the concept of diabetes & cv risk: a lifetime risk challenge john deanfield, md university...
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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