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Diabetes and CVD complications

Diabetes and CVD complications. Karin Jandeleit-Dahm, MD, PhD, FRACP NHMRC Senior Research fellow Diabetes Complications Division Baker IDI Heart and Diabetes Institute Melbourne. Nephropathy. Retinopathy. High Risk Foot. Cardiovascular Disease.

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Diabetes and CVD complications

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

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

  3. AusDiab studyCV mortality * * * Circulation, 2007

  4. 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

  5. Differences in CVD risk profile 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

  6. An epidemic of renal failure amongAustralian Aboriginals J Spencer et al, MJA 1998

  7. The NEFRON study: National Evaluation of the Frequency of Renal Impairment cO-existing with NIDDMBaker IDI Heart and Diabetes InstituteKidney Health AustraliaServier MC Thomas et al: The burden of chronic kidney disease in Australian patients with type 2 diabetes, MJA 2006

  8. NEFRON-results Micro-and macroalbuminuria NEFRON study 1 in 4 had eGFR < 60 ml/min 1 in 3 had ACR 27.3 % had microalbuminuria 7.3 % had macroalbuminuria M Thomas, MJA 2006

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

  10. 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

  11. 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

  12. Frequency of macrovascular disease stratified for age and ethnicity 43% had 1st degree relative with CVD < 50 years M Thomas et al BMC 2007

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

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

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

  16. ADVANCE-BPEffects on Mortality All cause mortality Cardiovascular death 10 10 Placebo Placebo Perindopril-indapamide Perindopril-indapamide Cumulative incidence (%) Relative risk reduction 14%; p=0.025 Relative risk reduction 18%; p=0.027 0 0 12 24 0 6 18 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months) Follow-up (months)

  17. 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

  18. Glycemic Control and Diabetic Macrovascular Complications • 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?

  19. DCCT/EDIC Metabolic Results DCCT Intervention Training EDIC Observation Conventional EDIC mean 8.2% Intensive EDIC mean 8.0% 1 2 3 4 5 6 7 8 9 DCCT EDIC S t u d y Y e a r DCCT/EDIC Study Research Group, NEJM 2005

  20. Cardiovascular Events Non-Fatal MI, Stroke or CVD Death 0.12 0.10 Risk reduction 57% 95% CI: 12, 79 Log-rank P = 0.018 0.08 Cumulative Incidence 0.06 Conventional 0.04 0.02 Intensive 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years from Study Entry Number at Risk Intensive: 705 686 640 118 Conventional: 721 694 637 96 DCCT/EDIC Study Research Group, NEJM 2005

  21. Major 3 glucose lowering studies 2008 and CV disease * *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 Med2008;358:2545-2559; 3The ADVANCE Collaborative Group N Engl J Med2008,358:2560-2572

  22. 0.94 ( 0.80 , 1.10 ) 0.93 1.07 ( ( 0.83 0.80 , , 1.06 1.40 ) ) 1.22 ( 1.01 , 1.46 ) Turnbull et al. Diabetologia in press Nov 2009 Mortality (meta-analysis) Hazard ratio (95% CI) UKPDS ADVANCE VADT ACCORD Overall 0.5 1 2 Risk ratio (95% CI) Favors intensive glucose control Favors standard glucose control

  23. Population Clinical Basic Acute Complications • SubClinical • organ damage • Arteries • Heart • Brain • Kidneys • Eyes etc Sudden Death Thrombosis Aneurysm Chronic Complications Diabetes Dyslipidaemia Hypertension Nutrition Exercise Angina Kidney Failure Dementia Risk Factors Heart Failure Early life Pregnancy Childhood obesity Terminal Disease

  24. Prevent Prevent Diabetes Complications Metabolic imprinting/memory

  25. Potential causes of diabetes-induced macrovascular disease Conventional risk factors Diabetes specific risk factors Defective insulin action AGEs Dyslipidaemia ROS Hypertension Hyperglycaemia Altered matrix Protein production Coagulopathy Altered endothelium, SMCs, macrophages Goldberg, JCI, 2004

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

  27. Heart/vessel stiffness MMP insensitivity Endothelial dysfunction Enzyme dysfunction P21ras NFκB NTFα ROS TGFβ1 IL6 Background - AGE/RAGE pathway Modified from Kass, D. A. (2003). Circ Res 92, 704-706.

  28. Cellular Responses Elicited by AGEs Cytokines (TNF, IL-1) Cell Growth Macrophages Podocytes Epithelial Cells Mesangial Cells Endothelial Cells AGE R Extracellular Matrix Protein Production Angiogenesis RAGE AGE-R 1-3 MSRs LOX-1 CD 36 Growth Factors TGF, CTGF, PDGF Multispecfic AGE-receptors Adapted Raj et al, AJKD, 2000.

  29. Can we stop diabetes and its complications without the prison of glycaemic control?

  30. So which part is the most important? AGE/RAGE axis Renin Angiotensin System Oxidative Stress Blood pressure Dyslipidemia Glucose control It is likely that combination approaches will be required No one pathway is sufficient to give all the answers

  31. Acknowledgements: The Diabetes Complications Group Merlin Thomas Mark Cooper

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