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Heart and Diabetes Baker IDI in the Centre

Heart and Diabetes Baker IDI in the Centre. Professor Garry Jennings Director Baker IDI Heart and Diabetes Institute. Themes. Outcomes in diabetes Atherosclerosis and diabetes Coronary disease in the diabetic patient Diabetic heart Therapeutic aspects

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Heart and Diabetes Baker IDI in the Centre

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  1. Heart and DiabetesBaker IDI in the Centre Professor Garry Jennings Director Baker IDI Heart and Diabetes Institute

  2. Themes • Outcomes in diabetes • Atherosclerosis and diabetes • Coronary disease in the diabetic patient • Diabetic heart • Therapeutic aspects • What Baker IDI is doing relevant to indigenous health

  3. Hypertension Abdominal obesity Dyslipidaemia Diabetes • 80% of deaths in diabetes due to CVD • 80% of heart attack sufferers have impaired glucose tolerance • 85% of the population have one or more of these risk factors

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

  5. T2D complications- mainly vascular Stroke 2- to 4-fold increasein cardiovascular mortality and stroke3 Diabeticretinopathy Leading cause of blindness in working-age adults1 Cardiovasculardisease 8/10 diabetic patients die from cardiovascular events4 Diabetic nephropathy Diabeticneuropathy Leading cause of end-stage renaldisease2 Leading cause of non-traumatic lower extremity amputations5 Disability from 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.

  6. Cardiovascular disease in people with diabetes 60 28d–1yHospitalization–28dOut of Hospital 50 9.1 40 11.1 15.4 4.2 % of deaths (crude rate) 30 9.6 22.7 2.8 20 9.0 28.6 22.1 10 10.9 11.9 0 Diabetes No Diabetes Diabetes No diabetes Men Women Adapted from Miettinen H et al Diabetes Care. 1998;21:69-75.

  7. Cardiovascular disease in people with diabetes - Morbidity Proportion of hospital bed days for the treatment of the complications of diabetes Diabetes impacts on “Human Capital” as an economic issue Men Women Workforce participation rate - + - + Diabetes Council of Australian Governments – Elevating diabetes above a health issue

  8. Insulin Resistance and metabolic syndrome Central obesity Endothelial dysfunction/ microalbuminuria Hyperglycemia Insulin Resistance Dyslipidemia Hypertension Cardiovascular Disease

  9. Cardiovascular disease risk factors in diabetes 1.8 1.6 1.4 Odds ratio for incident CVD 1.2 1.0 0.8 0.6 Age Smoking (log)HOMA-IR Total-C:HDL-C Bonora E, Formentini G, Calcaterra F, et al. Diabetes Care 2002; 25:1135–1141.

  10. Other features of the Metabolic Syndrome increase the risk of coronary heart disease still further 30 Metabolic syndrome P < 0.001 No metabolic syndrome 20 Prevalence of coronary heart disease (%) P = 0.06 P = 0.04 10 0 NGT IFG/IGT Type 2 diabetes Isomaa B, Almgren P, Tuomi T, et al. Diabetes Care 2001; 24:683–689.

  11. ‘Double jeopardy’: type 2 diabetes and hypertension and cardiovascular risk 250 No diabetes Diabetes 200 150 CVD death rate (per 10,000 person-year) 100 50 0 < 120 120–139 140–159 160–179 180–199  200 Systolic blood pressure (mmHg) Stamler J, Vaccaro O, Neaton JD, et al. Diabetes Care 1993; 16:434–444.

  12. Hypertension management in diabetes Treatment gap- drugs indicated Treatment gap- OK with lifestyle Therapeutic inertia- more therapy needed Therapeutic inertia- OK with lifestyle Meeting target 9857 males and 8332 females in Australian general practice Owen, Retegan, Rockell, Jennings and Reid CEPP Nov 2008

  13. % Reduction Yudkin & Richter Lancet 374:522 2009 25 26 46 NNT to prevent CHD 10 y (UKPDS cohort) 118 49 3333 NNT to prevent stroke10 y (UKPDS

  14. Atherosclerosis in the setting of diabetes

  15. Are there biological links or is it a collection of unrelated biological consequences of lifestyle? Insulin resistance Lifestyle Obese Sedentary High TG’s High blood pressure Low HDL

  16. A biological link- rHDL infusion lowers glucose and increases insulin levels

  17. Cellular and biochemical drivers of atherosclerosis All atherosclerosis: Lipid retention by vascular matrix(proteoglycans)(Skalen et al., 2002) “Inflammation”(Ross, 1999; Libby, 2006) Oxidation (Witztum, 1994; Stocker and Keaney, 2004; Steinberg et al., 1989) Endothelial injury/dysfunction(Ross, 1992; Davignon and Ganz, 2004) Also in diabetes: Hyperglycaemia Advanced glycation end products (AGEs and RAGEs) (Brownlee, 2001, Forbes et al., 2004) Hyperglycaemia/Oxidation/ROS

  18. Diabetes has a predilection for peripheral arteries

  19. Clinical tip- ACE inhibitors improve exercise tolerance in PAD

  20. Walking Distance 6% - 23% 6% - 4% Ahimastos et al Annals Internal Medicine 2006;144:660-4

  21. Coronary disease in diabetes More common More silent infarcts More silent ischaemia More plaque instability More sudden death

  22. 0.25 0.5 1 2 4 8 OR (99% CI) INTERHEART: Association of Risk Factors with AMI in Men & Women (1)

  23. Single vessel disease is less common in diabetes 80 n = 148 60 n = 923 Incidence of multivessel disease (%) 40 20 0 No diabetes Diabetes Granger CB, Califf RM, Young S, et al. J Am Coll Cardiol 1993; 21:920–925.

  24. A gene that predisposes to coronary disease in the presence of poor glycaemic control in T2D (9P21 locus) HbA at Study Entry Weighted Av (7yr) HbA level before Study Entry 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

  25. CLINICAL TIP Restenosis is 3x more common in diabetic than non diabetic subjects with bare metal stent. Less likely with drug eluting stent but still more than in non diabetics Early outcomes with drug eluting stent match CABG (NY registry) but confounding likely- await FREEDOM results

  26. CABG better than DES better than BMS-ARTS ARTS I-BMS vs. CABG (96/112 diabetes) ARTS II DES (sirolimus) (159 diabetes) Daemen JACC 2008:52;1957

  27. Importance of good (oral) glycaemic control after PCI revascularization Corpus et al JACC 2004;43: 8-14

  28. Heart Failure Heart Failure in patients receiving dialysis & Medicare recipients with & without CKD Prevalence of Heart Failure Patients with & without Diabetes Gilbert et al. 2006 Heart Failure & Neuropathy Clin J Am Soc Nephrol1:193-208

  29. Heart failure with preserved LVEF (HFPEF) N Engl J Med 2001;344:17-22

  30. Early detection of Cardiomyopathy Control Diabetic Conventional echocardiograhy Tissue Doppler Imaging Insulin Resistance Di Bonito et al. 2005 Early Detection of Diabetic Cardiomyopathy: usefulness of tissue Doppler imaging Diabetic Medicine 22, 1720-1725

  31. IDNT :HF hospitalisations(Secondary endpoint) 30 Irbesartan Amlodipine Control RRR 37%p<0.001 n = 579 RRR 23%p=0.15 n = 569 20 Subjects (%) n = 567 10 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (mo) Berl, et al. Ann Intern Med. 2003; 138: 542–549.

  32. I-PRESERVE: Primary Endpoint Placebo Irbesartan Death or protocol specified CV hospitalization(Mean follow-up 49.5 months) 40 - HR (95% CI) = 0.95 (0.86-1.05) Log-rank p=0.35 30 - Cumulative Incidence of Primary Events (%) 20 - 10 - 0 - 0 6 12 18 24 30 36 42 48 54 60 Months from Randomization No. at Risk 2067 1929 1812 1730 1640 1569 1513 1291 1088 816 497 Irbesartan 2061 1921 1808 1715 1618 1539 1466 1246 1051 776 446 Placebo

  33. Risk ratio Study (95% CI) % Weight CHARM 0.81 (0.66,0.99) 8.7 LIFE 0.75 (0.64,0.89) 13.8 HOPE 0.66 (0.52,0.84) 6.6 ANBP2 0.69 (0.56,0.85) 8.6 CAPPP 0.89 (0.78,1.03) 16.2 ALLHAT 0.66 (0.54,0.81) 9.7 VALUE 0.81 (0.74,0.89) 36.4 0.78 (0.74,0.83) Overall (95% CI) 1 0.5 2.0 Risk ratio New Onset Diabetes in comparative outcome trials involving RAS versus non-RAS blockade Jandeleit-Dahm et al., J Hypertens 2005

  34. Cardiovascular Outcomes – Rosiglitazone and Pioglitazone Favours pioglitazone 95% CI Favours rosiglitazone 2008 Winkelmayer et al Comparison of Cardiovascular Outcomes in Elderly Patients with Diabetes who initiated Rosiglitazone Vs Pioglitazone Therapy Arch Intern Med 168 no.21

  35. Most guidelines recommend aspirin as primary prevention in those with diabetes • Evidence is circumstantial • Japanese aspirin trial in diabetics (2009) • Primary end point not met • 90% reduction in secondary end point- fatal coronary disease and stroke • Sub study of Nurse Health Study also supportive (2008)

  36. What can Baker IDI bring to indigenous CVD and diabetes?

  37. Years of Life Lost (YLL) for the leading disease and injury categories – Indigenous persons 2003 CVD & Diabetes

  38. Disability Adjusted Life Years (DALY’S)By broad cause group - Indigenous Persons 2003 CVD & Diabetes

  39. Prevalence of long term health conditions

  40. Prevalence of Diabetes/High sugar levels

  41. Risk Factors - Daily Smokers Males Females

  42. The best predictor of future events is past events General population High risk Extant disease Absolute risk History &/or biological markers

  43. General population High risk • Sometimes this is the entire population • Indigenous • Chronic kidney disease • Major psychiatric illness • Rheumatoid arthritis Extant disease Absolute risk History &/or biological markers

  44. Age – Indigenous population relatively young Median Age: 21 37 65+yrs 3% 13% <15yrs 37% 19%

  45. Rate of Low Birth Weight Babies- by Indigenous status of mother

  46. Benefits of hypertension treatment in HDFP % events Penalty for waiting until an event

  47. Prevention X Novel anti thrombotics CIN Unstable plaque markers Aneurysm treatment Acute Complications Prevention of diabetes complications LVH PAD treatment • SubClinical • organ damage • Arteries • Heart • Brain • Kidneys • Eyes etc Sudden Death Thrombosis Aneurysm Prevention X Prevention X Chronic Complications Metabolic syndrome/obesity Screening and intervention in rural and remote communities Nutritional interventions Polypill Resistant hypertension Hearts and minds Diabetes Dyslipidaemia Hypertension Nutrition Exercise Angina Kidney Failure Dementia Heart failure screening Disease management Gene and stem cell therapies HFPEF Risk Factors Prevention X Basic research on metabolic memory (epigenetics) Maternal interventions Gestational diabetes markers (proteomics) Heart Failure Early life Pregnancy Childhood obesity Terminal Disease Prevention X

  48. Basic research on metabolic memory (epigenetics) Maternal interventions Gestational diabetes markers (proteomics) Prevention of diabetes complications LVH PAD treatment Novel anti thrombotics CIN Unstable plaque markers Aneurysm treatment Heart failure screening Disease management Gene and stem cell therapies HFPEF Metabolic syndrome/obesity Screening and intervention in rural and remote communities Nutritional interventions Polypill Resistant hypertension Hearts and minds

  49. Conclusions • The link between diabetes and CVD is strong but can be mitigated • Primary and ‘secondary’ prevention • Achieve blood pressure targets • Achieve glycaemia targets (?) • Special role for RAS inhibition? • Integrated care

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