Canadian Diabetes Association
Clinical Practice Guidelines
Vascular Protection in People with
Diabetes
Chapter 22
James A. Stone, David Fitchett, Steven Grover,
Richard Lewanczuk, Peter Lin
Vascular Protection Checklist
2013

A • A1C – optimal glycemic control (usually ≤7%)

B • BP – optimal blood pressure control (<130/80)

C • Cholesterol – LDL ≤2.0 mmol/L if decided to treat

D • Drugs to protect the heart (regardless of baseline BP or LDL)
A – ACEi or ARB │ S – Statin │ A – ASA if indicated

E • Exercise / Eating healthily – regular physical
activity, achieve and maintain healthy body weight

S • Smoking cessation
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Absolute Risk of MI is Higher in Patients
with DM
No. events per 100 person- years
Diabetes n = 379,003
No Diabetes n = 9,018,082
Database 1994-2000
3.0
Diabetes
Men
2.5
Women
2.0
No diabetes
Men
1.5
Women
1.0
0.5
0
20-30
31-40
41-45
46-50
51-55
56-60
61-65
Age group
66-70
71-75
All lines fitted according to a polynomial equation; R2= 0.99–1.00 for each
Booth GL, et al. Lancet 2006;368:29-36.
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76-80
81-85
MI = myocardial infarction
MRFIT: Impact of Diabetes on
Cardiovascular Mortality
140
120
Mortality per 10,000
125
Nondiabetes (n = 342,815)
Diabetes (n = 5,163)
100
91
80
59
60
47
40
20
0
31
22
12
6
None
One only
Two only
Number of risk factors*
*Risk factors analyzed: smoking, hypercholesterolemia and hypertension.
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Stamler J, et al. Diabetes Care 1993; 16(2):434-44
Copyright © 2013 Canadian Diabetes Association
All three
T2DM for > 15 Years Duration Confers a Similar
Risk of Fatal CHD as Prior CHD and No Diabetes
20 year followup of 121,046
women aged
30 to 55 years
in Nurses’
Health Study
Hu F, et al. Arch Intern Med. 2001;161:1717-1723.
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Multifaceted Management is Essential for
T2DM
•
Intensive multifaceted management in patients
with Type 2 diabetes lowers overall mortality
•
Multifaceted treatment strategy includes:
–
Glucose, lipid, BP control
–
Health behavior optimization
–
Use of vascular protective medications
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STENO-2
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Multifaceted Approach for CVD Prevention
Among Patients with T2DM
Intensive Arm
Type 2 Diabetes
+
Microalbuminuria
n = 160
Therapies to achieve targets in
glycemia, lipids, BP and
microalbuminuria
Multidisciplinary care q3mo
ASA and ACE inhibitors
(independent of BP)
Conventional Arm
MD follows clinical practice
guidelines
8-year follow-up composite outcome:
CV death, MI, CABG, PCI, Stroke, Amputation, or PVD surgery
Gaede et al. NEJM. 2003: 348;383-393
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STENO-2: Intensive Group Achieved Targets
Gaede et al. NEJM. 2003: 348;383-393
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Intensive Group had Improved CV Outcomes
60
50
Any CV
event
P = 0.007
53 % RRR
Conventional therapy
40
Intensive therapy
30
NNT = 5
20
10
0
12
24 36
48 60
72
Months of Follow-up
RRR= relative risk reduction
Gaede et al. NEJM. 2003: 348;383-393
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84
96
STENO 2 – Microvascular Disease
Gaede et al. NEJM. 2003: 348;383-393
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Use a Multifaceted Vascular Protection
Strategy
Healthy
Lifestyle/weight
BP <130/80
Smoking
Cessation
A1C ≤7%
Physical
Activity
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Rx:
Statins
ACEi/ARB
Vascular protective medications
•
Statins
•
ACE-inhibitors or Angiotensin receptor
blockers (ARB)
•
ASA selective use
HPS: Statin Therapy Beneficial Among
Patients with Diabetes
SIMVASTATIN PLACEBO
Rate ratio & 95% CI
(10269)
(10267) STATIN better PLACEBO better
Previous MI
999 (23.5%)
1250 (29.4%)
Other CHD (not MI)
460 (18.9%)
591 (24.2%)
No prior CHD
CVD
172 (18.7%)
212 (23.6%)
PVD
327 (24.7%)
420 (30.5%)
Diabetes
276 (13.8%)
367 (18.6%)
ALL PATIENTS
2033 (19.8%)
2585 (25.2%)
HPS: Heart protection study
HPS Lancet 2002;360:7-22
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0.4
24%
reduction
(P<0.00001)
0.6
0.8
1.0
1.2
1.4
CARDS: Effect of Statin for PRIMARY
Prevention in DM
•
•
•
n = 2838
Age 40-75, no history of CVD
T2DM plus one or more:
–
–
–
–
•
•
Retinopathy
Albuminuria
Hypertension
Smoking
Intervention: Atorvastatin 10 mg vs. Placebo
Outcome: ACS, revascularization, stroke
Colhoun HM, et al. Lancet 2004;364:685.
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CARDS: Statins Reduced CVD in Patients with DM
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Colhoun
et al.
Lancet 2004;364:685.
CopyrightHM,
© 2013
Canadian
Diabetes Association
Who Should Receive Statins?
(regardless of baseline LDL-C)
•
•
•
•
•
2013
≥40 yrs old or
Macrovascular disease or
Microvascular disease or
DM >15 yrs duration and age >30 years or
Warrants therapy based on the 2012 Canadian
Cardiovascular Society lipid guidelines
Among women with childbearing potential, statins should only
be used in the presence of proper preconception counseling &
reliable contraception. Stop statins prior to conception.
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What if baseline LDL-C ≤2.0 mmol/L?
•
Within CARDS and HPS, the subgroups that started
with lower baseline LDL-C still benefited to the same
degree as the whole population
•
If the patient qualifies for statin therapy based on the
algorithm, use the statin regardless of the baseline
LDL-C and then target an LDL reduction of ≥50%
HPS Lancet 2002;360:7-22
Colhoun HM, et al. Lancet 2004;364:685.
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Vascular protective medications
•
Statins
•
ACE-inhibitors or Angiotensin receptor
blockers (ARB)
•
ASA selective use
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Association of SBP and CV Mortality in Men
With T2DM
CV mortality rate
Per 10,000 person-years
250
No diabetes
Diabetes
200
150
100
50
0
<120
120-139
140-159
160-179
SBP (mmHg)
Stamler J, et al. Diabetes Care. 1993;16:434-444.
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180-199
≥200
Hypertension in Diabetes UKPDS
50
Less tight control (mean BP 154/87 mmHg)
Patients with events (%)
Tight control (mean BP 144/82 mmHg)
40
30
20
Tight BP control:
24% reduction of events
(95% CI 8-38)
10
0
0
1
2
3
4
5
6
Years from randomization
UKPDS Study Group. BMJ 1998; 317:703-13.
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7
8
9
HOT: BP Control Reduces CV Events
Diabetes Subgroup
30
MI, stroke, CV
mortality/1000 pt-y
25
20
P<0.005
24.4
Goal of therapy: target
diastolic BP
 90 mm Hg (n=501)
 85 mm Hg (n=501)
 80 mm Hg (n=499)
18.8
15
11.9
10
5
0
Hansson et al. Lancet. 1998;351:1755.
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Micro-HOPE (ACEi): CV Benefits
Primary Outcome (NNT 22)
0.2
All Mortality
(NNT 31)
Placebo
Ramipril 10 mg
Kaplan-Meier rates
0.16
0.08
0.1
RR = 0.75 (0.64-0.88)
p = 0.0004
0
RR = 0.76 (0.63-0.92)
p = 0.004
0
0
400
800
0.16
1200
0.08
Stroke
(NNT 53)
MI
(NNT 37)
0.08
0.04
0
RR = 0.78 (0.64-0.94)
p = 0.01
0
0
1000
2000
0
1600
400
800
1200
1600
0.12
CV Death
(NNT 29)
0.06
RR = 0.67 (0.5-0.9)
p = 0.0074
0
1000
0
2000
Duration of follow-up (days)
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HOPE study investigators.
Lancet.
2000;355:253-59.
Copyright © 2013 Canadian Diabetes Association
RR = 0.63 (0.49-0.79)
p = 0.001
0
1000
2000
ONTARGET: ARB Therapy is as Effective as ACEi
for CVD Prevention
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ONTARGET study investigators. NEJM. 2008:358:1547-59.
Copyright © 2013 Canadian Diabetes Association
2013
Who Should Receive ACEi or ARB Therapy?
(regardless of baseline blood pressure)
•
≥55 years of age or
•
Macrovascular disease or
•
Microvascular disease
At doses that have shown vascular protection
[perindopril 8 mg daily (EUROPA), ramipril 10 mg daily
(HOPE), telmisartan 80 mg daily (ONTARGET)]
Among women with childbearing potential, ACEi or ARB should
only be used in the presence of proper preconception
counseling & reliable contraception. Stop ACEi or ARB either
prior to conception or immediately upon detection of pregnancy
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EUROPA Investigators, Lancet 2003;362(9386):782-788.
HOPE study investigators. Lancet. 2000;355:253-59.
ONTARGET study investigators. NEJM. 2008:358:1547-59
Vascular protective medications
•
Statins
•
ACE-inhibitors or Angiotensin receptor
blockers (ARB)
•
ASA selective use
What About ASA for 1⁰ Prevention of CVD?
Included: Six studies, n = 10,117 participants
De Berardis G et al. BMJ 2009;339:b4531
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No. of events/No. in group
ASA for 1⁰
Prevention in
Diabetes
Meta analysis of 6 studies
(n = 10,117)
No overall benefit for:
• Major CV events
• MI
• Stroke
• CV mortality
• All-cause mortality
JPAD = Japanese Primary Prevention of Atherosclerosis
with Aspirin for Diabetes
POPADAD = Prevention of Progression of Arterial
Disease and Diabetes
PPP = Primary Prevention Project
ETDRS = Early Treatment Diabetic Retinopathy Study
PHS = Physicians’ Health Study
WHS = Women’s Health Study
ASA Control/placebo
Major CV events
JPAD
68/1262
86/1277
POPADAD
105/638
108/638
WHS
58/514
62/513
PPP
20/519
22/512
ETDRS
350/1856
379/1855
Total
601/4789
657/4795
RR (95% CI)
RR (95% CI)
0.80 (0.59-1.09)
0.97 (0.76-1.24)
0.90 (0.63-1.29)
0.90 (0.50-1.62)
0.90 (0.78-1.04)
0.90 (0.81-1.00)
Myocardial infarction
JPAD
28/1262
POPADAD
90/638
WHS
36/514
PPP
5/519
ETDRS
241/1856
PHS
11/275
Total
395/5064
14/1277
82/638
24/513
10/512
283/1855
26/258
439/5053
0.87 (0.40-1.87)
1.10 (0.83-1.45)
1.48 (0.88-2.49)
0.49 (0.17-1.43)
0.82 (0.69-0.98)
0.40 (0.20-0.79)
0.86 (0.61-1.21)
Stroke
JPAD
POPADAD
WHS
PPP
ETDRS
Total
32/1277
50/638
31/513
10/512
78/1855
201/4795
0.89 (0.54-1.46)
0.74 (0.49-1.12)
0.46 (0.25-0.85)
0.89 (0.36-2.17)
1.17 (0.87-1.58)
0.83 (0.60-1.14)
Death from CV causes
JPAD
1/1262
POPADAD
43/638
PPP
10/519
ETDRS
244/1856
Total
298/4275
10/1277
35/638
8/512
275/1855
328/4282
0.10 (0.01-0.79)
1.23 (0.80-1.89)
1.23 (0.49-3.10)
0.87 (0.73-1.04)
0.94 (0.72-1.23)
All-cause mortality
JPAD
34/1262
POPADAD
94/638
PPP
25/519
ETDRS
340/1856
Total
493/4275
38/1277
101/638
20/512
366/1855
525/4282
0.90 (0.57-1.14)
0.93 (0.72-1.21)
1.23 (0.69-2.19)
0.91 (0.78-1.06)
0.93 (0.82-1.05)
12/1262
37/638
15/514
9/519
92/1856
181/4789
De Beradis G, et al. BMJ 2009; 339:b4531.
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0.03 0.125
Favors ASA
0.5 1
2
8
Favors control/placebo
ASA Not Routinely Recommended for 1⁰
Prevention for CVD Among Patients with DM
Insufficient evidence to support use of ASA
for primary prevention
2013
Risk of bleeding
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CVD protection
Don`t Forget To…………..
•
Do your part
•
Protect their heart
Multifaceted approach
+
Individualize therapy
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Vascular Protection Checklist
2013

A • A1C – optimal glycemic control (usually ≤7%)

B • BP – optimal blood pressure control (<130/80)

C • Cholesterol – LDL ≤2.0 mmol/L if decided to treat

D • Drugs to protect the heart (regardless of baseline BP or LDL)
A – ACEi or ARB │ S – Statin │ A – ASA if indicated

E • Exercise / Eating healthily – regular physical
activity, achieve and maintain healthy body weight

S • Smoking cessation
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Recommendation 1
1. All individuals with diabetes (type 1 or type 2)
should follow a comprehensive, multifaceted
approach to reduce cardiovascular risk including:
–
Achievement and maintenance of healthy body weight
–
Healthy diet
–
Regular physical activity
–
Smoking cessation
–
Optimal glycemic control (usually A1C <7%)
–
Optimal blood pressure control (<130/80 mmHg)
–
Additional vascular protective medications in the majority
of adult patients
[Grade D, consensus for T1DM, children/adolescents; Grade A, Level 1 for T2DM]
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Recommendation 2
2013
2. Statin therapy should be used to reduce CV risk in
adults with type 1 or type 2 diabetes with any of the
following features:
–
Clinical macrovascular disease [Grade A, Level 1]
–
Age ≥40 years [Grade A, Level 1 T2DM; Grade D Consensus T1DM]
–
Age <40 and one of the following:
•
Diabetes duration > 15 years and age >30 yrs
•
Microvascular complication
•
Warrants therapy for other reasons based on the 2012
CCS guidelines for the management of dyslipidemia
[Grade D, consensus]
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Recommendation 3
2013
3. ACE inhibitor or ARB, at doses that have
demonstrated vascular protection, should be used
to reduce CV risk in adults with type 1 or type 2
diabetes with any of the following:
–
Clinical macrovascular disease [Grade A, Level 1]
–
Age ≥55 years [Grade A, Level 1 for those with an additional risk factor
or end organ damage; Grade D, consensus for all others]
–
Age <55 years and microvascular complications [Grade
D, consensus]
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Among women with childbearing
potential, ACE inhibitor, ARB, or statin
should only be used if there is reliable
contraception.
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Recommendation 4
2013
4. ASA should not be routinely used for the primary
prevention of cardiovascular disease in people with
diabetes [Grade B, Level 2]
ASA may be used in the presence of additional
cardiovascular risk factors [Grade D, Consensus]
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Recommendation 5 and 6
5. Low-dose ASA therapy (81–325 mg) may be used
for secondary prevention in people with
established cardiovascular disease [Grade D, Consensus]
6. Clopidogrel (75 mg) may be used in people unable
to tolerate ASA [Grade D, Consensus]
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CDA Clinical Practice Guidelines
www.guidelines.diabetes.ca – for professionals
1-800-BANTING (226-8464)
www.diabetes.ca – for patients
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