Cardiology and their ‘sweet hearts’

1. Cardiology and their ‘sweet hearts’ Jay Shavadia Cardiology Resident, UofA MAHI Cardiology Update, 2014

2. Disclosures • None

4. Diabetes: Global Burden 6 % of the global population diagnosed, ~ 6% remain undiagnosed

5. Diabetes: Morbidity and Mortality

6. Introduction • New cases occurring in context of ‘western’ lifestyles obesity, insulin resistance, with beta cell failure and T2DM • Insulin resistance associated with clustering of vascular risk - ‘metabolic syndrome’ • Metabolic syndrome: dysglycemia, dyslipidemia, HTN and obesity • Hyperglycemia – heterogenous – impaired fasting glucose, impaired glucose tolerance and overt diabetes

7. Diabetes: Sub types

8. Diabetes : subtypes • T1DM – insulin deficiency from pancreatic beta cell destruction from auto antibodies • T2DM – insulin resistance and beta cell failure • Gestational – develops during pregnancy; euglycemia after delivery. Increased risk to develop T2DM • Others – associated with pancreatitis, surgery

10. How and when of screening • FBG, HbA1c, OGTT to screen • If screening normal, then Q 3 yearly

11. Definitions Caveats to current definition: The definitions are based glucose levels at which retinopathy occurs Glycosylated HB measurements are affected by medical conditions that increase RBC turnover

12. Glycemic continuum and CV disease Window of Opportunity 1. Aggressive screen 2. Aggressive intervention

13. Why is presence of diabetes considered a high CV risk?

15. How does diabetes increase the cardiovascular risk?

17. Insulin resistance • Central in development of CVD in T2DM • Release of cytokines and FFA by the ‘fat cells’ which impair insulin action • Increasing amounts of insulin secreted by pancreas • Eventually beta cell failure, and hyperglycemia

19. Dyslipidemia in T2DM • Increased triglycerides, increased LDL (small dense LDL, apo B rich), reduced HDL • Accumulation of IR macrophages, with promotion of foam cell formation

20. Endothelial dysfunction • FFA induced impairment of NO producing pathway, endothelial dysfunction and vascular remodeling • Accumulation of ROS  NF kBinflammatory adhesion molecules, AGEs • ROS involved in persistence of vascular dysfunction, despite glucose control (metabolic memory’)

21. Interim summary • Production of cytokines and FFA responsible for development of insulin resistance • Down regulation of the cells glucose absorbing machinery hyperglycemia • Generation of large VLDL particles by the liver, and subsequent breakdown to LDL, sLDLdyslipidemia

22. Case 1: Hyperglycemia in ACS

23. Case 1: Mr K • 52 banker, current smoker and BMI 26, with no other traditional cardiovascular risk factors • Admitted with an inferior STEMI s/p primary PCI to RCA • On arrival from cath, RBG 14mmol/l and repeat 4 hrs later 16 mmol/l; screening HbA1c 5.6% two months ago

24. Mr K How would you manage his blood glucose in CCU? • Observe for now, and follow trend • Start metformin • Start sulfonylurea • Start insulin • Start insulin- potassium-glucose infusion

25. Mr K Is an elevated random glucose on admission prognostic? • Yes, only for in hospital MACE • Yes, for both in hospital and long term • No, it indicates a stress response

26. 4196 patients, 25 countries – not known to have diabetes; suspected CAD, screened for DM with OGTT

27. Hyperglycemia in ACS n = 141, 680, 1994 -1996

28. Hyperglycemia in ACS: GKI infusion • Glucose – potassium – insulin combination infusion • Utilization of insulin to help reduce circulating excess FFA – myotoxic • Potassium – concurrent intracellular K shift with utilization of glucose and insulin. In ACS, thought to reduce arrhythmias

29. DIGAMI-2 Trial 1253 diabetic patients, admitted with ACS Randomized to GKI infusion for 24 hrsfollowed by SQ insulin GKI infusion for 24 hrs, followed by standard of care Standard of care RBG 12.8, 12.9 and 12.5 at baseline; 9.1, 9.1 and 10 at 24hrs Malmberg K et al. Eur Heart J 2005;26:650-661

30. CREATE ECLA Trial 20201 STEMI patients in 470 centers, randomized to: 1. GKI infusion for 24 hrs 2. Standard of care Mean RBG 9.0 at baseline, 8.6 in GKI, 7.5 in control at 24hrs ‘reliably established that high dose GKI infusion is unlikely to be of any material value in STEMI’

31. N = 6104, 42 ICUs Randomized to: Intense glucose control (4.5 – 6mmol/l) Conventional arm (8-10mmol/l)

32. Interim Summary:Hyperglycemia in ACS • Abnormal glucose regulation ~ 50% in patients with ACS, not known to have DM (“stress hyperglycemia”) • These patients have worse short- and long term outcomes • No difference in short term mortality with GKI infusion cf. standard of care • Target glycemic control favors a non intensive approach (8-10mmol/l)

33. Case 2: Mr B • Mr B 60 yr old farmer, T2DM for 10 years, HTN, BMI 28 • On oral hypoglycemic agents, HBa1c 8%; only other medication is HCTZ • Been in otherwise good health; never had an MI, stroke or renal dysfunction • Sent by his family MD for atypical chest pain

34. Case 2 How would you proceed to evaluate this patient? • No further testing, optimize medical management • Exercise stress test • Coronary angiogram

35. Ischemia evaluation in diabetes • Typical / atypical cardiac symptoms • Signs or symptoms of associated disease • Peripheral arterial disease • Carotid bruit • TIA / stroke 3. Resting EKG abnormalities (eg. Q wave)

36. Case 2 • Resting EKG: sinus and normal • Lipid battery: LDL 4.0, HDL 1.3, TG 2.2 • He underwent an exercise stress test – completed 9mins (functional class 1) with no ischemic EKG changes, normal BP/HR response • You decide on ‘medical management’ to reduce his vascular risk

37. Diabetes and Vascular risk • DM accelerates atherosclerosis and promotes cardiovascular aging • Significantly reduced life expectancy, ~ 12 years • Health behavior education and pharmacologic vascular protection to promote CV risk reduction

38. Reducing vascular risk 1. Non pharmacologic intervention 2. Pharmacologic • Intensify glycemic control • BP control • Aspirin • RAAS blockade

39. Glycemic targets • Hyperglycemia is associated with adverse CV outcomes • Intensive glucose control then seems to be the natural thing to do

40. 3867 newly diagnosed type 2 diabetics, follow up 10 years Intensive control (metformin, SU) – HbA1c 7% Conventional (diet, medication) – HbA1c 7.9%

41. What about glycemic control and vascular risk in long standing diabetics?

42. Intensify Glycemic Control

43. Intensive glycemic control • In already established DM, intensive glucose control may have a potential for harm • Real risk of hypoglycemia in univerally adopting an intensive strategy

44. Glycemic targets: CDA Recommendation

45. Aspirin • In vitro data suggests increased platelet reactivity and aggregation • In theory, makes sense to use an anti platelet to prevent CV events

46. 2539 diabetes, with no documented coronary or cerebrovascular disease, ASA 81-100 mg or placebo Clinical composite of coronary or cerebrovascular events

47. ASA on CAD ASA on stroke

49. Lipid Modification • Any clinical atherosclerotic cardiovascular disease • Diabetes age 40-75 yrs, with LDL 1.8 – 4.9 without clinical atherosclerotic cardiovascular disease • Primary LDL > 4.9 • LDL 1.8-4.9 with 10- year risk of ASCVD >7.5% Recommendation : moderate intensity statin, or if 10 yr risk >7.5% high dose statin

50. RAAS modulation