Diabetes and CVD complications Karin Jandeleit-Dahm, MD, PhD, FRACP NHMRC Senior Research fellow Diabetes Complications Division Baker IDI Heart and Diabetes Institute Melbourne

Micro-and macrovascular complications of diabetes Nephropathy Retinopathy Cardiovascular Disease High Risk Foot

AusDiab study CV 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 higher   Disproportionately higher rates of CKD and renal failure   Prevalence 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 renal failure among Australian Aboriginals J Spencer et al, MJA 1998

The NEFRON study: National Evaluation of the Frequency of Renal Impairment cO-existing with NIDDM Baker IDI Heart and Diabetes Institute Kidney Health Australia Servier 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 in 4 had eGFR < 60 ml/min 1 in 3 had ACR 27.3 % had microalbuminuria 7.3 % had macroalbuminuria NEFRON-results

M Thomas, MJA 2006 Higher frequency of macroalbuminuria in Indigenous Australians

The management of diabetes in Indigenous Australians from primary care Indigenous patients enrolled in NEFRON study I=144, NI= 449, TN=3893  60% vs 33% macrovascular disease  More established macrovascular disease  Poor glycaemic control (HbA1c > 8%, 55 %)  Smoking  LDL 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 % had 1 st degree relative with CVD < 50 years

Frequency of chronic kidney disease Stratitified for age and ethnicity M Thomas et al, BMC 2007

Diabetes Atherosclerotic vessel Normal aorta ? Diabetes is a major risk factor for CV disease

1. BP control 2. Lipids 3. Glucose 4. Inflammation Treatment and prevention of CV disease in diabetes

Cumulative incidence (%) ADVANCE-BP Effects on Mortality All cause mortality Cardiovascular death 0 10 Follow-up (months) Placebo Perindopril-indapamide 0 10 Follow-up (months) Placebo Perindopril-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 Diabetic Macrovascular Complications Epidemiologic data demonstrating a 2 – 4x increased in CVD outcomes Epidemiologic data demonstrating a 2 – 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/EDIC Metabolic Results DCCT Intervention DCCT Intervention S t u d y Y e a r DCCT EDIC Observation EDIC ObservationTraining EDIC Conventional EDIC mean 8.2% Intensive EDIC mean 8.0% DCCT/EDIC Study Research Group, NEJM 2005

Conventional Intensive Non-Fatal MI, Stroke or CVD Death Cardiovascular Events Number at Risk Intensive: Conventional: Years from Study Entry Cumulative Incidence Risk reduction 57% 95% CI: 12, 79 Log-rank P = DCCT/EDIC Study Research Group, NEJM 2005

*p= Duckworth W et al for the VADT Investigators. N Engl J Med 2009; 360: 129–39. 2 The ACCORD Study Group N Engl J Med 2008;358: ; 3 The ADVANCE Collaborative Group N Engl J Med 2008,358: * Major 3 glucose lowering studies 2008 and CV disease

Risk ratio (95% CI) VADT ADVANCE UKPDS 0.94(0.80,1.10) 0.93(0.83,1.06) Favors intensive glucose controlFavors 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

Diabetes Dyslipidaemia Hypertension Nutrition Exercise Clinical Population Basic Early life Pregnancy Childhood obesity Risk Factors SubClinical organ damage Arteries Heart Brain Kidneys Eyes 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 macrovascular disease Defective insulin action Hyperglycaemia Conventional risk factors Conventional risk factors Diabetes specific risk factors Diabetes specific risk factors Dyslipidaemia Hypertension Coagulopathy AGEs ROS Altered matrix Protein production Altered endothelium, SMCs, macrophages Goldberg, JCI, 2004

Formation of advanced glycation end products via the ‘Browning’ reaction Diet, smoking Glucose, Lipids, Inflammation “Ageing”

P21rasNFκB NTFαROS TGFβ1IL6 Background - AGE/RAGE pathway Heart/vessel stiffness MMP insensitivity Endothelial dysfunction Enzyme dysfunction Modified from Kass, D. A. (2003). Circ Res 92,

RR Macrophages Podocytes Epithelial Cells Mesangial Cells Endothelial Cells Cytokines (TNF, IL-1) Angiogenesis Cell Growth Growth Factors TGF , CTGF, PDGF Extracellular Matrix Protein Production Adapted Raj et al, AJKD, Cellular Responses Elicited by AGEs RAGE AGE-R 1-3 MSRs LOX-1 CD 36 Multispecfic AGE-receptors AGE

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 System Oxidative 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 Group Merlin Thomas Mark Cooper