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

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

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

’

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

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)

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

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

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.

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

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)

TG-rich lipoproteins

VLDL VLDLR IDL LDL Small,denseLDL

Atherogenic Particles

• MEASUREMENTS: Apolipoprotein B or Non-HDL-C

Recommendations for lipid analyses as

treatment target in the prevention of CVD

CARDIOVASCULAR RISK FACTORS IN TYPE 2

DIABETES: the UKPDS data

UKPDS 23. BMJ 1998; 316: 823-8

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

Statins- reduce CV events consistently(per 39mg/dl lower LDL-C)

CTT Lancet 2008 ,

371, 117-25

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.

Diabetes and CHD derive benefit from a lower achieved LDL-C (~ 80mg/dl)

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

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

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

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

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

Diabetics derive similar proportional reductions in risk as non-diabetics

with BP lowering

BP treatment Trialists. Archives 2005, 165, 1410-1419

UKPDS lowering SBP reduces principally Strokes

BMJ 1998;317:703-713

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

ACCORD

Average after 1st year: 133.5 Standard

119.3 Intensive, Delta = 14.2

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

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

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

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%

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.

STENO 2- Combination of BP/ lipid lowering/ glycaemic control/lifestyle

reduces mortality

Gaede NEJM 2008, 358, 580-591

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