The concept of Diabetes & CV risk:A lifetime risk challenge

John Deanfield, MD University College LondonLondon, United Kingdom

Cardio Diabetes Master ClassAsian chapterJanuary 28-30 2011, Shanghai

Slide lecture prepared and held by:

Presentation topic

Heart Protection Study: Impact of Diabetes on CV outcome

HPS Collaborative Group. Lancet. 2003;361:2005

0

10

20

30

40

50

Inci

denc

e of

maj

or v

ascu

lar

even

ts (

%)

Placebo Simvastatin 40 mg

RRR12%RRR12%

RRR23%RRR23%

RRR22%RRR22%

RRR19%RRR19%

RRR31%RRR31%

Diabetes + CHD

Diabetes + CHD

No diabetes + CHD

No diabetes + CHD

Diabetes + other CVD

Diabetes + other CVD

No diabetes + other CVDNo diabetes + other CVD

Diabetes + no CVDDiabetes + no CVD

1009 972 5683 5722 519 551 1481 1449 1455 1457

CVD Accounts for 71% of Costs of Chronic Complications of Diabetes

11%

8%

5%

71%

Cardiovascular disease

Neurological symptoms

Renal complications

Peripheral vascular disease

Endocrine/metabolic

Ophthalmic complications

Other

Total US expenditure in 2002 = US$ 24.6 billion

American Diabetes Association. Diabetes Care 2003;26:917-32

Cholesterol in China (2000-2001)

Jiang H. Circulation, 2004;110:405-411

112,500,000 Borderline HC 42,540,000 HC 90,803,000 Low HDL

≥ 200 mg/dl25

20

15

10

5

0

Prp

ortio

n %

Men Women

21.3

14.0

11.3

18.1

11.6

9.5

AwareTreatedControlled

10

8

6

4

2

0

Prp

ortio

n %

Men Women

8.8

3.5

1.9

7.5

3.4

1.5

≥ 240 mg/dl

Diabetes in China : 1994-2008

Yang NEJM 2010 362 1090-101

Potentially Modifiable Risk Factorsand MI : INTERHEART Study

15152 Cases 14820 Controls in 262 Centres in 52 Countries

Yusuf Lancet September 11 2004

0

1

2

3

Smoking

BP Alcohol

-20

0

20

40

60

ApoB/ApoA1

DM Stress

Obesity

Fr/Veg

Phys Act.

OddsRatio

PAR(%)

9 RFs acounted for 90% of MI in men and 94% in women

Cubbon RM et al. Eur Heart J 2007; 28: 540–545

Temporal Mortality Trends in MI in Patients with and without Diabetes (a comparison of 1762 patients in 1995 with 1642 patients in 2003)

Atherosclerosis:Risk Reduction Strategy Lifetime Risk

Treat to lower levels Target global risk Start earlier

CARDS: Cumulative Hazard for MI and CV death

Atorvastatin

Cum

ulat

ive

Haz

ard

(%)

Relative Risk -37% (95% CI: -52, -17)

P=0.001

Years

Placebo

0

5

10

15

0 1 2 3 4 4.75

Time to First Major Cardiovascular Eventin Patients With Diabetes TNT Study

HR = 0.75 (95% CI 0.58, 0.97) P=0.026

Atorvastatin 10 mg

Atorvastatin 80 mg

0 1 2 3 4 5 6

Time (years)

0.20

0.10

0.15

0.05

0Cum

ulat

ive

inci

denc

e of

maj

or c

ardi

ovas

cula

r ev

ents

Relative risk reduction = 25%

Atorvastatin 80mg

Atorvastatin 10mg

Residual Disease Progression in Diabetes Despite Intensive LDL-C Lowering

Δ P

erce

nt A

ther

oma

Vol

ume

No DMLDL<80

DMLDL>80

DMLDL<80

No DMLDL>80

Nicholls J Amer Coll Cardiol 2008;52:255-62

-0.5

0.0

0.5

1.0

1.5

Multiple Risk Factors and CVD Death in Diabetic and Non diabetic Men (MRFIT)

Stamler J et al Diabetes Care 1993;16:434.

Age

-adj

uste

d C

VD

dea

th r

ate/

10,0

00

pers

on-y

ears

140

120

100

80

60

40

20

0

No Diabetes

Diabetes

None One only Two only All three

Number of risk factors

Steno-2 Study in T2 DM: CV Outcome*

*Death from CVD, MI, CABG,PCI, stroke, amputation, or surgery for PAD

Gæde P et al N Engl J Med 2003;348:383-393.

Prim

ary

endp

oint

(%

)

0 3612 966048 847224

0

60

30

40

20

10

50

Intensive therapy

Conventional therapy

Months of follow-up

P=0.007

Atherosclerosis:‘Investing in your Arteries’

Early Intervention for Lifetime Risk management

Coronary Heart Disease Mortalityin Beijing 1984-1999

Critchley J. Circulation, 2004;110:1236-1244

2500

2000

1000

500

0

-500

-1000

1984 1999

Cholesterol 77%

1822 Extra deaths Attributableto Risk Factor Changes

Diabetes 19%

BMI 4%

Smoking 1%

642 fewer deaths by treatments

AMI treatments 41%

Hypertension treatment 24%

Secondary prevetion 11%

Heart failure 10%

Aspirin for Angina 10%

Angina: CABG & PTCA 2%

Tuzcu Circ 2001 103:2075-10

5.07mm2

EEM Area13.2 mm2

Atheroma Area 8.13 mm2

32 Year Old Female

17%

37%

60%

85%

71%

0

20

40

60

80

100

<20 20-2930-3940-49≥50

Pre

vale

nce

ofA

ther

oscl

eros

is (

%)

Donor Age (years)

Prevalence of Atherosclerosis by Donor Age

CV Risk Factors in Childhood andCarotid IMT in Adults

Raitakari et al JAMA 2003;290;2277-2283

Men Women

P<0.001 P<0.0010.88

0.80

0.72

0.64

0.56

0.48

Mea

n m

axim

um c

arot

id I

MT

(m

m)

Risk factors measured at ages 12-18yrsNo. of risk factors

0 1 2 3 or 4

Framingham Heart Study Lifetime RiskA

dju

ste

d C

umul

ativ

e In

cid

ence

50%

39%

27%

Attained Age

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

50 60 70 80 90

69%

50%46%

36%

5%

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

50 60 70 80 90

8%

≥2 Major RFs1 Major RF≥ Elevated RF≥ Not Elevated RFAll Optimal RFs

Men Women

Lloyd-Jones Circ. 2006; 113: 791-798

Age and CV Risk in Diabetes

Booth Lancet 2006; 368: 29-36

30

25

20

15

10

5

0

20-3

0

31-4

0

41-4

5

46-5

0

51-6

0

56-6

0

61-6

5

66-7

0

71-7

5

76-8

0

81-8

5

Women

Women with diabetesWomen without diabetes

Age (years)

30

25

20

15

10

5

0

20-3

0

31-4

0

41-4

5

46-5

0

51-6

0

56-6

0

61-6

5

66-7

0

71-7

5

76-8

0

81-8

5

Men

Men with diabetesMen without diabetes

Age (years)

LDL Cholesterol and Coronary Heart Disease among Black Subjects by PCSK9142X or PCSK9679X Allele

LDL Cholesterol in Black Subjects (mg/dl)

PCSK9142X or PCSK9679X

300

30

20

10

00 50 100 150 200 250 300

No NonsenseMutation(n=3278) 50th Percentile

Fre

quen

cy (

%)

PCSK9142X

or PCSK9679X

(N=85)30

20

10

00 50 100 150 200 250

Cohen NEJM 2006; 354:1264-72

28%C

oron

ary

Hea

rt D

isea

se (

%)

No Yes

P=0.008

12

8

4

0

88%

-60%-40%-20%0%

Primary Prevention: Influence of Age on Relationship Between Cholesterol and CHD

Law MR et al. BMJ 1994;308:367-372.

Age 70

Reduction in risk in men with 10% reductionin total cholesterol (10 cohort studies)

Age 50

Age 40

Vasan et al. N Engl J Med. 2001;345:1291-1297.

High-Normal BP and CVD Risk: Framingham Study

Women

Time (years)

10

8

6

4

2

0

0 2 4 6 8 10 12 14

P<.001

Men

Cum

ulat

ive

Inci

denc

e (%

)14

12

10

8

6

4

2

0

Time (years)

0 2 4 6 8 10 12 14

P<.001

High normal 130-139/85-89 mm HgNormal 120-129/80-84 mm HgOptimal <120/80 mm Hg

Prehypertension

Anderson, BMJ 1998; 317: 167

Screening BP (mmHg)Final BP (mmHg)CHD (%)Stroke (%)Cancer (%)All-cause death (%)

Treated BP

185 / 114145 / 89

20.1* 4.5* 8.937.4*

“Normotensive”

145 / 93--

10.3 1.810.829.2

*p <0.02

Beyond BP?:Outcome in treated BP (n=686) vs. “Normotensive” (n=6810) Men after > 20yrs

BP Treatment in Type 2 DM4733 age 62.2 years intensive vs standard BP treatment over 4.7 years

ACCORD Study Group NEJM 2010;362:1575-1585

TROPHY Study: ARB in ‘Prehypertension’

100

80

60

40

20

0

Cum

ulat

ive

Inci

denc

e (%

)

0 1 2 3 4

Placebo

Candesartan

Study YearJulius NEJM 2006; 354 : 1685-97

Lifetime Management of Atherosclerosis Risk

Benefits of early intervention from Less Exposure / burden? Disease modification?

Cardiovascular Continuum: Vascular Biology Targets

Tissue injury(MI, stroke, renal

insufficiency, peripheral arterial

insufficiency)Pathological remodelling

Target organ damage

End-organ failure (CHF, ESRD)

Death

Early tissue dysfunction - endothelium

Atherothrombosis and progressive CV disease

Risk factors

Oxidative and mechanical

stress Inflammation

Dzau V Circ 2006 114; 2850-2870

RAS Blockade, Adipocytes and Diabetes

Lenz O Kidney International 2008 74: 851-853

Intravascular Ultrasound of Coronary Arteries Determining the Atheroma Area

EEM Area

LumenArea

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

(EEM Area — Lumen Area)

Precise planimetry of EEM and lumen bordersallows calculation of atheroma cross-sectional area

On multivariate analysis the only parameter independently associated with slowing of disease progression in the Pioglitazone group was

Triglyceride/HDL-C ratio P=0.03

Nicholls et al JACC 57 No 2 2011

Benefit of Treating the Metabolic Syndrome

Tuomilehto J et al. N Engl J Med 2001;344:1343-1350.

0%

5%

10%

15%

20%

25%

Intervention Control

After 4 years risk of

diabetes reduced by 58%

11%

23%

% with Diabetes

….It is essential that the new guidelines incorporate the logical concept that a long term disease requires a long term solution

Forrester JACC 2010; 56: 630-636

….Consider statins for younger persons, perhaps starting at 30 in those with risk factors that convey high lifetime risk (as opposed to 10 yr risk) for CHD Pletcher JACC 2010; 56: 637-640

A reasonable next step for ATP IV?

CV Risk Management-Long way to go?

Lifetime risk reduction is the target More active management of high risk

subjects such as diabetics In addition to ‘Lower and Broader’ RF

treatment, Early Management key to further reduction in CV events