ralph a. defronzo, m.d. professor of medicine division of ... · relation between body mass index...
TRANSCRIPT
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]