Insulin Resistance and Cardiovascular Disease:

1
Insulin Resistance and Cardiovascular
Disease New Perspectives FromVascular Biology

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Contents
I. CV disease and insulin resistance
Challenges and opportunities II. New
perspectives in cardioprotection Focus on
PPAR? activation III. Insulin sensitizers
Surrogate and clinical outcomes
studies IV. Identifying and treating patients
with insulin resistance
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Cardiovascular Disease and Insulin
ResistanceChallenges and Opportunities
4
The majority of Americans do not follow a
healthy lifestyle
2000 Behavioral Risk Factor Surveillance System
N 153,805
100
77.8
76.7
80
59.9
60
Respondents
40
24
20
0
Smokers
BMI 25 kg/m2
Consumes fruits/vegetables lt5x/day
Infrequentexercise(lt5x/week)
Reeves MJ, Rafferty AP. Arch Intern Med.
2005165854-7.
5
Numbers of persons with diabetes will more than
double by 2030
40
118 increase
30.3
30
US population with diabetes(millions)
20
13.9
10
0
2002
2030
Year
AHA. Heart Disease and Stroke Statistics2005
Update.Wild S et al. Diabetes Care.
2004271047-53.
6
Increasing problem of obesity and diabetes among
US adults
Obesity (BMI 30 kg/m2)
Diabetes
36 increase
30
8
7.2
31 increase
USadults()
25.4
5.3
19.4
15
4
0
0
1997
2005
1997
2005
JanSep
CDC. 2005 NHIS. www.cdc.gov/nchs/nhis/released2006
03.htm. Accessed April 2006.
7
Cumulative lifetime risk for diagnosis of
diabetes
55
Hispanic females
50
NonHispanic black females
Hispanic males
45
NonHispanic black males
40
Risk ofdiagnosisof diabetes ()
35
NonHispanic white females
30
NonHispanic white males
25
20
15
10
5
0
0
10
20
30
40
50
60
70
80
90
100
Age (years)
Adapted from Narayan et al. JAMA.
20032901884-90.
8
Over half of patients referred to cardiologists
have insulin resistance syndrome
Cardiac rehabilitation
Acute MI
59
58
60
50
Patients withinsulin resistance syndrome ()
40
20
0
N 1912Savage, 2005
N 235 Milani, 2003
N 85 Curran, 2004
Savage PD et al. Am Heart J. 2005149627-31. Mila
ni RV, Lavie CJ. Am J Cardiol. 20039250-4. Curra
n PJ et al. J Am Coll Cardiol. 200443(suppl
A)249A.
9
Almost 70 of patients with first MI have IGT or
undiagnosed diabetes
N 181 consecutive patients admitted to CCU
66
70
Undiagnosed diabetes
31
50
Patients ()
30
Impaired glucose tolerance (IGT)
35
10
0
Glucose tolerance test results
Norhammar A et al. Lancet. 20023592140-4.
10
Role of obesity in insulin resistance
? Caloric intake Sedentarylifestyle Genetic
factors
? Free fatty acids ? Glucose ? Lipids
Oxidativestress Inflammation
VisceralObesity
Insulinresistance
Adapted from Wellen KE, Hotamisligil GS. J Clin
Invest. 20051151111-9.
11
Elevated glucose increases risk in elderly
patients with acute MI
Cooperative Cardiovascular Project 19941996 N
141,680
100
80
Mortalityrate ()
60
40
20
0

110
gt110140
gt140170
gt170240
gt240
Glucose groups (mg/dL)
Without diabetes
With diabetes
Kosiborod M et al. Circulation. 20051113078-86.
12
Insulin resistance associated with coronary
vasomotor abnormalities
Myocardial blood flow (MBF) response to cold
pressor test
75
P 0.003
50
? MBF ()
25
0
Insulin sensitive
Insulin resistant
Quiñones MJ et al. Ann Intern Med. 2004140700-8.
vs baseline
13
Insulin resistance to diabetes Coronary
vasomotor abnormalities progressively worsen
40
Cold pressor test
44
30
? MBF ()

20
14


10
10
7
Diabetes Hypertension
0
Insulinsensitive
Insulinresistant
IGT
Diabetes
2

10

• vs baseline
• P lt 0.05 vs insulin sensitive

Prior JO et al. Circulation. 20051112291-8.
14
Insulin resistance increases risk of target
organ damage in hypertension
N 354 with untreated hypertension
P 0.003
59
60
45
40
Patients ()
P 0.04
30
19
15
10
0
Microalbuminuria
LV hypertrophy
With insulin resistance syndrome
Leoncini G et al. J Intern Med. 2005257454-60.
Modified ATP III definition
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Clinical manifestations of insulin resistance

• Type 2 diabetes and glycemic disorders
• Dyslipidemia
• Low HDL
• Small, dense LDL
• Hypertriglyceridemia
• Hypertension
• Endothelial dysfunction/inflammation (hsCRP)
• Impaired thrombolysis
• ? PAI-1

Insulin resistance Glucotoxicity Lipotoxicity ?
Adiponectin
VisceralObesity
Atherosclerosis
Courtesy of Selwyn AP, Weissman PN.