Overview and Clinical Considerations Highlighting Results of the Diabetes SubStudy of the Heart Prot

1
Overview and Clinical ConsiderationsHighlighting
Results of the Diabetes Sub-Study of the Heart
Protection Study
The Link Between
Diabetes and Atherosclerosis
2
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 199720935-942 American
Diabetes Association Diabetes Care 200225(suppl
1)S33-S49.
3
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 2000 30.8M 2025 38.5M
ASIA 2000 71.8M 2025 165.7M
JAPAN 2000 6.9M 2025 8.5M
USA 2000 15M 2025 21.9M
AFRICA 2000 9.2M 2025 21.5M
AMERICAS (Ex-US) 2000 20M 2025 42M
OCEANIA 2000 0.8M 2025 1.5M
Adapted from King H et al Diabetes Care
1998211414-1431.
4
Atherosclerosis Is Common in Newly Diagnosed
Diabetes Mellitus

• CVDs are common causes of morbidity and mortality
  in people with diabetes
• gt50 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
• gt75 of hospitalizations for individuals with
  diabetes are for atherosclerotic disease

CVD cardiovascular disease Adapted from Amos AF
et al Diabet Med 199714S7-S85 Hill Golden S
Adv Stud Med 20022364-370 Haffner SM et al N
Engl J Med 1998339229-234 Sprafka JM et al
Diabetes Care 199114537-543.
5
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

Causes of mortality in people with diabetes
CHD, stroke, and peripheral vascular disease Other

Adapted from Alexander CM, Antonello S Pract
Diabet 20022121-28.
6
Mortality Following First MI in People with and
without Diabetes

• Many patients with diabetes will not survive
  their first MI

With diabetes Without diabetes
50
44
37
40
33
30
Mortality rate ()
20
20
10
n437
n2699
n183
n743
0
Men
Women
1 Year, hospitalized and nonhospitalized
Time post-first MI
MI myocardial infarction plt0.001 Adapted from
Miettinen H et al Diabetes Care 19982169-75.
7
People with Diabetes Have MI Risk Levels
Comparable to People with Prior MI
25
20
19
20
15
Incidence of fatal or nonfatal MI ()
10
5
0
Diabetes (no prior MI) (n890)
Prior MI (no diabetes) (n69)
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
1998339229-234.
8
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 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, 1994648-664.
9
Greater Risk of Death with Diabetes and One Risk
Factor than with No Diabetes and Three Risk
Factors
140
Diabetes No diabetes
120
100
Age-adjusted CVD death rate per 10,000
person-years
80
60
40
20
0
None
One only
Two only
All three
Risk factors
Serum cholesterol gt200 mg/dl, smoking, systolic
blood pressure gt120 mmHg Adapted from Stamler J
et al Diabetes Care 199316434-444.
10
Patients with Diabetes and Low Cholesterol Had
Higher Risk of Cardiovascular Mortality than
Those without Diabetes and High Cholesterol
DiabetesNo diabetes
160
140
120
Cardiovascular mortality per 10,000 person-years
100
80
60
40
20
0
lt4.7
4.75.1
5.25.7
5.86.2
6.36.7
6.87.2
?7.3
Total cholesterol (mmol/L)
Adapted from Stamler J et al Diabetes Care
199316434-444.
11
Normal LDL-C Levels in People with Diabetes Can
Be Misleading...Small, Dense LDL-C Particles Are
More Atherogenic
apoB LDL-C
No diabetes
Diabetes
LDL particles
LDL particles
Small, dense LDL with more apoB
Normal LDL-C level, however
Normal LDL-C level
Number of LDL particles Concentration of apoB
Higher
Lower
CHD risk
Adapted from Austin MA, Edwards KL Curr Opin
Lipidol 19967167-171 Austin MA et al JAMA
19882601917-1921 Sniderman AD et al Diabetes
Care 200225579-582.
12
In People with Diabetes, Macrovascular
Complications Are Two Times Greater than
Microvascular Complications
25
20
20
15
People with diabetes developing complications
within 9 years of diagnosis ()
9
10
5
n5102
n5102
0
Macrovascular complications
Microvascular complications
Adapted from Turner R et al Ann Intern Med
1996124136-145.
13
In UKPDS Intensive Glucose Control Significantly
Reduced Microvascular Disease

• Rate Conventional Intensive
• glucose glucose control control Risk
• (n2729) (n1138) 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-yearsCombined
microvascular and macrovascular events Adapted
from United Kingdom Prospective Diabetes Study
Group (UKPDS) Lancet 1998352837-853.
14
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 riskin people with diabetes mellitus.
Glucose control is also important in reducing the
risk of microvascular complications.
Adapted from Turner RC et al BMJ 1998316823-828.
15
Lipid Guidelines for Patients with
DiabetesAmerican 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 lt100 mg/dl ?100 mg/dl ?130
mg/dl With CHD lt100 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 200225(suppl 1)S33-S49 American
Diabetes Association Diabetes Care 200225(suppl
1)S74-S77.
16
Lipid Guidelines for Patients with
DiabetesEuropean Societies
patients with diabetes, the cholesterol
treatment goals should be lower.

• CHD risk increases with diabetes
• LDL-C goal lt100 mg/dl (2.5 mmol/L)
• For patients with diabetes or established CVD

Adapted from De Backer G et al Eur Heart J
2003241601-1610.
17
Lipid Guidelines for Patients with
DiabetesNational 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 treatmentAdults with
diabetes LDL goal initiation level initiation
level With or without CHD lt100 mg/dl ?100 mg/dl
?130 mg/dl (100129 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 20012852486-2497.
18
Lipid Guidelines for Patients with Diabetes
International Atherosclerosis Society
Patients with diabetes experience significant
CVD risk reduction with control of other risk
factors . . . including LDL-C.
Drug treatment Drug treatmentAdults with
diabetes LDL goal recommended optional High
risk lt100 mg/dl ?100 mg/dl lt100 mg/dl Multiple
risk factors lt130 mg/dl ?130 mg/dl lt130 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
gt20). 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.
19
Heart Protection StudyDiabetes Sub-Study

• Almost 6000 men and women, aged 4080 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-upfive years
• Objectiveto evaluate the long-term benefits of
  simvastatin and/or antioxidants in people with
  diabetes with or without CHD regardless of
  cholesterol level
• Primary endpointsfirst 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
199920725-741 Heart Protection Study
Collaborative Group Lancet 20023607-22 Heart
Protection Study Collaborative Group Lancet
20033612005-2016.
20
Impact of Simvastatin on LDL-CNine Out of 10
Patients with Diabetes Achieved Goal
92
91
100
80
60
Patients ()
40
20
n3985
n1978
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 lt3 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
200084357-360.
21
Impact of Simvastatin on First Major Vascular
EventsAll Patients and Patients with Diabetes
24 risk reduction(plt0.0001)
22 risk reduction(plt0.0001)
30
25.2
25.1
20.2
19.8
20
Patients with major vascular events by year 5 ()
2585patients with events
749patients with events
2033 patients with events
601 patients with events
10
n10,267
n10,269
n2985
n2978
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 20023607-22 Heart
Protection Study Collaborative Group Lancet
20033612005-2016.
22
Impact of Simvastatin on First and Subsequent
Major Vascular EventsAll Patients and Patients
with Diabetes
85 events avoided per 1000 patients taking
simvastatin
91 events avoided per 1000 patients taking
simvastatin
371
360
400
286
269
300
Number of first and subsequent major vascular
events per 1000 patients by year 5
2585patients with 3697 events
748patients with 1109events
200
2033 patients with 2763 events
601 patients with 852events
100
n10,267
n10,269
n2985
n2978
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 20033612005-2016.
23
Impact of Simvastatin on First Major Vascular
EventsSignificant Risk Reduction Within 2 Years
1.4
1.2
1.0
Risk ratio(95 CI)

0.8

22 risk reduction(plt0.0001)
0.6
0.4
Year 2
Year 3
Year 4
Year 5
Allfollow-up
Year 1
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 20023607-22
Heart Protection Study Collaborative Group.
Available at http//www.ctsu.ox.ac.uk/hps/.
Accessed November 4, 2003.
24
Impact of Simvastatin in Patients with
DiabetesMajor Coronary Events, Stroke, and
Revascularization
Placebo Simvastatin
27risk reduction
17risk reduction
15
12.6
24risk reduction
10.4
9.4
10
8.7
Patients with event by year 5 ()
6.5
5.0
5
n2985
n2978
n2985
n2978
n2985
n2978
0
Major coronary event
Stroke
Revascularization
plt0.0001 plt0.01 p0.02 Adapted from Heart
Protection Study Collaborative Group Lancet
20033612005-2016.
25
Impact of Simvastatin in Patients with Diabetes
and No Prior CVDMajor Vascular Events
33 risk reduction(p0.0003)
15
13.5
9.3
10
Patients with major vascular events by year 5 ()
5
n1455
n1457
0
Placebo
Simvastatin
Adapted from Heart Protection Study Collaborative
Group Lancet 20033612005-2016.
26
Impact of Simvastatin in Patients with Diabetes
With Low LDL-C
27 risk reduction (p0.0007)
Placebo Simvastatin
25
20.9
20
30 risk reduction (p0.05)
15.7
15
Patients with major vascular events by year 5
()
11.1
10
8.0
5
n1207
n1219
n668
n675
0
Baseline LDL-Clt3.0 mmol/L
Baseline LDL-Clt3.0 mmol/L without CVD
Adapted from Heart Protection Study Collaborative
Group Lancet 20033612005-2016.
27
Impact of Simvastatin in Patients with Diabetes
With or without Optimal Glycemic Control
21 risk reduction (p0.002)
21 risk reduction (p0.002)
30
27.5
22.6
22.6
18.3
20
Patients with major vascular events by year 5
()
10
n1355
n1334
n1595
n1610
0
Suboptimal glycemic control (HbA1c ?7.0)
Optimal glycemic control (HbA1c lt7.0)
Adapted from Heart Protection Study Collaborative
Group Lancet 20033612005-2016.
28
Impact of Simvastatin in Patients with
DiabetesWith or without Treated Hypertension or
Obesity
Regardless of treated hypertension
Regardless of bodymass index
Placebo Simvastatin
22 risk reduction
17 risk reduction
21 risk reduction
22 risk reduction
29.1
30
30
24.0
24.0
23.6
22.3
20.3
Patients with major vascular events by year 5 ()
19.6
17.9
20
20
10
10
n1783
n1782
n1202
n1196
n646
n629
n1123
n1060
0
0
Without treatedhypertension
With treated hypertension
Lean
Obese
plt0.05 Adapted from Heart Protection Study
Collaborative Group Lancet 20033612005-2016.
29
Impact of Simvastatin in Patients with
DiabetesBy Age and Gender
Placebo Simvastatin
Regardless of age
Regardless of gender
21 risk reduction
21 risk reduction
40
40
31.6
24 risk reduction
25 risk reduction
27.8
30
30
25.9
22.8
Patients with major vascular events by year 5 ()
20.1
18.6
20
20
15.7
14.2
10
10
n1696
n1675
n1289
n1303
n2083
n2064
n902
n914
0
0
Age lt65 years
Age ?65 years
Male
Female
plt0.05 Adapted from Heart Protection Study
Collaborative Group Lancet 20033612005-2016.
30
In Over 20,000 Patients in HPSSimvastatin 40 mg
Had a Safety Profile Comparable to Placebo
100
10
8
5.1
Patients ()
4.8
6
4
2
0
Simvastatin (n10,269)
Placebo(n10,267)
Discontinuations due to any adverse event
Adapted from Heart Protection Study Collaborative
Group Lancet 20023607-22.
31
In Over 20,000 Patients in HPSSimvastatin 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 gt10 times the upper limit of
normal Adapted from Heart Protection Study
Collaborative Group Lancet 20023607-22.
32
In Over 20,000 Patients in HPSImpact of
Simvastatin 40 mg on Renal Function
Placebo Simvastatin
2.2(plt0.05)
1.8(plt0.0001)
15
12.9
1.7(plt0.001)
10.7
10
8.9
Increase in plasma creatinine concentration
(µmmol/L)
7.4
7.1
5.7
5
n7697
n7999
n2172
n2291
n5525
n5708
0
All patients
Patients withdiabetes
Patients withoutdiabetes
Adapted from Heart Protection Study Collaborative
Group Lancet 20033612005-2016.
33
Lipid Lowering in Patients with
DiabetesConclusions

• 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 200225(suppl 1)S33-S49 Miettinen
H et al Diabetes Care19982169-75 Expert Panel
on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults JAMA
20012852486-2497 United Kingdom Prospective
Diabetes Study Group Lancet 1998352837-853
American Diabetes Association Diabetes Care
200225(suppl 1)S74-S77 De Backer G et al Eur
Heart J 2003241601-1610.
34
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 (plt0.0001)
• Stroke by 24 (p0.01)
• Revascularization by 17 (p0.02)
• 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
20023607-22 Armitage J, Collins R
Heart200084357-360 Heart Protection Study
Collaborative Group Lancet 20033612005-2016.
35
Heart Protection StudyMedical 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)

Adapted from Heart Protection Study Collaborative
Group Lancet 20033612005-2016.
36
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 Harrisons Principles
of Internal Medicine. 15th ed. New York
McGraw-Hill, 20012109-2137 American Diabetes
Association Diabetes Care 200225(suppl
1)S74-S77.
37
References

• Please refer to notes page.

38
References (contd)

• Please refer to notes page.