Page 1: Baker IDI

Heart and DiabetesBaker IDI in the Centre

Professor Garry Jennings

Director

Baker IDI Heart and Diabetes Institute

Page 2: Baker IDI

Themes

• Outcomes in diabetes

• Atherosclerosis and diabetes

• Coronary disease in the diabetic patient

• Diabetic heart

• Therapeutic aspects

• What Baker IDI is doing relevant to indigenous health

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Hypertension

Dyslipidaemia

Diabetes

Abdominal obesity

•80% of deaths in diabetes due to CVD•80% of heart attack sufferers have impaired glucose tolerance•85% of the population have one or more of these risk factors

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DiabetesDyslipidaemiaHypertension

NutritionExercise

Early lifePregnancy Childhood obesity

Risk Factors

SubClinicalorgan damage

ArteriesHeartBrain KidneysEyes etc

Acute Complications

Chronic Complications

Heart Failure

Terminal Disease

Angina

Kidney Failure

Dementia

Sudden Death

Thrombosis

Aneurysm

Prevention X

Prevention X

Prevention X

Prevention X

Prevention X

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T2D complications- mainly vascular

DiabeticretinopathyLeading causeof blindnessin working-ageadults1

DiabeticnephropathyLeading cause of end-stage renaldisease2

Cardiovasculardisease

Stroke2- to 4-fold increasein cardiovascular mortality and stroke3

DiabeticneuropathyLeading cause of non-traumatic lower extremity amputations5

Disability from autonomic neuropathy

8/10 diabetic patients die from cardiovascular events4

1. Fong DS et al. Diabetes Care 2003; 26 (Suppl 1): S99–102; 2. Molitch ME et al. Diabetes Care 2003; 26 (Suppl 1): S94–8; 3. Kannel WB et al. Am Heart J 1990; 120: 672–6; 4. Gray RP, Yudkin JS. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 2nd Edn.

Oxford: Blackwell Science, 1997; 5. Mayfield JA et al. Diabetes Care 2003; 26 (Suppl 1): S78–9.

Page 7: Baker IDI Adapted from Miettinen H et al Diabetes Care. 1998;21:69-75.

Diabetes No Diabetes Diabetes No diabetes

% o

f de

ath

s (c

rude

ra

te)

60

40

30

20

10

0

Men

28.6

15.4

9.1

22.1

9.6

4.2

10.9

22.7

11.1

11.9

9.0

2.8

28d–1yHospitalization–28dOut of Hospital

Women

50

Cardiovascular disease in people with diabetes

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Proportion of hospital bed days for the treatment of the complications of

diabetes

Diabetes- - ++

Men Women

Wo

rkfo

rce

p

artic

ipat

ion

rate

Diabetes impacts on “Human Capital” as an economic issue

Council of Australian Governments – Elevating diabetes above a health issue

Cardiovascular disease in people with diabetes - Morbidity

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Insulin Resistance and metabolic syndromeCentral obesity

HyperglycemiaEndothelial

dysfunction/microalbuminuria

Cardiovascular Disease

HypertensionDyslipidemia

Insulin Resistance

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Cardiovascular disease risk factors in diabetes

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Od

ds

rati

o f

or

inci

den

t C

VD

Age Smoking Total-C:HDL-C (log)HOMA-IR

Bonora E, Formentini G, Calcaterra F, et al. Diabetes Care 2002; 25:1135–1141.

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Other features of the Metabolic Syndrome increase the risk of coronary heart disease still further

Pre

vale

nce

of

coro

nar

y h

eart

dis

ease

(%

)

30

20

10

NGT IFG/IGT Type 2diabetes

No metabolic syndrome

Metabolic syndrome

P = 0.04P = 0.06

P < 0.001

0

Isomaa B, Almgren P, Tuomi T, et al. Diabetes Care 2001; 24:683–689.

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‘Double jeopardy’: type 2 diabetes and hypertension and cardiovascular risk

Diabetes

No diabetes

CV

D d

eath

rat

e(p

er 1

0,00

0 p

erso

n-y

ear)

250

0

200

150

100

50

Systolic blood pressure (mmHg)

< 120 120–139 140–159 160–179 180–199 200

Stamler J, Vaccaro O, Neaton JD, et al. Diabetes Care 1993; 16:434–444.

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Hypertension management in diabetes

Treatment gap- drugs indicatedTreatment gap- OK with lifestyle

Therapeutic inertia- more therapy needed

Therapeutic inertia- OK with lifestyle

Meeting target

9857 males and 8332 females in Australian general practiceOwen, Retegan, Rockell, Jennings and Reid CEPP Nov 2008

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-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Cholesterol-1 mmol/L

BP -10/5mmHg

Hb A1C -1%

CHD Epidemiology

CHD Intervention

Stroke Epidemiology

Stroke Intervention

25 26 46 NNT to prevent CHD 10 y (UKPDS cohort)

118 49 3333 NNT to prevent stroke10 y (UKPDS

%R

educ

tion

Yudkin & RichterLancet 374:522 2009

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Atherosclerosis in the setting of diabetes

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Are there biological links or is it a collection of unrelated biological consequences of lifestyle?

LifestyleObese

Sedentary

Insulin resistance

High blood pressure

Low HDL

HighTG’s

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A biological link- rHDL infusion lowers glucose and increases insulin levels

Infusion duration (hrs)0 1 2 3 4

P

lasm

a G

luco

se (

mm

ol/

L)

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

rHDLPlacebo

*

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Cellular and biochemical drivers of atherosclerosisAll atherosclerosis:

• Lipid retention by vascular matrix (proteoglycans) (Skalen et al., 2002)• “Inflammation” (Ross, 1999; Libby, 2006)• Oxidation (Witztum, 1994; Stocker and Keaney, 2004; Steinberg et al., 1989)• Endothelial injury/dysfunction (Ross, 1992; Davignon and Ganz, 2004)

Also in diabetes:

• Hyperglycaemia• Advanced glycation end products (AGEs and RAGEs)

(Brownlee, 2001, Forbes et al., 2004)• Hyperglycaemia/Oxidation/ROS

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Diabetes has a predilection for peripheral arteries

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Coronary disease in diabetes

More commonMore silent infarctsMore silent ischaemiaMore plaque instabilityMore sudden death

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INTERHEART: Association of Risk Factors with AMI in Men & Women (1)

Risk Factor Gender Contribution %

Smoker F 9.3M 33.0

Diabetes F 7.9M 7.4

Hypertension F 28.3M 19.7

Abdominal Obesity F 33.3M 33.3

0.25 0.5 1 2 4 8

OR (99% CI)

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Inci

den

ce o

f m

ult

ives

sel

dis

ease

(%

)

Single vessel disease is less common in diabetes

80

0

60

40

20

No diabetes Diabetes

n = 148

n = 923

Granger CB, Califf RM, Young S, et al. J Am Coll Cardiol 1993; 21:920–925.

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A gene that predisposes to coronary disease in the presence of poor glycaemic control in T2D (9P21 locus)

HbA at Study Entry

Weighted Av (7yr) HbA level before Study Entry

Doria et al. 2008 Interaction between Poor Glycemic Control and 9p21 Locus on Risk Of Coronary Artery Disease in T2D JAMA 300;20:2389-2397

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Restenosis is 3x more common in diabetic than non diabetic subjects with bare metal stent. Less likely with drug eluting stent but still more than in non diabetics

Early outcomes with drug eluting stent match CABG (NY registry) but confounding likely- await FREEDOM results

CLINICAL TIP

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CABG better than DES better than BMS-ARTS

ARTS I-BMS vs. CABG (96/112 diabetes)ARTS II DES (sirolimus) (159 diabetes)

Daemen JACC 2008:52;1957

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Importance of good (oral) glycaemic control after PCI revascularization

Corpus et al JACC 2004;43: 8-14

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Heart Failure

Gilbert et al. 2006 Heart Failure & Neuropathy Clin J Am Soc Nephrol 1: 193-208

Prevalence of Heart Failure Patients with & without Diabetes

Heart Failure in patients receiving dialysis & Medicare recipients with & without CKD

Page 28: Baker IDI N Engl J Med 2001;344:17-22

Heart failure with preserved LVEF (HFPEF)

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Early detection of Cardiomyopathy

Di Bonito et al. 2005 Early Detection of Diabetic Cardiomyopathy: usefulness of tissue Doppler imaging Diabetic Medicine 22, 1720-1725

Conventional echocardiograhy

Control

Diabetic

Tissue Doppler Imaging

Insulin Resistance

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Subjects(%)

Irbesartan

Amlodipine

Control

RRR 37% p<0.001

RRR 23%p=0.15

0 6 12 18 24 30 36 42 48 54Follow-up (mo)

60

0

10

20

30

IDNT :HF hospitalisations(Secondary endpoint)

Berl, et al. Ann Intern Med. 2003; 138: 542–549.

n = 579

n = 569

n = 567

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I-PRESERVE: Primary Endpoint

Months from Randomization

Cu

mu

lati

ve In

cid

enc

e o

f P

rim

ary

Eve

nts

(%

)

40 -

0 -

10 -

20 -

30 -

0 6 12 18 24 36 4230 48 6054

2067 1929 1812 1730 1640 1513 12911569 1088 4978162061 1921 1808 1715 1618 1466 12461539 1051 446776

No. at Risk

IrbesartanPlacebo

HR (95% CI) = 0.95 (0.86-1.05)Log-rank p=0.35

Placebo

Irbesartan

Death or protocol specified CV hospitalization (Mean follow-up 49.5 months)

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Risk ratio

0.5 1 2.0

Study % Weight Risk ratio (95% CI)

0.81 (0.66,0.99) CHARM 8.7

0.75 (0.64,0.89) LIFE 13.8

0.66 (0.52,0.84) HOPE 6.6

0.69 (0.56,0.85) ANBP2 8.6

0.89 (0.78,1.03) CAPPP 16.2

0.66 (0.54,0.81) ALLHAT 9.7

0.81 (0.74,0.89) VALUE 36.4

0.78 (0.74,0.83) Overall (95% CI)

New Onset Diabetes in comparative outcome trials involving RAS versus non-RAS blockade

Jandeleit-Dahm et al., J Hypertens 2005

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Cardiovascular Outcomes – Rosiglitazone and Pioglitazone

Incidence Rate Ratio (Adjusted)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

All-causemortality

MI Prior CAD No PriorCAD

Stroke Prior CVD No PriorCVD

Hosp. forCHF

Prior CHF No PriorCHF

2008 Winkelmayer et al Comparison of Cardiovascular Outcomes in Elderly Patients with Diabetes who initiated Rosiglitazone Vs Pioglitazone Therapy Arch Intern Med 168 no.21

95% CI

Favours pioglitazone

Favours rosiglitazone

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Most guidelines recommend aspirin as primary prevention in those with diabetes• Evidence is circumstantial

• Japanese aspirin trial in diabetics (2009)– Primary end point not met– 90% reduction in secondary end point- fatal

coronary disease and stroke

• Sub study of Nurse Health Study also supportive (2008)

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WHAT CAN BAKER IDI BRING TO INDIGENOUS CVD AND DIABETES?

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Years of Life Lost (YLL) for the leading disease and injury categories – Indigenous persons 2003

Years of Life Lost (YLL) Indigenous Persons 2003

31%

14%

11%

9%

5%

5%

5%

4%

3%

13%

CVD + Diabetes

Cancers

Injuries -unintentional

Injuries -intentional

Chronic Resp Disease

Mental Disorders

Neonatal causes

Infectious & parasitic diseases

Nervous systen & sense disorders

Other

CVD & Diabetes

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Disability Adjusted Life Years (DALY’S)By broad cause group - Indigenous Persons 2003 DALYS - Indigenous Persons 2003

8.9%8.5%

7.3%

5.6%

15.5%

28.2%26.4% CVD + Diabetes

Mental Disorders

Chronic Resp Disease

Cancers

Injuries -unintentional

Injuries -intentional

Other

CVD & Diabetes

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Prevalence of long term health conditions

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Prevalence of Diabetes/High sugar levels

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Risk Factors - Daily Smokers

Males

Females

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The best predictor of future events is past events

General populationGeneral population

High riskExtant

disease

Absolute risk History&/or biological markers

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General populationGeneral population

High riskExtant

disease

Absolute risk History&/or biological markers

Sometimes this is the entire population

•Indigenous•Chronic kidney disease•Major psychiatric illness

•Rheumatoid arthritis

Sometimes this is the entire population

•Indigenous•Chronic kidney disease•Major psychiatric illness

•Rheumatoid arthritis

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Age – Indigenous population relatively young

Median Age: 21 37

65+yrs 3% 13%

<15yrs 37% 19%

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Rate of Low Birth Weight Babies- by Indigenous status of mother

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Benefits of hypertension treatment in HDFP% events

Penalty for waiting until an event

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DiabetesDyslipidaemiaHypertension

NutritionExercise

Early lifePregnancy Childhood obesity

Risk Factors

SubClinicalorgan damage

ArteriesHeartBrain KidneysEyes etc

Acute Complications

Chronic Complications

Heart Failure

Terminal Disease

Angina

Kidney Failure

Dementia

Sudden Death

Thrombosis

Aneurysm

Prevention X

Prevention X

Prevention X

Prevention X

Prevention XBasic research on

metabolic memory (epigenetics)

Maternal interventionsGestational diabetes markers (proteomics)

Metabolic syndrome/obesity

Screening and intervention in rural and

remote communitiesNutritional interventions

PolypillResistant hypertension

Hearts and minds

Prevention of diabetes complications

LVHPAD treatment

Novel anti thromboticsCIN

Unstable plaque markers

Aneurysm treatment

Heart failure screeningDisease managementGene and stem cell

therapiesHFPEF

Page 47: Baker IDI

Basic research on metabolic memory

(epigenetics)Maternal interventionsGestational diabetes markers (proteomics)

Metabolic syndrome/obesity

Screening and intervention in rural and

remote communitiesNutritional interventions

PolypillResistant hypertension

Hearts and minds

Prevention of diabetes complications

LVHPAD treatment

Novel anti thromboticsCIN

Unstable plaque markersAneurysm treatment

Heart failure screeningDisease management

Gene and stem cell therapiesHFPEF

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Conclusions

• The link between diabetes and CVD is strong but can be mitigated– Primary and ‘secondary’ prevention– Achieve blood pressure targets– Achieve glycaemia targets (?)– Special role for RAS inhibition?– Integrated care

Page 49: Baker IDI