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The Link Between

Diabetes and Atherosclerosis


Overview and Clinical Considerations
Highlighting Results of the Diabetes
Sub-Study of the Heart Protection Study

Slide 1
Problems and Challenges in Managing
Type 2 Diabetes Mellitus

 The Problem
Atherosclerosis is a prominent but underappreciated complication
associated with diabetes mellitus
 The Challenge
Therapies to reduce coronary heart disease (CHD) risk are
effective. Our challenge is to routinely apply the available
therapies to adult patients with diabetes mellitus, in conjunction
with appropriate glucose control

Adapted from Folsum AR et al Diabetes Care 1997;20:935-942; American Diabetes Association Diabetes Care 2002;
25(suppl 1):S33-S49.
Slide 2
Type 2 Diabetes Prevalence Is Projected to
Reach 300 Million by 2025
 About 155 million adults worldwide diagnosed with diabetes in 2000
– 83 million women and 72 million men
 Between 1995 and 2025, the prevalence of diabetes in adults will increase by 35% and
the number of people with diabetes will increase
by 122%

EUROPE ASIA
JAPAN
USA 2000: 30.8M 2000: 71.8M
2000: 6.9M
2000: 15M 2025: 38.5M 2025: 165.7M
AFRICA 2025: 8.5M
2025: 21.9M
AMERICAS 2000: 9.2M OCEANIA
(Ex-US)
2025: 21.5M 2000: 0.8M
2000: 20M
2025: 1.5M
2025: 42M
Adapted from King H et al Diabetes Care 1998;21:1414-1431.
Slide 3
Atherosclerosis Is Common
in Newly Diagnosed Diabetes Mellitus

 Cardiovascular diseases are common causes of morbidity


and mortality in people with diabetes
 >50% of patients with newly diagnosed type 2 diabetes show
evidence of cardiovascular disease
 Atherosclerosis is a major cause of death among patients
with diabetes mellitus
– 75% from coronary atherosclerosis
– 25% from cerebral or peripheral vascular disease
 >75% of hospitalizations for individuals with diabetes are for
atherosclerotic disease

Adapted from Amos AF et al Diabet Med 1997;14:S7-S85; Hill Golden S Adv Stud Med 2002;2:364-370; Haffner SM et al
N Engl J Med 1998;339:229-234; Sprafka JM et al Diabetes Care 1991;14:537-543.
Slide 4
Two-Thirds of People with Diabetes Die
of Cardiovascular Disease

 Among people with diabetes, macrovascular complications,


including CHD, stroke, and peripheral vascular disease, are
the leading causes of morbidity and mortality.

Causes of mortality in people with diabetes

CHD, stroke, and peripheral


67% vascular disease
Other

Adapted from Alexander CM, Antonello S Pract Diabet 2002;21:21-28.


Slide 5
Mortality Following First MI in People
with and without Diabetes
 Many patients with diabetes will not survive their first MI
50 With diabetes
44%*
Without diabetes
Mortality rate (%)

40 37%*
33%
30
20%
20

10
n=437 n=2699 n=183 n=743
0
Men Women
1 Year, hospitalized and nonhospitalized

MI = myocardial infarction
Time post-first MI
*p<0.001
Adapted from Miettinen H et al Diabetes Care 1998;21:69-75.
Slide 6
People with Diabetes Have MI Risk Levels
Comparable to People with Prior MI
25
20%
or nonfatal MI (%)

19%
Incidence of fatal

20

15

10

0
Diabetes (no prior MI) Prior MI (no diabetes)
(n=890) (n=69)
Patient type
 Patients with diabetes without previous MI have as high of a risk of MI as
nondiabetic patients with previous MI.
 These data provide a rationale for treating cardiovascular risk factors in diabetic
patients as aggressively as in nondiabetic patients with prior MI.
Adapted from Haffner SM et al N Engl J Med 1998;339:229-234.
Slide 7
People with Diabetes Have Increased
Cardiovascular Risk Factors

Risk factor Type 1 Type 2


Dyslipidemia
Small, dense LDL + ++
Increased apoB + ++
Low HDL +/– ++
Hypertriglyceridemia ++ ++
Hypertension + ++
Hyperinsulinemia/insulin resistance + ++
Central obesity – ++
Family history of atherosclerosis – +
Cigarette smoking – –

+ = moderately increased compared with nondiabetic population; ++ = markedly increased compared with nondiabetic population;
– = no increase compared with nondiabetic populations; LDL = low-density lipoprotein; apoB = apolipoprotein B; HDL = high-
density lipoprotein
Adapted from Chait A, Bierman EL. In: Joslin's Diabetes Mellitus. 13th ed. Philadelphia: Lea & Febiger, 1994:648-664.
Slide 8
Greater Risk of Death with Diabetes and
One Risk Factor than without Diabetes and
Three Risk Factors*
140 Diabetes
No diabetes
10,000 person-years

120
Age-adjusted CVD
death rate per

100
80
60
40
20
0
None One only Two only All three

Risk factors

*Serum cholesterol >200 mg/dl, smoking, systolic blood pressure >120 mmHg
Adapted from Stamler J et al Diabetes Care 1993;16:434-444.
Slide 9
Patients with Diabetes and Low Cholesterol
Had Higher Risk of CV Mortality than Those
without Diabetes and High Cholesterol
160 Diabetes
No diabetes
10,000 person-years

140
CV mortality per

120
100
80
60
40
20
0
<4.7 4.7–5.1 5.2–5.7 5.8–6.2 6.3–6.7 6.8–7.2 >7.3

Total cholesterol (mmol/L)

CV = cardiovascular
Adapted from Stamler J et al Diabetes Care 1993;16:434-444.
Slide 10
“Normal” LDL-C Levels in People with Diabetes Can Be Misleading...
Small, Dense LDL-C Particles Are More Atherogenic

No diabetes Diabetes apoB


LDL particles LDL particles LDL-C

Small, dense
LDL with more
apoB

“Normal” LDL-C level, however:


“Normal” LDL-C level Number of LDL particles
Concentration of apoB
Lower Higher
CHD risk

Adapted from Austin MA, Edwards KL Curr Opin Lipidol 1996;7:167-171; Austin MA et al JAMA 1988;260:1917-1921;
Sniderman AD et al Diabetes Care 2002;25:579-582.
Slide 11
In People with Diabetes Macrovascular
Complications Are Two Times Greater than
Microvascular Complications
25
People with diabetes developing

20%
9 years of diagnosis (%)

20
complications within

15

10 9%

n=5102 n=5102
0
Macrovascular complications Microvascular complications

Adapted from Turner R et al Ann Intern Med 1996;124:136-145.


Slide 12
In UKPDS
Intensive Glucose Control Significantly Reduced
Microvascular Disease
Rate*
Conventional Intensive
glucose glucose
control control % Risk
(n=2729) (n=1138) reduction p
Macrovascular events
MI 17.4 14.7 16 0.052
Stroke 5.0 5.6 –11 NS
PVD 1.6 1.1 35 NS
Diabetes-related death 11.5 10.4 10 NS
All-cause mortality 18.9 17.9 6 NS
Microvascular events 11.4 8.6 25 0.0099
All events** 46.0 40.9 12 0.029

NS = not significant; PVD = peripheral vascular disease


*Per 1000 patient-years
**Combined microvascular and macrovascular events
Adapted from United Kingdom Prospective Diabetes Study Group (UKPDS) Lancet 1998;352:837-853.
Slide 13
In UKPDS
LDL-C Was the Strongest Predictor of CHD Risk
in People with Diabetes

% Increase in CHD risk


LDL-C ↑ of 1 mmol/L 57
HDL-C ↑ of 0.1 mmol/L –15
Systolic blood pressure ↑ of 10 mmHg 15
HbA1c level ↑ of 1% 11
Smoking was also a major contributor to CHD risk

These data support the need for reducing LDL-C to lower CHD risk
in people with diabetes mellitus. Glucose control is also important in
reducing the risk of microvascular complications.

Adapted from Turner RC et al BMJ 1998;316:823-828.


Slide 14
Lipid Guidelines for Patients with Diabetes
American Diabetes Association Guidelines

Patients with diabetes need lipid-lowering therapy because effective


management of blood glucose only modestly improves plasma levels
of LDL-C or HDL-C.

Dietary therapy Drug treatment


Adults with diabetes LDL goal initiation level initiation level

Without CHD <100 mg/dl ≥ 100 mg/dl ≥ 130 mg/dl


With CHD <100 mg/dl ≥ 100 mg/dl ≥ 100 mg/dl

“...people with type II diabetes typically have a preponderance of smaller,


denser, LDL particles, which possibly increases atherogenicity….”

Adapted from American Diabetes Association Diabetes Care 2002;25(suppl 1):S33-S49; American Diabetes Association
Diabetes Care 2002;25(suppl 1):S74-S77.
Slide 15
Lipid Guidelines for Patients with Diabetes
European Societies

“Both major types of diabetes mellitus… were associated with


a markedly increased risk of CHD….”

 CHD risk increases with diabetes


– Approximately doubled in men
– More than doubled in women
 LDL-C goal: <115 mg/dl (3.0 mmol/L)
– More aggressive control for patients with high CHD risk*

*CHD risk ≥ 20% over 10 years or will exceed 20% if projected to age 60
Adapted from Wood D et al Atherosclerosis 1998;140:199-270.
Slide 16
Lipid Guidelines for Patients with Diabetes
National Cholesterol Education Program (NCEP)
Intensive CHD prevention strategy is warranted [for patients with diabetes],
with LDL-C as a primary treatment target

Dietary therapy Drug treatment


Adults with diabetes LDL goal initiation level initiation level
With or without CHD <100 mg/dl ≥ 100 mg/dl ≥ 130 mg/dl
(100–129 mg/dl:
drug optional)

 Diabetes is a CHD risk equivalent


– Diabetes confers same risk of CHD as does prior history of CHD
– Patients with diabetes have unusually high death rates following MI

Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;
285:2486-2497.
Slide 17
Lipid Guidelines for Patients with Diabetes
International Atherosclerosis Society
“Patients with diabetes experience significant cardiovascular disease risk
reduction with control of other risk factors . . . including LDL-C.”

Drug treatment Drug treatment


Adults with diabetes LDL goal recommended optional
High risk* <100 mg/dl ≥ 100 mg/dl <100 mg/dl
Multiple risk factors** <130 mg/dl ≥ 130 mg/dl <130 mg/dl

 All patients should undergo therapeutic lifestyle changes

*High-risk patients include those with established CHD (history of MI, stable or unstable angina, or coronary artery
procedures), noncoronary forms of atherosclerotic disease, or multiple risk factors (10-year risk >20%).
**Risk factors that modify LDL-C goals are smoking, hypertension, low HDL-C, and advanced age (men ≥ 45 years;
women ≥ 55 years).
Adapted from International Atherosclerosis Society Harmonized Clinical Guidelines on Prevention of Atherosclerotic Vascular
Disease. Available at: http://www.athero.org/download/guidelines.pdf.
Slide 18
Heart Protection Study
Diabetes Sub-Study
 Almost 6000 men and women, aged 40–80 years with diabetes mellitus
– 1981 persons with history of CHD
– 3982 persons with no history of CHD
 People randomized to simvastatin 40 mg or placebo
 Mean duration of follow-up 5 years
 Objective—to evaluate the long-term benefits of simvastatin and/or
antioxidants in people with diabetes with or without CHD regardless
of cholesterol level
 Primary endpoints—first major coronary events* and first major vascular
events**
 Statin not considered clearly indicated or contraindicated by patients’ primary
physicians
*Nonfatal MI or death from coronary disease
**Major coronary events, stroke of any type, and coronary or noncoronary revascularizations
Adapted from Heart Protection Study Collaborative Group Eur Heart J 1999;20:725-741; Heart Protection Study
Collaborative Group Lancet 2002;360:7-22; Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.
Slide 19
Impact of Simvastatin on LDL-C
Nine Out of 10 Patients with Diabetes Achieved Goal*
100 92% 91%

80
Patients (%)

60

40

20
n=3985** n=1978**
0
Without CHD With CHD
 Results from the five-year Heart Protection Study (HPS) of almost 6000 patients with
diabetes with or without CHD indicated that 92% of patients with diabetes, but without
CHD, and 91% of patients with CHD who received simvastatin 40 mg achieved
the European Guidelines LDL‑C treatment goal of <3 mmol/L (115 mg/dl)***
*By the four-month point in HPS
**These populations differ from those reported in later HPS publications (3982 and 1981) because three patients were
reclassified after the four-month point. The percentages of patients achieving LDL-C goal are not affected.
***Based on random sampling of patients with diabetes
Adapted from Armitage J, Collins R Heart 2000;84:357-360.
Slide 20
Impact of Simvastatin on First Major Vascular Events
All Patients and Patients with Diabetes
Placebo
Simvastatin
24% risk reduction 22% risk reduction
(p<0.0001) (p<0.0001)
30
25.2 25.1
Patients with major
vascular events

20.2
by year 5 (%)

19.8
20
2585 748
patients 2033 patients 601
10 with events patients with events patients
with events with events

n=10,267 n=10,269 n=2985 n=2978


0
All patients* Patients with diabetes
*Includes patients with CHD, occlusive disease of noncoronary arteries, diabetes, or treated hypertension
Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; Heart Protection Study Collaborative
Group Lancet 2003;361:2005-2016.
Slide 21
Impact of Simvastatin on First and Subsequent Major Vascular Events
All Patients and Patients with Diabetes
Placebo
Simvastatin 85 events avoided
91 events avoided
per 1000 patients per 1000 patients
taking simvastatin taking simvastatin

400 371
360
subsequent major vascular
events per 1000 patients
Number of first and

300 286
269
by year 5

2585 748
200 patients patients
2033 601
with 3697 patients with 1109 patients
events with 2763 events with 852
100 events events

n=10,267 n=10,269 n=2985 n=2978


0
All patients* Patients with diabetes
*Includes patients with CHD, occlusive disease of noncoronary arteries, diabetes, or treated hypertension
Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.
Slide 22
Impact of Simvastatin in Patients with Diabetes
Major Coronary Events, Stroke,
and Revascularization
Placebo
Simvastatin
27%
risk reduction* 17%
15 risk reduction***
12.6
Patients with event

24% 10.4
by year 5 (%)

10
9.4 risk reduction**
8.7
6.5
5.0
5

n=2985 n=2978 n=2985 n=2978 n=2985 n=2978


0
Major coronary Stroke Revascularization
event
*p<0.0001; **p<0.01; ***p=0.02
Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.
Slide 23
Impact of Simvastatin in Patients with Diabetes and No Prior CVD
Major Vascular Events

33% risk reduction


(p=0.0003)

15 13.5
Patients with major
vascular events
by year 5 (%)

10 9.3

n=1457 n=1455
0
Placebo Simvastatin

Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.


Slide 24
Impact of Simvastatin in Patients with Diabetes
With Low LDL-C
27% risk reduction Placebo
(p=0.0007)
25 Simvastatin

20.9
20
Patients with major

30% risk reduction


vascular events

(p=0.05)
by year 5 (%)

15.7
15
11.1
10 8.0

n=1207 n=1219 n=668 n=675


0
Baseline LDL-C Baseline LDL-C
<3.0 mmol/L <3.0 mmol/L without CVD

Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.


Slide 25
Impact of Simvastatin in Patients with Diabetes
With or without Optimal Glycemic Control
21% risk reduction Placebo
(p=0.002) Simvastatin
21% risk reduction
30 27.5 (p=0.002)

22.6 22.6
Patients with major
vascular events
by year 5 (%)

20 18.3

10

n=1355 n=1334 n=1595 n=1610


0
Suboptimal glycemic control Optimal glycemic control
(HbA1C ≥ 7.0%) (HbA1C <7.0%)
Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.
Slide 26
Impact of Simvastatin in Patients with Diabetes
with or without Treated Hypertension or Obesity
Regardless of treated Regardless of body
hypertension Placebo mass index
Simvastatin

22%
Patients with major vascular

risk reduction* 21% 17%


22% risk reduction* risk reduction*
events by year 5 (%)

risk reduction* 29.1


30 30
22.3 23.6 24.0 24.0
20.3
17.9 19.6
20 20

10 10

n=1783 n=1782 n=1202 n=1196 n=646 n=629 n=1123 n=1060


0 0
Without treated With treated Lean Obese
hypertension hypertension

*p<0.05

Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.


Slide 27
Impact of Simvastatin in Patients with Diabetes
By Age and Gender
Placebo
Regardless of age Regardless of gender
Simvastatin

21%
risk reduction* 21%
Patients with major vascular

40 40 risk reduction*
31.6
events by year 5 (%)

24% 27.8 25%


30 risk reduction* 25.9 30 risk reduction*
22.8
20.1 18.6
20 20
15.7 14.2

10 10

n=1696 n=1675 n=1289 n=1303 n=2083 n=2064 n=902 n=914


0 0
Age <65 years Age ≥ 65 years Male Female

*p<0.05

Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.


Slide 28
In Over 20,000 Patients in HPS
Simvastatin 40 mg Had a Safety Profile
Comparable to Placebo

100

10
Patients (%)

8
6 5.1% 4.8%

4
2
0
Placebo Simvastatin
(n=10,267) (n=10,269)
Discontinuations due to any adverse event

Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22.


Slide 29
In Over 20,000 Patients in HPS
Simvastatin 40 mg Comparable to Placebo
Incidence of Muscle Pain

Percentage of Patients with Muscle Pain over the Study Duration

Year 1 2 3 4 5 6
Simvastatin 40 mg 5 6 6 6 6 7
Placebo 5 6 6 6 7 7

 The risk of myopathy* with simvastatin 40 mg was 0.01% above placebo


on an annualized basis

*Myopathy defined as muscle symptoms plus creatine kinase >10 times the upper limit of normal
Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22.
Slide 30
In 20,000 Patients in HPS
Simvastatin 40 mg Helped Preserve
Renal Function
–20%
(p<0.0001)

10 8.9%
creatinine concentration

after 5 years (µmol/L)


Increase in plasma

8 7.1%

0
Placebo Simvastatin
(n=7697) (n=7999)
Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.
Slide 31
Lipid Lowering in Patients with Diabetes
Conclusions
 Patients with diabetes have a substantial number of CHD events,
and many do not survive their first MI
 LDL-C has been identified in UKPDS and by all major guidelines
as a primary target for reducing CHD risk in patients with diabetes
 In UKPDS, intensive glucose control significantly reduced microvascular
events such as retinopathy; however, it produced
a modest and nonsignificant reduction in macrovascular events,
such as MI and stroke
 Patients with diabetes need lipid-lowering therapy because effective
management of blood glucose only modestly improves plasma levels
of LDL-C or HDL-C; this improvement frequently does not meet levels
recommended by guidelines
Adapted from American Diabetes Association Diabetes Care 2002;25(suppl 1):S33-S49; Miettinen H et al Diabetes Care
1998;21:69-75; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:
2486-2497; United Kingdom Prospective Diabetes Study Group Lancet 1998;352:837-853; American Diabetes Association
Diabetes Care 2002;25(suppl 1):S74-S77; Wood D et al Atherosclerosis 1998;140:194-270.
Slide 32
Heart Protection Study
Major Medical Conclusions
In almost 6000 patients with diabetes
 Over 90% reached the European Guidelines LDL-C goal
on simvastatin 40 mg*
 Simvastatin significantly reduced the risk of
– major vascular events by 22% (p<0.0001)
– stroke by 24% (p=0.01)
– revascularization by 17% (p=0.02)
 Benefits of simvastatin were evident regardless of CHD history, blood
glucose control, baseline LDL-C, hypertension status, obesity, age, and
gender
 Simvastatin therapy was well tolerated and had a safety profile
comparable to placebo
*By the four-month point in HPS, based on random sampling of patients with diabetes
Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; Armitage J, Collins R Heart
2000;84:357-360; Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.
Slide 33
Heart Protection Study
Medical Implications
 Based on the results of HPS, simvastatin 40 mg daily should
be considered routinely for patients with diabetes
– Simvastatin 40 mg is the only statin proven in a wide range
of patients with diabetes to
 reduce the risk of major coronary events
 reduce the risk of stroke
 reduce the risk of both coronary and noncoronary
revascularization
 reduce the risk of developing peripheral macrovascular
complications (including peripheral revascularization,
limb amputations, and leg ulcers)

Adapted from Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.


Slide 34
Treatment Strategies for Patients with Diabetes
Treatment goals for diabetes should include
 Optimum glycemic control and elimination of hyperglycemia-related symptoms
– Dietary and lifestyle changes
– Exercise
– Medication
 Prevention of microvascular complications
– Control of glycemia
– Control of blood pressure
– Monitoring and screening
 Prevention of CHD, MI, and other macrovascular complications
– Control dyslipidemia: ↓ LDL-C, ↑ HDL-C, ↓ TG
 Dietary and lifestyle changes and exercise
 Drug therapy with statins

Adapted from Powers AC. In Harrison’s Principles of Internal Medicine. 15th ed. New York: McGraw-Hill, 2001:2109-2137;
American Diabetes Association Diabetes Care 2002;25(suppl 1):S74-S77.
Slide 35
References
Please refer to notes page.

Slide 36
References (cont’d)
Please refer to notes page.

Slide 37