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ThemesThemes
• Outcomes in diabetes• Outcomes in diabetes• Atherosclerosis and diabetes• Coronary disease in the diabetic patient• Diabetic heart• Therapeutic aspects
Page 1: Baker IDI
Years of Life Lost (YLL) for the leading disease gand injury categories – Indigenous persons 2003
Years of Life Lost (YLL) Indigenous Persons 2003Years of Life Lost (YLL) Indigenous Persons 2003
31%3%
13%
CVD + DiabetesCancers
CVD & Diabetes
5%
4% Injuries -unintentionalInjuries -intentionalChronic Resp Disease
5%
5% Mental DisordersNeonatal causesInfectious & parasitic diseasesNervous systen & sense disorders
14%
11%
9%
Nervous systen & sense disordersOther
Page 2: Baker IDI
Hypertension
DyslipidaemiaAbdominal obesity
•80% of deaths in
Di b t
80% of deaths in diabetes due to CVD•80% of heart attack sufferers have impaired l t lDiabetes glucose tolerance
•85% of the population have one or more of these risk factors
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The same factors drive ‘epidemics’ of diabetes, phypertension, dyslipidaemia and CVD
A i f th l ti• Ageing of the population• Dietary changesDietary changes• Reduction in physical activityp y y• The obesity phenomenon• Treatment gaps
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N ti lNational averageHbA1c 7.3<7% 53%
Ave HbA1c 8%Ave HbA1c 8%<7% 45.4%
Page 5: Baker IDI http://www.glycomate.com/changingdiabetes
T2D complications‐mainly vascular
DiabeticStroke2- to 4-fold increaseDiabetic
retinopathyLeading causeof blindnessin working age C di l
in cardiovascular mortality and stroke3
in working-ageadults1 Cardiovascular
disease8/10 diabetic patients die from cardiovascular
DiabeticnephropathyLeading cause of
Diabeticneuropathy
events4
gend-stage renaldisease2
Leading cause of non-traumatic lower extremity amputations5
Disability from autonomic neuropathy
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autonomic neuropathy
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.
Type 2 diabetes increases the risk of a r) No diabetes
broad range of cardiovascular diseasesn = 342,815
erso
n-ye
a
75Diabetes n = 5,163
10,0
00 p
e
50
ates
(per
1
25
Ra
Total CVD CHD Stroke Other CVD0
Relative risk3 0 3 2 2 8 2 3
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Adjusted for age, race, income, cholesterol, systolic blood pressure, smoking3.0 3.2 2.8 2.3
Stamler J, Vaccaro O, Neaton JD, et al. Diabetes Care 1993; 16:434–444.
Cardiovascular disease in people with diabetes
60
Cardiovascular disease in people with diabetesde
rate
) 60
9.1
28d–1yHospitalization–28dOut of Hospital50
aths
(cru
d 40
3015.4
9.6
4.2
11.1
% o
f dea 20
1028.6
22.1
10 9
22.7
9.02.8
Diabetes No Diabetes Diabetes No diabetes0
Men
10.9 11.9
WomenPage 8: Baker IDI Adapted from Miettinen H et al Diabetes Care. 1998;21:69-75.
Men Women
Diabetes & Cardiac Outcomes
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Aksnes et al. 2007 New Onset Diabetes & Cardiac Outcome Hypertension 50:467-473
Average annual costs of diabetesAverage annual costs of diabetesType 1 diabetes Type 2 diabetes
No complications of diabetes $3,468 $4,025
Microvascular complications only $8,122 $7,025
Macrovascular complications only $12,105 $9,055
Micro‐ and macrovascular $16,698 $9,645
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complications
DiabCo$t studies
Cardiovascular disease in people with diabetes
Proportion of hospital bed days for thetreatment of the complications of diabetes
Diabetes impacts on “Human Capital” as an economic issue
p p‐Morbiditytreatment of the complications of diabetes
Men Women
rate
an economic issue
Wor
kfor
ceci
patio
n r
Wpa
rtiDiabetes
- - ++
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Council of Australian Governments – Elevating diabetes above a health issue
Cardiovascular disease risk factors in diabetes
1.6
1.8
1.2
1.4
0.8
1.0
0.6Age Smoking Total-C:HDL-C (log)HOMA-IR
Page 12: Baker IDI Bonora E, Formentini G, Calcaterra F, et al. Diabetes Care 2002; 25:1135–1141.
Metabolic Syndrome increases the risk of coronary heart disease still further
30 Metabolic syndrome P < 0.001
rona
ry
(%)
No metabolic syndrome
nce
of c
ordi
seas
e ( 20
Prev
alen
hear
t
10 P = 0.04P = 0.06
NGT IFG/IGT T 20
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NGT IFG/IGT Type 2diabetes
Isomaa B, Almgren P, Tuomi T, et al. Diabetes Care 2001; 24:683–689.
‘Double jeopardy’: type 2 diabetes and hypertension d di l i kand cardiovascular risk
DiabetesNo diabetes250
rate
son-
year
)
200
150
VD d
eath
,0
00 p
ers 150
100
CV
(per
10
50
0< 120 120–139 140–159 160–179 180–199 ≥ 200
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Systolic blood pressure (mmHg)
Stamler J, Vaccaro O, Neaton JD, et al. Diabetes Care 1993; 16:434–444.
Hypertension management in diabetesHypertension management in diabetes
Treatment gap- drugs indicatedTreatment gap- OK with lifestyle
Therapeutic inertia- more therapy needed
Therapeutic inertia- OK with lifestyle
Meeting target
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9857 males and 8332 females in Australian general practiceOwen, Retegan, Rockell, Jennings and Reid CEPP Nov 2008
Atherosclerosis in the setting of diabetesAtherosclerosis in the setting of diabetes
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Features of atherosclerosis in diabetesHuman carotid artery specimensMonocyte
Features of atherosclerosis in diabetes
carotid artery specimensmacrophages
Atherosclerosis of diabetes is
T cellsassociated with higher levelsof inflammatory cells –
Composition varies but not
Lymphocytes
pextent of restenosis
Implication? –Increased plaque instability
Leukocytes
Increased plaque instability
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y(neutrophils)
Cipollone et al. Circ. 2003
Diabetes has a predilection for peripheral p p parteries
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Coronary diseaseCoronary disease
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Single vessel disease is less common in e
(%)
diabetes80
el d
isea
se
60
n = 148
mul
tives
se
40
n = 923
ence
of m
20
Inci
de
0No diabetes Diabetes
Page 20: Baker IDI Granger CB, Califf RM, Young S, et al. J Am Coll Cardiol 1993; 21:920–925.
Human coronary artery disease
“Normal” acute proximal lesion Coronary artery atherosclerosis
Human coronary artery disease
p y y
Diffuse distal disease of diabetes
Causes: Matrix production/lipoprotein binding/cell proliferation etccell proliferation etc.
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A gene that predisposes to coronary disease in the presence of g p p y ppoor glycaemic control in T2D (9P21 locus)
HbA at Study EntryHbA at Study Entry
Weighted Av (7yr) HbA level b f St d E tbefore Study Entry
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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
CLINICAL TIPRestenosis is 3x more common in diabetic than non diabetic subjects with bare metal stent. Less likely with drug eluting stentLess likely with drug eluting stent but still more than in non diabetics
E l t ith d l tiEarly outcomes with drug eluting stent match CABG (NY registry) but confounding likely-FREEDOMFREEDOM
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CABG better than drug eluting stent better than bare g gmetal stent in diabetes‐ARTS
ARTS I-BMS vs. CABG (96/112 diabetes)
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ARTS II DES (sirolimus) (159 diabetes)
Daemen JACC 2008:52;1957
Revascularisation in diabetesRevascularisation in diabetes
CABG Angioplasty and stentCABG• Early and long-term morbidity and
mortality higher than in non diabetics• Less likely to have CK rise!
Si il
Angioplasty and stent• Procedural complications more likely
(risk related)• Mortality higher long term(1.8 vs.
1 3% ACC NCV data registry)• Similar – graft patency @ 4y (BARI)– Cognitive decline
• More likely to have
1.3% ACC-NCV data registry)• LOS longer (2.7 vs. 2.4 days)• Renal dysfunction more common• Similar enzyme rise
– Wound infection– Stroke– Reduced QOL
y• PCI for vein graft problematic (Insulin
treated DM associated with calcific vein graft degeneration)
• No difference in stent thrombosis• More new lesions in the treated
vessel @ 9 months (PRESTO)
Page 25: Baker IDIBerry et al JACC 2007; 49: 643-656
Flow diagram of cardiac event patient journeys in Central Australia
Home in Tennant Creek
Home in remote
communities
Home in Alice Springs
in Central Australia
Remote Health Centres
CAACSt John’s Ambulance
DMOs GPsAnyinginyi Congress
St JohAn’s Ambulance
GPs
Tennant CreekRFDS
Tennant Creek Hospital ED
Medical/Renal/Paeds Team/ General Physicians
ASH Paediatric Liaison
CTSHome
TCH Ward
PATS ASH ED
MSOAP
ASH Outpatients Clinics: General
Physicians
ASH O i
RHD NurseASH Wards
RFDS/ Commercial
ASH ICU/HDU
Diabetes EducatorsPATS
RDH
ASH Outpatients Clinics: NT Cardiac
ASH Outpatients Clinics: Cardiologists
ASH Outpatients
PCD Educatoroperator
RAH FMC WCH
RCH
Healthy Living NT
Renal Educators
Page 26: Baker IDI
Paediatric cardiac patients only
ASH Outpatients Clinics: PaediatricCardiologists
RFDS/ Commercial operator
RCH
HomeAnyinginyi
Congress, CAAC, GPs, RHCs, DMOs
70
Rates of Cardiac Procedures During Index ACSNT ACS Cohort 2001-2002p = 0.014 p = 0.015 p = 0.001
50
60Indigenous
30
40
50
%
20
30
0
10
Angio/PCI/CABG Angiography Angio [High Risk ACS] Angio/PCI/CABG RDH Angio/PCI/CABG ASH PCI CABG
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g g g p y g [ g ] g g
Is there a diabetic cardiomyopathy?y p y
• Some due to complications of– Hypertension– Coronary heart disease etc
• Experimental models convincingExperimental models convincing• Diabetes over represented in IDCM• Mostly associated with micro vascular complications of
diabetes (these parallel hyperglycaemia)• Metabolic factors are associated with fibrosis/hypertrophy
Directly– Directly– Indirectly via RAS, autonomic neuropathy, Ca++
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Diabetes effects on the myocardiumDiabetes effects on the myocardium• A distinct diabetic cardiomyopathy
– independent of diabetic macrovascular disordersindependent of diabetic macrovascular disorders – cardiomyocyte hypertrophy, cardiac fibrosis– Early LV diastolic impairment
l d LV filli & l ti• prolonged LV filling & relaxation• ↓ diastolic distensibility
– Rubler et al 1972, Galderisi et al 1991, Shimizu et al 1993, Gilbert et al 2006 Mizushige et al 2000 Schannwell et al 2002 Di Bonito et al 2005 AksnesMizushige et al 2000, Schannwell et al 2002, Di Bonito et al. 2005, Aksnes
et al 2007 Diastolic function
(↓ LV filling)
Control
Diabetes
Page 29: Baker IDI
Diabetes and cardiomyopathy
LVD49%
100 diabetics with no Left Ventricular Dysfunction (LVD) highNo LVD
51%
49%evidence of structural heart disease:Echo findings
Dysfunction (LVD) – high negative predictability with clinical variables but not BNP:SBP
Event free survival over 48.5
SBPGenderBMI
87%
Event free survival over 48.5 + 9 months
BNP predicted events:OR 3.5
54 %
Kienke et al Eur J H t f il 2010
37.5% deteriorated NYHA
8.7% deteriorated NYHA
Page 30: Baker IDI LVD No LVD
Heart failure 2010 June 25 E pub
NYHA NYHA
Heart failure with preserved ejection fraction (HFPEF)(HFPEF)
Page 35: Baker IDI N Engl J Med 2001;344:17-22
Both presentations of heart failure have adverse prognosisadverse prognosis
Survival Preserved ejection function
Reduced ejection function
Page 37: Baker IDI N Engl J Med 2006;355:251-9
Year
Systolic BP difference and riskS k M di l i f iStroke Myocardial infarction
Page 38: Baker IDI Reboldi et al Journal of Hypertension 2011, Vol 29 No 7 p.1253-1269
Avoid hypoglycaemiaSevere Hypoglycemia and the Risk of an Adverse Clinical Outcome or Death- ADVANCESevere Hypoglycemia and the Risk of an Adverse Clinical Outcome or Death ADVANCE
Page 39: Baker IDI Zoungas S et al. N Engl J Med 2010;363:1410-1418.
Therapeutic targets for hyperglycaemiaTherapeutic targets for hyperglycaemia
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Ismail-Beigi F. N Engl J Med 2012;366:1319-1327
We treat diabetes to reduce complicationspHypoglycaemic drugs are a mixed blessing
May increase CVD:Thiazolidinedione (rosiglitazone)Thiazolidinedione (rosiglitazone)
May reduce CVD:Biguanides (metformin)GLP1 t i t ( tid li l tid )GLP1 receptor agonist (exanatide, liraglutide)Thiazolidinedione (pioglitazone)α glucosidase inhibitor (miglitol, voglibose, acarbose)
Page 41: Baker IDI
acarbose)
We treat diabetes to reduce complicationspHypoglycaemic drugs are a mixed blessing
Increase weight:Increase weight:Thiazolidinediones (rosiglitazone, pioglitazone)MeglitinideInsulin
Decrease weightSulphonylureasGLP1 receptor agonist (exanatide, liraglutide)Amylin analogue (pramlinitide)
Page 42: Baker IDI
Amylin analogue (pramlinitide)
Aspirin in diabetes CVDp CVD
Stroke
Meta-analysis of trials examining the effects of aspirin on risk of CVD events in patients with diabetes. ETDRS, Early Treatment of
Stroke
Diabetic Retinopathy Study; HOT, Hypertension Optimal Treatment; JPAD, Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; PHS, Physicians' Health Study; POPADAD, Prevention of Progression of Arterial Disease and Diabetes; PPP, Primary Prevention Project; TPT, Thrombosis Prevention Trial; and WHS, Women's Health Study.
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; , y
Diabetes Care. 2010 June; 33(6): 1395–1402.doi: 10.2337/dc10-0555
Diabetes risk and statinsDiabetes risk and statins
But CVD risk reduced in diabetes withdiabetes with statin therapy
Diabetes Care. 2009 October; 32(10): 1924–1929.d i 10 2337/d 09 0738
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doi: 10.2337/dc09-0738
ConclusionsConclusions
• The link between diabetes and CVD is strong• The link between diabetes and CVD is strong but can be mitigated
P i ti– Primary prevention– Achieve blood pressure targets– Achieve glycaemia targets (?)– Special role for RAS inhibition
Page 46: Baker IDI
Percentage NHMRC CVD research commitment 2007‐2010
Administering Institution 2007 2008 2009 2010
Baker IDI Heart and Diabetes Institute 20 2% 6 9% 16 5% 17 9%Baker IDI Heart and Diabetes Institute 20.2% 6.9% 16.5% 17.9%
Monash University 17.7% 16.3% 15.0% 18.2%
University of Adelaide 3.9% 6.2% 7.4% 3.3%
University of Melbourne 6.3% 5.4% 6.2% 9.0%
University of New South Wales 2.3% 6.2% 2.4% 5.4%
University of Queensland 5.6% 7.5% 5.2% 2.4%
University of Sydney 15.6% 22.1% 19.2% 11.1%
University of Western Australia 3.4% 2.9% 8.4% 6.4%
Victor Chang Cardiac Research Institute 0.5% 11.3% 2.3% 2.9%
Total 75.6% 85.0% 82.6% 76.6%
Page 47: Baker IDI
Percentage NHMRC diabetes research commitment 2007‐2010
Administering�Institution� 2007%� 2008%� 2009%� 2010%�Baker�IDI�Heart�and�Diabetes�Institute� 4 1%� 13 0%� 14 9%� 12 8%�Baker�IDI�Heart�and�Diabetes�Institute� 4.1%� 13.0%� 14.9%� 12.8%�Garvan�Institute�of�Medical�Research� 8.1%� 17.7%� 3.7%� 8.2%�Monash�University� 9.0%� 14.2%� 12.3%� 12.5%�St.�Vincent's�Institute�of�Medical�Research� 3.1%� 1.1%� 2.5%�St.�Vincent s�Institute�of�Medical�Research� 3.1%� 1.1%� 2.5%�University�of�Adelaide� 3.1%� 1.3%� 7.8%� 5.3%�University�of�Melbourne� 6.0%� 5.5%� 3.9%� 25.9%�University�of�Queensland� 12.9%� 4.8%� 6.0%� 3.7%�y� � � � � � �University�of�Sydney� 5.7%� 17.1%� 22.3%� 9.7%�University�of�Western�Australia� 4.6%� 2.0%� 9.0%� 3.5%�Walter�and�Eliza�Hall�Institute� 18.9%� 2.2%� 5.7%� 2.9%�Grand�Total� 75.6%� 78.9%� 88.2%� 84.4%�
Page 48: Baker IDI
