Chapter 22 James A. Stone, David Fitchett , Steven Grover, Richard Lewanczuk , Peter Lin

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


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.

eve

nts

per 1

00 p

erso

n- y

ears

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


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 threeNumber 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


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.


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


STENO-2


Multifaceted Approach for CVD Prevention Among Patients with T2DM

Type 2 Diabetes +

Microalbuminuria

n = 160Conventional 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 microalbuminuriaMultidisciplinary care q3moASA and ACE inhibitors(independent of BP)


Gaede et al. NEJM. 2003: 348;383-393

STENO-2: Intensive Group Achieved Targets


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


Gaede et al. NEJM. 2003: 348;383-393

STENO 2 – Microvascular Disease


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


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 CHD172 212(18.7%) (23.6%)CVD327 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


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.


CARDS: Statins Reduced CVD in Patients with DM

Colhoun HM, et al. Lancet 2004;364:685.


• ≥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)


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.






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.


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)

Hypertension in Diabetes UKPDS


P<0.005

MI,

stro

ke, C

V

mor

talit

y/10

00 p

t-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


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 1200 1600

0

0.1

0.2 Placebo

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 20000

0.06

0.12

0 1000 20000

0.04

0.08

0 1000 20000

0.08

0.16

Duration of follow-up (days)

Kap

lan-

Mei

er ra

tes

RR = 0.75 (0.64-0.88) p = 0.0004

HOPE study investigators. Lancet. 2000;355:253-59.


ONTARGET: ARB Therapy is as Effective as ACEi for CVD Prevention

ONTARGET study investigators. NEJM. 2008:358:1547-59.


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





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


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


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


• Do your part

• Protect their heart

Multifaceted approach + Individualize therapy

Don`t Forget To…………..


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


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


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


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


Among women with childbearing

potential, ACE inhibitor, ARB, or statin

should only be used if there is reliable

contraception.


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


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]


CDA Clinical Practice Guidelines

www.guidelines.diabetes.ca – for professionals

1-800-BANTING (226-8464)

www.diabetes.ca – for patients

http://guidelines.diabetes.ca/

http://diabetes.ca/

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Chapter 22 James A. Stone, David Fitchett , Steven Grover, Richard Lewanczuk , Peter Lin

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