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Diabetes and CVD complications
Karin Jandeleit-Dahm, MD, PhD, FRACPNHMRC Senior Research fellowDiabetes Complications Division
Baker IDI Heart and Diabetes InstituteMelbourne
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Micro-and macrovascular
complications of diabetes
Nephropathy Retinopathy
CardiovascularDisease
High RiskFoot
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AusDiab studyAusDiab studyCV mortalityCV mortality
Circulation, 2007
**
*
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From undernutrition to lifestyle diseases-
shifting causes of death and disease
CV disease leading cause of death, relative mortality rates 3-4 times higherDisproportionately higher rates of CKD and renal failurePrevalence of overweight and obesity in Aboriginal adults is at least 40-45%Incidence and prevalence of diabetes is at least 2-4 times higher (or higher)Newly diagnosed diabetes in children in WA 18x higher in Indigenous children
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Diabetes Prevalence in Indigenous Australians (35-44 years) as high as prevalence in other Australians
> 55years
Prevalence for CV disease increases rapidly: 16 % (35-44 years)
31 % (45-54 years) 47% >55Y years
Heart, stroke, vascular disease, Australian facts, 2004
Differences in CVD risk profile
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An epidemic of An epidemic of renal failure renal failure
amongamongAustralian Australian AboriginalsAboriginals
J Spencer et al, MJA 1998
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The NEFRON study: National Evaluation of the Frequency of Renal Impairment cO-existing
with NIDDMBaker IDI Heart and Diabetes Institute
Kidney Health AustraliaServier
MC Thomas et al: The burden of chronic kidney disease in Australian patients with type 2 diabetes, MJA 2006
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Micro-and macroalbuminuria
NEFRON study
M Thomas, MJA 2006
1 in 4 had eGFR < 60 ml/min1 in 3 had ACR
27.3 % had microalbuminuria7.3 % had macroalbuminuria
NEFRON-results
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M Thomas, MJA 2006
Higher frequency of macroalbuminuria in Indigenous Australians
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The management of The management of diabetes in Indigenous diabetes in Indigenous
Australians from Australians from primary careprimary care
Indigenous patients enrolled in Indigenous patients enrolled in NEFRON study NEFRON study
I=144, NI= 449, TN=3893I=144, NI= 449, TN=3893
60% vs 33% macrovascular disease60% vs 33% macrovascular diseaseMore established macrovascular More established macrovascular diseasediseasePoor glycaemic control (HbA1c > Poor glycaemic control (HbA1c > 8%, 55 %)8%, 55 %)SmokingSmokingLDL and BP similarLDL and BP similar
M Thomas et al, BMC Public Health, 2007
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The management of diabetes in indigenous Australians from primary care: The frequency of elevated urinary ACR
Indigenous
Total cohort
Thomas M et al, BMC 2007
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Frequency of macrovascular disease stratified for age and ethnicity
M Thomas et al BMC 200743% had 1st degree relative with CVD < 50 years
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Frequency of chronic kidney diseaseStratitified for age and
ethnicity
M Thomas et al, BMC 2007
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DiabetesAtherosclerotic
vesselNormalaorta
?
Diabetes is a major risk factor for CV disease
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1. BP control1. BP control
2. Lipids2. Lipids
3. Glucose3. Glucose
4. Inflammation4. Inflammation
Treatment and prevention of CV disease in diabetes
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Cu
mu
lat i
ve
in
cid
en
ce
(%
)ADVANCE-BP
Effects on Mortality
All cause mortality Cardiovascular death
0
10
Follow-up (months)0 6 12 18 24 30 36 42 48 54 60
PlaceboPerindopril-indapamide
0
10
Follow-up (months)
0 6 12 18 24 30 36 42 48 54 60
PlaceboPerindopril-indapamide
Relative risk reduction
18%; p=0.027
Relative risk reduction
14%; p=0.025
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Summary – Main results, Blood pressure lowering comparison
•Routine treatment of type 2 diabetic patients with perindopril-indapamide resulted in:
– 14% reduction in total mortality– 18% reduction in cardiovascular death– 9% reduction in major vascular events– 14% reduction in total coronary events– 21% reduction in total renal events
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Glycemic Control and Glycemic Control and Diabetic Diabetic Macrovascular Macrovascular
ComplicationsComplications Epidemiologic data demonstrating a Epidemiologic data demonstrating a
2 – 4x increased in CVD outcomes2 – 4x increased in CVD outcomes Blood Sugar Related to Lipoproteins,
Syndrome X, Clotting, AGE, Renal Disease
Therefore, improved glycemic control over a long period of time should lead to a decrease in CVD outcomes?
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DCCT/EDICDCCT/EDICMetabolic Results
DCCT InterventionDCCT Intervention
S t u d y Y e a rS t u d y Y e a rDCCT DCCT
1 2 3 4 5 6 7 8 9
EDIC ObservationEDIC ObservationTrainingTraining
EDIC EDIC
ConventionalConventionalEDIC mean 8.2%EDIC mean 8.2%
IntensiveIntensiveEDIC mean 8.0%EDIC mean 8.0%
DCCT/EDIC Study Research Group, NEJM 2005
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ConventionalConventional
IntensiveIntensive
Non-Fatal MI, Stroke or CVD DeathNon-Fatal MI, Stroke or CVD DeathCardiovascular EventsCardiovascular Events
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 210 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Number at Risk Intensive: 705 686 640 118 Conventional: 721 694 637 96
Years from Study EntryYears from Study Entry
0.000.00
0.020.02
0.040.04
0.060.06
0.080.08
0.100.10
0.120.12
Cu
mu
lati
ve I
nci
den
ce
Cu
mu
lati
ve I
nci
den
ce
Risk reduction 57% Risk reduction 57% 95% CI: 12, 7995% CI: 12, 79Log-rank P = 0.018Log-rank P = 0.018
DCCT/EDIC Study Research Group, NEJM 2005
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*p=0.04
1 Duckworth W et al for the VADT Investigators. N Engl J Med 2009; 360: 129–39. 2The ACCORD Study Group N Engl J Med 2008;358:2545-2559;3The ADVANCE Collaborative Group N Engl J Med 2008,358:2560-2572
*
Major 3 glucose lowering studies 2008 and CV disease
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Risk ratio (95% CI)
0.5 1 2
VADT
ADVANCE
UKPDS 0.94 (0.80, 1.10)
0.93(0.83, 1.06)
Favors intensive glucose control Favors standard glucose control
Hazard ratio (95% CI)
Mortality (meta-analysis)
1.07(0.80, 1.40)
1.22 (1.01, 1.46)ACCORD
Overall
Turnbull et al. Diabetologia in press Nov 2009
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DiabetesDyslipidaemiaHypertension
NutritionExercise
Clinical
Population
Basic
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
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Prevent Prevent Diabetes Complications
Metabolic imprinting/memory
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Potential causes of diabetes-induced Potential causes of diabetes-induced macrovascular diseasemacrovascular disease
Defective insulin actionDefective insulin action
HyperglycaemiaHyperglycaemia
Conventionalrisk factors
Conventionalrisk factors
Diabetes specificrisk factors
Diabetes specificrisk factors
Dyslipidaemia
Hypertension
Coagulopathy
AGEs
ROS
Altered matrixProtein production
Altered endothelium,SMCs, macrophages
Goldberg, JCI, 2004
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Formation of advanced glycation end Formation of advanced glycation end products via the ‘Browning’ reactionproducts via the ‘Browning’ reaction
Diet, smokingGlucose, Lipids, Inflammation
“Ageing”
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P21ras NFκBNTFα ROSTGFβ1 IL6
Background - AGE/RAGE pathway
Heart/vessel stiffnessMMP insensitivityEndothelial dysfunctionEnzyme dysfunction
Modified from Kass, D. A. (2003). Circ Res 92, 704-706.
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RRRR
Macrophages
Podocytes
Epithelial Cells
Mesangial Cells
Endothelial Cells
Cytokines (TNF, IL-1)
Angiogenesis
Cell Growth
Growth Factors TGF, CTGF, PDGF
Extracellular MatrixProtein Production
Adapted Raj et al, AJKD, 2000.
Cellular Responses Elicited by AGEsCellular Responses Elicited by AGEs
RAGE
AGE-R 1-3
MSRs
LOX-1
CD 36
Multispecfic
AGE-receptors
AGEAGE
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Can we stop diabetes and its complications
without the prison of glycaemic control?
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So which part is the most important?
AGE/RAGE axis
Renin Angiotensin
SystemOxidative Stress
Blood pressure
Dyslipidemia
It is likely that combination approaches will be required
No one pathway is sufficient to give all the answers
Glucose control
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Acknowledgements:
The Diabetes Complications GroupMerlin ThomasMark Cooper