Cardio Diabetes Master ClassApril 15 – 16, 2016 - Dubai, UAE

Understanding the natural

course of diabetes and CVD

Kausik Ray, MDImperial College London

London, United Kingdom

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

?The Future is Already Here!

Central Adiposity

Adapted from DeFronzo RA. BR J Diabetes Vasc Dis. 2003;3(Suppl1):S24-40

Insulin Resistance Syndrome and Risk Factors for CVD in Type 2 Diabetes

Aging

Obesity

Dyslipidemia– decreased HDL– increased

triglycerides

Genetics

Hyperinsulinemia

Sedentary lifestyle

InsulinResistance

Hyperglycemia

Altered fibrinolysis,Inflammation,Endothelial dysfunction

Hypertension

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

Malmberg K et al. Circulation 2000;102:1014–1019.

Patients with Diabetes at Similar Risk to No Diabetes with CVD: OASIS

0 3 18 21 246 9 12 15

Months of follow-up

0.25

0.20

0.15

0.10

0.05

0

diabetes plus CVD (n=1448)RR 2.88

no diabetes/no CVD (n=2796)RR 1.0

no diabetes plus CVD (n=3503)RR 1.71

diabetes plus no CVD (n=569)RR 1.99

RR relative reduction

’

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: Not Always a CVD Risk Equivalent

Sattar N; Diabetologia 2013

CHD equivalence threshold

Diagnosis

8-10years’duration

Age

CH

D r

isk

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

Risk of Major CHD Event Associated with High Insulin Levels in Men without

Diabetes

Q1 to Q5 = quintiles of area under the curve (AUC) insulin (Q1=lowest quintile; Q5=highest quintile).

YearsPro

po

rtio

n w

ith

a m

ajo

r C

HD

eve

nt

0

0

5

0.05

0.10

0.15

0.20

0.25

1.00

10 15 20 25

Log rank:

Overall p=0.001

Q5 vs. Q1 p<0.001

Q1

Q2

Q3Q4

Q5

Pyörälä M et al. Circulation 1998;98:398–404.

Combination of Risk Factors Increases Risk of MI: PROCAM

Assmann G, Schulte H. Am Heart J 1988;116:1713–1724.

0

20

40

60

80

100

120

Inci

den

ce o

f M

I/1

00

0 p

ts

Prevalence (%): 54.9 22.9 2.6 2.3 9.4 8.0

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.

UKPDS Brit Med J 2000;321:405

Haz

ard

rat

io 12% rise per 1%P <0.035

Fatal and non-fatal stroke

14% rise per 1% P <0.000110

1

0.5

Fatal and non-fatal MI

10

43% rise per 1%

P <0.0001

Amputation/Death from PVD

65 7 8 9

16% rise per 1% P <0.021

Heart failure

65 7 8 9 10

HbA1 c (%)

Impact of Increasing HbA1c

Diabetes and Cardiovascular Disease

HbA1 c (%)

Haz

ard

rat

io

10

1

0.5

Del Prato S, et al. Int J Clin Pract 2010;64:295–304.

6.5

6.0

7.0

7.5

8.0

9.5

9.0

8.5

1 2 3 4 5 6 7 8 109 1211 1413 15 1716

Time since diagnosis (years)

Before entering VADT intensive treatment arm After entering VADT intensive treatment arm

Hb

A1

c(%

)

Generation of a ‘bad glycemic legacy’

Drives risk of complications

Modelling the prior history of patients recruited in VADT illustrates the drawbacks of late intervention

Legacy of ‘Bad Metabolic Memory’

• Solid line: changes in HbA1c in response to intensive treatment in VADT

• Upper broken line: theoretical reconstruction of prior diabetes progression based on UKPDS

• Lower broken line: the ideal time course of glycemic control

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.

Survival Post-MI in Men and Women With and Without Diabetes

Sprafka JM et al. Diabetes Care 1991;14:537–543.

0 10 20 30 40 50 60

n=156

100

90

80

70

60

50

40

0 10 20 30 40 50 60

100

90

80

70

60

50

40

Months Post-MI

Men Women

Surv

ival, %

Surv

ival, %

Diabetes

No diabetes

n=228

n=1628 n=568

Months Post-MI

Mortality after Coronary Intervention in Those With and Those Without Diabetes:

BARI

0

5

10

15

20

25

30

35

No diabetes(n=1476)

Diabetes(n=353)

5-y

ear

mo

rtal

ity

(%)

CABG

PTCA

BARI Investigators. N Engl J Med 1996:335:217–225.

0

10

20

30

40

DM Alone CHD Alone CHD + DM

Prior Disease

Pati

ents

dev

elo

pin

g 1

stm

ajo

r C

V e

ven

t in

pla

ceb

o g

rou

p (

%)

HPS Collaborative Group. Lancet 2003;361:2005–2016.

Patients with Major CV Events by Prior Disease: HPS

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

Summary

• DM is Common

• It doubles CVD risk

• It is Progressive

• The combination of DM with vascular disease states further doubles risk

• Earlier the better wrt intervention