The concept of diabetes cv risk a lifetime risk challenge
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The concept of Diabetes & CV risk: A lifetime risk challenge. Cardio Diabetes Master Class Asian chapter January 28-30 2011, Shanghai. Presentation topic. Slide lecture prepared and held by:. John Deanfield, MD University College London London, United Kingdom.

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The concept of diabetes cv risk a lifetime risk challenge

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

Cardio Diabetes MasterClass

Asianchapter

January 28-30 2011, Shanghai

Presentation topic

Slide lecture prepared and held by:

John Deanfield, MD

University College London

London, United Kingdom


Heart protection study impact of diabetes on cv outcome

Heart Protection Study: Impact of Diabetes on CV outcome

50

Placebo

Simvastatin 40 mg

40

RRR12%

Incidence of major vascular events (%)

RRR22%

30

RRR19%

RRR23%

20

RRR31%

10

1009

972

5683

5722

519

551

1481

1449

1455

1457

0

Diabetes + CHD

No diabetes + CHD

Diabetes + other CVD

No diabetes + other CVD

Diabetes + no CVD

HPS Collaborative Group. Lancet. 2003;361:2005


Cvd accounts for 71 of costs of chronic complications of diabetes

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

Total US expenditure in 2002 = US$ 24.6 billion

Cardiovascular disease

Neurological symptoms

11%

71%

Renal complications

8%

Peripheral vascular disease

5%

Endocrine/metabolic

Ophthalmic complications

Other

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


Cholesterol in china 2000 2001

Cholesterol in China (2000-2001)

Aware

Treated

Controlled

≥ 240 mg/dl

≥ 200 mg/dl

10

25

8.8

21.3

8

20

7.5

18.1

Prportion %

14.0

Prportion %

6

15

11.6

11.3

9.5

4

10

3.5

3.4

1.9

2

5

1.5

0

0

Men

Women

Men

Women

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

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


The concept of diabetes cv risk a lifetime risk challenge

Diabetes in China : 1994-2008

Yang NEJM 2010 362 1090-101


Potentially modifiable risk factors and mi interheart study

Potentially Modifiable Risk Factorsand MI : INTERHEART Study

15152 Cases 14820 Controls in 262 Centres in 52 Countries

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

3

Odds

Ratio

2

1

0

BP

DM

Stress

Fr/Veg

Obesity

Alcohol

Smoking

Phys Act.

ApoB/ApoA1

60

40

PAR

(%)

20

0

-20

Yusuf Lancet September 11 2004


The concept of diabetes cv risk a lifetime risk challenge

Temporal Mortality Trends in MI in

Patientswithandwithout Diabetes

(a comparisonof 1762 patients in 1995 with 1642 patients in 2003)

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


Atherosclerosis risk reduction strategy lifetime risk

Atherosclerosis:Risk Reduction Strategy Lifetime Risk

  • Treat to lower levels

  • Target global risk

  • Start earlier


Cards cumulative hazard for mi and cv death

CARDS: Cumulative Hazard for MI and CV death

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

15

Placebo

P=0.001

10

Atorvastatin

Cumulative Hazard (%)

5

0

0

1

2

3

4

4.75

Years


Time to first major cardiovascular event in patients with diabetes tnt study

Time to First Major Cardiovascular Eventin Patients With Diabetes TNT Study

Atorvastatin 10 mg

Atorvastatin 80 mg

HR = 0.75 (95% CI 0.58, 0.97)

P=0.026

0.20

Atorvastatin 10mg

0.15

Atorvastatin 80mg

Cumulative incidence of major cardiovascular events

0.10

0.05

Relative risk reduction = 25%

0

0123456

Time (years)


Residual disease progression in diabetes despite intensive ldl c lowering

Residual Disease Progression in Diabetes Despite Intensive LDL-C Lowering

1.5

1.0

Δ Percent Atheroma Volume

0.5

0.0

DM

LDL<80

DM

LDL>80

No DM

LDL<80

No DM

LDL>80

-0.5

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


Multiple risk factors and cvd death in diabetic and non diabetic men mrfit

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

140

No Diabetes

Diabetes

120

100

Age-adjusted CVD death rate/10,000 person-years

80

60

40

20

0

None

One only

Two only

All three

Number of risk factors

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


Steno 2 study in t2 dm cv outcome

60

50

40

30

20

10

0

Steno-2 Study in T2 DM: CV Outcome*

Conventional therapy

P=0.007

Primary endpoint (%)

Intensive therapy

24

36

48

0

12

60

72

84

96

Months of follow-up

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

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


Atherosclerosis investing in your arteries

Atherosclerosis:‘Investing in your Arteries’

Early Intervention for

Lifetime Risk management


Coronary heart disease mortality in beijing 1984 1999

Coronary Heart Disease Mortalityin Beijing 1984-1999

2500

1822 Extra deaths Attributable

to Risk Factor Changes

2000

Cholesterol 77%

1000

Diabetes 19%

BMI4%

Smoking1%

500

0

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%

-500

-1000

1999

1984

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


The concept of diabetes cv risk a lifetime risk challenge

EEM Area13.2 mm2

5.07mm2

Atheroma Area 8.13 mm2

Prevalence of Atherosclerosis by Donor Age

100

85%

80

71%

60%

60

Prevalence ofAtherosclerosis (%)

37%

40

17%

20

0

<20

20-29

30-39

40-49

≥50

Donor Age (years)

32 Year Old Female

Tuzcu Circ 2001 103:2075-10


Cv risk factors in childhood and carotid imt in adults

CV Risk Factors in Childhood andCarotid IMT in Adults

Risk factors measured at ages 12-18yrs

No. of risk factors

0

1

2

3 or 4

P<0.001

P<0.001

0.88

0.80

Mean maximum carotid

IMT (mm)

0.72

0.64

0.56

0.48

Women

Men

Raitakari et al JAMA 2003;290;2277-2283


Framingham heart study lifetime risk

Framingham Heart Study Lifetime Risk

Women

Men

0.7

0.7

69%

≥2 Major RFs

1 Major RF

≥ Elevated RF

≥ Not Elevated RF

All Optimal RFs

0.6

0.6

50%

0.5

0.5

46%

0.4

0.4

36%

0.3

0.3

0.2

0.2

0.1

0.1

8%

5%

0

0

70

70

60

90

60

90

50

80

50

80

50%

39%

Adjusted Cumulative Incidence

27%

Attained Age

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


Age and cv risk in diabetes

Age and CV Risk in Diabetes

Men

Women

30

30

Women with diabetes

Women without diabetes

Men with diabetes

Men without diabetes

25

25

20

20

15

15

10

10

5

5

0

0

20-30

31-40

41-45

46-50

51-60

56-60

61-65

66-70

71-75

76-80

81-85

20-30

31-40

41-45

46-50

51-60

56-60

61-65

66-70

71-75

76-80

81-85

Age (years)

Age (years)

Booth Lancet 2006; 368: 29-36


The concept of diabetes cv risk a lifetime risk challenge

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

No Nonsense

Mutation

(n=3278)

12

50th Percentile

30

P=0.008

20

8

88%

10

Frequency (%)

Coronary Heart Disease (%)

0

0

100

200

250

50

150

300

PCSK9142X

or PCSK9679X

(N=85)

4

28%

30

20

0

No Yes

10

PCSK9142Xor PCSK9679X

0

0

100

200

50

150

300

250

Cohen NEJM 2006; 354:1264-72

LDL Cholesterol in Black Subjects (mg/dl)


Primary prevention in fluence of age on relationship between cholesterol and chd

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

Age 70

Age 50

Age 40

-60%

0%

-20%

-40%

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

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


High normal bp and cvd risk framingham study

14

12

10

8

6

4

2

0

High-Normal BP and CVD Risk: Framingham Study

High normal 130-139/85-89 mm Hg

Prehypertension

Normal 120-129/80-84 mm Hg

Optimal<120/80 mm Hg

Women

Men

10

8

P<.001

P<.001

6

Cumulative Incidence (%)

4

2

0

0

2

4

6

8

10

12

14

0

2

4

6

8

10

12

14

Time (years)

Time (years)

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


The concept of diabetes cv risk a lifetime risk challenge

“Normotensive”

145 / 93

--

10.3

1.8

10.8

29.2

Treated BP

185 / 114

145 / 89

20.1*

4.5*

8.9

37.4*

Screening BP (mmHg)

Final BP (mmHg)

CHD (%)

Stroke (%)

Cancer (%)

All-cause death (%)

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

*p <0.02

Anderson, BMJ 1998; 317: 167


The concept of diabetes cv risk a lifetime risk challenge

BP Treatment in Type 2 DM

4733 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

TROPHY Study: ARB in ‘Prehypertension’

100

80

Placebo

60

40

Candesartan

Cumulative Incidence (%)

20

0

0

1

2

3

4

StudyYear

Julius NEJM 2006; 354 : 1685-97


Lifetime management of atherosclerosis risk

Lifetime Management of Atherosclerosis Risk

  • Benefits of early intervention from

  • Less Exposure / burden?

  • Disease modification?


Cardiovascular continuum vascular biology targets

Cardiovascular Continuum: Vascular Biology Targets

Pathological remodelling

Atherothrombosis and progressive CV disease

Target organ damage

Early tissue dysfunction - endothelium

End-organ failure (CHF, ESRD)

Oxidative and mechanical stress Inflammation

Death

Risk factors

Dzau V Circ 2006 114; 2850-2870

Tissue injury

(MI, stroke, renal insufficiency, peripheral arterial insufficiency)


Ras blockade adipocytes and diabetes

RAS Blockade, Adipocytes and Diabetes

Lenz O Kidney International 2008 74: 851-853


Intravascular ultrasound of coronary arteries determining the atheroma area

Intravascular Ultrasound of Coronary Arteries Determining the Atheroma Area

EEM Area

LumenArea

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

(EEM Area — Lumen Area)

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

Nicholls et al JACC 57 No 2 2011


Benefit of treating the metabolic syndrome

Benefit of Treating the Metabolic Syndrome

23%

After 4 years risk of diabetes reduced by 58%

11%

Intervention

Control

% with Diabetes

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


The concept of diabetes cv risk a lifetime risk challenge

….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


The concept of diabetes cv risk a lifetime risk challenge

A reasonable next step for ATP IV?

….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


The concept of diabetes cv risk a lifetime risk challenge

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


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