Presentation at Calicut Endocrinology club

1. Cardiovascular Risk and Diabetes DR. S. ASWINI KUMAR. MD Professor of Medicine Medical College Hospital Thiruvananthapuram 1

2. New definition for Diabetes Type 2 diabetes is a condition of premature cardiovascular complications in the setting of chronic hyperglycaemia 2

3. Cardiometabolic Risk A patient with diabetes Normal person with MI 3 Consider yourself having a heart attack already, when you develop diabetes

4. Diabetes as a new risk factor for cardiovascular mortality 4 Diabetes

5. Framingham Heart Study 30-Year Follow-Up:CVD Events in Patients With Diabetes (Ages 35-64) 10 10 9 Men Women 8 11 Risk ratio 6 30 19 4 9 6 38 20 3* 2 0 Total Cardiac and vascular events Coronary Heart Disease Cardiac Failure Stroke Intermittent Claudication Age-adjusted annual rate/1,000 P<0.001 for all values except *P<0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992. 5

6. Coronary Heart Disease - Mortality Male 60 50 40 30 20 10 0 With Diabetes* Female Without Diabetes CHD Mortality/1,000 Male Female 0-3 4-7 8-11 12-15 16-19 20-23 Duration of Follow-up (yrs) * Diagnosed between 35 and 65 years of age Am J Med 90(2A): 56S-61S,1991 6

7. What if a diabetic had a coronary event? 7 Coronary Events Multivessel disease Complications PC Interventions Diabetic ketosis Bypass surgery

8. Natural History of Type2 Diabetes 8

9. The continuum of Cardiovascular Risk in Diabetes 9

10. Diabetes and Cardiovascular risk Endothelialdysfunction Dyslipidemia Total-C  LDL-C  Triglycerides  Apo-B  HDL-C  AdvancedGlycationProducts Type 2Diabetes ProthrombosisFibrinogen  PAI-1  Hypertension 10

11. Diabetes and Endothelial Dysfunction 11

12. Relationship between obesity, insulin resistance and dyslipidemia 12

13. Diabetic vascular pathology 13

14. Common pathways of diabetic complications 14 Glucose Peripheral & Autonomic Neuropathy Polyol Pathway Hexosamine Pathway AGE Formation Nephropathy Oxidative Stress Cellular Dysfunction ROS Vascular Damage Coronary Artery Disease Cell Damage Different complications (eye, kidney, nerve, blood vessels) arise from limited number of triggers perturbing a limited number of metabolic pathway(s)(Brownlee, 2001) Retinopathy

15. Cardiovascular risk factors specific for diabetes 15 Microalbuminuria Massive proteinuria Abn. Platelet function Microalbuminuria Fibrinogen levels Serum insulin PAI-1

16. Accelerated CAD progression in Diabetes - Summary 16

17. Can you prevent the premature Cardiovascular Events in Diabetes? Optimal control of glycemia, BP, lipids, regimens optimized to reverse LVH, dysfunction & plaque 17

18. DCCT and other studies Research studies between 1970 and 2000 showed that complications could be prevented by lowering high glucose levels Studies DCCT 1984-1992 EDIC 1996 UKPDS 1978-1998 Kumamoto 1992-2000 Results Better health Fewer complications Sense of well-being More flexible lifestyle 18 GOAL: A1c < 6.5% HB Mortensen et al: Diabetes Care. 1997 May;20(5):714-20 Diabetes Care. 1997 May;20(5):714-20 Horm Res 1998;50:107–140

19. UKPDS Findings 19 16% 19% 37% 43% Micro-vascular Disease PVD Heart Failure Cataract Extraction Risk reduction with 1% decline in annual mean A1C P <.0001 P = .035 P = .021 P = .0001 0% 12% 14% 15% 30% 45% MI Stroke Stratton IM, et al. BMJ. 2000;321:405-412.

20. EDIC Findings: Cardiovascular Events 20 Cumulative Incidence of First of Any Event 0.12 0.10 Risk reduction:42% 95% CI: 9% to 63% P = 0.02 Conventional 0.08 Cumulative Incidence 0.06 0.04 Intensive 0.02 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 DCCT/EDIC N Engl J Med 2005: 353:2643-2653.

21. AHA/ACC 2006 Secondary prevention guidelines: Risk factor modification in diabetic patients 21

22. Diet and Diabetes – A days menu 06.30 am Tea without 08.30am Break fast 10.30am Snack 01.30pm Lunch 02.30pm Fruits 04.30pm Tea without 08.30pm Dinner 06.30pm Green salad 22

23. Diet and Diabetes – What not to eat Vada Sweets Pastry Sugar Mutton Beef fry Colas Chips 23

24. Benefits of 10% Weight Loss 24 20% fall in total mortality 30% fall in diabetes related death 40% fall in obesity related death 20% fall in Systolic BP 10% fall in Diastolic BP 50% fall Fasting Glucose 10% fall in Total Cholesterol 15% fall in LDL 8% increase in HDL 30% fall in Triglyceride

26. Standing, desk work, driving 2

27. Level walking, level bicycling 3

28. Social doubles badminton 4

29. Social singles badminton 5

30. Gardening , swimming 6

31. Competitive badminton 7

32. Jogging 8

33. Basketball 9

35. * Exercise Guidelines Medical evaluation for CAD, PVD, and neuropathy Choose activity patient enjoys Walking - minimum 20 min 5x/wk Five minutes warm up Five minutes cool down Educate on hypoglycemia Proper foot care and footwear RBS monitoring - pre and post Insulin or carbohydrate adjustments Medical Identity card 27

36. Use of Aspirin in Diabetes Mellitus for prevention of Cardiovascular events 25 22% 20 18% PatientsExperiencingCardiovascularEvents(%) 15 12% 10% 10 9% 5 4% 0 Placebo Placebo Placebo ASA ASA ASA US MDs* APT† ETDRS‡ * Physician’s Health Study (US MDs); relative risk (RR) = 0.39 (NS), NEJM 1989 †AntiplateletTrialists’ Collaboration (APT); 2 P < 0.002, BMJ 1994 ‡ Early Treatment Diabetes Retinopathy Study (ETDRS); relative risk (RR) = 0.83 (P= 0.04), JAMA 1992 28

37. How do treat hypertension in association with DM in order to reduce cardiac risk? 29 Thiazide diuretics Captopril  Blockers ↑ IR ↑ LDL HDL ↓ slightly ↓IR ↓ LDL HDL↑ slightly Beta blockers Calcium channel blockers ↓IR ↓ LDL HDL↑ slightly Glucose & lipid neutral ↑ IR ↑ LDL HDL ↓ slightly

38. Travelling with cholesterol 30 HDL seeks out excess cholesterol and cholesterol & prevents CAD HDL returns excess cholesterol to liver to be converted to bile acids Excess cholesterol deposited in arterial walls to form plaques Saturated and trans fat in the diet act on the liver to increase excess LDL cholesterol in blood LDL delivers cholesterol throughout the body Liver regulates production of cholesterol Liver packages TG & TC into VLDL and sends to blood VLDL broken down to LDL and TG. TG is used as energy and stored

39. How do treat dyslipidemia in association with DM in order to reduce cardiac risk? 31 High levels of TG Low levels of HDL Preponderance of small dense LDL Absolute LDL normal HDL is lower in men and women with diabetes Increase in TG predicts heart disease morbidity and mortality in diabetes Diabetes Atherosclerosis Intervention study Fenofibrate reduced atherosclerosis by 40% and deaths by 23%

40. ADA recommendations: Lipid lowering drugs by treatment goal 32

41. The Polypill concept Aspirin Ramipril Atorvostatin Beta blocker Thiazide Folic acid Dr. Nicholas Wald 33

42. Rimonobant in Type2 Diabetes – The SERENADE Study 34

43. Having diabetes is as bad as having an acute myocardial infarction Death in diabetic patient is usually due to acute coronary event Insulin resistance plays a vital role in the pathogenesis of increased risk Coronary event are more extensive in presence of diabetes Management of patients with acute MI are no different in DM patients PCI in diabetic patients have unfavourable outcomes CABG may be preferred in diabetic patients Dietary & life style modifications are vital in reducing cardiovascular risk Hypertensive medications are to be chosen with care in diabetics Lipid management is slightly different from non-diabetic patients Summary 35

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