressure* 1.87 1.37 2.56

Impaired fasting glucose 0.96 0.60 1.54

Diabetes* 1.55 1.07 2.25

Metabolic syndrome 0.94 0.54 1.68

Different Components of the NCEP Metabolic Different Components of the NCEP Metabolic Syndrome Predict CHD: Syndrome Predict CHD: NHANESNHANES

*Significant predictors of prevalent CHD*Significant predictors of prevalent CHD

Prediction of CHD Prevalence using Multivariate Logistic Prediction of CHD Prevalence using Multivariate Logistic RegressionRegression

Copyright © 2003 American Diabetes AssociationFrom Diabetes, Vol. 52, 2003; 1210-1214Reprinted with permission from The American Diabetes Association.



0% 2% 4% 6% 8% 10%

BMI per kg/m2

HDL-C per mg/dl decrease

SBP per mm Hg

FPG per mg/dl

Different Components of the NCEP Metabolic Different Components of the NCEP Metabolic Syndrome Predict Diabetes: Syndrome Predict Diabetes: San Antonio Heart StudySan Antonio Heart Study

Stern MP et al. Ann Intern Med 2002;136:575-581.

Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsRisk of Type 2 Diabetes per Unit Change in Risk Trait Levels

8%8%

2%2%

4%4%

7%7%



WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999.

WHO Metabolic Syndrome Definition 1999: WHO Metabolic Syndrome Definition 1999: Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes, IFG, IGT)*

Plus any 2 of the following:

Elevated BP (≥140/90 or drug Rx)

Plasma TG ≥150 mg/dl

HDL <35 mg/dl (men); <40 mg/dl (women)

BMI >30 and/or W/H >0.9 (men), >0.85 (women)

Urinary albumin >20 mg/min; Alb/Cr >30 mg/g

* Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR.



Must Insulin Resistance be Present for a Patient Must Insulin Resistance be Present for a Patient to Have the Metabolic Syndrome?to Have the Metabolic Syndrome?

WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No, but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome without

insulin resistance

WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. | Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.



WHO Metabolic Syndrome Definition 1999: WHO Metabolic Syndrome Definition 1999: Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome



Therapeutic Implications of Definition of Therapeutic Implications of Definition of Metabolic SyndromeMetabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors



Criteria for Comparing Different Definitions of Criteria for Comparing Different Definitions of Metabolic SyndromeMetabolic Syndrome

Risk of:

CHD

DM

Relation to:

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition?



Intensity of Therapy Should be Proportionate Intensity of Therapy Should be Proportionate to Level of Riskto Level of Risk

What is the impact of the metabolic syndrome on health outcomes?

Cardiovascular disease

Type 2 diabetes



Cardiovascular Disease Mortality Increased in the Cardiovascular Disease Mortality Increased in the Metabolic Syndrome: Metabolic Syndrome: Kuopio Ischaemic Heart Kuopio Ischaemic Heart Disease Risk Factor StudyDisease Risk Factor Study

Lakka HM et al. JAMA 2002;288:2709-2716.

Cum

ula

tive

Haz

ard,

%

0 2 6 8 12Follow-up, y

YESYES

Metabolic Syndrome:

NONO

Cardiovascular Disease Mortality

RR (95% CI), 3.55 (1.98–6.43)

4 100

5

10

15



NCEP MetS WHO MetS

Total Population

All Cause 1.43 (1.10–1.87) 1.25 (0.96–1.63)

CVD 2.55 (1.75–3.72) 1.64 (1.13–2.37)

Disease Free*

All Cause 1.11 (0.74–1.67) 0.87 (0.57–1.33)

CVD 2.04 (1.14–3.63) 0.77 (0.38–1.55)

Cox Proportional Hazard Ratios (and 95% Confidence Cox Proportional Hazard Ratios (and 95% Confidence Intervals) Predicting All-Cause and Cardiovascular Intervals) Predicting All-Cause and Cardiovascular Mortality: Mortality: San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-upup

Hunt KJ et al. Diabetes 2003;52:A221-A222.

* Those without diabetes, cardiovascular disease, or cancer.

Adjusted for age, gender, and ethnic group.



Comparison of NCEP and 1999 WHO Metabolic Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Resistant Subjects: Syndrome to Identify Insulin-Resistant Subjects: IRASIRAS

% in L

ow

est

Quar

tile

of S

i

Hanley AJ et al. Diabetes 2003;52:2740-2747.

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090



Relative R

iskCRP Adds Prognostic Information at All Levels of Risk as CRP Adds Prognostic Information at All Levels of Risk as Defined by the Framingham Risk ScoreDefined by the Framingham Risk Score

<1.0 hs-CRP(mg/L)

Framingham 10-Year Risk (%)

1.0–3.0

>3.0

Ridker PM et al. N Engl J Med 2002;347:1557-1565.

10+ 5–9 2–4 0–10

5

10

15

20

25

Copyright © 2002 Massachusetts Medical Society. All rights reserved. Adapted with permission.



Partial Spearman Correlation Analysis of Inflammation Markers Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Adjusted for Age, Sex, Clinic, Ethnicity, and with Variables of IRS Adjusted for Age, Sex, Clinic, Ethnicity, and Smoking Status: Smoking Status: IRASIRAS

CRP WBC Fibrinogen

BMI 0.40‡ 0.17‡ 0.22‡

Waist 0.43‡ 0.18‡ 0.27‡

Systolic BP 0.20‡ 0.08* 0.11†

Fasting glucose 0.18‡ 0.13‡ 0.07*

Fasting insulin 0.33‡ 0.24‡ 0.18‡

Si –0.37‡ –0.24‡ –0.18‡

Festa A et al. Circulation 2000;102:42–47.

*P<0.05, †P<0.005, ‡P<0.0001

CRP=C-reactive protein; IRS=insulin-resistance syndrome; WBC=white blood cell count.



0

Mea

n V

alu

e of Lo

g C

RP

Mean Values of CRP by Number of Metabolic Disorders Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia, Upper Body Adiposity, Insulin Resistance, (Dyslipidemia, Upper Body Adiposity, Insulin Resistance, Hypertension): Hypertension): IRASIRAS

Festa A et al. Circulation 2000;102:42–47.

Number of Metabolic Disorders

1 2 3 40.00.20.40.60.81.01.21.41.6



Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Stratified Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Proteins: by Quartiles of Inflammatory Proteins: IRASIRAS

Inci

den

ce,

%

1st

Festa A et al. Diabetes 2002;51:1131-1137.

2nd 3rd 4thQuartiles:

P=0.06P=0.06 P=0.001P=0.001 P=0.001P=0.001

0

5

10

15

20

25



The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al. Circulation 2002;106:679-684.

Rosiglitazone8 mg/d8 mg/d


Chan

ge

from

Bas

elin

e to

W

eek

26,

%

Difference = –26.8 Difference = –26.8 (95% CI: –39.7, –21.8)(95% CI: –39.7, –21.8)

Placebo

Difference = –21.8 (95% CI: –34.7, –5.6)Difference = –21.8 (95% CI: –34.7, –5.6)

-50

-40

-30

-20

-10

0n=95 n=124 n=134



The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al. Circulation 2002;106:679-684.



Difference = –1.9 Difference = –1.9 (95% CI: –11.3, 9.3)(95% CI: –11.3, 9.3)

Placebo

Difference = 0.0 (95% CI: –9.0, 10.0)Difference = 0.0 (95% CI: –9.0, 10.0)

Chan

ge

from

Bas

elin

e to

W

eek

26,

%

-50

-40

-30

-20

-10

0 n=91 n=120 n=132



0

1

2

3

4

5

6

hs-C

RP

(mg

/L)ReductionReduction of CRP Levels with Statin of CRP Levels with Statin Therapy (n=22)Therapy (n=22)

Jialal I et al. Circulation 2001;103:1933-1935.

** ** **

AtorvastatinAtorvastatin(10 mg/d)(10 mg/d)

SimvastatinSimvastatin(20 mg/d)(20 mg/d)

PravastatinPravastatin(40 mg/d)(40 mg/d)

BaselineBaseline

* * p<0.025 vs. Baselinep<0.025 vs. Baseline* * p<0.025 vs. Baselinep<0.025 vs. Baseline



Insulin resistance is related to increased PAI-1, fibrinogen, and CRP levels cross-sectionally

Increased levels of PAI-1, CRP, and fibrinogen (weak) predict the development of type 2 diabetes. In some analyses, these associations are independent of obesity and insulin resistance

Rosiglitazone, a TZD, decreases levels of PAI-1, CRP, and MMP-9

SummarySummary



Does Lipid and Blood Pressure Therapy Work Does Lipid and Blood Pressure Therapy Work in Subjects with the Metabolic Syndrome?in Subjects with the Metabolic Syndrome? Diabetic subjects

Blood pressure: YES

Statin therapy: YES

Nondiabetic subjects

Little data available



StudyStudy DrugDrug No.No.

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPS/TexCAPS Lovastatin 155 37% 43% (NS)

HPS Simvastatin 2912 24% 33% (p=.0003)

Secondary PreventionSecondary Prevention

CARE Pravastatin 586 23% 25% (p=.05)

4S Simvastatin 202 32% 55% (p=.002)

LIPID Pravastatin 782 25% 19%

4S Reanalysis Simvastatin 483 32% 42% (p=.001)

HPS Simvastatin 1981 24% 15%

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects: Diabetic Subjects: Subgroup AnalysesSubgroup Analyses

Downs JR et al. JAMA 1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Goldberg RB et al. Circulation 1998;98:2513-2519. | Pyörälä K et al. Diabetes Care 1997;20:614-620. | LIPID Study Group. N Engl J Med 1998;339:1349-1357. | Haffner SM et al. Arch Intern Med 1999;159:2661-2667.



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

Trial Diabetic/Total Results

SHEP 583/4736 Beneficial

GISSI-3 2790/18,131 Beneficial

Syst-Eur 492/4695 Beneficial

HOT 1501/18,790 Beneficial

UKPDS 1148 Beneficial

CAPPP 572/10,985 Beneficial

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. | UKPDS Group. BMJ 1998;317:703-713. | Hansson L et al. Lancet 1999;353:611-616.



Isolated Isolated ↑↑ LDL-C LDL-CRR=0.86 (0.59–1.26)RR=0.86 (0.59–1.26)

0

10

20

30

40

221

““Metabolic Syndrome” in 4SMetabolic Syndrome” in 4SEve

nt

Rat

e, %

Ballantyne CM et al. Circulation 2001;104:3046-3051.

Simvastatin

Placebo

237 261 284

18.020.319.0

36.9

Lipid TriadLipid TriadRR=0.48 (0.33–0.69)RR=0.48 (0.33–0.69)



0

10

20

30

40

50

60

70

80

Glycosylatedhemoglobin

<6.5%

Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with Microalbuminuria): (Type 2 Diabetes with Microalbuminuria): Steno-2Steno-2

Patien

ts R

each

ing I

nte

nsi

ve-

Tre

atm

ent

Goal

s at

Mea

n 7

.8 y

, (%

)

Gæde P et al. N Engl J Med 2003;348:383-393.

Intensive Therapy

Cholesterol<175 mg/dl

Triglycerides<150 mg/dl

Systolic BP<130 mm Hg

Diastolic BP<80 mm Hg

Conventional Therapy

P=0.06

P<0.001P=0.19

P=0.001

P=0.21

Copyright © 2003 Massachusetts Medical Society. All rights reserved.



0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes, Nonfatal MI, Composite Endpoint of Death from CV Causes, Nonfatal MI, CABG, PCI, Nonfatal Stroke, Amputation, or Surgery for PAD: CABG, PCI, Nonfatal Stroke, Amputation, or Surgery for PAD: STENO-2STENO-2

Prim

ary

Com

posi

te

Endpoin

t (%

)

Months of Follow-upGæde P et al. N Engl J Med 2003;348:383-393.

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0.007P=0.007

Hazard ratio = 0.47 Hazard ratio = 0.47 (95% CI, 0.24–0.73; (95% CI, 0.24–0.73; P=0.008)P=0.008)

Copyright © 2003 Massachusetts Medical Society. All rights reserved.



Summary: Metabolic SyndromeSummary: Metabolic Syndrome

The metabolic syndrome predicts the development of both diabetes and CHD

Insulin resistance and obesity characterize most individuals subjects with the metabolic syndrome, although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome, although no recommendations have so far suggested intensification of risk factor management

No consensus exists on whether insulin sensitizers should be used in nondiabetic individuals with the metabolic syndrome

epidemiología de la resistencia a la insulina, diabetes mellitus y enfermedad coronaria

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