Diabetes & Heart Diseases
ACROSS T2D educational slide modules
Module A
• CV disease and T2D
Module B
• Approaches to managing CV risk in patients with T2D
Module C
• Evidence for effects of older glucose-lowering agents on CV risk
Module D
• Evaluating CV safety and potential for CV risk reduction with
newer T2D agents
Module E
• EMPA-REG OUTCOME® results
3
The size of
the problem
Additional
risk factors
are common
in T2D
CV
disease
T2D as a
major
risk factor
4
Pathophysiology
The size of
the problem
Additional
risk factors
are common
in T2D
CV
disease
T2D as a
major
risk factor
5
Pathophysiology
CVD as a significant global burden
7.4
million
due to
CHD
31% due
to CVD
Total global deaths in
2012 ~56 million1
1. WHO. CVD Fact sheet N°317, Jan 2015. http://www.who.int/mediacentre/factsheets/fs317/en/#.
6
6.7
million
due to
stroke
T2D is increasingly prevalent and CVD is the leading
cause of death in this population
• Globally, 387 million people are living
with diabetes1
• T2D approximately doubles the risk
of death2
Relative risk for
1.85 all-cause mortality
1.76
1
1.5
Relative risk for
CV mortality
2.0
• Diabetes caused 4.9 million deaths
in 20141
• Rising to 592 million by 20351
• CVD is the principal cause of death
in T2D2,3
Represents 2 million people.
Diabetes is mostly (85–95%) T2D.1
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.
7
The size of
the problem
Additional
risk factors
are common
in T2D
CV
disease
T2D as a
major
risk factor
8
Pathophysiology
Key manifestations of CV disease
Stroke
Coronary
heart disease
Disease of blood vessels
supplying heart muscle1
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
Peripheral arterial
disease
Disease of blood vessels
supplying arms and legs1
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#
T2D is a major and independent risk
factor for both microvascular and
macrovascular complications
Macrovascular
Microvascular
1. World Health Organization. http://www.who.int/diabetes/action_online/basics/en/index3.html
10
Endothelial dysfunction is common to microvascular
and macrovascular events
Remodelling – hypertrophy
Peripheral artery disease
TIA, stroke
Aortic aneurism
Remodelling – plaque
Microalbuminuria/mild insufficiency
Normal conditions
Risk factors
Endothelial function
11
Versari
11et al. Diabetes Care 2009;32(suppl 2):S314-321.
Myocardial infarction
Heart failure
Subclinical organ factors
Overt proteinuria
End-stage renal failure
Clinical events
Endothelial dysfunction drives atherosclerotic
progression
Atherosclerosis is accelerated in T2D by hyperglycaemia, insulin resistance, inflammation
and diabetic dyslipidaemia
Figure adapted from Libby. Circulation 2001;104:365‒72.
Zeadin et al. Can J Diabetes 2013;37:345e350.
Visceral adiposity is related to inflammation, insulin
resistance, dyslipidaemia and atherosclerosis
Interactions are complex, inter-related and not necessarily causal
Dyslipidaemia
 Adiponectin
T2D
OBESITY
Adipocytokines
 inflammatory
cytokines*
Endothelial
dysfunction
Hypertension
Insulin
resistance
Age
 Oxidative
stress
*including: TNFα, IL-6, resistin, PAI-1, angiotensinogen
Lau et al.13
Am J Physiol Heart Circ Physiol 2005;288:H2031‒41.
 Atherosclerosis
Section
recap
Summary: 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
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.
The size of
the problem
Additional
risk factors
are common
in T2D
CV
disease
T2D as a
major
risk factor
15
Pathophysiology
Diabetes doubles the risk of vascular events
Outcome
Number
of cases
HR (95% CI)
Coronary heart disease
26,505
2.00 (1.83–2.19)
Coronary death
11,556
2.31 (2.05–2.60)
Non-fatal MI
14,741
1.82 (1.64–2.03)
Ischaemic stroke
3799
2.27 (1.95–2.65)
Haemorrhagic stroke
1183
1.56 (1.19–2.05)
Unclassified stroke
4973
1.84 (1.59–2.13)
Other vascular deaths
3826
1.73 (1.51–1.98)
Cerebrovascular disease
2
1
2
Hazard ratio (diabetes vs no diabetes)
Sarwar et al. Lancet 2010;375(9733):2215–2222.
16
4
Diabetes is associated with significant loss of life
years
Men
Women
7
Non-vascular deaths
Years of life lost
6
Vascular deaths
7
6
5
5
4
4
3
3
2
2
1
1
0
0
0 40
50
60
70
Age (year)
80
90
0 40
50
60
70
80
Age (year)
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
Seshasai et al. N Engl J Med 2011;364:829-41.
17
90
Life expectancy is reduced by multiple morbidities of
diabetes, stroke and MI
Age- and sex-adjusted HRs for mortality by baseline disease status
Disease status at baseline No. of
participants
No. of
deaths
Personyears
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]
1
Adapted from Danesh et al. for ERFC JAMA 2015;314:52–60.
18
4
2
8
Hazard ratio
(95% CI)
16
CV mortality event rate/1000 personyears
Diabetes confers significant CV risk;
combination of diabetes and history of MI
further increases
Men risk
Women
250
250
200
200
150
150
100
100
50
50
0
0
30–39 40–49 50–59 60–69 70–79 80–89
30–39 40–49 50–59 60–69 70–79 80–89
Age
Age
No diabetes, no prior MI
Diabetes
Schramm et al. Circulation 2008;117:1945–54.
19
Prior MI
Diabetes + prior MI
Diabetes-related CV complications have declined with
improved care, but substantial burden remains
Events per 10,000
adult population with diabetes
150
MI
ESRD
100
50
0
1990
Adapted from Gregg et al. N Engl J Med 2014;370:1514‒23.
20
Stroke
2000
Years
2010
Renal disease is associated with increased
all-cause mortality
All-cause mortality
Rates (per 1000 person-years)
75
60
45
30
15
0
Previous MI*
*Includes participants with or without diabetes and chronic kidney disease.
Tonelli et al. Lancet 2012;380(9844):807–14.
21
Diabetes
and CKD
CKD (eGFR <60
mL/min per 1.73
m2)
Diabetes
No diabetes
or CKD
Summary: 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
1.
2.
3.
4.
5.
6.
Sarwar et al. Lancet. 2010;375(9733):2215–2222.
Seshasai et al. N Engl J Med 2011;364:829-41.
Haffner SM, et al. N Engl J Med. 1998;339:229–234.
Schramm TK, et al. Circulation. 2008;117:1945–1954.
Gregg EW, et al. N Engl J Med. 2014;370:1514-1523.
Tonelli M et al. Lancet 2012.;380(9844):807–814.
The size of
the problem
Additional
risk factors
are common
in T2D
CV
disease
T2D as a
major
risk factor
23
Pathophysiology
Modifiable CV risk factors are common in patients
with T2D1,2
Almost a third of diabetes patients were current smokers 2
1. Svensson et al. Diab Vasc Dis Res 2013;10:520–9. 2. Das et al. Am Heart J 2006;151:1087–93.
24
Age-adjusted CVD death risk/10,000
person-years
CV death is increased in patients with diabetes and
multiple risk factors
Diabetes
140
No diabetes
120
100
80
60
40
20
0
0
Risk factors were serum cholesterol ≥200 mg/dL, current smoker, SBP ≥120 mmHg
Stamler et al. Diabetes Care 1993;16:434.
1
2
Number of risk factors
3
Dysglycaemia is an independent risk factor for
adverse CV outcomes
Coronary heart disease1
2.5
Adjusted HR (95% CI)
Adjusted HR (95% CI)
4.0
3.0
2.0
1.0
0
0
3
4
5
6
7
8
9
Mean FBG concentration (mmol/L)
No known history of diabetes at baseline survey
Known history of diabetes at baseline survey
1. Sarwar et al. Lancet 2010;375:2215–22.
2. Seshasai et al. N Engl J Med 2011;364:829–41.
Vascular death2
10
2.0
1.5
1.0
0.9
0
0
3
4
5
6
7
8
9
Mean FBG concentration (mmol/L)
No history of diabetes at baseline
History of diabetes at baseline
10
Hypertension: each 20/10 mmHg BP increase
doubles the risk of CV mortality
Fold increase in relative
CV risk
10
8-fold
8
6
4-fold
4
2
2-fold
1-fold
0
115/75
135/85
155/95
SBP/DBP mmHg
175/105
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.
Dyslipidaemia: increased LDL-C increases risk
of CHD
Relative risk for CHD (log scale)
3.7
2.9
2.2
1.7
1.3
1.0
40
70
100
130
LDL-C (mg/dL)
Grundy et al. Arterioscler Thromb Vasc Biol 2004;24:e149-e161.
160
190
Dyslipidaemia: increased LDL-C and decreased HDL-C
are associated with raised risk of CHD
Relative risk of CHD
3.0
2.0
1.0
45
0.0
85
100
160
LDL-C (mg/dL)
Taylor. Eur Heart J Suppl 2006;8:F74–80.
220
65
25
Abdominal obesity is associated with increased risk of
both diabetes and CVD
CVD
Men
Diabetes
20
Frequency (%)
15
10
5
0
<84
≥84–<92
≥92–<99
Waist circumference (cm)
Population of 168,000 primary care patients across 63 countries
Balkau et al. Circulation 2007;116:1942–51.
≥99–<107
≥107
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
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.
.
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
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.
Diabetes confers significant CV risk; the combination
of diabetes and history of MI further increases risk
50
No diabetes, no prior MI
Incidence of CV events (%)
45
Diabetes
Prior MI
Diabetes + prior MI
40
35
30
25
20
15
10
5
0
MI
P<0.001 for all subjects for prior MI vs. no prior MI, and for diabetes vs. no diabetes
33 et al. N Engl J Med 1998;339:229–34.
Haffner
Stroke
CV Death
Whether presence of diabetes and a prior MI
confer equivalent CV risk is not supported by all
analyses
Study
Lee et al. 2004
Evans et al. 2002
Haffner et al. 1998
Hu FB et al. 2001
Lotufo et al. 2001
Eberly et al. 2003
Hu G et al. 2005
Cho et al. 2002
Wannamathee et al. 2004
Natarajan et al. 2003
Vaccaro et al. 2004
Pajunen et al. 2005
Natarajan et al.2005
Total
Diabetes alone
(No. of MI/
No. of subjects)
Prior MI alone
(No. of MI/
No. of subjects)
141/1460
113/1155
180/890
161/3705
89/2317
171/1122
159/962
113/1285
36/202
35/178
1087/4809
191/525
127/462
59/283
274/1347
13/69
61/1302
445/5906
177/658
373/1308
364/2038
140/517
92/300
1468/4625
254/559
207/594
2603/19,072
3927/19,506
0.2
Odds ratio (95% CI)
0.56 (0.53–0.60)
0.5
Favours diabetes as not
a CHD risk equivalent
34
Bulugahapitiya et al. Diabet Med 2009;26:142–48.
Odds ratio (95% CI)
1
1.5
2
Favours diabetes as a
CHD risk equivalent