Health

1. EDUCATIONAL SLIDE MODULES
Module A:
Cardiovascular disease and
Type 2 Diabetes
Date of preparation: August 2015

2. ACROSS T2D educational slide modules
• CV disease and T2D
Module A
• Approaches to managing CV risk in patients with T2D
Module B
• Evidence for effects of older glucose-lowering agents on CV risk
Module C
• Evaluating CV safety and potential for CV risk reduction with
newer T2D agents
Module D
• EMPA-REG OUTCOME® results
Module E
2

3. 3
CV
disease
The size of
the problem
Patho-
physiology
T2D as a
major
risk factor
Additional
risk factors
are
common in
T2D

4. 4
CV
disease
The size of
the problem
Patho-
physiology
T2D as a
major
risk factor
Additional
risk factors
are
common in
T2D

5. CVD is a significant global burden
5
1. WHO. CVD Fact sheet N°317, Jan 2015. http://www.who.int/mediacentre/factsheets/fs317/en/#.
31% due
to CVD
7.4
million
due to
CHD
6.7
million
due to
stroke
Total global deaths
in 2012 ~56 million1

6. Represents 2 million people.
Diabetes is mostly (85–95%) T2D.1
• T2D approximately doubles the
risk of death2
• Diabetes caused 4.9 million
deaths in 20141
• CVD is the principal cause of
death in T2D2,3
1.76
1.85
1 1.5 2.0
T2D is increasingly prevalent and CVD is the
leading cause of death in this population
6
1. IDF Diabetes Atlas, 2014. 6th Edition. http://www.idf.org/diabetesatlas.
2. Nwaneri et al. Br J Diabetes Vasc Dis 2013;13:192–207. 3. Morrish et al. Diabetologia 2001;44(suppl 2):S14–21.
• Globally, 387 million people are
living with diabetes1
• Rising to 592 million by 20351
Relative risk for
all-cause mortality
Relative risk for
CV mortality

7. 7
CV
disease
The size of
the problem
Patho-
physiology
T2D as a
major
risk factor
Additional
risk factors
are
common in
T2D

8. Key manifestations of CV disease
8
1. World Health Organization 2015: http://www.who.int/cardiovascular_diseases/en/cvd_atlas_01_types.pdf?ua=1
2. http://www.heart.org/HEARTORG/Caregiver/Resources/WhatisCardiovascularDisease/What-is-Cardiovascular-Disease_UCM_301852_Article.jsp#
Peripheral
arterial disease
Disease of blood vessels
supplying arms and legs1
Coronary
heart disease
Disease of blood vessels
supplying heart muscle1
Stroke
Caused by disruption of blood
supply to the brain1
Heart failure
Failure of the heart to pump
blood with normal efficiency
(sometimes called congestive
heart failure)2

9. T2D is a major and independent risk factor for both
microvascular and macrovascular complications
9
1. World Health Organization. http://www.who.int/diabetes/action_online/basics/en/index3.html
Macrovascular
Microvascular

10. Endothelial dysfunction is common to microvascular
and macrovascular events
10
Versari et al. Diabetes Care 2009;32(suppl 2):S314-321.
10
Normal conditions Risk factors Subclinical organ factors Clinical events
Remodelling – hypertrophy
Remodelling – plaque
Microalbuminuria/mild insufficiency
Endothelial function
Myocardial infarction
Heart failure
Peripheral artery disease
TIA, stroke
Aortic aneurism
Overt proteinuria
End-stage renal failure

11. Endothelial dysfunction drives atherosclerotic
progression
11
Figure adapted from Libby. Circulation 2001;104:365‒72.
Zeadin et al. Can J Diabetes 2013;37:345e350.
Atherosclerosis is accelerated in T2D by hyperglycaemia, insulin resistance,
inflammation and diabetic dyslipidaemia

12. Visceral adiposity is related to inflammation, insulin
resistance, dyslipidaemia and atherosclerosis
12
*including: TNFα, IL-6, resistin, PAI-1, angiotensinogen
Lau et al. Am J Physiol Heart Circ Physiol 2005;288:H2031‒41.
OBESITY
 Adiponectin
Adipocytokines
 inflammatory
cytokines*
T2D
Insulin
resistance
Dyslipidaemia
Endothelial
dysfunction
Hypertension
Age
 Oxidative
stress
 Atherosclerosis
Interactions are complex, inter-related and not necessarily causal

13. Burden and pathophysiology of CVD
and T2D
• CVD is a significant cause of morbidity and mortality globally
and is the leading cause of death in people with T2D1-4
• T2D is a major independent risk factor for CVD5
• Endothelial dysfunction:6
– Affects microvascular and macrovascular risk
– Drives atherosclerosis
• Atherosclerosis is accelerated in patients with T2D7,8
• Visceral adiposity is associated with increased insulin
resistance, inflammation and atherogenic dyslipidaemia9
13
Section
recap
1. http://www.who.int/mediacentre/factsheets/fs317/en/#. 2. http://www.idf.org/diabetesatlas.
3. Nwaneri et al. Br J Diabetes Vasc Dis 2013;13:192–207. 4. Morrish et al. Diabetologia 2001;44 Suppl 2:S14–21.
5. http://www.who.int/diabetes/action_online/basics/en/index3.html. 6. Versari D, et al. Diabetes Care. 2009;32(Suppl
2):S314-321. 7. Libby P. Circulation. 2001;104:365-372. 8. Zeadin, et al. Can J Diabetes. 2013;37:345e350.
9. Lau et al. Am J Physiol Heart Circ Physiol 2005;288:H2031-H2041.

14. 14
CV
disease
The size of
the problem
Patho-
physiology
T2D as a
major
risk factor
Additional
risk factors
are
common in
T2D

15. Coronary heart disease
Coronary death
Non-fatal MI
Cerebrovascular disease
Ischaemic stroke
Haemorrhagic stroke
Unclassified stroke
Other vascular deaths
2.00 (1.83–2.19)
2.31 (2.05–2.60)
1.82 (1.64–2.03)
2.27 (1.95–2.65)
1.56 (1.19–2.05)
1.84 (1.59–2.13)
1.73 (1.51–1.98)
HR (95% CI)
26,505
11,556
14,741
3799
1183
4973
3826
Number
of cases
1
1 2 4
Hazard ratio (diabetes vs no diabetes)
Outcome
Diabetes doubles the risk of vascular events
Sarwar et al. Lancet 2010;375(9733):2215–2222.
15
2

16. Diabetes is associated with significant loss of
life years
16
Seshasai et al. N Engl J Med 2011;364:829-41.
0
7
6
5
4
3
2
1
0
40 50 60 70 80 90
Age (year)
Years
of
life
lost
Men
7
6
5
4
3
2
1
0
40 50 60 70 80 90
0
Age (year)
Women
Non-vascular deaths
Vascular deaths
On average, a 50-year old with diabetes but no history of vascular disease is
~6 years younger at time of death than a counterpart without diabetes

17. Disease status at
baseline
No. of
participants
No. of
deaths
Person-
years
Hazard ratio
(95% CI)
Diabetes, stroke and MI 541 379 3584 6.9 (5.7–8.3)
Stroke and MI 1836 1174 14,210 3.5 (3.1–4.0)
Diabetes and stroke 1321 778 10,234 3.8 (3.5–4.2)
Diabetes and MI 3233 1794 25,321 3.7 (3.3–4.1)
MI 21,591 9636 216,081 2.0 (1.9–2.2)
Stroke 8583 3814 82,208 2.1 (2.0–2.2)
Diabetes 24,677 8087 254,608 1.9 (1.8–2.0)
None 627,518 103,181 8,772,977 1 [Reference]
Life expectancy is reduced by multiple morbidities
of diabetes, stroke and MI
17
Adapted from Danesh et al. for ERFC JAMA 2015;314:52–60.
Age- and sex-adjusted HRs for mortality by baseline disease status
1 2 4 8 16
Hazard ratio
(95% CI)

18. Diabetes confers significant CV risk; combination of
diabetes and history of MI further increases risk
18
Schramm et al. Circulation 2008;117:1945–54.
CV
mortality
event
rate/1000
person-years
250
200
150
100
50
0
30–39 40–49 50–59 60–69 70–79 80–89
Age
Men Women
250
200
150
100
50
0
30–39 40–49 50–59 60–69 70–79 80–89
Age
No diabetes, no prior MI
Diabetes
Prior MI
Diabetes + prior MI

19. Diabetes-related CV complications have declined
with improved care, but substantial burden remains
19
Adapted from Gregg et al. N Engl J Med 2014;370:1514‒23.
0
50
100
150
1990 2000 2010
Events
per
10,000
adult
population
with
diabetes
MI Stroke ESRD
Years

20. Renal disease is associated with increased
all-cause mortality
20
*Includes participants with or without diabetes and chronic kidney disease.
Tonelli et al. Lancet 2012;380(9844):807–14.
75
60
45
15
0
Rates
(per
1000
person-years)
Previous MI* Diabetes
and CKD
CKD (eGFR
<60 mL/min per
1.73 m2)
Diabetes No diabetes
or CKD
30
All-cause
mortality

21. T2D increases CV risk
• Diabetes doubles the risk of vascular events, and reduces life
expectancy1,2
– Risk is further increased in patients with T2D and CVD3,4
• Incidence of T2D-related CV complications have declined with
improved standard of care5
– However, rates remain higher than in adults with no diabetes
and rising incidence of T2D will increase overall burden
• Combination of T2D and renal disease further increases CV
risk6
21
Section
recap
1. Sarwar et al. Lancet. 2010;375(9733):2215–2222. 2. Seshasai et al. N Engl J Med 2011;364:829-41. 3. Haffner SM, et al.
N Engl J Med. 1998;339:229–234. 4. Schramm TK, et al. Circulation. 2008;117:1945–1954. 5. Gregg EW, et al. N Engl J
Med. 2014;370:1514-1523. 6. Tonelli M et al. Lancet 2012.;380(9844):807–814.

22. 22
CV
disease
The size of
the problem
Patho-
physiology
T2D as a
major
risk factor
Additional
risk factors
are
common in
T2D

23. Modifiable CV risk factors are common in patients
with T2D1,2
23
Almost a third of diabetes patients were current smokers2
1. Svensson et al. Diab Vasc Dis Res 2013;10:520–9. 2. Das et al. Am Heart J 2006;151:1087–93.

24. CV death is increased in patients with diabetes and
multiple risk factors
24
Risk factors were serum cholesterol ≥200 mg/dL, current smoker, SBP ≥120 mmHg
Stamler et al. Diabetes Care 1993;16:434.
0
20
40
60
80
100
120
140
0 1 2 3
Age-adjusted
CVD
death
risk/10,000
person-years
Number of risk factors
Diabetes
No diabetes

25. Dysglycaemia is an independent risk factor for
adverse CV outcomes
25
1. Sarwar et al. Lancet 2010;375:2215–22.
2. Seshasai et al. N Engl J Med 2011;364:829–41.
Vascular death2
Adjusted
HR
(95%
CI)
2.5
2.0
0
3
1.5
0.9
4 10
0 5 6 7 8 9
Mean FBG concentration (mmol/L)
1.0
No history of diabetes at baseline
History of diabetes at baseline
No known history of diabetes at baseline survey
Known history of diabetes at baseline survey
Adjusted
HR
(95%
CI)
4.0
3.0
0
3
2.0
1.0
4 10
0 5 6 7 8 9
Mean FBG concentration (mmol/L)
Coronary heart disease1

26. Hypertension: each 20/10 mmHg BP increase
doubles the risk of CV mortality
26
Population of 1 million adults with no previous vascular disease recorded at baseline in 61 prospective observational studies of
blood pressure and mortality
Lewington et al. Lancet 2002;360:1903–13.
1-fold
2-fold
4-fold
8-fold
0
2
4
6
8
10
135/85 155/95 175/105
Fold
increase
in
relative
CV
risk
115/75
SBP/DBP mmHg

27. Dyslipidaemia: increased LDL-C increases risk
of CHD
27
Grundy et al. Arterioscler Thromb Vasc Biol 2004;24:e149-e161.
40 70 100 130 160 190
1.0
1.3
1.7
2.2
2.9
3.7
Relative
risk
for
CHD
(log
scale)
LDL-C (mg/dL)

28. Dyslipidaemia: increased LDL-C and decreased
HDL-C are associated with raised risk of CHD
28
Taylor. Eur Heart J Suppl 2006;8:F74–80.
3.0
2.0
1.0
0.0
100 160 220
85
65
45
25
LDL-C (mg/dL)
Relative
risk
of
CHD

29. Abdominal obesity is associated with increased
risk of both diabetes and CVD
29
Population of 168,000 primary care patients across 63 countries
Balkau et al. Circulation 2007;116:1942–51.
20
15
10
5
0
<84 ≥84–<92 ≥92–<99 ≥99–<107 ≥107
Waist circumference (cm)
Frequency
(%)
CVD Diabetes
Men

30. Additional risk factors in T2D
• Modifiable CV risk factors are common in patients with T2D1,2
• CV mortality is higher in patients with T2D and multiple risk
factors
– Hyperglycaemia is associated with a non-linear increase in risk
of CV events and mortality3,4
– Hypertension leads to a non-linear increase in mortality5
– Increased LDL leads to a non-linear increase in risk of CHD6,7
– Visceral obesity is associated with increased risk of both
diabetes and CVD8
30
Section
recap
1. Svensson et al. Diab Vasc Dis Res 2013;10:520–9. 2. Das et al. Am Heart J 2006;151:1087–93. 3. Sarwar et al. Lancet.
2010;375:2215–2222. 4. Seshasai et al. N Engl J Med. 2011;364:829–841. 5. Lewington S, et al. Lancet. 2002;360:1903–
1913. 6. Grundy et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:e149-e161. 7. Taylor AJ. European
Heart Journal. Supplement 2006;8:F74–80. 8. Balkau B, et al. Circulation. 2007;116:1942–1951.
.

31. Summary
• T2D is a major independent risk factor for CVD1
• Endothelial dysfunction and progression of atherosclerosis
is accelerated in patients with T2D2,3
• Patients with T2D are at significantly increased CV risk4
• Additional risk factors associated with T2D4-9
– Hypertension, dyslipidaemia, visceral adiposity,
hyperglycaemia and renal dysfunction are all associated
with further increasing CV risk
31
1. World Health Organization. http://www.who.int/diabetes/action_online/basics/en/index3.html. 2. Libby P. Circulation.
2001;104:365-372. 3. Zeadin, et al. Can J Diabetes. 2013;37:345e350. 4. Sarwar et al. Lancet. 2010;375(9733):2215–2222.
5. Seshasai et al. N Engl J Med. 2011;364:829–841. 6. Lewington S, et al. Lancet. 2002;360:1903–1913. 7. Grundy et al.
Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:e149-e161. 8. Taylor AJ. European Heart Journal.
Supplement 2006;8:F74–80. 9. Balkau B, et al. Circulation. 2007;116:1942–1951.