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
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
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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20-30 31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85
Absolute Risk of MI is Higher in Patients with DM
Age group
0.5
1.0
1.5
2.0
2.5
3.0
0No
. ev
ents
per
100
per
so
n-
year
s
Booth GL, et al. Lancet 2006;368:29-36.
All lines fitted according to a polynomial equation; R2= 0.99–1.00 for each
MI = myocardial infarction
Diabetes n = 379,003 No Diabetes n = 9,018,082 Database 1994-2000
No diabetesMen
Women
DiabetesMen
Women
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MRFIT: Impact of Diabetes on Cardiovascular Mortality
Mor
talit
y pe
r 10
,000
140
120
100
80
60
40
20
0None
6
One only Two only All three
Number of risk factors*
1222
47
31
59
91
125Nondiabetes (n = 342,815)
Diabetes (n = 5,163)
*Risk factors analyzed: smoking, hypercholesterolemia and hypertension.
Stamler J, et al. Diabetes Care 1993; 16(2):434-44
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T2DM for > 15 Years Duration Confers a Similar Risk of Fatal CHD as Prior CHD and No Diabetes
20 year follow-up 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
Type 2 Diabetes +
Microalbuminuria
n = 160
Conventional ArmMD 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
Intensive ArmTherapies to achieve targets in glycemia, lipids, BP and microalbuminuria
Multidisciplinary care q3mo
ASA and ACE inhibitors
(independent of BP)
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Gaede et al. NEJM. 2003: 348;383-393
STENO-2: Intensive Group Achieved Targets
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Intensive Group had Improved CV Outcomes
12 24 36 48 60 72 84 960
10
20
30
40
50
60P = 0.007
Conventional therapy
Intensive therapy
Months of Follow-upRRR= relative risk reduction
53 % RRRAny CV event
NNT = 5
Gaede et al. NEJM. 2003: 348;383-393
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Gaede et al. NEJM. 2003: 348;383-393
STENO 2 – Microvascular Disease
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Use a Multifaceted Vascular Protection Strategy
BP <130/80
A1C ≤7%
Rx:StatinsACEi/ARB
Healthy Lifestyle/weight Smoking Cessation
PhysicalActivity
Vascular protective medications
• Statins
• ACE-inhibitors or Angiotensin receptor
blockers (ARB)
• ASA selective use
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HPS: Statin Therapy Beneficial Among Patients with Diabetes
(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI
STATIN better PLACEBO better
999 1250(23.5%) (29.4%)Previous MI
460 591(18.9%) (24.2%)Other CHD (not MI)
No prior CHD
172 212(18.7%) (23.6%)CVD
327 420(24.7%) (30.5%)PVD
276 367(13.8%) (18.6%)Diabetes
24%reduction(P<0.00001)
2033 2585(19.8%) (25.2%)ALL PATIENTS
0.4 0.6 0.8 1.0 1.2 1.4
HPS Lancet 2002;360:7-22
HPS: Heart protection study
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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
Colhoun HM, et al. Lancet 2004;364:685.
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• ≥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.
2013Who Should Receive Statins? (regardless of baseline LDL-C)
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
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.
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
Vascular protective medications
• Statins
• ACE-inhibitors or Angiotensin receptor
blockers (ARB)
• ASA selective use
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
Association of SBP and CV Mortality in Men With T2DM
250
200
150
100
50
0<120 120-139 140-159 160-179 180-199
SBP (mmHg)
CV
mor
talit
y ra
teP
er 1
0,00
0 pe
rson
-yea
rs
No diabetesDiabetes
≥200
Stamler J, et al. Diabetes Care. 1993;16:434-444.
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
UKPDS Study Group. BMJ 1998; 317:703-13.
50
40
30
20
10
0
Years from randomization
Pat
ient
s w
ith e
vent
s (%
)
0 1 2 3 4 5 6 7 8 9
Less tight control (mean BP 154/87 mmHg)
Tight control (mean BP 144/82 mmHg)
Tight BP control:24% reduction of events(95% CI 8-38)
Tight BP control:24% reduction of events(95% CI 8-38)
Hypertension in Diabetes UKPDS
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P<0.005
MI,
str
oke,
CV
m
orta
lity/
1000
pt-
yDiabetes Subgroup
90 mm Hg (n=501) 85 mm Hg (n=501) 80 mm Hg (n=499)
Goal of therapy: target diastolic BP
24.4
18.8
11.9
30
25
20
15
10
5
0Hansson et al. Lancet. 1998;351:1755.
HOT: BP Control Reduces CV Events
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Micro-HOPE (ACEi): CV Benefits
RR = 0.67 (0.5-0.9) p = 0.0074
RR = 0.78 (0.64-0.94) p = 0.01
RR = 0.63 (0.49-0.79) p = 0.001
Stroke(NNT 53)
CV Death(NNT 29)
MI(NNT 37)
0 400 800 12001600
0
0.1
0.2Placebo
Ramipril 10 mg
Primary Outcome (NNT 22)
0 400 800 1200 16000
0.08
0.16 All Mortality(NNT 31)
RR = 0.76 (0.63-0.92) p = 0.004
0 1000 2000
0
0.06
0.12
0 1000 2000
0
0.04
0.08
0 1000 20000
0.08
0.16
Duration of follow-up (days)
Kap
lan
-Mei
er r
ates RR = 0.75 (0.64-0.88)
p = 0.0004
HOPE study investigators. Lancet. 2000;355:253-59.
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
ONTARGET: ARB Therapy is as Effective as ACEi for CVD Prevention
ONTARGET study investigators. NEJM. 2008:358:1547-59.
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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
2013
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
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
What About ASA for 1 Prevention of CVD? ⁰
Included: Six studies, n = 10,117 participants
De Berardis G et al. BMJ 2009;339:b4531
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JPAD = Japanese Primary Prevention of Atherosclerosis with Aspirin for DiabetesPOPADAD = Prevention of Progression of Arterial Disease and DiabetesPPP = Primary Prevention ProjectETDRS = Early Treatment Diabetic Retinopathy StudyPHS = Physicians’ Health StudyWHS = Women’s Health Study
De Beradis G, et al. BMJ 2009; 339:b4531.
ASA for 1⁰Prevention in DiabetesMeta analysis of 6 studies(n = 10,117)
No overall benefit for: • Major CV events • MI• Stroke• CV mortality• All-cause mortality
0.03 0.125 0.5 12
8Favors ASA Favors control/placebo
JPADPOPADADWHSPPPETDRSTotal
68/1262105/63858/51420/519
350/1856601/4789
86/1277108/63862/51322/512
379/1855657/4795
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)
Major CV events
No. of events/No. in group
ASA Control/placebo RR (95% CI) RR (95% CI)
JPADPOPADADWHSPPPETDRSPHSTotal
28/126290/63836/5145/519
241/185611/275
395/5064
14/127782/63824/51310/512
283/185526/258
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)
Myocardial infarction
JPADPOPADADWHSPPPETDRSTotal
12/126237/63815/5149/519
92/1856181/4789
32/127750/63831/51310/51278/1855
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)
Stroke
JPADPOPADADPPPETDRSTotal
1/126243/63810/519
244/1856298/4275
10/127735/6388/512
275/1855328/4282
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)
Death from CV causes
JPADPOPADADPPPETDRSTotal
34/126294/63825/519
340/1856493/4275
38/1277101/63820/512
366/1855525/4282
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)
All-cause mortality
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Insufficient evidence to support use of ASA for primary prevention
Risk of bleeding CVD protection
2013
ASA Not Routinely Recommended for 1 ⁰Prevention for CVD Among Patients with DM
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• Do your part
• Protect their heart
Multifaceted approach + Individualize therapy
Don`t Forget To…………..
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
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
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
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]
Recommendation 1
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Recommendation 2
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]
2013
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Recommendation 3
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]
2013
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association
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
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]
2013
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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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