Ralph A. DeFronzo, M.D. Professor of Medicine Division of ... · RELATION BETWEEN BODY MASS INDEX...

Type 2 Diabetes, Insulin Resistance,

and ASCVD: Pathogenic Links and

Therapeutic Interventions

Ralph A. DeFronzo, M.D.Professor of MedicineDivision of DiabetesUTHSCSA

MICROVASCULAR DISEASEMICROVASCULAR DISEASERetinopathy Nephropathy

Neuropathy

MACROVASCULAR DISEASE

Heart attack

Stroke

PVD (Amputation)

Atherosclerosis in Diabetes● Accounts for ~ 80% of all mortality in

diabetic patients– 75% from coronary atherosclerosis– 25% from cerebrovascular or peripheral

vascular disease● > 50% of patients with newly

diagnosed type 2 diabetes have CHD

National Diabetes Data Group. Diabetes in America, 2nd ed. NIH;1995.

100

75

50

25

0

Age 45-64

Years of Follow-up

% A

live

100

0

Age 65-74

0 105 150 105 15

Gu K, et al. Diabetes Care, 21:1138-1145, 1998

Natural History of Type 2 Diabetes: Natural History of Type 2 Diabetes: NHANES I (n=13,830)NHANES I (n=13,830)

Nondiabeticmen

Diabetic men

Diabetic women

Nondiabetic women

Diabetic women

Diabetic men

20 20

75

50

25

Heart diseases were involved in the majority of deaths (69.5%).Diabetes infrequently was listed as cause of death: 7.7% of males; 13.4% of females.

Type 2 Diabetes and Coronary Heart Disease Seven-Year Incidence of Fatal/Nonfatal MI

20.2%18.8%

3.5%

45.0%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0%

45.0%

50.0%

n = 1,304 n = 69 n = 890 n = 169Non-Diabetic Diabetic

No Myocardial InfarctionMyocardial Infarction

7-Ye

ar In

cide

nce

Rat

e of

Myo

card

ial I

nfar

ctio

n (M

I)

Haffner S, et al. N Engl J Med. 1998;339:229.

WHAT ROLE DOES HYPERGLYCEMIA PLAY IN THE

PATHOGENESIS OF ATHEROSCLEROSIS IN T2DM?

DOES GLYCEMIC CONTROL ALONE IMPROVE

CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES?

UKPDS: RISK REDUCTION IN DIABETES-RELATED COMPLICATIONS

FOR 1% DECLINE IN HbA1C

Stratten, BMJ 321:405, 2000

Micro-vascular

MI Stroke CHF-37%**

-14%* -12%*-16%*

-40

-30

-20

-10

0

Ris

k R

educ

tion

(%)

UKPDS: EPIDEMIOLOGY ANALYSIS

FATAL AND NON-FATALMYOCARDIAL INFARCTION

FATAL AND NON-FATALSTROKE

HbA1C (%)

Haz

ard

Rat

io

0.5

1

10

0.5

1

1012% decrease per 1% reduction in HbA1C

14% decrease per 1% reduction in HbA1C

P<0.0001 P<0.035

MICROVASCULAREND POINTS

0.5

1

1037% decrease per 1% reduction in HbA1C

P<0.0001

5 6 7 8 9 10 5 6 7 8 9 10

Stratton et al, BMJ 321:405-412, 2000

5 6 7 8 9 10

SYNDROME OF INSULIN RESISTANCE

ObesityDiabetes

HypertensionDyslipidemia

Hypercoagulability (PAI-1, platelets)Endothelial Dysfunction

ASCVDHyperinsulinemiaInsulin Resistance

TYPE 2 DIABETES IS 2 DISEASES

• MICROVASCULAR• MACROVASCULAR

WITH 2 DISTINCT PATHOGENIC SEQUENCES

LEADING TO 2 DISTINCT CLINICAL PRESENTATIONS

Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

ComponentsNCEP ATP III

≥3IDF

Waist + ≥2AHA-NHLBI

≥3

Waist (cm) >102 (m) >88 (f)

≥94 (m) ≥80 (f)

>102 (m) >88 (f)

TG (mg/dL) ≥150 ≥150* ≥150*HDL-C (mg/dL) <40 (m)<50 (f) <40 - 50 (m/f)* <40 - 50(m/f)*

BP (mm Hg) ≥130/85 ≥130 or ≥85* ≥130 or ≥85*FPG (mg/dL) ≥110 ≥100* ≥100*

Or on drug treatment* ICD-9-CM Code = 277.7

Definitions of Metabolic Syndrome

Waist Circumference

IDF: Europoid ≥94 (m) ≥ 80 (f)S. Asia ≥90 (m) ≥80 (f)Japanese ≥85 (m) ≥90 (f)

AHA-NHLBI: Asian Americans≥90 (m) ≥80 (f)

PREVALENCEAND CLINICAL

IMPORTANCE OFTHE METABOLIC

(INSULIN RESISTANCE)SYNDROME

AGEAGE--SPECIFIC PREVALENCE OF THE METABOLIC SPECIFIC PREVALENCE OF THE METABOLIC SYNDROME AMONG 8814 US ADULTS (NHANES III)SYNDROME AMONG 8814 US ADULTS (NHANES III)

~47 million (23.7%) US residents have the metabolic syndrome

20-29 30-39 40-49 50-59 60-69 ≥70

Prev

alen

ce (%

) MenWomen

50

40

30

20

10

0

Ford ES et al, JAMA 287:356-359, 2002

Age (years)

PROCAM (PROCAM (ProProspective spective CCoronary oronary AArtery rtery MMunster)unster)Study: Incidence of Myocardial InfarctionStudy: Incidence of Myocardial Infarction

2,754 Men, Age 40-65, 4 Year Duration

0

20

40

60

80

100

120 114

Inci

denc

e (p

er 1

,000

)

None HypertensionOnly

DiabetesOnly

Hypertension+ Diabetes

Hyper-lipidemia

Only

614 15

48

96Assmann G et al.Am Heart J 116:1713-24, 1988

Hyper-lipidemia +

Hypertensionand/or Diabetes

RAD 6 19 06

INSULIN RESISTANCE

IS THE UNIFYINGPATHOGENIC DISTURBANCE

THAT LINKS ALLCOMPONENTS OF THE

METABOLIC SYNDROME

“INSULIN CLAMP” FOREVALUATION OF INSULIN SENSITIVITY

“M”

PlasmaGlucose

Plasma Insulin

0

120

100

80

60

40

20

8

6

4

2

0-60 -40 -20 0 20 40 60 12010080

TIME (minutes)

GLU

CO

SE IN

FUSI

ON

“M”

(mg/

kg m

in)

PLA

SMA

GLU

CO

SE (m

g/dl

)PL

ASM

A IN

SULI

N (µ

U/m

l)

“M”= Glucose infusion Rate = Glucose Metabolized127401-4/04

SR121262-3/03

GLUCOSEUPTAKE

(mg/m2 min)

GlucoseStorage

GlucoseOxidation

* p<0.001 vs Control

CONTROL NORMALWEIGHT

DIABETIC

OBESENON-

DIABETIC

**

**

300

250

200

150

100

50

0

INSULIN RESISTANT STATES ASSOCIATED WITH ACCELERATED

ATHEROSCLEROSIS

RELATIVE RISKObesity 2-3XIGT 2-2.5X

T2DM 3X

0

5

10

15

EFFECT OF DIABETESON ENDOTHELIAL FUNCTION

Johnstone, Circ 88:2510, 1993

Methacholine (mg/min)

∆ F

orea

rm B

lood

Flo

w(m

l/min

per

100

ml)

Non-diabetic(n=16)

Diabetic(n=15)

0 0.3 1 3 10

SR121262-3/03

EXCESSIVECALORICINTAKE

INHERITEDGENETICDEFECT

INSULINRESISTANCE

HYPERINSULINEMIA

HYPERTENSION ATHEROSCLEROSIS

OBESITY DIABETES (T2DM)

HYPERTRIGLYCERIDEMIAABNORMAL LDL CHOL PARTICLE

DECREASED HDL CHOL

What does hypertension have in common with type 2 diabetes mellitus and

obesity?

SR121262-3/03

*

MECHANISM OF INSULIN RESISTANCE IN MECHANISM OF INSULIN RESISTANCE IN ESSENTIAL HYPERTENSION, T2DM, AND OBESITYESSENTIAL HYPERTENSION, T2DM, AND OBESITY

LeanControl(n=109)

Glu

cose

Upt

ake

mg/

m2 -

min

* p<0.001 vs Con

HTN(n=22)

ObeseNon-

Diabetic(n=42)

LeanT2DM(n=57)

0

300

200

100GlucoseStorage

GlucoseOxidation

**

0

5

10

15

20

EFFECT OF HYPERTENSION ON ENDOTHELIAL FUNCTION IN NON-DIABETIC INDIVIDUALS

Baseline 7.5 15 30

Panza, J Amer Coll Cardiol 21:1145, 1993

Acetylcholine (mg/min)

Fore

arm

Blo

od F

low

(ml/m

in p

er 1

00m

l)

Normotensive

Hypertensive

108182

124165-8/03

RELATIONSHIP BETWEEN QUARTILE OF RELATIONSHIP BETWEEN QUARTILE OF INSULIN SENSITIVITY (SINSULIN SENSITIVITY (SII) AND INCIDENCE ) AND INCIDENCE

OF HYPERTENSION OVER 5 YEARS (n=840)OF HYPERTENSION OVER 5 YEARS (n=840)

0

1

2

3

4

5

OD

DS

RA

TIO

Q1 Q2 Q4Q3

Goff, Diabetes Care 26:805, 2003

WHAT DOES DYSLIPIDEMIA HAVE

IN COMMON WITH T2DM, OBESITY, AND

HYPERTENSION?

SR121262-3/03

CONTROLS HYPERCHOLES-TEROLEMIA

HYPERTRI-GLYCERIDEMIA

*Non-oxidat iveGlucoseDisposal

GlucoseOxidat ion

0

6

4

2

P<0.01

(mg/

kg•m

in)

INSULININSULIN--MEDIATED GLUCOSE DISPOSALMEDIATED GLUCOSE DISPOSAL

24.9 nm

25.4 nm

26.2 nm

25.4 nm

SSPG(mmol/l)

OGTT - IRI(pmol/l•h)

LDL SUBCLASSPATTERN A

LDL SUBCLASSPATTERN B

*6.0 ± 0.4 10.4 ± 1.0

856 ± 60 **1,743 ± 293*p<0.002**p<0.001

SR121262-3/03

+

+

–

FFAGlucose

Insulin

LDLIDL

VLDL

HDL

Tissues

LipoproteinLipase

Insulin

113177

WHAT DOESCORONARY ARTERY

DISEASE HAVE IN COMMON WITH T2DM,

OBESITY, DYSLIPIDEMIA, AND HYPERTERTENSION

SR121262-3/03

CORONARY ARTERY DISEASE AND CORONARY ARTERY DISEASE AND INSULIN RESISTANCEINSULIN RESISTANCE

Controls

Glu

cose

Upt

ake

mg/

m2 -

min ?

EssentialHyper-tension

ObeseNon-

Diabetic

NormalWeightT2DM

0

300

200

100

CAD

SR121262-3/03

INSULIN SENSITIVITY IN THE IRSINSULIN SENSITIVITY IN THE IRS

CON

Glu

cose

Upt

ake

mg/

m2 -

min

Hyper-tension

ObeseLeanT2DM

0

300

200

100

CADHyper-Trigly

DOES THE PRESENCE OF INSULIN

RESISTANCE PREDICT THE DEVELOPMENT

OF ASCVD?

SR121262-3/03

0.7

0.75

0.8

0.85

RELATIONSHIP BETWEEN CAROTIDRELATIONSHIP BETWEEN CAROTIDIMT AND IRIMT AND IR* * IN 4816 NONIN 4816 NON--DIABETICSDIABETICS

IN MALMO, SWEDENIN MALMO, SWEDENHedbladHedblad, , DiabDiab Med Med 17:299, 200017:299, 2000

Car

otid

IMT

(mm

) * > 75th%,based on HOMA-IR

CON IRS

P<0.001

112849

MULTIPLE PROSPECTIVE EPIDEMIOLOGIC STUDIES

HAVE DEMONSTRATED THAT IRS PREDICTS FUTURE CAD (Botnia, Framingham, SAHS,

Bruneck)

Studies Demonstrating Increased Cardiovascular Risk Studies Demonstrating Increased Cardiovascular Risk Associated With the Metabolic SyndromeAssociated With the Metabolic Syndrome

2004 CV mortality (2.8- to 4.7-fold)

2005 Coronary events (38%)

2001 CHD and Stroke (3-fold)2002 CHD (70%)2003 CHD (37%)2004 CVD mortality (89%)

Cardiovascular RiskYearStudy Group

Isomaa B, et al.Onat A, et al.Alexander CM, et al.

Ford ES, et al.

Katzmarzyk PT, et al.

CVD mortality (37%) Stroke mortality (60%)

2004

Girman CJ, et al.

2004 CHD mortality (2-fold)

2004 Major coronary events (40-50%)

Malik S, et al.

Hunt KJ, et al.

Scuteri A, et al.

SR121262-3/03

ASSOCIATION BETWEEN HOMAASSOCIATION BETWEEN HOMA--IRIRAND 8AND 8--YEAR INCIDENCE OF CVDYEAR INCIDENCE OF CVD

IN NONIN NON--DIABETIC SUBJECTS IN SAHS:DIABETIC SUBJECTS IN SAHS:187 events in 2,569 subjects187 events in 2,569 subjects

OD

DS

RA

TIO

Q5

Hanly, Diabetes Care 25:1177, 2002

1.0

1.5

2.0

2.5

Q4 Q3 Q2 Q5 Q4 Q3 Q2

adjusted for age, sex, BP, LDL, HDL,TG, smoking, exercise, waist circum.

SR121262-3/03

CARDIOVASCULAR MORBIDITY AND MORTALITY CARDIOVASCULAR MORBIDITY AND MORTALITY ASSOCIATED WITH THE METABOLIC SYNDROMEASSOCIATED WITH THE METABOLIC SYNDROME

IN BOTNIA STUDY: 3,606 SUBJECTSIN BOTNIA STUDY: 3,606 SUBJECTSFOLLOWED FOR 6.9 YEARS FOLLOWED FOR 6.9 YEARS

0

1

2

3

Rel

ativ

e R

isk

CV Morbidity CV Mortality

Isomaa, Diabetes Care 24:683, 2001

2.96

1.81

SR121262-3/03

RISK OF CARDIOVASCULAR DISEASE IN RISK OF CARDIOVASCULAR DISEASE IN INDIVIDUALS WITH THE METABOLIC SYNDROME INDIVIDUALS WITH THE METABOLIC SYNDROME

(MS) IN BOTNIA STUDY: 3,606 SUBJECTS (MS) IN BOTNIA STUDY: 3,606 SUBJECTS FOLLOWED FOR 6.9 YEARSFOLLOWED FOR 6.9 YEARS

Isomaa, Diabetes Care 24:683, 2001

0

1

2

3

Rel

ativ

e R

isk

MS OBIR*Dyslipid-emia

HTN

* highest HOMA quartile

SR121262-3/03

INSULIN RESISTANCE

HYPERINSULINEMIA

ATHEROSCLEROSIS

DYSLIPIDEMIA HYPERTENSION OBESITY T2DM

129928-11/04

Syndrome of Insulin ResistanceSyndrome of Insulin ResistanceObesityDiabetes

HypertensionAging

DyslipidemiaIncreased PAI-1

Platelet DysfunctionEndothelial Dysfunction

ASCVDHyperinsulinemiaInsulin Resistance

0

25

50

75

100

EXCESS CAROTID IMT IN RELATIONEXCESS CAROTID IMT IN RELATIONTO IRS COMPONENTS: ARIC STUDYTO IRS COMPONENTS: ARIC STUDY

EXC

ESS

CA

RO

TID

IMT

(µm

)

Golden, Diabetes 51: 3069, 2002HTN/TG/INS

+HDL/GLU

+OBESITY

HTN+TG

HTN/TG

+ INS

HTN/TG/INS

+ HDL

HTN/TG+

INS/HDL

+ GLU

121290

MOLECULAR ETIOLOGY

OF THEINSULIN

RESISTANCE SYNDROME

IS THERE A BASIC UNDERLYING BIOCHEMICAL/MOLECULAR

DISTURBANCE THAT ACCOUNTS FOR THE DIVERSE PHENOTYPE OF THE INSULIN RESISTANCE (METABOLIC)

SYNDROME?

InsulinReceptor

Plasma MembraneIRS-1

p85 p110

GLUT 4

IRS-1

PI-3K

ProteinSynthesis

LipidSynthesis

GlycogenSynthesis

106606

INSULIN SIGNAL TRANSDUCTION SYSTEM

InsulinReceptor

Shc

Mitogenesis/Atherosclerosis

MAP

kinase

Plasma Membrane

PI-3-KinaseIRS-2

IRS-1p85 p110

GLUT 4

IRS-1

131361-5/05

INSULIN SIGNAL TRANSDUCTION SYSTEM

InsulinReceptor

Shc

Mitogenesis/Atherosclerosis

MAP

kinase

Plasma Membrane

PI-3-KinaseIRS-2

IRS-1p85 p110

GLUT 4

+

–

TZD

SYN 4SYN 4

SNAP 23SNAP 23

131361-5/05

GLUT4

Insulin Receptor

ANGIOTENSIN 2ANGIOTENSIN 2

Mitogenesis

–

+

GlycogenSynthesis

r∂fr∂s ShcSOS

Grb2MEKK

IRS-1p85p85

p110p110

PI3K

NOS+

+

+

112849

127493-4/04

SerineKinases

PPase

FACoA

Ceramides

PKC

DAG

- - -

InsulinReceptor

Plasma MembraneGLUT 4

IRS-1p85 PI-3K

Insulin ResistanceHyperinsulinemiaInsulin ResistanceHyperinsulinemia

BPBP DIABDIAB HDLHDL TGTG ASCVDASCVD

TREAMENT OF THE IRSTREAMENT OF THE IRS

COMPREHENSIVE TREATMENT

OF TYPE 2 DIABETICPATIENTS REDUCESCARDIOVASCULAR

DISEASE

STENO 2: KAPLANSTENO 2: KAPLAN--MEIER CURVES FOR TIME TO FIRST EVENT MEIER CURVES FOR TIME TO FIRST EVENT FOR PRIMARY COMPOSITE ENDPOINTFOR PRIMARY COMPOSITE ENDPOINT

Gaede P et al, NEJM 348:383-393, 2003

50

30

00

10

20

40

60

24 48 72 96

Primary Endpoint:CV Death, MI, Stroke,

Revascularization,Amputation

Intervention:Diet, Exercise,

BP, Lipids,OHA, ASA

Conventionaltherapy

Intensivetherapy

Prim

ary

Com

posi

teEn

d Po

int (

%)

HR=0.47P=0.007

Months of Follow-up

INSULIN RESISTANCE SYNDROME

NO STUDIES HAVE EXAMINED WHETHER ANY TREATMENT PREVENTS CAD IN PATIENTS

WITH IRS

AT A MINIMUM, ONE MUST TREAT THE

INDIVIDUAL COMPONENTS

OF IRS

2626--Year Incidence of Cardiovascular Year Incidence of Cardiovascular Disease Based Upon IBW at Entry:Disease Based Upon IBW at Entry:

Framingham Study Framingham Study

Men Women

Inci

denc

e/1,

000

500

400

300

200

100

0<110 ≥110-129 130 <110 ≥110-129 130

Ideal Body Weight (%)

RELATION BETWEEN BODY MASS INDEX AND RISKOF DIABETES, HYPERTENSION, AND CAD

Nurses Health Survey & Health Prof Follow-up StudyWillata, NEJM 341:427, 1999

Rel

ativ

e R

isk

Body-Mass Index≤ 21 23 25 27 29

0

2

4

6 MEN

T2DMHTN

CAD

WOMEN

0

2

4

6T2DM HTN

CAD

≤ 21 23 25 27 29

Fat Topography In Type 2 Diabetic SubjectsDeFronzo RA JCEM 89:463-478, 2004

Hi TGHi FFA

IntramuscularFat

IntrahepaticFat

IntraabdominalFat

SubcutaneousFat

OVERFLOW HYPOTHESISAdipocytes represent a storage depot for energy (i.e., fat). When the capacity of adipocytes to store fat is exceed, there is an overflow of fat to:

Muscle insulin resistanceLiver HGP (GN)Pancreas insulin secretion Arteries atherosclerosis

NFκB

- Serine KinaseTNFαInflam CytokinesGrowth factorsiNOS

NFκB

IKBFACoAIKB

Phos

INFLAMMATION

ATHEROSCLEROSIS

CytosolNucleus

127493-4/04

InsulinReceptor

Plasma MembraneGLUT 4

IRS-1p85 PI-3K

Rad 10/29/02

MODEST WEIGHT LOSS (5%)

HAS A MAJOR BENEFICIAL EFFECT ON OBESITY-RELATED ILLNESSES

IMPROVES INSULIN SENSITIVITY AND GLYCEMIC CONTROL

Rad 10/29/02

0

100

200

300

400

EFFECT OF WEIGHT LOSS ON INSULIN-MEDIATED GLUCOSE DISPOSAL

IN OBESE T2DM PATIENTSHenry, Diabetes 35:990, 1986

Before After LeanControlsObese Diabetics

Glu

cose

Dis

posa

l(m

g/m

2• m

in) *

Rad 10/29/02

EFFECT OF WEIGHT LOSS ON FASTING PLASMA GLUCOSE

Days on Diet

FastingPlasmaGlucose (mg/dl)

CUMWeight

Loss (kg)

500400300200100

012

96

3

00 3 5 7 10 20 40

XENDOS:XENDOS:Effect of Orlistat on Body WeightEffect of Orlistat on Body Weight

p<0.001 vs placebo

-4.1 kg

-6.9 kg

0 52 104 156 208-12

-9

-6

-3

0

Placebo + lifestyle

Orlistat + lifestyle

Week

Cha

nge

in W

eigh

t (kg

)

Sjostrom et al. 9th ICO, Sao Paulo 2002. Poster Presentation

118963-11/02

XENDOS:XENDOS:Cumulative Incidence of Type 2 DiabetesCumulative Incidence of Type 2 Diabetes

Sjostrom et al. 9th ICO, Sao Paulo 2002. Poster Presentation

Inci

denc

e of

T2D

M (%

)

p=0.0032

0 26 52 78 104 130 156 182 2080

2

4

6

8

10

Week

9.0%

6.2%

Placebo + lifestyle

Orlistat + lifestyle

118963-11/02

RR37%

131348-5/05

EFFECT OF ORLISTAT PLUS DIET (WEIGHT EFFECT OF ORLISTAT PLUS DIET (WEIGHT LOSS) ON PREVALENCE OF THE METABOLIC LOSS) ON PREVALENCE OF THE METABOLIC

SYNDROME BY ATP III CRITERIASYNDROME BY ATP III CRITERIAData on file, Hoffman-La Roche, Nutley, NJ

33%

BASAL

Perc

ent

AFTERWEIGHT LOSS

0

10

20

30

40

23%

ATHEROGENIC DYSLIPIDEMIA IN PATIENTS WITH TYPE 2 DIABETES AND THE METABOLIC SYNDROME

Incidence of hypercholesterolemia in T2DM patients is similar to that in the general population. HOWEVER,

• The number of LDL particles is increased.• LDL particles are small and dense.• HDL cholesterol concentration is reduced.• Triglyceride level is increased.

This atherogenic lipid/lipoprotein profile contributes to a 2-4-fold excess risk of

CVD in patients with type 2 diabetesGarvey WT, et al. Diabetes. 52:453-462, 2003. Haffner SM. Diabetes Care. 26:S83-S86, 2003.

HDLHDL--C and Coronary Artery DiseaseC and Coronary Artery Disease(CAD) Risk : Framingham Heart Study (Men)(CAD) Risk : Framingham Heart Study (Men)

Kwiterovich, Am J Cardiol 1998: 82:130-210

3.0

2.0

1.0

0

LDL-C (mg/dL)100 160 220

2545

6585 HDL-C

(mg/dL)

Rel

ativ

e R

isk

Relationship Between Apo B, LDL Size, and Relationship Between Apo B, LDL Size, and CVD Risk: Quebec CV Study (N=2,057)CVD Risk: Quebec CV Study (N=2,057)

Lamarche B. et al. Can J Cardiol 2001: 17:859-865

Adjusted for DM, SBP, Meds

Large Small

4

2

0

5

3

1Lowest Tertile

Middle Tertile

Highest TertileApo B

Rel

ativ

e R

ate

for I

HD

1.0

1.3

2.6

4.0

3.4

1.6

LDL Peak Particle Diameter

TRIGLYCERIDES: INDEPENDENT PREDICTOR OF CHD & STROKETRIGLYCERIDES: INDEPENDENT PREDICTOR OF CHD & STROKEAsia Pacific Cohort Studies CollaborationAsia Pacific Cohort Studies Collaboration

Fatal CHDFatal CHD Fatal or NonFatal or Non--fatal Strokefatal Stroke

Triglycerides (178 mg/dl)

1.0 mmol/L 2.0Triglycerides (178 mg/dl)

1.0 mmol/L 2.0

Most patients withTG > 2.0 mM have small dense LDL (Grundy,2005)

• N=96,224• Meta-analysis of prospective

studies• Adjusted for CV risk factors

Lancet April 16, 2005;365:1415Lancet April 16, 2005;365:1415Circ. Oct 26, 2004;110:2678Circ. Oct 26, 2004;110:2678--26862686

OUTCOMES IN FIBRATE TRIALS:TOTAL STUDY POPULATION

Rel.N Control Drug RR P

HHS 4,081 41.4% 27.3% 34% <0.02

BIP 3,090 15.0% 13.6% 9.4% 0.26

VA-HIT 2,531 21.7% 17.3% 22% 0.006

Major CVDEvent Rate

Primary Prevention

Secondary Prevention

BEZOFIBRATE INFARCTION PREVENTION (BIP) STUDYRelationship Between Baseline Triglyceride Concentration and Response to BezafibrateTG <200 mg/dL TG ≥200 mg/dL

0CVD

Eve

nt R

ate

(%)

18

12

6

0 2 4 6

Placebo

Bezafibrate

P=0.86

0

18

12

6

0 2 4 6TIME (years)

P=0.02

Placebo

Bezafibrate

Baseline LDL-C = 148-149 mg/dLThe BIP Study Group. Circ 102:21-27, 2000

VAVA--HIT:CHANGE IN LIPIDS FROM BASELINE HIT:CHANGE IN LIPIDS FROM BASELINE

0.93.8

00.9

-28.6

6.3

-30

-20

-10

0

10

LDL-CHOL

TRIGLY-CERIDES

HDL-CHOL

Cha

nge

From

B

asel

ine

( %)

PlaceboGemfibrozil

2351 men with CHDHDL < 40mg%

LDL < 140 mg%TG < 300mg%

Primary Outcome =Nonfatal MI +

Cardiac Mortality

112 111 161 32 32160Baseline:(mg/dL)

Rubins HB, et al. N Engl J Med 341:410-418, 1999

VAVA--HIT: CVD Risk Reduction in Diabetic HIT: CVD Risk Reduction in Diabetic Versus Nondiabetic subjectsVersus Nondiabetic subjects

40

30

20

10

0Combined End Point

Nonfatal MI

CHD Death Stroke

No DM

P=NS

P=NS

P=0.09

P=0.07

P=0.17

P=0.004

P=0.046P=0.02P=0.26

DM

1821

10

3

22

32

4041

% C

hang

e In

Cum

ulat

ive

Even

t Rat

e

Rubins HB, et al. Arch Intern Med 162:2597-2604, 2002

VAVA--HIT: CVD RISKHIT: CVD RISKREDUCTION IN NONDIABETIC PATIENTS REDUCTION IN NONDIABETIC PATIENTS

-30

-20

-10

0

+10

Rubins HB, et al. Arch Intern Med 162:2591-2604, 2002

N=43430-38

N=426N=44224-29

<23>39

N=431

-40

Quartiles of FPI (µU/mL)R

isk

Red

uctio

nFa

vors

Gem

fibro

zil

Favo

rs P

lace

bo

ANTIHYPERTENSIVETRIALS IN

PATIENTS WITHTYPE 2 DIABETES

MELLITUSALLHAT, ASCOT, VALUE, HOPE, HOT, CONVINCE, LIFE, UKPDS, SHEP, Syst-Eur, ABCD, ANBP-2

Diabetics Benefit More From Blood Pressure ControlDiabetics Benefit More From Blood Pressure Control

-80

-60

-40

-20

0

SHEP Syst-Eur HOT HOPEdiuretic-based CCB-based CCB-based ACEI-based

DiabeticsNon-diabetics* **M

yoca

rdia

lIn

farc

tion

(% re

duct

ion)

-80

-60

-40

-20

0

CV

Mor

talit

y(%

redu

ctio

n)

NS

* *

*

Rad 10/29/02

INSULIN SENSITIZERS

● Metformin● Thiazolidinediones

RAD 10/20/03

0

15

30

45

UKPDS: EFFECT OF METFORMINUKPDS: EFFECT OF METFORMINON DIABETIC COMPLICATIONSON DIABETIC COMPLICATIONSR

ISK

RED

UC

TIO

N(%

)

Micro-vascular MI Stroke Death

29%39% 41% 42%

RAD 10/20/03

CARDIOVASCULAR RISK FACTORS

CVRF Metformin1. Hyperglycemia2. Hypertriglyceridemia3. Hypercholesterolemia4. Obesity5. Hyperinsulinemia6. Insulin Resistance7. PAI-18. Endothelial Dysfunction

Rad 10/29/02

INSULIN SENSITIZERS

● Metformin● Thiazolidinediones

RAD 10/20/03

THIAZOLIDINEDIONES ANDCARDIOVASCULAR RISK FACTORS

HyperglycemiaInsulin resistanceHyperinsulinemiaHypertriglyceridemiaSmall, dense LDL-cholDecreased HDL-cholesterolIncreased PAI-1Elevated inflammatory cytokinesHypertensionEndothelial dysfunctionObesity

RAD 10/20/03

EFFECT OF THIAZOLIDINEDIONES ON EFFECT OF THIAZOLIDINEDIONES ON INSULININSULIN--MEDIATED GLUCOSE DISPOSALMEDIATED GLUCOSE DISPOSALm

g/kg

FFM

•min

Before PIO ROSI0

4

6

8

10* *

Miyazaki, Diabetologia 44: 2210, 2001Diabetes Care 24: 710, 2001

NOGD

GOX

RAD 10/20/03

PPARγ LIGANDS

VSMCMONOCYTES/MACROPHAGES

ENDOTHELIALCELLS

ProliferationMigrationMMPAdhesion moleculesPAI-1

EC attachmentMigration (MCP-1)Inflammation(TNFα, IL-1, IL-6)Chemokines(IP 10, Mig, I-TAC)

GrowthMigrationAngiogenesisNitric OxideEndothelinPAI-1

ATHEROSCLEROSIS

Effect of Thiazolidinediones on Fat TopographyDeFronzo RA, JCEM 89:463-478, 2004

IntramuscularFat

IntrahepaticFat

SubcutaneousFat

Hi TGHi FFA

TGFFATZD

IntraabdominalFat

PROACTIVE

In high risk type 2 diabetics:

● To examine whether pioglitazonereduces total mortality and macrovascular morbidity

19 European Countries

5238 Type 2 Diabetics

PlcPIO

358301

14.4%12.3%

HR P valuePlc vsPIO 0.84 0.027

Placebo

Pioglitazone

PROACTIVE (n=5238)PROACTIVE (n=5238)TIME TO DEATH, MI OR STROKETIME TO DEATH, MI OR STROKE

LANCET 366:1279-89,2005

0.15

0.05

00 12 24 36

TIME (months)

# Events3 Year

Estimate

Kap

lan-

Mei

er E

vent

Rat

e

0.10

SUBGROUP ANALYSIS OF PATIENTS WITH PREVIOUS MI

● Of the total PROactive cohort, 2,445 patients (46.7%) had a previous MI ≥6 months prior to randomization:

n=1,230 in pioglitazone groupn=1,215 in placebo group

● Pre-specified analyses for MI subgroup:Time to fatal or non-fatal MITime to CV death or non-fatal MITime to CV death, non-fatal MI, or stroke

American Heart Association, 2005

Time to Fatal/Nonfatal MI (excluding silent MI)

Placebo

Pioglitazone0

0.02

0.04

0.08

0.10

0.06

0

Kap

lan-

Mei

er E

vent

Rat

e Events/Number 65/1,230 88/1,215

Months

RR=28% P=0.045

3612 24

American Heart Association; 2005

Placebo

Pioglitazone0.00

0.05

0.10

0.20

0.25

0.15

0 36

Kap

lan-

Mei

er E

vent

Rat

eTime to Composite Cardiac Endpoint (Cardiac

Death, Non-fatal MI, Coronary Revascularization or ACS) (n=2445)

Events/Number 180/1,230 217/1,215

RR=19% P=0.034

Months12 24

American Heart Association; 2005

CARE Subgroup: Major Coronary Events in CARE Subgroup: Major Coronary Events in PaientsPaients With Diabetes and GlucoseWith Diabetes and Glucose--Intolerant MIIntolerant MI

Placebo

0

10

30

40

Maj

or C

oron

ary

Even

ts (%

)

RR=25% P=0.05

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

0 61 5432

Pravastatin

RR=19%

Follow-up (years)

Placebo:PROactivePioglitazone:PROactive

20

HPS Subgroup: Major Vascular Events (Major Coronary Events, StrHPS Subgroup: Major Vascular Events (Major Coronary Events, Stroke, and oke, and Revascularization) in Patients With DiabetesRevascularization) in Patients With Diabetes

RR=22% P=0.0001

Placebo

0

10

20

30

Maj

or C

oron

ary

Even

ts (%

)

HPS Lancet. 2003;361:2005-2016

0 61 5432

SimvastatinRR=-17%

Follow-up (years)

RR=-19%Placebo:PROactivePioglitazone:PROactive

Therapy Effect of Therapy Effect of StatinStatin TherapyTherapy on Five Year Risk of Recurrent MI on Five Year Risk of Recurrent MI in Type 2 Diabetic Patientsin Type 2 Diabetic Patients

Lancet June 14, 2003;361:2005Lancet June 14, 2003;361:2005

Statin Therapy

BaselineRisk

37.837.833.4%33.4%

Time to Acute Coronary Syndrome

Placebo

Pioglitazone0.00

0.01

0.02

0.05

0.06

0.04

0 36

Kap

lan-

Mei

er E

vent

Rat

e

0.03

Events/Number 35/1,230 54/1,215 RR=37%

P=0.035

Months12 24

American Heart Association; 2005

DeFronzo 9-6

PROACTIVE:PROACTIVE:EFFECT OF PIOGLITAZONE ON PREVENTION OF RECURRENT EFFECT OF PIOGLITAZONE ON PREVENTION OF RECURRENT

STROKE IN 894 T2DM INDIVIDUALS WHO ALREADY STROKE IN 894 T2DM INDIVIDUALS WHO ALREADY EXPERIENCED A STROKEEXPERIENCED A STROKE

0

5

10

PIO

47%10.2%

5.6%P=0.008

Perc

ent %

Placebo

126895-2/04

DIABETES PREVENTION PROGRAM (n=3234)

Intensive Lifestyle Change*

Follow up= 3 years

Screening(age = 51y;

BMI = 34 kg/m2 )

Metformin, 850 mg bid#

Standard LifestyleChange#

*Reduce weight by 7%; low-fat diet; exercise for 150 min/wk#Received information on diet and exercise

126895-2/04

DIABETES PREVENTION PROGRAMDIABETES PREVENTION PROGRAM

58%

0

20

40

60

% D

ecre

ase

IGT

T2D

M

31%

DIET +EXERCISE

METFORMIN

126895-2/04

DIABETES PREVENTION PROGRAMDIABETES PREVENTION PROGRAM

58%

0

20

40

60

% D

ecre

ase

IGT

T2D

M

31%23%

DIET +EXERCISE

METFORMIN TROGLIT-AZONE

126895-2/04

TROGLITAZONE AND PREVENTION OF T2DM IN TROGLITAZONE AND PREVENTION OF T2DM IN INDIVIDUALS WITH IGT: 1.5 YEAR FOLLOWINDIVIDUALS WITH IGT: 1.5 YEAR FOLLOW--UPUP

Diabetes Prevention Program, ADA, 2003

0

5

10

15 *p<0.01 vs LS-Light**p<0.01 vs LS-Heavy

Cas

es P

er 1

00-P

atie

nt

Trea

tmen

t Yea

rs

***

**

LS-Light MET LS-Heavy TROG

126895-2/04

DPPTRIPOD/PIPOD

DREAM

ACT NOW

SR112849-102

TREATMENT OF CADTREATMENT OF CAD

Insulin ResistanceHyperinsulinemiaInsulin ResistanceHyperinsulinemia

Insulin ResistanceHyperinsulinemiaInsulin ResistanceHyperinsulinemia

DRUG ADRUG A DRUG BDRUG B

BPBP DIABDIAB

HDLHDL TGTG ASCVDASCVD

BPBP DIABDIAB HDLHDL TGTG ASCVDASCVD

Rad 10/29/02

IDENTIFICATION OF INSULIN IDENTIFICATION OF INSULIN RESISTANT INDIVIDUALS IN CLINICAL RESISTANT INDIVIDUALS IN CLINICAL

PRACTICEPRACTICE● 2321 INDIVIDUALS

– 2138 non-diabetic– 183 type 2 diabetics

● 17 European sites (EGIR),San Antonio (SAM), Pimas

● Euglycemic insulin clamp● Measures of obesity, FPG, FPI,

lipids, blood pressure, FHD

Rad 10/29/02

DISTRIBUTION OF INSULIN SENSITIVITY IN DISTRIBUTION OF INSULIN SENSITIVITY IN DIABETIC AND NONDIABETIC AND NON--DIABETIC SUBJECTSDIABETIC SUBJECTS

Rel

ativ

e Fr

eque

ncy

M (µmol/min•kg LBM)1200 40 80

Non-diabetics

Diabetics0.08

0.06

0.04

0.02

0

Normal MixtureDensity Estimate

28

Rad 10/29/02

INSULIN RESISTANCE INSULIN RESISTANCE M<28 M<28 umol/kg•minumol/kg•min

Fasting plasma insulin >21 Fasting plasma insulin >21 uUuU/ml/mland HOMAand HOMA--IR*>4.65 wereIR*>4.65 were

Equally predictiveEqually predictiveoror

BMI>28.9 kg/mBMI>28.9 kg/m22

*HOMA-IR=[(FPIXFPG)/135]

Rad 10/29/02

INSULIN RESISTANCE M < 28 umol/kg.min

Fasting plasma insulin≥ 16 uU/ml

and

BMI ≥ 27.5 kg/m2

*HOMA-IR=[FPIXFPG)/135]