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Management of Cardiovascular Disease in Type 2 Diabetes. Based on clinical Trials.

Management of Cardiovascular Disease in Type 2 Diabetes. Based on clinical Trials. Prof. M. Serrano Ríos 9th Meeting of the MGSD Nice, France April 30 2005. The problem. The prevalence of type 2 diabetes has reached epidemic proportion world wide.

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Management of Cardiovascular Disease in Type 2 Diabetes. Based on clinical Trials.

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  1. Management of Cardiovascular Disease in Type 2 Diabetes. Based on clinical Trials. Prof. M. Serrano Ríos 9th Meeting of the MGSD Nice, France April 30 2005

  2. The problem • Theprevalence of type 2 diabetes has reachedepidemic proportion world wide. • Yet30-50%remainundiagnosed. • Furthermore, over 50% of those diagnosed already have complicationsat the time of diagnosis (UKPDS results). • The UKPDS has taught us that tightglycemic control in type 2 diabetes is very difficult to achieve. • Finally,there is a high prevalence of IGT, a population at high risk of developing type 2 diabetes and CVD.

  3. Estimated number of adults with diabetes by age-group, year and countries for the developed and developing categories and for the world Sarah Wild et al. Diabetes Care May 2004; 27: 1047-1053

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  5. The Modern Epidemic – Type 2 DM/Obesity/CVD Globalization Modernization Migration Life style changes (Westernization/Coca-colonization) Genetic factors HUGE SOCIO- ECONOMIC COSTS (individual & society) DIABETES & CVD RISK FACTORS OBESITY (INSULIN RESISTANCE/METABOLIC SYNDROME) MORBIDITY & MORTALITY DIABESITY (INSULIN RESISTANCE SYNDROME)

  6. Diabetes and Cardiovascular Risk Endothelialdysfunction Dyslipidaemia Total-C  LDL-C  Triglycerides  Apo-B  HDL-C  AdvancedGlycationProducts Type 2Diabetes Hypertension ProthrombosisFibrinogen  PAI-1 

  7. Multifactorial Intervention Studies • Steno - 2 • UKPDS (restricted)

  8. Gaede P et al. N Engl J Med. 2003; 348: 383-393.

  9. Gaede P et al. N Engl J Med. 2003; 348: 383-393.

  10. Objetivos Gaede P et al. N Engl J Med. 2003; 348: 383-393.

  11. UKPDS: Goals • Primary goal: to determine the effect of intensive blood glucose control (pharmacological management) versus conventional blood glucose control (lifestyle changes) on the development of macrovascular and microvascular complications in Type 2 diabetes • Secondary goal: to determine if a particular therapy for glycaemic control (insulin, sulphonylureas, or metformin) has any advantages or disadvantages UKPDS Group. Lancet. 1998;352:837–853.

  12. Risk reduction for each 1% reduction in updated mean HbA1c: 14% MI p < 0.0001 16% heart failure p = 0.016 21% any DM endpoint p < 0.0001 21% DM deaths p < 0.0001 37% microvascular complications p < 0.0001 43% amputation or death from PVD p < 0.0001 “Any reduction in HbA1c is likely to reduce the risk of complications” Treating to Target UKPDS 35 -Hyperglycemia UKPDS 35. BMJ 2000;321:405-412.

  13. Selvin E. e t al. Ann Intern Med. 2004 21;141:421-431.

  14.   • Del Pilar Solano M et al. Endocrinol Metab Clin North Am. 2005;34:1-25.

  15. Hyperglycemia

  16. Preventing Complications Hypertension • Complicates diabetes • Type 2 patients are often hypertensive at time of diagnosis • Higher incidence with  age • Dramatically increases morbidity and mortality in patients with diabetes Prevalence in general population: 22%1 Prevalence in type 2 diabetes:39%2 Prevalence of insulin resistance in hypertensive patients: 58%3 Meltzer et al. CMAJ 1998;159(Suppl 8):S1-S29. Joffres et al. Am J Hypertens 1997;10:1097-1102. Hypertension in Diabetes Study Group. J Hypertens 1993;11(3):309-317. Bonara et al. Diabetes 1998; 47:1643-1649.

  17. UKPDS intensive blood pressure control study: Results Less tight control† 160/94 154/87 Tight control† 161/94 144/82 Average difference — 10/5 Start (mm Hg) Finish (mm Hg) † Non-compliance of antihyperytensive agents was 43%of total person years in less tight control group and 6% of total person years in tight control group UKPDS Group. BMJ. 1998;317:703–713.

  18. Treating to Target Blood Pressure and Complications of Diabetes: UKPDS Relative Risk Reduction of Tight vs. Less Tight BP Control 24% for any diabetes-related endpoint p = 0.0046 32% for any diabetes-related death p = 0.019 18% for all-cause mortality p = 0.17 21% for myocardial infarction p = 0.13 44% for stroke p = 0.013 49% for peripheral vascular disease p = 0.17 37% for microvascular disease p = 0.0092 UKPDS 38. BMJ 1998;317:703-713.

  19. Yki-Järvinen H et al.Drugs 2000; 60: 975-983

  20. Preventing Complications Effect of ACE Inhibitionin Diabetes: HOPE Study Relative Risk Reduction of Ramipril vs. Placebo in Subjects with Diabetes 22% for myocardial infarction p = 0.01 33% for stroke p = 0.0074 37% for cardiovascular death p = 0.0001 24% for overt nephropathy p = 0.027 17% for revascularization p = 0.031 20% for heart failure p = 0.019 HOPE investigators. Lancet 2000;355:253-259.

  21. Treating to Target Treat to Target DBP:Lessons of the HOT Study 30 -2.1 mmHg = - 5.8 events/1000 py -2.1 mmHg = - 6.7 events/1000 py 25 20 CV Events /1,000 Patient-Years in Patients with Diabetes at Baseline 15 10 5 0 Target: (Achieved):  90 mmHg DBP  85 mmHg DBP 80 mmHg DBP (mean 85.2 mmHg)(mean 83.2 mmHg)(mean 81.1 mmHg) p for trend = 0.005 Adapted from Hansson et al. Lancet 1998;351(9118):1755-1762.

  22. Harris, R. et. al. Ann Intern Med 2003;138:215-229

  23. -3 ACEI • 17 • ACEI • 19 • ARB • + • 20 • ARB + -25 ACEI -74 ACEI Mancia G. et al. Acta Diabetol 2005; 42: S17-S25

  24. Preventing Complications Metabolic Abnormalities in Diabetes: Lipid Problems • Prevalence of elevated TC in general population: 44%1 • Hyperlipidemia = increased CHD risk in patients with diabetes2 • Coexistence of dyslipidemia, hyperuricemia, hypertension and glucose intolerance associated with 95% prevalence of insulin resistance3 1. Maclean et al. Can J Cardiol 1999;15(4):434-444. 2. Pyorala et al. Diabetes Care 1997 Apr;20(4):614-620. 3. Bonara et al. Diabetes 1998;47:1643-1649.

  25.    Yki-Järvinen H et al.Drugs 2000; 60: 975-983

  26. Del Pilar Solano M et al. Endocrinol Metab Clin North Am. 2005;34:1-25.

  27. a Relative risk < 1 favours statin • Hovens MM. et al. Drugs. 2005;65:433-445.

  28. Preventing Complications Lipid-Lowering Therapy in Diabetes • Lipid therapy: aim to  LDL,  HDL,  TG • Statins effective in lowering LDL1 • Fibrates effective for raising HDL, lowering TG1,2 • Some oral antihyperglycemic agents may benefit lipids, but are not indicated for lipid management3 1. Expert Panel on Detection, Evaluation and Treatment of High Blood Pressure in Adults. JAMA 2001;285. 2. Diabetes Atherosclerosis Intervention Study Investigators. Lancet 2001;357:905-910. 3. Lonnqvist et al. Poster 869 presented at EASD, 1999.

  29. Conclusions: Dyslipidemia In adults patients (with T2DM) a test for lipid disorders should be done annually and more often if needed to achieved goals. In adults hit low risk lipid values (LDL< 100 mg/dl; HDL > 50 mg/dl; TG< 150 mg/dl) lipid reassessment may be repeated every 2 years.

  30. XENDOS - Efecto de ORLISTAT en Prevención DM2 Incidencia de DM 2 (%) Placebo + cambio estilo vida Orlistat + cambio estilo vida 10 9.0% RR*37% 8 p=0.0032 6 6.2% 4 * Ratio reducción riesgo vs. placebo más cambio estilo de vida 2 0 0 1 año 2 años 3 años 4 años Años Sjostrom et al. 9th ICO, Sao Paulo 2002. Poster Presentation

  31. Lifestyle InterventionsIntegrated Approach to Lifestyle Modifications: Obesity / OverweightPhysical inactivityUnappropiate dietary habits (high caloric intake, high saturated fat content, low fiber, sugar, high alcohol intake. . . )Smoking

  32. Ratner R. et al. Diabetes Care. 2005 ;28:888-894.

  33. Ratner R. et al. Diabetes Care. 2005; 28:888-894.

  34. Early antidiabetic treatment can reduce the CV risk

  35. Hyperglycaemia D I S F U N C T I O N Postprandial Status in diabetics Endothelium F VIIa LDL oxidation Oxidative stress Antioxidants ... / ... Hypertriglyceridemia Atheroesclerosis Breakfast Lunch Dinner Ceriello A. Diabetes/Metabolism Research and Reviews. 2000. 16:125-132.

  36. ITT Effect of acarbose on glucose tolerance in individuals with IGT Glucose tolerance at end of treatment (%) IGT Diabetes NGT Acarbose 35.3* 28.4 32.4* (n=682) Placebo 30.9 24.9 41.5 (n=686) *p<0.001 Chiasson, J.-L. et al. Lancet 359:2072-2077, 2002.

  37. STOP-NIDDM Study And type 2 diabetic patients??

  38. Effect of acarbose on time to develop myocardial infarction (Meta-Analysis) Kaplan-Meier survival curve Hanefeld M et al. Eur Heart J 25, 10-16, 2004

  39. Panunti B et al. Curr Atheroscler Rep. 2005;7:50-57.

  40. Glitazones and CV HTN P.Q.O. & NASH ­TG ¯HDL ­ PAI-1 ­fibrinogen DM2 Central Obesity Insulin-Resistance - Hyperinsulinemia Pre-treatment Drug “Ideal” Cusi, 2005 Glitazones

  41. P 0.001 P = 0.04 Amlodipine Lisinopril Chlorthalidone ALLHAT: Incidence of New-Onset Diabetes at 4 Years 43.2% lower onset of new diabetes with lisinopril compared to chlorthalidone (P0.001 at 4 years) ALLHAT Officers and Coordinators. JAMA2002;288:2981-2997.

  42. Standards of Medical Care in Diabetes. Clin Prac. Recomm 2005

  43. Standards of Medical Care in Diabetes. Clin Prac. Recomm 2005

  44. T2DM and the control of CVD risk factors: The real World In the real Clinical setting Control of T2DM and associated CV risk factors is far from satisfactory and often very frustrating for both patient and clinicians. Reasons for that reality are many: Some associated to Diabetes itself. Other related to patients and /or Healthcare delivery problems. Cost of intensive care policies.

  45. UKPDS: Implications • The UKPDS results support the mandate that intensive glycaemic control is required to reduce the risk of microvascular complications in people with Type 2 diabetes • Macrovascular disease prevention requires management of cardiovascular risk factors in addition to hyperglycaemia • No increase in cardiovascular events or death was observed and the risk of atherosclerotic events should not discourage intensive management • The benefits of intensive glycaemic control outweigh the risk of hypoglycaemia • Tight blood pressure control reduces diabetes-related mortality, heart failure and stroke • The phrase ‘intensive’ in this study is somewhat misleading as it corresponds to usual clinical management in many centres

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