Cardiovascular disease

and type 2 diabetes

EDUCATIONAL SLIDE MODULE

Date of preparation: October 2018

Version 2.0

Date goes here

SC-CRP-02492
Cardiovascular disease and type 2 diabetes
Module content

The significance of CV disease in T2D

The CV disease continuum in T2D

Consequences of CV disease in T2D

The need for cardioprotection in patients with T2D

Cardiovascular disease and type 2 diabetes
Module content

The significance of CV disease in T2D

The CV disease continuum in T2D

Consequences of CV disease in T2D

The need for cardioprotection in patients with T2D

Diabetes greatly increases the risk of CV disease

2× Patients with T2D have twice the risk

of CV disease compared with the
general population

CV, cardiovascular; T2D, type 2 diabetes

Sarwar N et al. Lancet 2010;375:2215 4
A large proportion of patients with T2D have CV disease

Globally, approximately 1/3 of patients

with T2D have CV disease

Analysis of 60 studies with 4,549,481 patients with T2D

CV, cardiovascular; T2D, type 2 diabetes
Einarson TR et al. Cardiovasc Diabetol 2018;17:83 5
CV disease can occur even before diagnosis of T2D
Time to T2D diagnosis (years)
-15 -10 -5 0 5 10 15

Development of microvascular complications

Development of atherosclerotic disease

Risk factors for CV disease

CV, cardiovascular; T2D, type 2 diabetes

Adapted from Ramlo-Halsted BA & Edelman SV. Prim Care 1999;26:771; Nathan DM. N Engl J Med 2002;347:1342; UKPDS Group. Diabetes 1995;44:1249 6
However, most are not aware of the dangers of
CV disease

In the US, 67% of patients with T2D did

not know that CV disease is the leading
cause of mortality in patients with T2D

CV, cardiovascular; T2D, type 2 diabetes

Perreault L et al. JACC 2018;71:1820 7
Cardiovascular disease and type 2 diabetes
Module content

The significance of CV disease in T2D

The CV disease continuum in T2D

Consequences of CV disease in T2D

The need for cardioprotection in patients with T2D

The pathophysiology of CV disease in patients with
T2D is complex
T2D shares common risk factors with CV disease and contributes to
vascular damage
Risk factors for Direct effects of
T2D and CV disease hyperglycaemia

Physical inactivity Arterial stiffness

T2D
High blood pressure Endothelial dysfunction

Poor diet Oxidative stress

Smoking Platelet activation

Obesity Inflammation

Dyslipidaemia Metabolic syndrome

Metabolic syndrome CV disease Metabolic dysfunction

CV, cardiovascular; T2D, type 2 diabetes

Newman JD et al. J Am Coll Cardiol 2017;70:883 9
 CV disease exists as a continuum
Patients are at CV risk throughout the pathophysiological course, even before diagnosis

Risk factors Subclinical Clinical damage Event Further events/

mortality

T2D Endothelial dysfunction Myocardial ischaemia Myocardial infarction

Hypertension Atherosclerosis Coronary thrombosis HF
Dyslipidaemia Carotid artery disease Carotid thrombosis Stroke
Smoking Peripheral artery Angina
Obesity disease
LVH

CV, cardiovascular; HF, heart failure; LVH, left ventricular hypertrophy; T2D, type 2 diabetes
Adapted from: Dzau VJ et al. Circulation 2006;114:2850; Franklin BA & Cushman M Circulation 2011;123:2274; Ingelsson E et al. Diabetes 2007;56:1718 10
Coronary artery disease is a prevalent comorbidity of
CV disease

Approximately two-thirds of patients with CV disease…

…have coronary artery disease

Analysis of 60 studies with 4,549,481 patients with T2D
CV, cardiovascular disease; T2D, type 2 diabetes
Einarson TR et al. Cardiovas Diabetol 2018;17:83 11
Coronary artery disease is the leading cause of
CV disease mortality

Approximately 45% of all deaths due to CV disease…

…are caused by coronary artery disease

CV, cardiovascular
Data source: National Heart, Lung, and Blood Institute from National Center for Health Statistics reports and data sets. United States; 2015
Benjamin EJ et al. Circulation 2018;137e67 12
Coronary artery disease is caused by atherosclerotic
changes in the walls of the coronary arteries

Build-up of
atheromatous plaque
in the walls of the
coronary arteries
leads to subsequent
occlusion of vessels

Driven by hyperglycaemia, insulin resistance, inflammation and dyslipidaemia

Figure adapted from Libby P. Circulation 2001;104:365

Zeadin MG et al. Can J Diabetes 2013;37:345 13
Coronary artery disease is often associated with
other CV complications

Coronary
artery disease

Myocardial
Arrhythmia infarction

Heart failure

CV, cardiovascular
PubMed Health. Complications of coronary artery disease. July 2017. www.ncbi.nlm.nih.gov/pubmedhealth/PMH0086330/ (accessed July 2018). 14
 Patients with T2D and CAD are at higher risk of
left ventricular heart failure
Diastolic dysfunction Systolic dysfunction

Hypertension Myocardial infarction

Failure of Failure of
normal normal
relaxation contraction
and filling and emptying

Diabetes is a risk
factor for
diastolic
dysfunction Stiffened and thickened chambers Stretched and dilated chambers

CAD, coronary artery disease; T2D, type 2 diabetes

McMurray JVV et al. Lancet Diabetes Endocrinol 2014;2:843 15
Cardiovascular disease and type 2 diabetes
Module content

The significance of CV disease in T2D

The CV disease continuum in T2D

Consequences of CV disease in T2D

The need for cardioprotection in patients with T2D

CV disease occurs early and is the leading cause of
mortality in patients with T2D

CV disease can occur

10−15 years earlier Despite advances in standard
in patients with diabetes compared of care, most patients with T2D
with those without diabetes1 die from CV disease2

CV, cardiovascular; T2D, type 2 diabetes

1. Booth GL et al. Lancet 2006;368:29; 2. Morrish NJ et al. Diabetologia 2001;44(Suppl 2):S14 17
 Diabetes accelerates the time to first CV event
Time to first MI Time to first hospitalisation for heart failure
0.10 Diabetes No diabetes 0.10 Diabetes No diabetes
Proportion of patients with first event

Proportion of patients with first event

0.09 0.09

0.08 0.08

0.07 0.07

0.06 0.06

0.05 0.05

0.04 0.04

0.03 0.03

0.02 0.02

0.01 0.01

0 0
0 500 1000 1500 2000 0 500 1000 1500 2000
Time to fatal or non-fatal MI (days) Time to fatal or non-fatal heart failure (days)

CV, cardiovascular; MI, myocardial infarction

McMurray JJV et al. Lancet Diabetes Endocrinol 2014;2:843 18
Life expectancy is reduced by ~12 years in patients
with diabetes and CV disease
A 60-year-old patient with diabetes and CV disease dies, on average, 12 years
earlier than a person without diabetes and CV disease

60 years
End of life

No diabetes + CV disease

Diabetes -6 years*

Diabetes + CV disease -12 years*

In this case, CV disease is represented by MI or stroke

*Average for men and women
CV, cardiovascular, MI, myocardial infarction
The Emerging Risk Factors Collaboration. JAMA 2015;314:52 19
CV disease in patients with T2D is responsible for more
deaths than cancer* in the general population
2.5 times more deaths than cancer*

Deaths due to CV disease

in patients with T2D

Deaths due to cancer*

in patients with T2D

24-year follow-up of 7461 patients with T2D and 37,271 controls from the Skaraborg Diabetes Register
*Solid tumour cancers only
CV, cardiovascular disease; T2D, type 2 diabetes
Andersson T et al. Diabetes Res Clin Prac 2018;138:81 20
CV disease is also the biggest contributor to costs
related to T2D management

CV disease contributes up to 49% of

$ total direct costs of treating T2D

CV, cardiovascular disease; T2D, type 2 diabetes

Einarson TR et al. Value Health 2018;21:881 21
Cardiovascular disease and type 2 diabetes
Module content

The significance of CV disease in T2D

The CV disease continuum in T2D

Consequences of CV disease in T2D

The need for cardioprotection in patients with T2D

T2D is a CV risk factor that determines the need
for cardioprotection

Patients with diabetes and at least one

other CV risk factor or target organ
damage, should be considered at very
high CV risk…
2016 European Guidelines on cardiovascular
disease prevention in clinical practice
– European Society of Cardiology

CV, cardiovascular; T2D, type 2 diabetes

Piepoli MF et al. Eur Heart J 2016;37:2315 23
Despite improved prognosis with advancing standard of care,
patients with T2D remain at increased risk of CV mortality
Death from CV disease
Standardised incidence rate

T2D No T2D
(per 10,000 person-years)
250

200

150

100

50
0
1998– 1
2000– 2
2002– 3
2004– 4
2006– 5
2008– 6
2010– 7
2012–
1999 2001 2003 2005 2007 2009 2011 2013
Year
Data from 457,473 patients with T2D from the Swedish National Diabetes Register
CV, cardiovascular; T2D, type 2 diabetes
Rawshani A et al. N Engl J Med 2017;376:1407 24
Cardioprotection is a priority consideration for
patients with T2D

Despite advances in standard of care, most patients with diabetes die from CV causes 1

People with T2D and CV disease could die 12 years earlier than those without T2D or
CV disease2

CV disease in T2D is associated with:

• Earlier onset compared with patients without diabetes 3
• Accelerated organ damage4
• Worse outcomes compared with patients without diabetes 5
• Substantial costs6,7

T2D is, therefore, a CV risk factor that determines the need for cardioprotection,
as emphasised in clinical guidelines 8,9

See slide notes for abbreviations and references 25

Back-up slides
CV disease can manifest as atherosclerotic events,
arterial disease or heart failure
Types of CV disease in the
T2D population

21% coronary artery disease

15% heart failure

10% myocardial infarction

8% stroke

Analysis of 57 studies with 4,549,481 patients with T2D

CV, cardiovascular; T2D, type 2 diabetes
Einarson TR et al. Cardiovasc Diabetol 2018;17:83 27
Patients with diabetes experience worse outcomes
Patients with diabetes undergoing CABG surgery have a higher likelihood of
all-cause death and post-CABG complications than those without diabetes
All-cause death Post-CABG complications*

1.6–1.8× 1.5–1.7×
more likely
more likely

No diabetes Diabetes No diabetes Diabetes

Relative risk of all-cause death measured from 30 days to 10 years
Meta-analysis of 24 cohort studies with a total population of 28,168 patients with diabetes and 72,049 without diabetes
*Stroke, acute kidney failure, sternal wound infection or transfusions
CABG, coronary artery bypass graft
Zhang XH et al. J Cardiothorac Vasc Anesth 2011;25:288 28
 CV disease is frequently asymptomatic
and unrecognised

16% 44%
No CV disease Subclinical CV disease

Almost half of patients with diabetes

have subclinical CV disease*

40%
Clinical CV disease
Prevalence of subclinical CV disease across 1343 patients with diabetes aged ≥65 years in the US
*Absence of prevalent clinical disease at baseline: ankle–brachial index ≤0.9, internal carotid artery wall thickness >80th percentile, common carotid artery wall thickness
>80th percentile, carotid stenosis >25%, major electrocardiogram abnormalities (based on the Minnesota code), and a Rose Questionnaire positive for claudication or
angina pectoris in the absence of clinical diagnosis of angina pectoris or claudication
CV, cardiovascular
Kuller LH et al. Arterioscler Thromb Vasc Biol 2000;20:823 29
Diabetes is associated with an increased prevalence of
CV risk factors1–3

Hypertension Hypercoagulability

Adiposity Oxidative stress

Dyslipidaemia Vascular calcification

Systemic inflammation Chronic kidney disease

CV, cardiovascular
1. Low Wang CC et al. Circulation 2016;133:2459; 2. Newman JD et al. J Am Coll Cardiol 2017;70:883; 3. Thomas M et al. Nat Rev Nephrol 2016;12:73 30
Life expectancy is reduced by 12 years in patients with
diabetes and CV disease*
Modelling of years of life lost by disease status of participants at baseline
compared with those with no history of diabetes, stroke and MI
25 Diabetes Diabetes and MI Diabetes and stroke
Years of life lost vs none

20

15

10

0
40 45 50 55 60 65 70 75 80 85 90 95
Age, years
*Male, 60 years of age with history of MI or stroke
CV, cardiovascular; MI, myocardial infarction
The Emerging Risk Factors Collaboration. JAMA 2015;314:52 31
Despite advances in therapies, life expectancy is reduced by
multiple morbidities of diabetes, stroke and MI

All-cause mortality by disease status of participants at baseline

Disease status at baseline HR (95% Cl)
Diabetes, stroke and MI 6.9 (5.7, 8.3)
Stroke and MI 3.5 (3.1, 4.0)
Diabetes and stroke 3.8 (3.5, 4.2)
Diabetes and MI 3.7 (3.3, 4.1)
MI 2.0 (1.9, 2.2)
Stroke 2.1 (2.0, 2.2)
Diabetes 1.9 (1.8, 2.0)
None* 1.0 (ref)
1 2 4 8
Decreased risk Increased risk
MI, myocardial infarction
*Population with no history of diabetes, stroke or MI 32
The Emerging Risk Factors Collaboration. JAMA 2015;314:52
Diabetes* doubles the risk of vascular events
Outcome Number of cases HR (diabetes vs no diabetes) 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)

Cerebrovascular disease

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)

1 2 4
MI, myocardial infarction Decreased risk Increased risk
*Independent of age, smoking status, body mass index and systolic blood pressure 33
Sarwar N et al. Lancet 2010;375:2215
Mortality is substantially higher in patients with T2D and
chronic kidney disease
NHANES US population-based study (N=15,046)
Excess
70 =
mortality
Standardised 10-year cumulative
incidence of mortality (95% CI)

60

50

40

30
47.0%
20
4.1% 23.9%
10
17.8%

0
T2D alone T2D + T2D + eGFR T2D + albuminuria No T2D or CKD
albuminuria ≤60 ml/min/1.73 m² + eGFR
≤60 ml/min/1.73 m²
Percentages indicate absolute excess mortality above the reference group (individuals with no diabetes or kidney disease)
*Kidney disease defined as albuminuria, impaired GFR or both
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes
Afkarian M et al. J Am Soc Nephrol 2013;24:302 34
The presence of diabetes and chronic kidney disease
increases the risk of MI
Population-based cohort study in Alberta, Canada (N=1,268,029)
20
Rate (per 1000 person-years)

18
16
14
12
10
8
6
4
2
0
No diabetes + Diabetes + No diabetes + Diabetes + Previous MI*
eGFR eGFR eGFR eGFR
>60 ml/min/1.73 m² >60 ml/min/1.73 m² ≤60 ml/min/1.73 m² ≤60 ml/min/1.73 m²
Unadjusted rates and 95% CIs of MI per 1000 person-years
*Includes patients with and without diabetes and chronic kidney disease. eGFR, estimated glomerular filtration rate; MI, myocardial infarction
Tonelli M et al. Lancet 2012;380:807 35
Reduced kidney function significantly increases
the risk of CV events
ACCORD study: assessment of CV outcomes in 10,136 T2D patients with CKD
vs those without CKD
HR (95% CI)
3P-MACE* 1.86 (1.65, 2.11)
Non-fatal MI 1.62 (1.38, 1.90)
Any stroke 2.41 (1.81, 3.22)
Non-fatal stroke 2.49 (1.84, 3.38)
All-cause mortality 1.97 (1.70, 2.29)
CV death 2.19 (1.76, 2.73)
Non-fatal CHF 1.64 (1.51, 1.77)
Major coronary 1.56 (1.39, 1.75)
Any CHF 3.20 (2.62, 3.89)
0.25 1 4
Decreased risk Increased risk
*Primary outcome defined as the first occurence of non-fatal stroke, non-fatal MI or CV death
3P-MACE, 3-point major adverse cardiovascular events; CHF, congestive heart failure; CKD, chronic kidney disease;
CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes
Papademetriou V et al. Kidney Int 2015;87:649 36