the link between

Overview and Clinical Considerations

Highlighting Results of the Diabetes Sub-Study of the Heart Protection Study

The Link Between

Diabetes and Atherosclerosis

Problems and Challenges in Managing Type 2 Diabetes Mellitus

The Problem Atherosclerosis is a prominent but underappreciated complication associated with diabetes mellitus

The ChallengeTherapies to reduce 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

CHD = coronary heart disease

Adapted from Folsum AR et al Diabetes Care 1997;20:935-942; American Diabetes Association Diabetes Care 2002;25(suppl 1):S33-S49.

USA

2000: 15M

2025: 21.9M

JAPAN

2000: 6.9M

2025: 8.5M

EUROPE

2000: 30.8M

2025: 38.5M

AMERICAS(Ex-US)

2000: 20M

2025: 42M

AFRICA

2000: 9.2M

2025: 21.5M

ASIA

2000: 71.8M

2025: 165.7M

OCEANIA

2000: 0.8M

2025: 1.5M

Adapted from King H et al Diabetes Care 1998;21:1414-1431.

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%

Atherosclerosis Is Common in Newly Diagnosed Diabetes Mellitus

CVDs are common causes of morbidity and mortality in people with diabetes

>50% of patients with newly diagnosed type 2 diabetes show evidence of CVD

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

CVD = cardiovascular 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.

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

Two-Thirds of People with Diabetes Die of CVD

Among people with diabetes, macrovascular complications, including CHD, stroke, and peripheral vascular disease, are the leading causes of morbidity and mortality

67%

CHD, stroke, and peripheral vascular diseaseOther

Causes of mortality in people with diabetes

Many patients with diabetes will not survive their first MI

Mortality Following First MI in People with and without Diabetes

MI = myocardial infarction

*p<0.001

Adapted from Miettinen H et al Diabetes Care 1998;21:69-75.

Time post-first MI

Mo

rtal

ity

rate

(%

)

With diabetesWithout diabetes

0

10

20

30

40

50 44%*

33%37%*

20%

Men Women

1 Year, hospitalized and nonhospitalized

n=437 n=2699 n=183 n=743

People with Diabetes Have MI Risk Levels Comparable to People with Prior MI

Adapted from Haffner SM et al N Engl J Med 1998;339:229-234.

20%19%

0

5

10

15

20

25

Diabetes (no prior MI)(n=890)

Prior MI (no diabetes)(n=69)

Inci

den

ce o

f fa

tal

or

no

nfa

tal

MI

(%)

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

People with Diabetes Have Increased Cardiovascular Risk Factors

Risk factor Type 1 Type 2

DyslipidemiaSmall, 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 population; 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.

Greater Risk of Death with Diabetes and One Risk Factor than with No Diabetes and Three Risk Factors*

DiabetesNo diabetes

Ag

e-ad

just

ed C

VD

d

eath

rat

e p

er

10,0

00 p

erso

n-y

ears

*Serum cholesterol >200 mg/dl, smoking, systolic blood pressure >120 mmHg

Adapted from Stamler J et al Diabetes Care 1993;16:434-444.

None One only Two only All three

Risk factors

0

20

40

60

80

100

120

140

Adapted from Stamler J et al Diabetes Care 1993;16:434-444.

Car

dio

vasc

ula

r

mo

rtal

ity

per

10,

000

per

son

-yea

rs

Patients with Diabetes and Low Cholesterol Had Higher Risk of Cardiovascular Mortality than Those without Diabetes and High Cholesterol

DiabetesNo diabetes

Total cholesterol (mmol/L)

0

20

40

60

80

100

120

140

<4.7 4.7–5.1 5.2–5.7 5.8–6.2 6.3–6.7 6.8–7.2 7.3

160

“Normal” LDL-C Levels in People with Diabetes Can Be Misleading...

Small, Dense LDL-C Particles Are More Atherogenic

Diabetes

LDL particles

“Normal” LDL-C level, however:“Normal” LDL-C level

No diabetes LDL particles

Number of LDL particlesConcentration of apoB

Lower

CHD risk

Higher

Small, dense LDL with more apoB

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.

apoB

LDL-C

In People with Diabetes, Macrovascular Complications Are Two Times Greater than Microvascular Complications

20%

9%

0

5

10

15

20

25

Macrovascular complications Microvascular complications

Peo

ple

wit

h d

iab

etes

dev

elo

pin

g

com

plic

atio

ns

wit

hin

9

year

s o

f d

iag

no

sis

(%

)

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

n=5102 n=5102

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.

In UKPDS

Intensive Glucose Control Significantly Reduced Microvascular Disease

Rate*Conventional Intensive

glucose glucosecontrol control % Risk

(n=2729) (n=1138) reduction p

Macrovascular eventsMI 17.4 14.7 16 0.052Stroke 5.0 5.6 –11 NSPVD 1.6 1.1 35 NS

Diabetes-related death 11.5 10.4 10 NSAll-cause mortality 18.9 17.9 6 NSMicrovascular events 11.4 8.6 25 0.0099All events** 46.0 40.9 12 0.029

% 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

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

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

In UKPDS

LDL-C Was the Strongest Predictor of CHD Risk in People with Diabetes

Lipid Guidelines for Patients with Diabetes

American Diabetes Association Guidelines

Dietary therapy Drug treatmentAdults with diabetes LDL goal initiation level initiation level

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

“...people with type 2 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.

Patients with diabetes need lipid-lowering therapy because effective management of blood glucose only modestly improves plasma levels of LDL-C or HDL-C.

CHD risk increases with diabetes LDL-C goal: <100 mg/dl (2.5 mmol/L)

– For patients with diabetes or established CVD

Adapted from De Backer G et al Eur Heart J 2003;24:1601-1610.


European Societies

“…patients with diabetes, the [cholesterol] treatment goals should be lower….”


National Cholesterol Education Program (NCEP)

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

Dietary therapy Drug treatmentAdults 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)

Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:2486-2497.

Intensive CHD prevention strategy is warranted [for patients with diabetes], with LDL-C as a primary treatment target


International Atherosclerosis Society

All patients should undergo therapeutic lifestyle changes

Drug treatment Drug treatmentAdults 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

*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.

“Patients with diabetes experience significant CVD risk reduction with control of other risk factors . . . including LDL-C.”

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—five 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.

Impact of Simvastatin on LDL-C

Nine Out of 10 Patients with Diabetes Achieved Goal*

*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.

92% 91%

0

20

40

60

80

100

Without CHD With CHDResults 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)***

Pat

ien

ts (

%)

n=3985** n=1978**

Impact of Simvastatin on First Major Vascular Events

All Patients and Patients with Diabetes

25.2

19.8

0

10

20

30

All patients*

Pat

ien

ts w

ith

maj

or

vasc

ula

r ev

ents

by

year

5 (

%)

2585patients

with events

*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.

24% risk reduction(p<0.0001)

2033patients

with events

PlaceboSimvastatin

25.1

20.2

Patients with diabetes

749patients

with events

22% risk reduction(p<0.0001)

601patients

with events

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

Impact of Simvastatin on First and Subsequent Major Vascular Events

All Patients and Patients with Diabetes

360

269

0

200

300

400

All patients*

Nu

mb

er o

f fi

rst

and

su

bse

qu

ent

maj

or

vasc

ula

r ev

ents

per

100

0 p

atie

nts

b

y ye

ar 5 2585

patientswith 3697

events

*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.

91 events avoided per 1000 patients taking simvastatin

2033patients

with 2763events

PlaceboSimvastatin

371

286

Patients with diabetes

748patients

with 1109events

85 events avoided per 1000 patients taking simvastatin

601patientswith 852events

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

100

Impact of Simvastatin on First Major Vascular Events

Significant Risk Reduction Within 2 YearsR

isk

rati

o(±

95%

CI)

*Risk reduction was less pronounced in years 4 and 5 because by study end, one-third of placebo-allocated patients were taking a statin and about one-sixth of patients randomized to simvastatin had stopped their statin therapy. The increased risk reduction in years 2 and 3 would have likely continued if the patients remained compliant.

Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; Heart Protection Study Collaborative Group. Available at: http://www.ctsu.ox.ac.uk/~hps/. Accessed November 4, 2003.

Year 1

22% risk reduction

(p<0.0001)

Year 2 Year 3 Year 4 Year 5+ Allfollow-up

0.4

0.6

0.8

1.0

1.2

1.4

*

*

Impact of Simvastatin in Patients with Diabetes

Major Coronary Events, Stroke, and Revascularization

0

10

15

Major coronary event

Stroke Revascularization

Pat

ien

ts w

ith

eve

nt

by

year

5 (

%)

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

*p<0.0001; **p<0.01; ***p=0.02


12.6

6.5

9.4

5.0

27%risk reduction*

24%risk reduction**

10.4

8.7

17%risk reduction***

PlaceboSimvastatin

5

Impact of Simvastatin in Patients with Diabetes and No Prior CVD

Major Vascular Events

0

5

10

15

Pat

ien

ts w

ith

maj

or

vasc

ula

r ev

ents

by

year

5 (

%)

33% risk reduction(p=0.0003)

Placebo

n=1455

13.5

n=1457

9.3

Simvastatin



With Low LDL-C

0

5

10

20

25

Baseline LDL-C<3.0 mmol/L

20.9

15.7

n=1207 n=1219

Baseline LDL-C<3.0 mmol/L without CVD

11.1

8.0

n=668 n=675

Pat

ien

ts w

ith

maj

or

vasc

ula

r ev

ents

by

year

5 (

%)



PlaceboSimvastatin

15



With or without Optimal Glycemic Control

0

10

20

30

Suboptimal glycemic control(HbA1c 7.0%)

Optimal glycemic control(HbA1c <7.0%)

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

27.5

22.6 22.6

18.3



Pat

ien

ts w

ith

maj

or

vasc

ula

r ev

ents

by

year

5 (

%)

PlaceboSimvastatin



With or without Treated Hypertension or Obesity

0

10

20

30

Pat

ien

ts w

ith

maj

or

vasc

ula

r ev

ents

by

year

5 (

%)

Without treatedhypertension

22.3

17.9

n=1783 n=1782

With treatedhypertension

29.1

23.6

n=1202 n=1196

Lean

n=646

24.0

19.6

n=629

Obese

n=1123

24.020.3

n=1060

Placebo

Simvastatin

0

10

20

30

22% risk reduction*

22% risk reduction* 21%

risk reduction*17%

risk reduction*

Regardless of treated hypertension

Regardless of bodymass index

*p<0.05



By Age and Gender P

atie

nts

wit

h m

ajo

r va

scu

lar

even

ts b

y ye

ar 5

(%

)

0

10

20

30

40

Age <65 years

20.1

15.7

n=1696 n=1675

Age 65 years

31.6

25.9

n=1289 n=1303

Male

n=2083

27.8

22.8

n=2064

Female

n=902

18.6

14.2

n=914

Placebo

Simvastatin

0

10

20

30

40

24% risk reduction*

21% risk reduction* 21%

risk reduction*

25% risk reduction*

Regardless of age Regardless of gender

*p<0.05


In Over 20,000 Patients in HPS

Simvastatin 40 mg Had a Safety Profile Comparable to Placebo

0

2

4

6

8

Pa

tie

nts

(%

) 10

Simvastatin (n=10,269)

4.8%

Placebo(n=10,267)

5.1%

100


Discontinuations due to any adverse event

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


Simvastatin 40 mg Comparable to Placebo Incidence of Muscle Pain

*Myopathy defined as muscle symptoms plus creatine kinase >10 times the upper limit of normal


0

10

15

All patients Patients withdiabetes

Incr

ease

in

pla

sma

crea

tin

ine

con

cen

trat

ion

(µ

mm

ol/

L)

n=7697 n=7999 n=2172 n=2291 n=5525 n=5708


8.9

12.9

7.1

10.7

–1.8(p<0.0001)

–2.2(p<0.05)

7.4

5.7

–1.7(p<0.001)

PlaceboSimvastatin

5

Patients withoutdiabetes


Impact of Simvastatin 40 mg on Renal Function

Patients with diabetes have an alarming rate 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 Care1998;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; De Backer G et al Eur Heart J 2003;24:1601-1610.

Lipid Lowering in Patients with Diabetes

Conclusions


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 Heart2000;84:357-360; Heart Protection Study Collaborative Group Lancet 2003;361:2005-2016.


Medical Implications

Based on the results of HPS, simvastatin 40 mg daily shouldbe 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)


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.

References

Please refer to notes page.

References (cont’d)

Please refer to notes page.

the link between

Documents

diabetes prevalence

prevalence of diabetes

diabetes substudy

risk of mi

chd risk

previous mi

nondiabetic patients

nonfatal mi