managing cardiovascular disease in diabetes: why is it so ... · managing cardiovascular disease in...
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Managing cardiovascular
disease in diabetes:
Why is it so important
Kausik Ray, MDImperial College London
London, United Kingdom
Asian Cardio Diabetes ForumApril 23 – 24, 2016 – Kuala Lumpur, Malaysia
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IDF diabetes atlas, 4th edition, 2009
2010 2030
Total number of people with diabetes (age 20-79)
285 million 438 million
Prevalence of diabetes (age 20-79)
6.6 % 7.8 %
Prevalence of diabetes in 2030
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Patients with Diabetes at Similar Risk to No Diabetes with MI: East West Study
0
10
20
30
40
50
7-y
ea
r in
cid
en
ce
of
CV
eve
nts
(%
)
No prior MI
MI
Haffner SM et al. N Engl J Med 1998;339:229–234.
p<0.001
p<0.001
No diabetes (n=1373) Diabetes (n=1059)
ns
n=1304 n=890n=69 n=169
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’
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Progression of Diabetes
• Genetic susceptibility
• Environmental factors– Nutrition– Obesity– Inactivity
– Insulin resistance
– HDL-C
– Triglycerides
– Atherosclerosis
– Hypertension
DeathIGT Ongoing hyperglycemia
Diagnosis of diabetes
Appearance of complications
Disability
6 – 8 years
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DM duration matters to CVD
Men with diabetes without MI Men with MI
None
N=3197
Late onset
N=307
Mean duration
1.7 years
Early onset
N=107
Mean duration
16 years
Without
diabetes
N=368
CVD events (n=534)
Age 1.00 1.59 (1.19,2.12) 2.61 (1.73,3.96) 2.35 (1.88,2.95)
Adj 1.00 1.53 (1.15,2.06) 2.52 (1.65,3.84) 2.23 (1.76,2.83)
Wannamethee, Shaper, Whincup, Lennon, Sattar (Archives Int Med in press)
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Diabetes is associated with significant loss of life years
Seshasai et al. N Engl J Med 2011;364:829-41.
0
7
6
5
4
3
2
1
040 50 60 70 80 90
Age (year)
Years
of
life lost
Men7
6
5
4
3
2
1
040 50 60 70 80 900
Age (year)
Women
Non-vascular deaths
Vascular deaths
On average, a 50-year old with diabetes but no history of vascular disease is
~6 years younger at time of death than a counterpart without diabetes
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The Chronic Complications of Diabetes Mellitus (US)
Macrovascular complications:
• Cardiovascular disease
– Leading cause of diabetes related deaths (increases mortality and stroke by 2 to 4 times)
Microvascular complications:
• Retinopathy
– Leading cause of adult blindness
• Nephropathy
– Accounts for 44% of new cases of ESRD
• Neuropathy
– 60–70% of patients with diabetes have nervous system damage
National Diabetes Statistics US 2000.ESRD end-stage renal disease
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Levels of Risk Associated with Smoking, Hypertension and Hypercholesterolaemia
x1.6 x4
x3
x6
x16
x4.5 x9
Hypertension(SBP 195 mmHg)
Serum cholesterol level(8.5 mmol/L, 330 mg/dL)
Smoking
Poulter N et al., 1993.
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Schramm TK et al., Circulation, 2008; 117: 1945
Which Diabetics are at Highest Risk?
AGE
DM + Prior MI
Prior MI
DM
No DMNo Prior MI
HF and no DM
HF and DM
Burger A et al., Am J Cardiol 2005,95: 1117
Myocardial Infarction Heart Failure
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The dyslipidemia of intra-abdominal obesityand Type 2 diabetes
VLDL LDL HDL
Normal
Insulinresistance
VLDL triglycerides
VLDL apo B
LDL apo BParticle number
Particle size(small,dense)
HDL cholesterol
Particle number
Particle size(small,dense)
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TG-rich lipoproteins
VLDL VLDLR IDL LDL Small,denseLDL
Atherogenic Particles
• MEASUREMENTS: Apolipoprotein B or Non-HDL-C
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Recommendations for lipid analyses as
treatment target in the prevention of CVD
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CARDIOVASCULAR RISK FACTORS IN TYPE 2
DIABETES: the UKPDS data
UKPDS 23. BMJ 1998; 316: 823-8
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Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2010;376:1670-81
CTT meta-analysis: CV event reduction withstatins in diabetes
• CTT meta-analyses of individual participant data from randomised trials of more vs less intensive statin regimens (5 trials; 39612 individuals; median follow-up 5.1 years) and of statin vs control (21 trials; 129526 individuals; median follow-up 4.8 years)
• There was a ~20% risk reduction in major vascular events per 1.0 mmol/L LDL-C reduction with statins in patients with diabetes
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Statins- reduce CV events consistently(per 39mg/dl lower LDL-C)
CTT Lancet 2008 ,
371, 117-25
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The effect of lipid-lowering treatment in 18,686 individuals with diabetes was evaluated from 14 randomised statin trials (≥1,000 participants; treatment duration ≥2 years). The mean duration of follow-up was 4.3 years
Lipid lowering is effective in type 2 diabetes
Major vascular events All-cause mortality
Reductions per 1.0 mmol/L
Perc
en
tag
e (
%)
Adopted from Cholesterol Treatment Trialists’ (CCT) Collaborators, et al. Lancet 2008; 371(9607):117.
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Diabetes and CHD derive benefit from a lower achieved LDL-C (~ 80mg/dl)
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IMROVE-IT Baseline Characteristics
CharacteristicSimvastatin
(N=9077)%
EZ/Simva(N=9067)
%
Age – years 64 64
Female 24 25
Diabetes 27 27
MI prior to index ACS 21 21
STEMI/NSTEMI/UA 29/47/24 29/47/24
Days post ACS to rand (IQR) 5 (3,8) 5 (3,8)
Cath/PCI for ACS event 88/70 88/70
Prior lipid Rx 35 35
LDL-C at ACS event (mg/dL, IQR)
95 (79,110) 95 (79,110)
History of more than 1 prior MI 17
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Primary endpoint – ITT
20
Cardiovascular death, MI, documented unstable angina requiring rehospitalisation, coronary revascularisation (≥30 days), or stroke
Time since randomisation (years)0 1 2 3 4 5 6 7
Simva – 34.7% 2,742 events
EZ/Simva – 32.7%2,572 events
HR=0.936 CI (0.887, 0.988)
P=0.016
7-year event rates
NNT=50
0
10
20
30
40
Eve
nt
rate
(%
)
Braunwald E, AHA scientific sessions 2014, oral presentation
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Simva† EZ/Simva†
Male 34.9 33.3Female 34.0 31.0
Age <65 years 30.8 29.9Age ≥65 years 39.9 36.4
No diabetes 30.8 30.2Diabetes 45.5 40.0
Prior LLT 43.4 40.7No prior LLT 30.0 28.6
LDL-C >95 mg/dL31.2 29.6
LDL-C ≤95 mg/dl38.4 36.0
Major pre-specified subgroups
21
Ezetimibe/Simva better Simva better0.7 1.0 1.3
†7-year event rates
*
*p-interaction=0.023, otherwise >0.05
Braunwald E, AHA scientific sessions 2014, oral presentation
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Greater absolute risk reductions in individuals with higher absolute risk
Ab
so
lute
ris
k o
f C
HD
even
t %
Mean LDL-C level at follow-up (mg/dl)
0
5
10
15
20
25
30
90 109 129 148 172
DM
CVD
1° Prevention
70
ATP III
Ray IJCP 2007, 61, 1608-11
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Guidelines
ACC / AHA if 10 year risk <7.5% moderate intensity meaning a >30% LDL-C reduction, Risk >7.5% aim for 50% LDL-C reduction with high intensity statins
ESC/ EAS LDL-C of <1.8mmol/L if DM plus end organ damage/ risk factors otherwise <2.5mmol/L
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Diabetics derive similar proportional reductions in risk as non-diabetics
with BP lowering
BP treatment Trialists. Archives 2005, 165, 1410-1419
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UKPDS lowering SBP reduces principally Strokes
BMJ 1998;317:703-713
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BP lowering results in diabetes related deaths (myocardial
infarction, sudden death, stroke, peripheral vascular
disease, and renal failure).
BMJ 1998;317:703-713
©1998 by British Medical Journal Publishing Group
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ACCORD
Average after 1st year: 133.5 Standard
119.3 Intensive, Delta = 14.2
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Primary & Secondary Outcomes
Intensive Events (%/yr)
StandardEvents (%/yr)
HR (95% CI) P
Primary 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20
Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55
CardiovascularDeaths
60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74
Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25
NonfatalStroke
34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03
Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01
NEJM 2010, 362, 1575-1585
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NICE2011
ESH/ESC 2013
ASH/ISH 2014
AHA/ACC/CDC 2013
JNC 82014
Blood pressure target in patients with diabetes mellitus
Not addressed
<140/90 <140/90 <140/90
Lower targets may be considered
<140/90
Blood pressure targets in diabetes
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BP summary
Actual BP achieved critical rather than agent used
Meta-analysis
Target BP <140 mmHg in all guidelines
More intensive target < 120 SBP results in stroke benefits
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Effect of 0.9% lowering of HbA1c on CVD outcomes in 33,042 patients across five
studies
OR (95% CI) Outcome
10.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
Odds ratio
Intensive therapy better Standard therapy better
Non-fatal MI 0.83 (0.75, 0.93 )
0%CHD 0.85 (0.77, 0.93)
0%Stroke 0.93 (0.81, 1.06)
58%All-cause mortality 1.02 (0.87, 1.19)
Ray KK et al. Lancet. 2009;373, 765-72
I2
0%
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Changes in CAD Mortality Over Time in Men and Women with Diabetes and with
No Diabetes : NHANES I to NHEFS
-50
-40
-30
-20
-10
0
10
20
% c
han
ge in
mo
rtal
ity
du
e to
CA
D f
rom
N
HA
NES
I to
NH
EFS
(8-9
yea
rs) Men
Women
*p<0.001 vs. baseline
*Diabetes No diabetes
Gu K et al. JAMA 1999;281:1291–1297.
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STENO 2- Combination of BP/ lipid lowering/ glycaemic control/lifestyle
reduces mortality
Gaede NEJM 2008, 358, 580-591
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Summary
• DM is Common
• It doubles CVD risk
• It is Progressive
• The combination of DM with vascular disease states further doubles risk
• Global approach is needed to risk factor control