Diabetes and CVD complications

Karin Jandeleit-Dahm, MD, PhD, FRACPNHMRC Senior Research fellowDiabetes Complications Division

Baker IDI Heart and Diabetes InstituteMelbourne

Micro-and macrovascular

complications of diabetes

Nephropathy Retinopathy

CardiovascularDisease

High RiskFoot

AusDiab studyAusDiab studyCV mortalityCV mortality

Circulation, 2007

**

*

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

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

An epidemic of An epidemic of renal failure renal failure

amongamongAustralian Australian AboriginalsAboriginals

J Spencer et al, MJA 1998

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

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

M Thomas, MJA 2006

Higher frequency of macroalbuminuria in Indigenous Australians

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

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

Frequency of macrovascular disease stratified for age and ethnicity

M Thomas et al BMC 200743% had 1st degree relative with CVD < 50 years

Frequency of chronic kidney diseaseStratitified for age and

ethnicity

M Thomas et al, BMC 2007

DiabetesAtherosclerotic

vesselNormalaorta

?

Diabetes is a major risk factor for CV disease

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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)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

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

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?

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

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

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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

*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

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

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

Prevent Prevent Diabetes Complications

Metabolic imprinting/memory

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

Formation of advanced glycation end Formation of advanced glycation end products via the ‘Browning’ reactionproducts via the ‘Browning’ reaction

Diet, smokingGlucose, Lipids, Inflammation

“Ageing”

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.

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

Can we stop diabetes and its complications

without the prison of glycaemic control?

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

Acknowledgements:

The Diabetes Complications GroupMerlin ThomasMark Cooper