Prevention of CVD in Diabetes

15 March 2016, EADSG CONGRESS 2016

Fred Bukachi
MBChB, MMed, MSc, PhD
Consultant Physician/Cardiologist
The Heart Centre &
University of Nairobi
 Disclaimer

• Previously received honoraria and consultancy

fees from:

• AstraZeneca
• Bayer
• Boehringer Ingelheim
• Servier International
• MicroLabs

2
 Definitions and Facts

3
5 Author | 00 Month Year Set area descriptor | Sub level 1
Facts: Link between Diabetes and CVD I

• CVD is a major complication of DM and causes

premature death.

• About 65% of people with DM die from heart

disease and stroke.

• Adults with DM are x2-4 more likely to have

heart disease or suffer a stroke than people
without diabetes.

6
Facts: Link between Diabetes and CVD II

• Hyperglyceamia in adults with diabetes increases

the risk for Myocardial Infarction, Stroke, Angina,
and Coronary Artery Disease.

• People with T2 DM have high rates of high BP,

Dyslipidaemia, and Obesity, which contribute to
high rates of CVD.

• Smoking doubles the risk of CVD in people with

diabetes.

7
Complications of Diabetes: Mechanisms
• Diabetes affects the heart and the blood vessels.

• Effects on the arteries are due to atherosclerosis, while

effects in the heart are due to ventricular hypertrophy.

• LVH a characteristic of hypertensive /diabetic heart

disease, is an important cause of heart failure in Africa.

• Heart failure, a serious condition associated with repeated

hospitalizations and high in-hospital mortality.

8
Diabetes and Left Ventricular Hypertrophy I

Diabetes Care 26: 2764-2769, 2003

9
Diabetes and Left Ventricular Hypertrophy II

• In T2 DM Echo LVH is associated with:

susceptibility to atherothrombosis
increased albuminuria - a marker of microvascular
disease and endothelial dysfunction
Increased markers of inflammation

• High BMI is relevant in relation of LVH in T2DM

• Atherothrombotic risk profile associated with LVH is independent

of BMI

• LVH is associated with a higher degree of endothelial dysfunction.

Diabetes Care 26:2764–2769, 2003

10
Atherosclerosis and Diabetes
• Definition: Atherosclerosis is the progressive hardening and
narrowing of the arteries.

• Occurs when fat, cholesterol, and other substances build up

in the walls of arteries to form plaques.

• Ruptured or eroded plaques lead to clot formation in arteries

resulting in blockage

• Atherosclerosis is the most frequent underlying cause of

Ischaemic heart disease, stroke and peripheral arterial
disease.

11
 Risk factors for atherosclerotic disease

Atherosclerosis

Dyslipidaemia Smoking
Age
Hypertension Family History

Diabetes Gender

Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 10A):23S-27S. Schiffrin EL et al. Am

J Hypertens. 2002;15:115s-122s.
What is a Risk Factor?

• Risk is defined as percentage chance

of an individual developing a CVD
event over a given period of time.

• Risk Assessment Charts are available

including online.
ESC simplified risk chart
Cardiovascular risk factors

• Major modifiable CVD risk factors:

Hypertension, Dyslipideamia, Tobacco use,
Physical inactivity, Obesity, Unhealthy diets and
Diabetes mellitus (WHO, 2004).

• Non-modifiable CVD risk factors:

advancing age, heredity/family history, gender
and race/ethnicity (WHO, 2004).
INTERHEART Study: 9 for >90

Yusuf S. INTERHEART study, Lancet 2003

BRITISH REGIONAL HEART Study (2003):

Smoking, BP and Cholesterol ≈ 90% CVD RISK
Classification of hypertension: added CV risk

ESH and ESC Hypertension guidelines:

17
Journal of Hypertension 2013, 31:1281–1357
Staging of hypertension: CV Risk
profile
Majority of people with hypertension have multiple CV risk
factors.

Presence of any of the following significantly

increases cardiovascular risk:
-Diabetes mellitus (75% have high BP)
-Chronic kidney disease
-Stroke/TIA
-Myocardial infarction
-Peripheral artery disease
-Smoking
-Dyslipidaemia
18
Interventions to prevent
CVD Complications in
Diabetes
Stone JA et al. Canadian Diabetes Association Clinical Practice
Guidelines Vascular Protection in People with Diabetes
CVD prevention strategies

• Primordial
• Primary
• Secondary
• Tertiary

[Preventive efforts should be life-long, from birth (if not

before) to old age]
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
 Absolute Risk of MI is Higher in Patients
with DM
Diabetes n = 379,003 No Diabetes n = 9,018,082 Database 1994-2000

3.0 Diabetes
No. events per 100 person- years

Men
2.5 Women

2.0
No diabetes
1.5 Men

Women
1.0

0.5

0
20-30 31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85
MI = myocardial infarction
Age group
All lines fitted according to a polynomial equation; R2= 0.99–1.00 for each

Booth GL, et al. Lancet 2006;368:29-36.

 MRFIT: Impact of Diabetes on
Cardiovascular Mortality
140
Nondiabetes (n = 342,815) 125
120 Diabetes (n = 5,163)
Mortality per 10,000

100 91

80
59
60 47

40 31
22
20 12
6
0
None One only Two only All three
Number of risk factors*
*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 Study
Multifaceted Approach for CVD Prevention
Among Patients with T2DM
Intensive Arm
Therapies to achieve targets in
Type 2 Diabetes glycemia, lipids, BP and
+ microalbuminuria
Microalbuminuria Multidisciplinary care q3mo
n = 160 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
STENO-2: Intensive Group Achieved Targets

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

 Intensive Group had Improved CV Outcomes

60
P = 0.007
50
Any CV event 53 % RRR
Conventional therapy
40
Intensive therapy
NNT = 5
30

20

10

0
12 24 36 48 60 72 84 96
Months of Follow-up
RRR= relative risk reduction

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

STENO 2 – Microvascular Disease

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

Use a Multifaceted Vascular Protection
Strategy

Healthy BP <130/80
Lifestyle/weight

Smoking Cessation

Physical A1C ≤7%

Activity

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%) 24%

reduction
(P<0.00001)
HPS: Heart protection study 0.4 0.6 0.8 1.0 1.2 1.4

HPS Lancet 2002;360:7-22

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.

 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.
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.
Vascular protective medications

• Statins
• ACE-inhibitors or Angiotensin receptor
blockers (ARB)
• ASA selective use
 Association of SBP and CV Mortality in Men
With T2DM
250
No diabetes
Per 10,000 person-years

Diabetes
200
CV mortality rate

150

100

50

0
<120 120-139 140-159 160-179 180-199 ≥200
SBP (mmHg)
Stamler J, et al. Diabetes Care. 1993;16:434-444.
Hypertension in Diabetes UKPDS

50 Less tight control (mean BP 154/87 mmHg)

Tight control (mean BP 144/82 mmHg)
40
Patients with events (%)

30

20
Tight BP control:
10 24% reduction of events
(95% CI 8-38)

0
0 1 2 3 4 5 6 7 8 9
Years from randomization
UKPDS Study Group. BMJ 1998; 317:703-13.
HOT: BP Control Reduces CV Events
Diabetes Subgroup

30 P<0.005

25 24.4 Goal of therapy: target

diastolic BP
mortality/1000 pt-y
MI, stroke, CV

20
18.8  90 mm Hg (n=501)
 85 mm Hg (n=501)
15
 80 mm Hg (n=499)
11.9
10

Hansson et al. Lancet. 1998;351:1755.

BP Differences of 10 mmHg are associated
with up to a 40% effect on CV risk
• Meta-analysis of 61 prospective, observational studies
• 1 million adults
• 12.7 million person-years
30% reduction
in risk of IHD
10 mmHg mortality
decrease in
mean SBP 40% reduction
in risk of stroke
mortality

Lewington S et al. Lancet. 2002;360:1903–1913.

 Micro-HOPE (ACEi): CV Benefits
Primary Outcome (NNT 22)
0.16 All Mortality
0.2 (NNT 31)
Placebo
Ramipril 10 mg
0.08
0.1
Kaplan-Meier rates

RR = 0.75 (0.64-0.88)
RR = 0.76 (0.63-0.92)
p = 0.0004
p = 0.004
0 0
0 400 800 1200 0 400 800 1200 1600
160
0
0.16 0.08 0.12
MI Stroke CV Death
(NNT 37) (NNT 53) (NNT 29)

0.08 0.04 0.06

RR = 0.78 (0.64-0.94) RR = 0.67 (0.5-0.9) RR = 0.63 (0.49-0.79)

p = 0.01 p = 0.0074 p = 0.001
0 0 0
0 1000 2000 0 1000 2000 0 1000 2000

Duration of follow-up (days)

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? 2013
(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
EUROPA Investigators, Lancet 2003;362(9386):782-788.
HOPE study investigators. Lancet. 2000;355:253-59.
ONTARGET study investigators. NEJM. 2008:358:1547-59
CV continuum in Hypertension and the relative
preventive effect of BP Lowering and Ancillary
actions of Antihypertensive agents (RAS blockers)
BP 
BP  +
Specific
+ Ancillary
BP 
Specific Actions +
Ancillary Specific
Ancillary
Actions Clinical Actions
Disease

Subclinical Cardio-
Angina
Organ vascular
TIA Event
Damage Claudicatio
Proteinuria
LVH MI
BP  IMT
Moderate Renal Disease
Established Diabetes
Stroke
+ Microalb.
Mild Renal Disease
CHF
ESRD
Specific Recent Diabetes
Risk Endothelial Dysfunction
Ancillary Factors Death

Actions Metabolic Syndrome

Dyslipidemia
Hypertension

Zanchetti J Hypertens 2005;23:1113-20

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

 No. of events/No. in group

ASA Control/placebo RR (95% CI) RR (95% CI)

Major CV events
JPAD 68/1262 86/1277 0.80 (0.59-1.09)
ASA for 1⁰ POPADAD
WHS
105/638
58/514
108/638
62/513
0.97 (0.76-1.24)
0.90 (0.63-1.29)
PPP 20/519 22/512 0.90 (0.50-1.62)
Prevention in ETDRS
Total
350/1856
601/4789
379/1855
657/4795
0.90 (0.78-1.04)
0.90 (0.81-1.00)

Diabetes Myocardial infarction

JPAD 28/1262 14/1277 0.87 (0.40-1.87)
Meta analysis of 6 studies POPADAD 90/638 82/638 1.10 (0.83-1.45)
WHS 36/514 24/513 1.48 (0.88-2.49)
(n = 10,117) PPP 5/519 10/512 0.49 (0.17-1.43)
ETDRS 241/1856 283/1855 0.82 (0.69-0.98)
PHS 11/275 26/258 0.40 (0.20-0.79)
Total 395/5064 439/5053 0.86 (0.61-1.21)
No overall benefit for:
Stroke
• Major CV events JPAD 12/1262 32/1277 0.89 (0.54-1.46)
POPADAD 37/638 50/638 0.74 (0.49-1.12)
• MI WHS 15/514 31/513 0.46 (0.25-0.85)
PPP 9/519 10/512 0.89 (0.36-2.17)
• Stroke ETDRS 92/1856 78/1855 1.17 (0.87-1.58)
Total 181/4789 201/4795 0.83 (0.60-1.14)
• CV mortality
Death from CV causes
• All-cause mortality JPAD 1/1262 10/1277 0.10 (0.01-0.79)
POPADAD 43/638 35/638 1.23 (0.80-1.89)
PPP 10/519 8/512 1.23 (0.49-3.10)
JPAD = Japanese Primary Prevention of Atherosclerosis ETDRS 244/1856 275/1855 0.87 (0.73-1.04)
with Aspirin for Diabetes Total 298/4275 328/4282 0.94 (0.72-1.23)
POPADAD = Prevention of Progression of Arterial
Disease and Diabetes All-cause mortality
PPP = Primary Prevention Project JPAD 34/1262 38/1277 0.90 (0.57-1.14)
ETDRS = Early Treatment Diabetic Retinopathy Study POPADAD 94/638 101/638 0.93 (0.72-1.21)
PHS = Physicians’ Health Study PPP 25/519 20/512 1.23 (0.69-2.19)
ETDRS 340/1856 366/1855 0.91 (0.78-1.06)
WHS = Women’s Health Study
Total 493/4275 525/4282 0.93 (0.82-1.05)
De Beradis G, et al. BMJ 2009; 339:b4531. 2
0.03 0.125 0.5 1 8
Favors ASA 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 CVD protection

Consider use in (over age 40 or with other CVD risk

factors) for CV events
Diabetes Care 20:1767–1771, 1997.
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
 Does CVD Prevention work?

Over 50% of the reductions seen in CHD

mortality relate to changes in RISK FACTORS
and 40% to improved treatments.

Yes!

54
Additional Take Home Messages

All individuals with diabetes (type 1 or type 2) should follow

a comprehensive, multifaceted approach to reduce
CV risk including:
- Maintenance of healthy body weight
- Healthy diet
- Regular physical activity
- Smoking cessation
- Additional vascular protective medications in the
majority of adult patients
 …Join hands to prevent CVD
Complications in Diabetes

Thank you!