1. Epidemiology of Insulin Resistance,
Diabetes Mellitus, and Coronary
Heart Disease
Steven Haffner, MD
Slide Source
LipidsOnline
www.lipidsonline.org

2. Criteria for the Diagnosis of Diabetes
Mellitus and Hyperglycemia
Plasma Glucose Concentration
Fasting
Glucose
Diabetes Mellitus
2-Hour Post
Glucose Load
>7.0 (>126)
>11.1 (>200)
Impaired Glucose
Tolerance
Impaired Fasting
Glucose
>7.8 (>140) to
<11.1 (<200)
>6.1 (>110) to
<7.0 (<126)
Values are mmol/L (mg/dl)
Adapted from World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus
Slide Source
and its Complications. Geneva: World Health Organization:1999:52.
LipidsOnline
www.lipidsonline.org

3. Percent
Prevalence of Diabetes in Adult Population
(Aged >20 years) by Year and Region
9
8
7
6
5
4
3
2
1
0
1995
Developed
Developing
King H et al. Diabetes Care 1998;21:1414-1431.
2000
2025
World
Slide Source
LipidsOnline
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4. Hospitalization Costs for Chronic
Complications of Diabetes in the US
Ophthalmic
disease
Renal
disease
Others
Neurologic
disease
Peripheral
vascular
disease
 Total costs 12
billion US $
 CVD accounts
for 64% of
total costs
Cardiovascular
disease
American Diabetes Association. Economic Consequences of Diabetes Mellitus
in the US in 1997. Alexandria, VA: American Diabetes Association, 1998:1-14.
Slide Source
LipidsOnline
www.lipidsonline.org

5. Framingham Study: DM and CHD Mortality
20-Year Follow-up
Annual CHD Deaths per
1000 Persons
18
16
14
17
17
DM
Non-DM
12
10
8
8
6
4
4
2
0
Men
Kannel WB, McGee DL. JAMA 1979;241:2035-2038.
Women
Slide Source
LipidsOnline
www.lipidsonline.org

6. Mortality in People with Diabetes
Causes of Death
50
% of Deaths
40
30
20
10
0
Ischemic Other Diabetes Cancer
heart
heart
disease disease
Geiss LS et al. In: Diabetes in America. 2
nd
Stroke Infection Other
ed. 1995; chap 11.
Slide Source
LipidsOnline
www.lipidsonline.org

7. Mortality Due to Heart Disease in Men and
Women with or without Diabetes (US)
Mortality per 1000
person-years*
35
30
29.9
Diabetes
19.2
20
15
10
11.5
11.0
7.1
6.3
3.6
5
0
No Diabetes
23.0
25
Men
Women
All heart disease
Men
Women
Ischemic heart disease
*Age-adjusted
Adapted from Gu K et al. Diabetes Care 1998;21:1138-1145.
Slide Source
LipidsOnline
www.lipidsonline.org

8. Rate per 1000 person-years
Trends in Mortality Rates for Ischemic Heart
Disease in NHANES Subjects with and without
Diabetes*
20
15
Diabetes
Nondiabetes
17.0
Men, cohort 1*
Men, cohort 2**
Women, cohort 1*
Women, cohort 2**
14.2
10
6.8 7.6
7.4
4.2
5
2.4 1.9
0
-16.6%
(P=0.46)
+10.7%
(P=0.76)
-43.8%
(P<0.001)
*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.
-20.4%
(P=0.12)
Slide Source
LipidsOnline
www.lipidsonline.org

9. Survival Post-MI in Diabetic and Nondiabetic
Men and Women: Minnesota Heart Survey
100
MEN
WOMEN
100
80
60
n=1628
Diabetes
n=228
40
0
0
20
40
60
80
Months Post-MI
No diabetes
Survival (%)
Survival (%)
No diabetes
80
n=568
60
Diabetes
40
0
0
n=156
20
40
60
80
Months Post-MI
Adapted from Sprafka JM et al. Diabetes Care 1991;14:537-543.
Slide Source
LipidsOnline
www.lipidsonline.org

10. % of Deaths (Crude Rate)
Cardiovascular Mortality in People
with Diabetes
MEN
60
50
40
WOMEN
28 d – 1 y
Hospitalization
– 28 d
9.1
15.4
30
4.2
9.6
20
10
0
28.6
Diabetes
22.1
No Diabetes
11.1
22.7
Out of Hospital
2.8
9.0
10.9
11.9
Diabetes
No Diabetes
Adapted from Miettinen H et al. Diabetes Care. 1998;21:69-75.
Slide Source
LipidsOnline
www.lipidsonline.org

11. Age-adjusted CVD death rate
per 10,000 person-years
Influence of Multiple Risk Factors* on CVD
Death Rates in Diabetic and Nondiabetic Men:
MRFIT Screenees
140
120
No diabetes
Diabetes
100
80
60
40
20
0
None
One only
Two only
*Serum cholesterol >200 mg/dl, smoking, SBP >120 mmHg
Stamler J et al. Diabetes Care 1993;16:434-444
All three
Slide Source
LipidsOnline
www.lipidsonline.org

12. Putative Mechanism for Increased
Atherosclerosis in Type 2 Diabetes
BLACK BOX
 Dyslipidemia
 Hypertension
 Hyperinsulinemia/insulin resistance
 Hemostatic abnormalities
 Hyperglycemia
 AGE proteins
 Oxidative stress
AGE = advanced glycation end products
Adapted from Bierman EL. Arterioscler Thromb 1992;12:647-656.
Slide Source
LipidsOnline
www.lipidsonline.org

13. Prevalence of Cardiovascular Risk Factors in
Diabetic Subjects Relative to Nondiabetics
Risk Factor
Dyslipidemia
Hypertriglyceridemia
Low HDL
Small, dense LDL
Increased apo B
Hypertension
Hyperinsulinemia/insulin resistance
Central obesity
Family history of atherosclerosis
Cigarette smoking
Type 1
Type 2
+
–
–
–
+
–
–
–
–
++
++
++
++
++
++
++
+
–
+ = moderately increased compared with nondiabetic population
++ = markedly increased compared with nondiabetic population
– = not different compared with nondiabetic population
Adapted from Chait A, Bierman EL. In: Joslin’s Diabetes Mellitus. Philadelphia: Lea & Febiger,
Slide Source
LipidsOnline
1994:648-664.
www.lipidsonline.org

14. Differences in HDL Cholesterol and LDL Size
by Diabetic Status in Women and Men
Differences between participants
with and without diabetes
HDL Cholesterol
mg/dL
0
LDL Size
Å
0
-2
-2
-4
-4
-6
Women
-6
Men
-8
Women
Men
-8
Howard BV et al. Diabetes Care 1998; 21:1258-1265.
Slide Source
LipidsOnline
www.lipidsonline.org

15. Strategies for Reduction of Diabetic
Complications
 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
Slide Source
LipidsOnline
www.lipidsonline.org

16. 50
40
Years (%)
Incidence per 1000 Person
Incidence Rates of MI and Microvascular
Endpoints by Mean Systolic Blood Pressure:
UKPDS
Myocardial Infarction
30
20
10
0
110
Microvascular Endpoints
120
130
140
150
160
170
Updated Mean Systolic Blood Pressure (mmHg)
Adjusted for age, sex, and ethnic group
Adler AI et al. BMJ 2000;321:412-419.
Slide Source
LipidsOnline
www.lipidsonline.org

17. Incidence per 1000 Person
Years (%)
Incidence Rates of MI and Microvascular
Endpoints by Mean Hemoglobin A1c: UKPDS
80
60
Myocardial Infarction
40
20
Microvascular Endpoints
0
5
6
7
8
9
10
11
Updated Mean Hemoglobin A1c Concentration (%)
Adjusted for age, sex, and ethnic group
Stratton IM et al. BMJ 2000;321:405-412.
Slide Source
LipidsOnline
www.lipidsonline.org

18. Plasma Insulin and Triglycerides Predict
Ischemic Heart Disease: Quebec
Cardiovascular Study
6.7
Odds Ratio
8.0
5.4
6.0
P=0.002
p=0.005
4.0
1.5
2.0
0.0
4.6
P<0.001
p=0.001
5.3
1.0
<12
Triglycerides
>150 mg/dl
<150 mg/dl
12-15
F-Insulin (µU/ml)
Despres JP et al. N Engl J Med 1996;334:952-957.
>15
Slide Source
LipidsOnline
www.lipidsonline.org

19. Plasma Insulin and Apolipoprotein B
Predict Ischemic Heart Disease: Quebec
Cardiovascular Study
12.0
9.7
p<0.001
10.0
Odds Ratio
11.0
P<0.001
8.0
6.0
Apolipoprotein B
4.0
2.0
0.0
1.5
1.0
<12
3.0
3.2
p=0.04
p=0.04
12-15
>15
F-Insulin (µU/ml)
Despres JP et al. N Engl J Med 1996;334:952-957.
>119 mg/dl
<119 mg/dl
Slide Source
LipidsOnline
www.lipidsonline.org

20. LDL Particle Size and Apolipoprotein B Predict
Ischemic Heart Disease: Quebec Cardiovascular
Study
6
6.2
5
(p<0.001)
4
3
2.0
2
1
0
1.0
Apo B
1.0
>120 mg/dl
<120 mg/dl
>25.64
<25.64
LDL Peak Particle Diameter (nm)
Lamarche B et al. Circulation 1997;95:69-75.
Slide Source
LipidsOnline
www.lipidsonline.org

21. Baseline Anthropometric Variables and Cardiovascular Risk
Factors in Subjects with Normal Glucose Tolerance at
Baseline According to Conversion Status at 8-Year Followup: San Antonio Heart Study
Conversion Status at Follow-up
Diabetes (n=18)
Normal (n=490)
P
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
HDLC (mmol)
1.14 + 0.07
1.28 + 0.02
.045
SBP (mmHg)
116.8 + 3.0
108.8 + 0.8
.004
5.28 + 0.1
5.00 + 0.02
.032
157 + 27
81 + 5
.006
BMI (kg/m2)
Fasting glucose (mmol)
Fasting insulin (pmol)
* Ratio of subscapular to triceps skinfolds
Haffner SM et al. JAMA 1990;263:2893-2898.
Slide Source
LipidsOnline
www.lipidsonline.org

22. “Ticking Clock” Hypothesis
For
The “clock starts ticking”
Microvascular
complications
At onset of hyperglycemia
Macrovascular
complications
Before the diagnosis of
hyperglycemia
WHO. Diabetologia 1985;28:615-640; Haffner SM et al. JAMA 1990;263:2893-2898.
Slide Source
LipidsOnline
www.lipidsonline.org

23. The 7-Year Age-Adjusted Incidence of CHD
Mortality and All CHD Events: East-West Study
30
CHD Mortality
All CHD Events
20
10
0
40
% Incidence
% Incidence
40
Fasting Glucose
<9.6
9.6-13.4 >13.4
P-glucose (mmol/L)
Lehto S et al. Diabetes 1997;46:1354-1359.
30
Hemoglobin A1
CHD Mortality
All CHD Events
20
10
0
<8.9
8.9-10.7 >10.7
HbA1 (%) Source
Slide
LipidsOnline
www.lipidsonline.org

24. Stepwise Selection of Risk Factors* in 2693 White
Patients with Type 2 Diabetes with Dependent
Variable as Time to First Event: UKPDS
Coronary Artery Disease (n=280)
Position in Model
Variable
P Value
First
Low-Density Lipoprotein Cholesterol
<0.0001
Second
High-Density Lipoprotein Cholesterol
0.0001
Third
Hemoglobin A1c
0.0022
Fourth
Fifth
Systolic Blood Pressure
Smoking
*Adjusted for age and sex.
Turner RC et al. BMJ 1998;316:823-828.
0.0065
0.056
Slide Source
LipidsOnline
www.lipidsonline.org

25. Criteria for Accepting Cardiovascular Risk
Factor Management as Similar in Diabetic
and 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
Slide Source
LipidsOnline
www.lipidsonline.org

26. Incidence of Fatal or Nonfatal MI During a 7-Year
Follow-up in Relation to History of MI in
Nondiabetic vs Diabetic Subjects: East-West Study
Incidence During
Follow-up (%)
50
40
30
20
Nondiabetics with prior MI
Nondiabetics with no prior MI
p<0.001
Diabetics with prior MI
Diabetics with no prior MI
20.2
18.8
10
0
45.0
(n=69)
Events per
100 person-yr: 3.0
P<0.001
3.5
(n=1304)
0.5
Haffner SM et al. N Engl J Med 1998;339:229-234.
(n=169)
7.8
(n=890)
3.2
Slide Source
LipidsOnline
www.lipidsonline.org

27. Incidence of Fatal or Nonfatal Stroke During a
7-Year Follow-up in Relation to History of MI in
Nondiabetic vs Diabetic Subjects: East-West Study
Incidence During
Follow-up (%)
25
20
15
10
Nondiabetics with prior MI
Nondiabetics with no prior MI
p<0.001
Diabetics with prior MI
Diabetics with no prior MI
10.3
7.2
5
0
19.5
(n=69)
Events per
100 person-yr: 1.2
P=0.01
1.9
(n=1304)
0.3
Haffner SM et al. N Engl J Med 1998;339:229-234.
(n=169)
3.4
(n=890)
1.6
Slide Source
LipidsOnline
www.lipidsonline.org

28. Conclusions
 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.
Slide Source
LipidsOnline
www.lipidsonline.org

29. Clinical Trials and Guidelines for
Lipid Management in the Diabetic
Patient
Steven Haffner, MD
Slide Source
LipidsOnline
www.lipidsonline.org

30. UKPDS Design
Aim
 To determine whether intensified blood glucose
control, with either sulphonylurea or insulin, reduces
the risk of macrovascular or microvascular
complications in type 2 diabetes
Patients
 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;
Slide Source
LipidsOnline
Turner R et al. Ann Intern Med 1996;124:136-145.
www.lipidsonline.org

31. UKPDS 10-Year Follow-up Results:
Glycemic Control, Weight, and Plasma Insulin
Conventional
9
8
Intensive
7
6
0
7.5
Weight
Intensive
5
2.5
0
-2.5
Conventional
Baseline = 75 kg
0
1 2
3 4
5 6
7
8 9 10 11 12
Years from Randomization
UKPDS Group. Lancet 1998;352:837-853.
Median (%)
10
9
Fasting plasma glucose
Median Change (pmol/L)
Mean Change (kg)
Median (mmol/L)
11
Hemoglobin A1c
8
Conventional
Intensive
7
6
0
40
30
Plasma insulin
20
Intensive
10
0
-10
-20
Baseline = 89 pmol/L
0
1 2
3 4
5 6
Conventional
7
8 9 10 11 12
Years from Randomization
Slide Source
LipidsOnline
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32. UKPDS: Proportion of Patients Taking Different
Therapies in the Conventional-Therapy Group
100
Additional
pharmacologic
therapy
% of patients
80
60
40
Diet alone
20
1
Courtesy of Dr. Amanda Adler
3
5
7
9
11
Years from randomization
Slide Source
LipidsOnline
www.lipidsonline.org

33. UKPDS: Causes of Death by Glucose
Treatment Group
Cause
MI
Stroke
Sudden death
PVD
Intensive
Rate/1000
patient-years
%
Conventional
Rate/1000
patient-years
%
7.6
1.6
0.9
0.1
43
9
5
1
8.0
1.3
1.6
0.3
43
7
8
2
10.2
58
11.2
60
Renal disease
0.3
2
0.2
1
Cancer
Other specified
Unknown
4.4
2.4
0.5
25
13
3
4.4
2.7
0.2
24
14
1
17.8
100
18.7
100
All macrovascular
Total
UKPDS Group. Lancet 1998;352:837-853.
Slide Source
LipidsOnline
www.lipidsonline.org

34. UKPDS: Endpoints by Glucose
Treatment Group
Intensive
Cause
Conventional
Rate/1000
Rate/1000
Patient-Years Patient-Years
P
% Risk
Reduction
Any diabetes-related*
40.9
46.0
0.029
12
MI
14.7
17.4
0.052
16
Stroke
5.6
5.0
0.52
–
PVD**
1.1
1.6
0.15
–
Microvascular
8.6
11.4
0.0099
25
*Combined microvascular and macrovascular events
**Amputation or death from PVD
UKPDS Group. Lancet 1998;352:837-853.
Slide Source
LipidsOnline
www.lipidsonline.org

35. UKPDS: Impact of Glucose-Lowering
Agents 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;
Slide Source
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-865.
LipidsOnline
www.lipidsonline.org

36. UKPDS Results: Intensive Blood Pressure
Control
Intensive Blood
Pressure Control
Reduction
(%)
P Value
Any diabetes-related endpoint
24
0.0046
Deaths related to diabetes
32
0.019
Myocardial infarction
21
NS
Stroke
44
0.013
Microvascular disease
37
0.092
Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:703-713. Slide Source
LipidsOnline
www.lipidsonline.org

37. Comparison of Captopril vs. Atenolol
in UKPDS
RR for
Captopril
P Value
Any diabetes-related endpoint
1.10 (0.86–1.41)
0.43
Death related to diabetes
1.27 (0.82–1.97)
0.28
All-cause mortality
1.14 (0.81–1.61)
0.44
Myocardial infarction
1.20 (0.82–1.76)
0.35
Stroke
1.12 (0.59–2.12)
0.74
Peripheral vascular disease
1.48 (0.35–6.19)
0.59
Microvascular disease
1.29 (0.80–2.10)
0.30
Clinical Endpoint
 Primary
 Secondary
Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:713-720. Slide Source
LipidsOnline
www.lipidsonline.org

38. Comparison of Glucose Lowering and
Blood Pressure Lowering in UKPDS
Intensive Blood
Intensive Blood
Glucose Control (n=2729) Pressure Control (n=758)
Reduction
%
P
Value
Reduction
%
P
Value
Any diabetes-related
endpoint
12
0.029
24
0.0046
Myocardial infarction
16
0.052
21
NS
11↑
NS
44
0.013
25
0.0099
37
0.092
Stroke
Microvascular disease
↑ = Increase in risk
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853;
Slide Source
UK Prospective Diabetes Study Group. BMJ 1998;317:703-713.
LipidsOnline
www.lipidsonline.org

39. Treatment Strategies for Diabetic
Dyslipidemia
 Primary Strategy
- Lower LDL cholesterol
 Secondary Strategy
- Raise HDL cholesterol
- Lower triglycerides
 Other Approaches
- Non-HDL cholesterol
- ApoB
- Remnants
Adapted 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; Source
Slide
LipidsOnline
European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730.
www.lipidsonline.org

40. CHD Prevention Trials with Statins in
Diabetic Subjects: Subgroup Analyses
Study
Drug
No.
Baseline
LDL-C,
mg/dl
(mmol/L)
LDL-C
Lowering
Primary Prevention
AFCAPS/TexCAPS
Lovastatin
239
150 (3.9)
25%
CARE
Pravastatin
586
136 (3.6)
28%
4S
Simvastatin
202
186 (4.8)
36%
LIPID
Pravastatin
782
150* (3.9)
25%*
Secondary Prevention
*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
Slide
Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357. Source
LipidsOnline
www.lipidsonline.org

41. CHD Prevention Trials with Statins in
Diabetic Subjects: Subgroup Analyses (cont’d)
Study
Drug
CHD Risk
Reduction
No. (overall)
CHD Risk
Reduction
(diabetes)
Primary Prevention
AFCAPS/TexCAPS
Lovastatin
239
37%
43%
CARE
Pravastatin
586
23%
25% (p=0.05)
4S
Simvastatin 202
32%
55% (p=0.002)
LIPID
Pravastatin
782
25%
19%
4S-Extended
Simvastatin 483
32%
42% (p=0.001)
Secondary Prevention
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.
Slide Source
LipidsOnline
www.lipidsonline.org

42. Diabetic vs. Nondiabetic Patients in 4S
Placebo
Better
Simvastatin Better
P=0.001
P=0.087
Total mortality
CHD mortality
P<0.0001
P=0.242
Major CHD event
P<0.0001
P=0.002
Cerebrovascular
event
P=0.097
P=0.071
Any atherosclerotic
event
P<0.0001
P=0.018
0
No diabetes
Diabetes
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Relative Risk with 95% Confidence Intervals
Reduced
Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620.
Increased
Slide Source
LipidsOnline
www.lipidsonline.org

43. Major Coronary Events in 4S Patients with
or without Diabetes by History (n=202)
Proportion without Major
CHD Event
1.0
0.9
0.8
0.7
0.6
Diabetes by Hx, simvastatin
Diabetes by Hx, placebo
0.5
No diabetes by Hx, simvastatin
No diabetes by Hx, placebo
0
0
1
P=0.002
P=0.0001
2
3
4
5
Years Since Randomization
Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620.
6
Slide Source
LipidsOnline
www.lipidsonline.org

44. 4S: Extended Diabetic Subgroup Analysis:
Diabetes (n=483; 251 on Simvastatin) — Fasting
Glucose >7 mmol/L (126 mg/dl)
0.72
CHD mortality
(P=0.26)
0.79
Total mortality
(P=0.34)
0.52
Revascularizations
(P=0.005)
0.58
Major coronary events
(P=0.001)
0.0
0.2
0.4
0.6 0.8 1.0
Relative Risk
Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667
1.2
1.4
Slide Source
LipidsOnline
www.lipidsonline.org

45. 4S: Extended Diabetic Subgroup Analysis:
Impaired Fasting Glucose (n=678; 343 on Simvastatin) —
Fasting Glucose 6.0-6.9 mmol/L (110-125 mg/dl)
0.45
CHD mortality
(P=0.007)
0.57
Total mortality
(P=0.02)
0.57
Revascularizations
(P=0.01)
0.62
Major coronary events
(P=0.003)
0.0
0.2
0.4
0.6 0.8 1.0
Relative Risk
Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667
1.2
1.4
Slide Source
LipidsOnline
www.lipidsonline.org

46. 4S: Effect of Statin Therapy on Hospital Stay
Bed Days (per 100 Pts)
1200
↓ 55%
1000
800
600
(p<0.001)
↓ 28%
(p<0.001)
↓ 38%
(p=0.005)
400
200
0
Simvastatin
Placebo
Normal fasting
glucose
Simvastatin
Placebo
Simvastatin
Impaired fasting
glucose
Adapted from Herman WH et al. Diabetes Care 1999;22:1771-1778.
Placebo
Diabetes
mellitus
Slide Source
LipidsOnline
www.lipidsonline.org

47. CARE: Major Coronary Events in
Diabetic Subgroups
Relative risk = 0.77
P<0.001
35
30
25
Placebo
20
15
10
Pravastatin
5
0
0
1 2 3 4 5 6
Follow-up Time (years)
45
Percent with Event
Percent with Event
45
No Diabetes by History
35
30
25
Diabetes by History
Relative risk = 0.75
P=0.05
Placebo
20
Pravastatin
15
10
5
0
0
1 2 3 4 5 6
Follow-up Time (years)
Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519.
Slide Source
LipidsOnline
www.lipidsonline.org

48. AFCAPS/TexCAPS: Subgroup Analysis
0
Men
Women
Older
Smokers
HTN
Diabetes
% Risk Reduction
-10
-20
-30
-40
-50
-31
-37
-38
-46
-60
-70
-42
-58
Lovastatin Reduced the Risk of Acute MCE
Downs JR et al. JAMA 1998;279:1615-1622.
Slide Source
LipidsOnline
www.lipidsonline.org

49. 45
40
35
30
25
20
15
10
5
0
No Diabetes by History
Relative risk = 0.77
P<0.001
Placebo
Pravastatin
0
1 2 3 4 5 6
Follow-up Time (years)
Percent with Event
Percent with Event
CARE: Major Coronary Events in
Diabetic Subgroups
45
40
35
30
25
20
15
10
5
0
Diabetes by History
Relative risk = 0.75
P=0.05
Placebo
Pravastatin
0
1 2 3 4 5 6
Follow-up Time (years)
Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519.
Slide Source
LipidsOnline
www.lipidsonline.org

50. Per-Patient % of Grafts
POST-CABG: Effect of Aggressive Lipid
Lowering on Progression in a Diabetic
Subgroup
50
Diabetes (n=116)
No Diabetes (n=1235)
40
30
51% 
40% 
20
10
0
99% CI
(0.20-1.19)
Aggressive Moderate
Rx
Rx
Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294.
99% CI
(0.46-0.79)
Aggressive Moderate
Rx
Rx
Slide Source
LipidsOnline
www.lipidsonline.org

51. CHD Prevention Trials with Fibrates in
Diabetic Subjects: Subgroup Analyses
Drug
Dose
Study
Baseline
LDL-C,
mg/dl
No. (mmol/L)
LDL-C
CHD
Lowering Reduction
Primary Prevention
Helsinki
Heart Study
Gemfibrozil 135
(1200 mg/d)
203
(5.2)
6%
68%
NS
112
(2.9)
–
24%
p=0.05
Secondary Prevention
VA-HIT
Gemfibrozil 627
(1200 mg/d)
Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825;
Rubins HB et al. N Engl J Med 1999;341:410-418.
Slide Source
LipidsOnline
www.lipidsonline.org

52. 5-Year Incidence of CHD (%)
Primary CHD* Prevention in Type 2 Diabetic
Patients: The Helsinki Heart Study
15
P=0.19
10.5
P<0.02
10
7.4
5
0
3.4
3.3
Type 2
(n=135)
Others
(n=3946)
Type 2 on
Placebo
(n=76)
*Myocardial infarction or cardiac death
Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825.
Type 2 on
Gemfibrozil
(n=59)
Slide Source
LipidsOnline
www.lipidsonline.org

53. Cumulative Incidence (%)
VA-HIT: Incidence of Death from CHD
and Nonfatal MI
25
20
Placebo
15
Gemfibrozil
10
5
0
1
2
3
Year
4
Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418.
5
6
Slide Source
LipidsOnline
www.lipidsonline.org

54. VA-HIT: Death Due to CHD, Nonfatal MI,
and Confirmed Stroke in Diabetic Patients
Placebo*
88/309
24%
0.05
(28)
214/949
170/955
24%
0.009
(23)
No diabetes
116/318
(36)
Diabetes
Gemfibrozil*
Risk
Reduction
(18)
*Values are numbers with events/total numbers (%)
Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418.
P Value
Slide Source
LipidsOnline
www.lipidsonline.org

55. Future Directions
Ongoing Trials with
Lipid-Lowering Focus
Drug
HPS
Simvastatin
ASPEN
Atorvastatin
CARDS
Atorvastatin
LDS
Cerivastatin +
fenofibrate micronized
DAIS
Fenofibrate micronized
FIELD
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
Slide Source
and Event Lowering in Diabetes
LipidsOnline
www.lipidsonline.org

56. Heart 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
Slide Source
LipidsOnline
www.lipidsonline.org

57. Endpoint Studies: Treating to New Targets
(TNT): Study Design
Atorvastatin
80 mg
10,000 CAD Patients
LDL
75 mg/dL
5 Years
Atorvastatin
LDL
10 mg
100 mg/dL
Site Selection
November 1997
Investigator
Meeting
March 1998
Recruitment
Complete
June 1999
Study End
Dec 2004
Slide Source
LipidsOnline
www.lipidsonline.org

58. Study of the Effectiveness of Additional
Reductions in Cholesterol and Homocysteine
with Simvastatin and Folic Acid/Vitamin B12
(SEARCH): Study 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
Slide Source
LipidsOnline
www.lipidsonline.org

59. Lipids in Diabetes Study (LDS):
Two-by-Two Factorial Randomization
Fenofibrate Arm
Cerivastatin Arm
Cerivastatin
Fenofibrate
(n=1,250)
Placebo
Fenofibrate
(n=1,250)
2,500
active
fenofibrate
Cerivastatin
Placebo
(n=1,250)
Placebo
Placebo
(n=1,250)
2,500
placebo
fenofibrate
n=2,500 active
cerivastatin
n=2,500 placebo
cerivastatin
5,000 pts
in total
Slide Source
LipidsOnline
www.lipidsonline.org

60. Conclusions
 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
Slide Source
LipidsOnline
www.lipidsonline.org

61. Clinical Evaluation and Nonlipid
Treatment of Coronary Artery
Disease in the Diabetic Patient
Richard Nesto, MD
Slide Source
LipidsOnline
www.lipidsonline.org

62. Prevalence of Asymptomatic CAD in
Diabetes Mellitus
Positive
Positive
ETT
Koistinen MJ. BMJ 1990;301:92-95.
Type 2
Type 1
Controls
Angiography
n = 64
n = 72
n = 80
36%
24%
9%
9%
11%
9%
n = 142
n = 149
31%
30%
12.1%
5.3%
n = 925
12.1%
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
6.4% (thal201)
Rutter MK et al. Am J Cardiol 1999;83:27-31.
Type 2 w microalb
Type 2 w/o microalb
n = 43
n = 43
65%
40%
—
—
Le A et al. Am J Kidney Dis 1994;24:65-71.
Type 1 Renal Transplant
58%
35%
55%
43%
Holley JL et al. Am J Med 1991;90:563-570.
Type 1 & 2 Renal Transplant
Slide Source
LipidsOnline
www.lipidsonline.org

63. Indications for Cardiac Testing in
Diabetic 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
Slide Source
LipidsOnline
www.lipidsonline.org

64. Factors Limiting Accuracy of Noninvasive
"Stress" Tests for CAD
 Hypertensive Cardiomyopathy
 Diabetic Cardiomyopathy
 Autonomic Cardiomyopathy
 Renal Insufficiency
 Microvascular Dysfunction
Slide Source
LipidsOnline
www.lipidsonline.org

65. Benefits 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
Slide Source
LipidsOnline
www.lipidsonline.org

66. MEN
180
No Glucose
Intolerance
160
140
174
Glucose
Intolerance
120
119
100
90
80
77
60
40
20
0
59
50
38
24
105
135
165
Age-adjusted CV Event Rate/1,000
Age-adjusted CV Event Rate/1,000
Blood Pressure and CVD: Framingham Heart Study
WOMEN
180
No Glucose
Intolerance
160
140
Glucose
Intolerance
120
113
100
80
74
60
40
20
195
Systolic BP (mmHg)
Kannel WB et al. Am Heart J 1991;121:1268-1273.
0
56
48
31
15
105
36
23
135
165
195
Systolic BP (mmHg)
Slide Source
LipidsOnline
www.lipidsonline.org

67. Effect of Glycemic Control in the UK
Prospective Diabetes Study (UKPDS)
Endpoints
Intensive
(rate/1000
pt yrs)
Conventional
(rate/1000
pt yrs)
P
%
Decrease
Any diabetes related* 40.9
46
0.029
11
MI
17.4
0.052
16
14.7
Stroke
5.6
5
0.52
–
PVD
1.1
1.6
0.15
–
Microvascular
8.6
11.4
0.0099
25
* Combined microvascular and macrovascular events
UKPDS Group. Lancet 1998;352:837-853.
Slide Source
LipidsOnline
www.lipidsonline.org

68. Reasons for Death in UKPDS Intensive
Treatment Arm: 10-Year Follow-up
N=
2729
(%)
Fatal MI or SD
231
(8.4%)
Cancer
120
(4.4%)
Other
74
(2.9%)
Fatal Stroke
43
(1.6%)
Renal Disease
16
(0.6%)
Accidents
5
(0.2%)
PVD
2
(0.07%)
Hypo- or Hyperglycemia 1
(0.04%)
Accidents, PVD, Hypo& Hyperglycemia
Renal
3.3%
2.5%
15%
Other
24%
Cancer
47%
MI or SD
8.7%
Stroke
UKPDS Group. Lancet 1998;352:837-853.
Slide Source
LipidsOnline
www.lipidsonline.org

69. Effect of Blood Pressure Control in the UKPDS
Tight vs. Less Tight Control
 1,148 Type 2 patients
 Average BP lowered to 144/82 mmHg (controls: 154/87);
9-year follow-up
Tight Control
Risk Reduction (%)
P value
Any diabetes-related endpoint
24
0.0046
Diabetes-related deaths
32
0.019
Heart failure
56
0.0043
Stroke
44
0.013
Myocardial infarction
21
NS
Microvascular disease
37
0.0092
UKPDS Group. BMJ 1998;317:703-713.
Slide Source
LipidsOnline
www.lipidsonline.org

70. UKPDS: ACE Inhibitor vs. Beta-blocker for HTN
Aggregate Clinical Endpoints
Relative Risk & 95% CI
RR
p
Any diabetes-related endpoint 1.10
1.27
1.14
0.44
Myocardial infarction
1.20
0.35
Stroke
1.12
0.74
Microvascular
1.29
2
0.28
All-cause mortality
1
0.43
Diabetes-related deaths
0.5
0.30
Favors
ACE inhibitor
UKPDS Group. BMJ 1998;317:713-720.
Favors
Beta blocker
Slide Source
LipidsOnline
www.lipidsonline.org

71. Systolic Hypertension in Europe (Syst-Eur) Trial:
Events / 1000 Pt-Years
Effect of Systolic BP Control on All Cardiovascular Events
at 2 Years
70
60
50
40
30
20
10
0
57.6
25%
62%
Risk
Reduction
22.0
Placebo
Active Rx
Diabetic Patients
N=492; P=0.002
Tuomilehto J et al. NEJM 1999;340: 677-684.
31.4
Risk
Reduction
23.5
Placebo
Active Rx
Nondiabetic Patients
N=4,203; P=0.02
Slide Source
LipidsOnline
www.lipidsonline.org

72. Major Outcomes of the Hypertension Optimal
Treatment (HOT) Trial: Diabetes Subgroup
Events / 1000 Pt-Years
30
25
Diastolic Target
p<0.005
<90 mmHg (N=501)
<85 mmHg (N=501)
20
<80 mmHg (N=499)
15
p<0.045
10
p<0.016
5
0
Major CV Events
Hansson L et al. Lancet 1998;351: 1755-1762.
MI
CV Mortality
Slide Source
LipidsOnline
www.lipidsonline.org

73. Events / 1000 Pt-Years
HOT Trial:Cardiovascular Events in Diabetics and
Nondiabetics—Effect of Diastolic Target at 4 Years
30
25
20
15
10
24.4
48%
Risk
18.6 Reduction
11.9
5
0
<90
<85
<80
Diabetic Patients
n=1,501; p=0.016
Hansson L et al. Lancet 1998;351: 1755-1762.
9.9
10.0
9.3
<90
<85
<80
Nondiabetic Patients
n=18,790; p=NS
Slide Source
LipidsOnline
www.lipidsonline.org

74. Completed Clinical Trials with
Antihypertensive Agents in Diabetes
Trial
Diabetic/Total
SHEP
583/4736
Beneficial
GISSI-3
2790/18,131
Beneficial
Syst-Eur
492/4695
Beneficial
1501/18,790
Beneficial
UKPDS
1148
Beneficial
CAPPP
572/10,985
Beneficial
HOT
Results on CVD
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
Slide Source
Group. BMJ 1998;317:703-713; Hansson L et al. Lancet 1999;353:611-616.
LipidsOnline
www.lipidsonline.org

75. Heart Outcomes Prevention Evaluation (HOPE) Study
Effect of Ramipril on Cardiovascular Events (Myocardial
Infarction, Stroke, or CVD Death) ~ 4.5 Yrs
% of Patients
25
20
15
24%
19.8
Risk
Reduction
15.0
10
21%
16.4
Risk
Reduction
13.0
5
0
Placebo
Ramipril
Diabetic Patients
N=3,578, P=<0.001
Hope Study Investigators. NEJM 2000;342:145-153.
Placebo
Ramipril
Nondiabetic Patients
N=5,719, P=<0.001
Slide Source
LipidsOnline
www.lipidsonline.org

76. Diabetes Increases Risk of Coronary Plaque
Disruption and Thrombosis
Cause of Myocardial Infarction
Platelet Aggregation
F VII
Fibrinogen
F VIII
vWF
Coronary Artery
Thrombus
Plaque
Formation
Plaque
Disruption
Sympathetic Tone
PAI-1
TPA
PGI2
Slide Source
LipidsOnline
www.lipidsonline.org

77. Impact of Serum Fibrinogen and Total Cholesterol Levels
on Risk of Coronary Events in ECAT
21/305
16/304
7
6
Risk of
Coronary
Events
(%)
3/247
5
4
3
2
5/311
10/281
9/261
4/306
11/266
10/282
1
Total
Cholesterol
Higher
Middle
0
Lower
Middle
Fibrinogen
Thompson SG. N Engl J Med 1995;332:635-641.
Lower
Higher
Slide Source
LipidsOnline
www.lipidsonline.org

78. Effect of Aspirin on Mortality in Type 2 Patients with
CHD: Bezafibrate Infarction Prevention Study
100
Survival (%)
OR=0.7 (0.6-0.8)
No
diabetes
90
OR=0.8 (0.7-0.9)
80
Type 2
diabetes
No aspirin
Aspirin
70
0
1
2
3
4
Time (Years)
Harpaz D et al. Am J Med 1998;105:494-499.
5
6
Slide Source
LipidsOnline
www.lipidsonline.org

79. Antiplatelet Agents Reduce CVD Events in
Patients with Diabetes: Antiplatelet
Trialists’ Collaboration
CVD Events (%)
25
P<0.002
Antiplatelet Therapy
Control
20
P<0.00001
15
10
5
0
Diabetes
Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106.
No Diabetes
Slide Source
LipidsOnline
www.lipidsonline.org

80. Diabetes Mellitus Insulin Glucose Infusion in Acute
Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic
Control in No Insulin – Low Risk Cohort
Total Cohort
p = .0111
Mortality
0.6
0.7
0.5
Control
0.4
n=306
0.3
0.2
0
0
1
2
3
4
Years in Study
0.5
n=133
0.4
Control
0.3
0.2
Insulin-glucose
Infusion
0.1
p = .004
0.6
n=314
Mortality
0.7
No Insulin – Low Risk
n=139
0.1
5
Malmberg K et al. BMJ 1997;314:1512-1515.
0
0
Insulin-glucose
Infusion
1
2
3
4
Years in Study
Slide Source
LipidsOnline
www.lipidsonline.org
5

81. Effect of Trandolapril on Post-MI CHF Progression:
Trandolapril Cardiac Evaluation (TRACE)
Diabetics (n=237)
0.5
0.5
Placebo
0.4
Event Rate
Event Rate
0.4
0.3
Trandolapril
0.2
0.1
0.0
Nondiabetics (n=1512)
1
2
Years
3
Placebo
0.2
Trandolapril
0.1
Relative risk, 0.38
P<0.001
0
0.3
4
0.0
Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.
Relative risk, 0.81
P = 0.1
0
1
2
Years
3
Slide Source
LipidsOnline
www.lipidsonline.org
4

82. Effect of Trandolapril on Secondary
Endpoints in TRACE
Diabetics
End Point
RR (95% CI)
Interaction
Nondiabetics
P
RR (95% CI)
P
P
Cardiovascular death
0.56 (0.37-0.85)
0.01
0.79 (0.66-0.96)
0.02
0.17
Sudden death
0.46 (0.25-0.85)
0.01
0.84 (0.63-1.12)
0.23
0.09
Reinfarction
0.55 (0.29-1.07)
0.08
0.93 (0.69-1.26)
0.65
0.15
Progression in CHF
0.38 (0.21-0.67)
<0.001
0.81 (0.63-1.04)
0.10
0.03
CI = confidence interval; RR = relative risk.
Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.
Slide Source
LipidsOnline
www.lipidsonline.org

83. Effect of Diabetes on 30-Day Mortality: Global Utilization of
Streptokinase and Tissue Plasminogen Activator for Occluded
Coronary Arteries (GUSTO-I)
2.7
Diabetes vs no diabetes
(unadjusted)
2.1
Adjusted for clinical
variables
2.4
Adjusted for angiographic
variables
2.0
Adjusted for clinical &
angiographic variables
0
1
2
3
4
Odds Ratio for 30-Day Mortality
Woodfield SL et al. J Am Coll Cardiol 1996;28:1661-1669.
Slide Source
LipidsOnline
www.lipidsonline.org
5

84. Overall 5-Year Mortality in the Bypass Angioplasty
Revascularization Investigation (BARI-1)
1.0
DM-PTCA
Mortality
0.8
DM-CABG
Non DM-CABG
0.6
Non DM-PTCA
0.4
0.25
0.18
0.08
0.07
0.2
0.0
0
1
2
3
Follow-up (years)
Detre KM et al. N Engl J Med 2000;342:989-997.
4
5
Slide Source
LipidsOnline
www.lipidsonline.org

85. Impact of PTCA vs. CABG on Mortality
in BARI-1
Mortality in Patients
without Q-MI
1.0
DM-CABG
0.8
Non DM-CABG
Non DM-PTCA
0.6
Mortality
Mortality
1.0
DM-PTCA
0.8
0.4
0.2
0.0
0
1
2
3
4
Follow-up (years)
Mortality in Patients
After Q-MI
0.79
0.6
0.4
0.22 0.2
0.16
0.07
0.06
0.0
5
Detre KM et al. N Engl J Med 2000;342:989-997.
0.29
0.27
0.17
0
1
2
3
4
Years after Q-MI
5
Slide Source
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86. Impact of Diabetes on 7-year Survival in BARI
All Patients
84.4
80.9
80
60
40
CABG (n=914)
PTCA (n=915)
20
0
1
2
3
Patients with Treated Diabetes
100
% Survival
0
76.4
60
55.7
CABG (n=180)
PTCA (n=173)
20
0
0
1
2
3
4
p = 0.0011
4
5
6
5
6
7
80
86.8
86.4
60
40
CABG (n=734)
PTCA (n=742)
20
0
Years
7
Patients without Treated Diabetes
100
80
40
p = 0.0425
% Survival
% Survival
100
0
BARI Investigators. J Am Coll Cardiol 2000;35:1122-1129.
1
2
3
p = 0.7155
4
5 Source 7
Slide 6
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87. Eight-Year Mortality in Emory Angioplasty vs Surgery
Trial (EAST)
All EAST Patients
% Survival
100
80
60
40
CABG (n=194)
PTCA (n=198)
20
0
0
1
2
4
5
60
40
CABG (n=30)
PTCA (n=29)
20
p = 0.23
6
100
% Survival
80
0
3
p = 0.40
Treated Diabetic Patients
100
% Survival
82.7
79.3
7
8
Patients without Diabetes
80
60
40
20
CABG (n=164)
PTCA (n=169)
0
7 8
0 1 2
Years after Randomization
King SB III et al. J Am Coll Cardiol 2000;35:1116-1121.
0
1
2
3
4
5
6
3
4
p = 0.71
5
6
7
Slide Source
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8

88. 6-Month Angiographic Outcome after PTCA
in Diabetes (377 Patients with 476 Lesions)
Lesions (%)
75
62%
50
49%
25
0
Restenosis
(n = 237)
Total
Occlusion
(n = 60)
13%
100
Total Occlusion
75
Patients (%)
100
Overall Restenosis Rate
50
37%
25%
25
11%
0
Angiographic FU = 6 months
Van Belle E et al. J Am Coll Cardiol 1999;34:476-485.
1 Site
2 Sites
3 Sites
PTCA Site(s)
Slide Source
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89. Impact of Restenosis and Total Occlusion
on LV Function in Diabetes
15
Restenosis (–)
Restenosis (+)
Total Occlusion (+)
Total Occlusion (–) Total Occlusion (–)
(n = 297)
(n = 237)
(n = 60)
∆ in EF (%)
10
5
0
-5
-1.5+9.5
+0.5+9.9
-6.2+9.9
-10
-15
-20
p = ns
p = ns
Van Belle E et al. J Am Coll Cardiol 1999;34:476-485.
p = 0.0001
Slide Source
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90. Effect of Stents on Target Vessel
Revascularization (TVR) after PTCA in Diabetes
Proportion Free of TVR
1.00
p = 0.021
df = 3, Log-rank Test
0.95
0.90
0.85
1997
0.80
Year
0
17.4
425
24.9
1996
480
41.0
1997
0
305
1995
0.70
% Stent
1994
0.75
N
288
55.5
2
1996
1995
1994
4
6
8
10
12
Months Post PTCA
Rankin JM et al. Circulation 1998;98:I-79.
Slide Source
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91. Patients with Diabetes
(n = 491)
20
Stent + Placebo
Stent + Abciximab
Angioplasty + Abciximab
15
16.6%
10
8.1%
5
0
18.4%
0
30
60
90
120 150 180
Incidence of repeated TVR
at 6 mos. (%)
Incidence of repeated TVR
at 6 mos. (%)
Evaluation of Platelet IIb/IIIa Inhibitor for Stenting
Trial (EPISTENT): Benefit of Abciximab and Stenting in
Diabetes on Reducing TVR
Days after Randomization
Lincoff AM et al. N Engl J Med 1999;341:319-327.
Patients without Diabetes
(n = 1908)
20
Stent + Placebo
Stent + Abciximab
Angioplasty + Abciximab
15
9.0%
10
8.8%
5
0
14.6%
0
30
60
90
120 150 180
Days after Randomization
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92. EPISTENT: Optimization of PTCA/Stent
Outcomes with Platelet IIb/IIIa Inhibition
6-Month Death, MI for Diabetics
15
% of Patients
12.7%
p = 0.029
10
7.8%
6.2%
5
0
Stent + Placebo
Stent + Abciximab
PTCA + Abciximab
0
30
60
90
Days
Marso SP et al. Circulation 1999;100:2477-2484.
120
150
180
Slide Source
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93. Conclusions
In patients with diabetes mellitus, there are numerous opportunities
to reduce morbidity and mortality from CAD:
 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)
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94. Future 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
Slide Source
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95. Diabetic Dyslipidemia and
Atherosclerosis
Henry Ginsberg, MD
Slide Source
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96. Interrelation Between Atherosclerosis
and Insulin Resistance
Hypertension
Obesity
Hyperinsulinemia
Insulin
Insulin
Resistance
Resistance
Diabetes
Hypertriglyceridemia
Atherosclerosis
Atherosclerosis
Small, dense LDL
Low HDL
Hypercoagulability
Slide Source
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97. Insulin Resistance and Hyperinsulinemia:
Clinical Clues
 Abdominal obesity
  TG +  HDL-C
 Glucose intolerance
 Hypertension
 Atherosclerosis
 Ethnicity
Slide Source
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98. Dyslipidemia in the Insulin Resistance
Syndrome
 Elevated total TG
 Reduced HDL-C
 Small, dense LDL-C
Slide Source
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99. Dyslipidemias in Adults with Diabetes
Framingham Heart Study
MEN
WOMEN
Normal
DM
Normal
DM
Increased cholesterol
14%
13%
21%
24%
Increased LDL
11%
9%
16%
15%
Decreased HDL
12%
21%
10%
25%
9%
19%
8%
17%
Increased triglycerides
Garg A et al. Diabetes Care 1990;13:153-169.
Slide Source
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100. Mean Plasma Lipids at Diagnosis of
Type 2 Diabetes - UKPDS
MEN
Type 2
WOMEN
Control
Type 2
Control
2139
52
1574
143
TC (mg/dl)
213
205
224
217
LDL-C (mg/dl)
139
132
151*
135
43
43*
55
103
159*
95
Number of Pts
HDL-C (mg/dl)
TG (mg/dl)
39**
159*
* P<0.001, ** P<0.02 comparing type 2 vs. controll
UKPDS Group. Diabetes Care 1997;20:1683-1687.
Slide Source
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101. Relation Between Insulin Resistance and
Hypertriglyceridemia
Plasma TG (mg/dL)
625
500
r = 0.73
P < 0.0001
400
300
200
100
100 200 300 400 500 600
Insulin Response to Oral Glucose*
* Total area under 3-hour response curve (mean of 2 tests).
Olefsky JM et al. Am J Med. 1974;57:551-560.
Slide Source
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102. Association Between Hyperinsulinemia
and Low HDL-C
HDL-C (mg/dL)
60
50
Hyperinsulinemic
P<0.005
Normoinsulinemic
P<0.005
40
30
20
Nonobese
Reaven GM. In: LeRoith D et al., eds. Diabetes Mellitus.
Philadelphia: Lippincott-Raven,1996:509-519.
Obese
Slide Source
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103. Mechanisms Relating Insulin Resistance
and Dyslipidemia
Fat Cells
Liver
 FFA
IR X
Insulin
Slide Source
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104. Mechanisms Relating Insulin Resistance
and Dyslipidemia
Fat Cells
Liver
 FFA
IR X



TG
Apo B
VLDL
VLDL
Insulin
Slide Source
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105. Mechanisms Relating Insulin Resistance
and Dyslipidemia
Fat Cells
Liver
 FFA
IR X
Insulin



CE
TG
Apo B
VLDL
 VLDL
(CETP) HDL
TG
(hepatic
lipase)
Apo A-1
Kidney
Slide Source
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106. Mechanisms Relating Insulin Resistance
and Dyslipidemia
Fat Cells
Liver
 FFA
IR X



CE
TG
Apo B
VLDL
 VLDL
(hepatic
(CETP) HDL
lipase)
TG
Apo A-1
CE (CETP) TG
Insulin
LDL
Kidney
SD
LDL
(lipoprotein or hepatic lipase)
Slide Source
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107. Dyslipidemia in Diabetes
Increased
Decreased
 Triglycerides
 HDL
 VLDL
 Apo A-I
 LDL and small
dense LDL
 Apo B
Slide Source
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108. LDL Subclass Phenotypes in
Diabetes Mellitus
LDL Subclass
n
A
Int
B
51
24
36
6
Men*
Diabetic
Nondiabetic
29
87
28
47
Percent
21
29
Women**
Diabetic
Nondiabetic
54
543
34
85
30
9
* Feingold KR et al. Arterioscler Thromb 1992; 12:1496-1502.
** Selby JV et al. Circulation 1993; 88:381-387.
Slide Source
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109. Small Dense LDL and CHD:
Potential Atherogenic Mechanisms
 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
Austin MA et al. Curr Opin Lipidol 1996;7:167-171.
Slide Source
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www.lipidsonline.org

110. Hypertriglyceridemia and CHD Risk:
Associated Abnormalities
 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
Slide Source
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111. TG Metabolism in CHD: Studies in the
Postprandial State
Corrected for Fasting
TG (mg/dL)
400
300
Uncorrected
CHD
Cases
300
TG Level*
200
CHD
Cases
200
Controls
100
0 0
100
Controls
2
4
0 0
6
8
2
Hours after Test Meal
4
6
8
Error bars = SEM
Patsch JR et al. Arterioscler Thromb 1992;12:1336-1345.
Slide Source
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112. Factors Promoting Thromboembolic
Disease in Diabetes
 Increased plasma fibrinogen
 Increased plasminogen activator inhibitor 1
 Increased platelet aggregability
Thompson SG et al. N Engl J Med 1995;332:635-641.
Slide Source
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113. Adverse Effects on Balance Between
Thrombosis and Fibrinolysis in Subjects
with Diabetes
 Predisposition to thrombosis
- Platelet hyperaggregability
- Elevated concentrations of procoagulants
- Decreased concentration and activity of
antithrombotic factors
 Predisposition to attenuation of fibrinolysis
- Decreased t-PA activity
- Increased PAI-1
- Decreased concentrations of α2-antiplasmin
Sobel BE. Circulation 1996;93:1613-1615.
Slide Source
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114. PAI-1 Activity in Blood in Patients with
Type 2 Diabetes
PAI-1 Activity (AU/mL)
20
15
No Diabetes
Diabetes
10
5
0
Lean
PAI-1 = plasminogen activator inhibitor type 1
McGill JB et al. Diabetes. 1994;43:104-109.
Obese
Slide Source
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115. Elevation of PAI-1 Induced by
Hyperinsulinemia, Hyperglycemia, and
Increased FFA in Blood of Normal Subjects
PAI-I (mg/mL)
21
18
Infusion of glucose
and intralipid
15
12
*
9
6
3
0
0
Values are mean + SD
2
4
6
Time (h)
*P<0.05 vs saline infusions in same subjects
Calles-Escandon J et al. Diabetes. 1998;47:290-293.
8
10
12
Slide Source
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116. Pharmacologic Agents for Treatment of
Dyslipidemia
Effect on lipoprotein
LDL
HDL
Triglyceride
First-line agents
 HMG CoA reductase inhibitor
 Fibric acid derivative
Second-line agents
 Bile acid binding resins
 Nicotinic acid
In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting
nicotinic acid is preferred.
American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.
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117. Order of Priorities for Treatment of
Diabetic Dyslipidemia in Adults*
 LDL cholesterol lowering*
- First choice:
HMG CoA reductase inhibitor (statin)
- Second choice:
Bile acid binding resin or fenofibrate
 HDL 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 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.
Slide Source
Adapted from American Diabetes Association. Diabetes Care
2000;23(suppl 1):S57-S60.
LipidsOnline
www.lipidsonline.org

118. Update on the Metabolic Syndrome
Steven Haffner, MD
Slide Source
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119. Metabolic Syndrome Increases Risk for CHD
and Type 2 Diabetes
High
LDL-C
Metabolic
Syndrome
Type 2
Diabetes
Coronary Heart Disease
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-2497.
Slide Source
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120. High Risk of Impaired Glucose Tolerance and Type 2
Diabetes by OGTT in Post-MI Patients without Known
Diabetes
% of Patients
100
IGT
n = 181
80
60
40
New DM
35%
40%
31%
25%
20
0
At
discharge
3 mo
later
Norhammar A et al. Lancet 2002;359:2140-2144.
At
discharge
3 mo
later
Slide Source
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121. Increased Metabolic Syndrome in Prediabetic Subjects: Baseline
Risk Factors in Subjects with Normal Glucose Tolerance at
Baseline according to Conversion Status at
8-Year Follow-up: San Antonio Heart Study
Conversion Status at Follow-up
Diabetes (n=18)
Normal (n=490)
P
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
5.28 ± 0.1
5.00 ± 0.02
.032
157 ± 27
81 ± 5
.006
BMI (kg/m2)
Fasting glucose (mmol)
Fasting insulin (pmol)
* Ratio of subscapular to triceps skinfolds
Haffner SM et al. JAMA 1990;263:2893-2898.
Slide Source
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122. Elevated Risk of CVD Prior to Clinical Diagnosis of
Type 2 Diabetes:
Nurses’ Health Study
Relative Risk
6
5.02
5
3.71
4
2.82
3
2
1
1
0
Nondiabetic
throughout
the study
Prior to
diagnosis of
diabetes
Copyright © 2002 American Diabetes Association
From Diabetes Care, Vol. 25, 2002; 1129-1134
Reprinted with permission from The American Diabetes Association.
After
diagnosis of
diabetes
Diabetic
at
baseline
Slide Source
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123. Risk of Major CHD Event Associated with Insulin
Quintiles in Nondiabetic Subjects: Helsinki
Policemen Study
Proportion without
Major CHD Event
1.00
0.95
0.90
Q1
0.85
Q2
Log rank:
Overall P = .001
Q5 vs. Q1 P < .001
0.80
0.75
Q3
Q4
Q5
0
0.70
0
5
10
Years
Pyörälä M et al. Circulation 1998;98:398-404.
15
20
25
Slide Source
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124. CVD Risk Factors across HOMA-IR Quintiles:
San Antonio Heart Study (Phase II)
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
69.0
70.4
71.9
73.1
75.4
Diastolic BP (mm Hg)
Adjusted for age, sex, ethnicity
All p(trend) < 0.0001; quintile cutpoints: 1.0, 1.6, 2.5, 4.8
Copyright © 2002 American Diabetes Association
From Diabetes Care, Vol. 25, 2002; 1177-1184
Reprinted with permission from The American Diabetes Association.
Slide Source
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125. Definitions of the Metabolic Syndrome
 According to clinical outcomes
 According to underlying causes
 According to metabolic components
 According to clinical criteria
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126. Definition of Metabolic Syndrome:
According 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.
Slide Source
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127. Therapeutic Implications: According to
Underlying Causes
 Insulin resistance
 Treat insulin resistance
 Lifestyle: especially obesity
 Prevent and treat obesity
 Subclinical inflammation
 Treat obesity
 Statins, TZDs, etc.
Slide Source
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128. ATP III: The Metabolic Syndrome
Diagnosis is established when ≥ 3 of these risk factors are
present
Risk Factor
Defining Level
Abdominal obesity
(Waist circumference)
Men
Women
>102 cm (>40 in)
>88 cm (>35 in)
≥150 mg/dl
TG
HDL-C
Men
Women
<40 mg/dl
<50 mg/dl
Blood pressure
≥130/≥85 mm Hg
Fasting glucose
≥110 mg/dl
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-2497.
Slide Source
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129. Prevalence of the NCEP Metabolic Syndrome:
NHANES III by Age
Prevalence, %
50%
44% 44%
Men
40%
Women
30% 24%
23%
20%
10%
0%
8%
6%
20–70+ 20–29
20
30–39
30
40–49
50–59
Age, years
Ford ES et al. JAMA 2002;287:356-359.
60–69
60
≥70
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130. Prevalence of the NCEP Metabolic Syndrome:
NHANES III by Sex and Race/Ethnicity
White
African American
Mexican American
Other
Prevalence, %
40%
30%
28%
25%
26%
21%
20%
36%
23%
20%
16%
10%
0%
Men
Ford ES et al. JAMA 2002;287:356-359.
Women
Slide Source
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131. Prevalence of CHD by the Metabolic Syndrome and
Diabetes in the NHANES Population Age 50+
25%
CHD Prevalence
19.2%
20%
13.9%
15%
10%
8.7%
7.5%
5%
0%
No MS/No DM
% of
Population = 54.2%
MS/No DM
28.7%
Alexander CM et al. Diabetes 2003;52:1210-1214..
DM/No MS
2.3%
DM/MS
14.8%
Slide Source
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132. ATP III Metabolic Syndrome:
Therapeutic 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)
Slide Source
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133. Different Components of the NCEP Metabolic
Syndrome Predict CHD: NHANES
Prediction of CHD Prevalence using Multivariate Logistic
Regression
Odds
Ratio
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
Variable
*Significant predictors of prevalent CHD
Copyright © 2003 American Diabetes Association
From Diabetes, Vol. 52, 2003; 1210-1214
Reprinted with permission from The American Diabetes Association.
Slide Source
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134. Different Components of the NCEP Metabolic
Syndrome Predict Diabetes: San Antonio Heart Study
Risk of Type 2 Diabetes per Unit Change in Risk Trait Levels
8%
FPG per mg/dl
2%
SBP per mm Hg
HDL-C per mg/dl
decrease
4%
7%
BMI per kg/m2
0%
2%
4%
Stern MP et al. Ann Intern Med 2002;136:575-581.
6%
8%
10%
Slide Source
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135. WHO Metabolic Syndrome Definition 1999:
Based 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.
WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and
Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999.
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136. Must Insulin Resistance be Present for a Patient
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.
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137. WHO Metabolic Syndrome Definition 1999:
Therapeutic 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
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138. Therapeutic Implications of Definition of
Metabolic 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
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139. Criteria for Comparing Different Definitions of
Metabolic Syndrome
 Risk of:
 CHD
 DM
 Relation to:
 Insulin resistance
 Obesity
 Prevalence in community could differ by race
 How simple is the definition?
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140. Intensity of Therapy Should be Proportionate
to Level of Risk
 What is the impact of the metabolic
syndrome on health outcomes?
 Cardiovascular disease
 Type 2 diabetes
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141. Cumulative Hazard, %
Cardiovascular Disease Mortality Increased in the
Metabolic Syndrome: Kuopio Ischaemic Heart
Disease Risk Factor Study
15
10
Cardiovascular Disease Mortality
Metabolic
Syndrome:
RR (95% CI), 3.55 (1.98–6.43)
YES
5
0
0
NO
2
4
6
8
Follow-up, y
Lakka HM et al. JAMA 2002;288:2709-2716.
10
12
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142. Cox Proportional Hazard Ratios (and 95% Confidence
Intervals) Predicting All-Cause and Cardiovascular
Mortality: San Antonio Heart Study 14-Year Followup
NCEP MetS
WHO MetS
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)
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)
Total Population
Disease Free*
* Those without diabetes, cardiovascular disease, or cancer.
Adjusted for age, gender, and ethnic group.
Hunt KJ et al. Diabetes 2003;52:A221-A222.
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143. % in Lowest Quartile of Si
Comparison of NCEP and 1999 WHO Metabolic
Syndrome to Identify Insulin-Resistant Subjects:
IRAS
90
80
70
60
50
40
30
20
10
0
Overall
Hispanics
Non-Hispanic whites
African Americans
Neither
NCEP Only
Hanley AJ et al. Diabetes 2003;52:2740-2747.
WHO Only
Both
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144. CRP Adds Prognostic Information at All Levels of Risk as
Defined by the Framingham Risk Score
25
20
15
ks R ev t a e R
i
i l
10
>3.0
5
0
1.0–3.0
<1.0 hs-CRP
10+
5–9
2–4
0–1
(mg/L)
Framingham 10-Year Risk (%)
Ridker PM et al. N Engl J Med 2002;347:1557-1565.
Copyright © 2002 Massachusetts Medical Society. All rights reserved. Adapted with permission.
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145. Partial Spearman Correlation Analysis of Inflammation Markers
with Variables of IRS Adjusted for Age, Sex, Clinic, Ethnicity, and
Smoking Status: IRAS
CRP
WBC
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‡
–0.37‡
–0.24‡
–0.18‡
Si
Fibrinogen
*P<0.05, †P<0.005, ‡P<0.0001
CRP=C-reactive protein; IRS=insulin-resistance syndrome; WBC=white blood
cell count.
Festa A et al. Circulation 2000;102:42–47.
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146. e u a V nae M
l
Mean Values of CRP by Number of Metabolic Disorders
(Dyslipidemia, Upper Body Adiposity, Insulin Resistance,
Hypertension): IRAS
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0
1
2
3
Number of Metabolic Disorders
Festa A et al. Circulation 2000;102:42–47.
4
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147. Five-Year Incidence of Type 2 Diabetes Stratified
by Quartiles of Inflammatory Proteins: IRAS
Quartiles:
Incidence, %
25
1st
P=0.06
2nd
P=0.001
3rd
4th
P=0.001
20
15
10
5
0
Fibrinogen
Festa A et al. Diabetes 2002;51:1131-1137.
CRP
PAI-1
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148. The Effect of Rosiglitazone on CRP
Difference = –21.8 (95% CI: –34.7, –5.6)
Change from Baseline to
Week 26, %
Difference = –26.8
(95% CI: –39.7, –21.8)
0
n=95
n=124
n=134
Rosiglitazone
4 mg/d
Rosiglitazone
8 mg/d
-10
-20
-30
-40
-50
Placebo
Haffner SM et al. Circulation 2002;106:679-684.
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149. The Effect of Rosiglitazone on IL-6
Difference = 0.0 (95% CI: –9.0, 10.0)
Change from Baseline to
Week 26, %
Difference = –1.9
(95% CI: –11.3, 9.3)
0
n=91
n=120
n=132
Placebo
Rosiglitazone
4 mg/d
Rosiglitazone
8 mg/d
-10
-20
-30
-40
-50
Haffner SM et al. Circulation 2002;106:679-684.
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150. Reduction of CRP Levels with Statin
Therapy (n=22)
6
** p<0.025 vs. Baseline
p<0.025 vs. Baseline
5
*
4
*
3
*
) L/ g m P RC s h
(
-
2
1
0
Baseline
Pravastatin
(40 mg/d)
Jialal I et al. Circulation 2001;103:1933-1935.
Simvastatin
(20 mg/d)
Atorvastatin
(10 mg/d)
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151. Summary
 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
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152. Does Lipid and Blood Pressure Therapy Work
in Subjects with the Metabolic Syndrome?
 Diabetic subjects
 Blood pressure: YES
 Statin therapy: YES
 Nondiabetic subjects
 Little data available
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153. CHD Prevention Trials with Statins in
Diabetic Subjects: Subgroup Analyses
Study
Drug
No.
CHD Risk
Reduction
Overall
CHD Risk
Reduction in
Diabetics
Primary Prevention
AFCAPS/TexCAPS
Lovastatin
155
37%
43% (NS)
Simvastatin
2912
24%
33% (p=.0003)
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%
HPS
Secondary Prevention
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;339:1349Slide Source
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1357. | Haffner SM et al. Arch Intern Med 1999;159:2661-2667.
www.lipidsonline.org

154. Completed Clinical Trials with
Antihypertensive Agents in Diabetes
Trial
Diabetic/Total
Results
SHEP
583/4736
Beneficial
GISSI-3
2790/18,131
Beneficial
Syst-Eur
492/4695
Beneficial
1501/18,790
Beneficial
UKPDS
1148
Beneficial
CAPPP
572/10,985
Beneficial
HOT
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;317:703Slide Source
LipidsOnline
713. | Hansson L et al. Lancet 1999;353:611-616.
www.lipidsonline.org

155. “Metabolic Syndrome” in 4S
Lipid Triad
40
RR=0.48 (0.33–0.69)
Isolated ↑ LDL-C
RR=0.86 (0.59–1.26)
Event Rate, %
36.9
Placebo
30
20
Simvastatin
19.0
18.0
20.3
10
0
221
237
Ballantyne CM et al. Circulation 2001;104:3046-3051.
261
284
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156. Patients Reaching IntensiveTreatment Goals at Mean 7.8 y, (%)
Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects
(Type 2 Diabetes with Microalbuminuria): Steno-2
Intensive Therapy
80
70
P<0.001
60
Conventional Therapy
P=0.21
P=0.19
P=0.001
50
40
30
20
P=0.06
10
0
Glycosylated Cholesterol
Triglycerides Systolic BP
Diastolic BP
hemoglobin
<175 mg/dl <150 mg/dl <130 mm Hg <80 mm Hg
<6.5%
Slide Source
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Gæde P et al. N Engl J Med 2003;348:383-393.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.
www.lipidsonline.org

157. Composite Endpoint of Death from CV Causes, Nonfatal MI,
CABG, PCI, Nonfatal Stroke, Amputation, or Surgery for PAD:
STENO-2
Primary Composite
Endpoint (%)
60
P=0.007
50
Hazard ratio = 0.47
(95% CI, 0.24–0.73;
P=0.008)
40
Conventional
Therapy
30
20
Intensive
Therapy
10
0
0
12
24
36
48
60
72
Months of Follow-up
Gæde P et al. N Engl J Med 2003;348:383-393.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.
84
96
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158. Summary: 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
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159. Slide Source
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