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Intense Insulin Therapy in Diabetics after Myocardial Infarction : An underutilized therapy ?

Intense Insulin Therapy in Diabetics after Myocardial Infarction : An underutilized therapy ?. Jeffrey Hyde M.D. December 7, 1999 Resident Grand Rounds. CASE PRESENTATION.

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Intense Insulin Therapy in Diabetics after Myocardial Infarction : An underutilized therapy ?

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  1. Intense Insulin Therapy in Diabetics after Myocardial Infarction : An underutilized therapy ? Jeffrey Hyde M.D. December 7, 1999 Resident Grand Rounds

  2. CASE PRESENTATION • 52 y/o obese white male with DM, HTN, and hypercholesterolemia is admitted to the CCU after AMI followed by PTCI to LAD. Presently patient is pain free and without complaints. • Medications: (prior to hospitalization) • Glucotrol XL 5mg • Lipitor 20mg • Tenormin 50mg

  3. CASE PRESENTATION • Physical Exam: • Vitals: T 98.4 HR 68 BP 106/82 RR 16 • Neck: No JVD • Lungs: Minimal bibasilar crackles • CV: RRR nl S1,S2 No M/R/G • Ext: No edema • Labs: • CK 486/CKMB 128 and Troponin 16 • CMP normal except for Blood Glucose of 286

  4. CLINICAL QUESTIONS • Would rapid control of blood sugar benefit our patient ( morbidity and/or mortality )? • Would long term ( > 1 year ) insulin therapy effect mortality post MI? (i.e. secondary prevention)

  5. DIABETES and HEART DISEASE • Framingham Study • Diabetes Mellitus doubles risk of Cardiovascular disease in men and triples risk in women • Multiple Risk Factor Intervention Trial (MRFIT) • Cardiovascular death three times higher in diabetic men as compared to men without diabetes • Cardiovascular death five times higher in diabetic men as compared to men without diabetes when ‘optimal risk factor status’ is obtained

  6. DIABETES MELLITUS : Mortality after Myocardial Infarction • Multiple prospective studies approximate in-hospital mortality after myocardial infarction to be two times greater in diabetics than non diabetics • FINMONICA MI Register (1988-1992) - one year mortality after MI • 44.2% diabetic men vs 32.6 non diabetic men • 36.9% diabetic women vs 20.2% non diabetic women • Increased mortality is attributed to left ventricular dysfunction despite no significant difference in infarct size

  7. DIABETES MELLITUS : Extensive nature of Coronary Artery Disease • Coronary Artery Disease is more extensive in patients with diabetes mellitus proven angiographically and at autopsy • Higher incidence of two and three vessel disease • Lower incidence of one vessel disease • Why is atherosclerosis accelerated and more severe in diabetics?

  8. DIABETES MELLITUS : Lipid Abnormalities • Increased VLDL • Increased atherogenicity of VLDL • Increased apo E • Increased Small density LDL • Decreased HDL • Increased oxidation and glycation of LDL • Increased free fatty acids • Increased oxidation of free fatty acids

  9. Platelet function in diabetes • Platelets play important role in atherosclerotic plaque formation and thrombus formation during plaque rupture • Platelet function is ABNORMAL in DM with higher rates of aggregation and consumption • Substances elevated in hyperglycemia include: • Thromboxane A2 (platelet aggregation and vascular spasm) • Beta-thromboglobulin (increased platelet activity) • platelet factor-4 (increased platelet activity)

  10. Platelet function in diabetes • Prostacyclin, which ‘slows’ platelet-platelet interactions, found at lower levels in DM • Platelet aggregation linked to recurrent MI • Coincident with these findings: • time of onset of AMI parallels the circadian variation in platelet reactivity

  11. Coagulopathy in diabetes mellitus • Abnormalities in coagulation, hemostasis, and fibrinolysis • lower AT-III levels and an ‘acquired’ Protein C deficiency • increased intrinsic pathway activity secondary to increased kallikrein, factor XII, factor VIII • increased plasminogen activator inhibitor-1 (PAI-1)

  12. Acute Coronary Syndromes(ACS) • PAST: Slow progression of luminal obstruction secondary to atherosclerosis responsible for ACS • PRESENT: Coronary atherosclerosis progresses in a nonlinear, abrupt fashion leading to occlusion or near occlusion (i.e. thrombosis complicating atherosclerosis)

  13. Acute Coronary Syndromes: Vascular Lesions

  14. Acute Coronary Syndrome • Whether plaque disruption leads to coronary thrombosis depends on several factors: • (1) the thrombogenicity of the exposed components (i.e.balance of thrombotic and thrombolytic components) • (2) endothelial function • (3) presence of ‘trigger’ activities (acute risk factors)

  15. Acute Coronary Syndromes • Thrombogenicity • Intrinsic components (within plaque) • lipid core (tissue factor) and collagen matrix • Extrinsic components • tissue factor vs protein C and S • tPA vs PAI-1 • Endothelial function • atherosclerosis associated with dysfunction (paradoxical vasoconstriction) • nitric oxide

  16. Acute Coronary Syndromes • Trigger activities (acute risk factors) • vigorous exercise • emotional stress • cold weather • time of day

  17. Acute Coronary Syndromes • Complex interaction of these factors determines whether plaque disruption leads to coronary thrombosis • Would modification of ‘negative’ biochemical factors (prothrombotic, antifibrinolytic, platelet aggregation) produce stabilization of plaque or reduction in propagation of thrombosis?

  18. The Effect of Insulin (Improved Glycemic Control) on Biochemical Parameters in Diabetes Mellitus • Suppresses Free Fatty Acid (FFA) levels • Reduces FFA oxidation • Decreases Thromboxane A2 levels • Decreases Plasminogen Activator Inhibitor - 1 levels • Correction of disturbed lipoprotein pattern • Preservation of myocardium through unclear mechanisms

  19. Glucose-Insulin-Potassium (GIK) Infusions • GIK infusions as treatment for AMI in nondiabetic patients dates to 1960 s • Individual trials inconclusive secondary to low numbers, poor design, and methodological differences • In 1997 a meta-analysis was performed by Fath-Ordoubadietal et al

  20. Glucose-Insulin-Potassium Therapy for Treatment of Acute Myocardial Infarction: Meta-analysis • Using MEDLINE, 15 randomized placebo-controlled studies identified between 1965-1987 • 6 studies excluded (5 for poor randomization and 1 because diabetic patients were included) • 9 studies included (2 double blinded and 7 open label)

  21. GIK Infusions: Meta-analysis

  22. GIK Infusions: Meta-analysis data

  23. GIK Infusions: Meta-analysis • Study Concerns • much heterogeneity • delay between onset of chest pain and treatment varied between 12-48 hours • duration of therapy varied between 6 hours and 14 days • marked differences between infusion protocols (concentration and rate of administration) • lack of blinding in majority of studies

  24. Effect of intravenous insulin infusion on mortality among diabetic patients after myocardial infarction British Heart Journal Gwilt et al

  25. Gwilt et al • Objective: To determine whether IV insulin reduced mortality after MI in diabetics • Location: General Hospital, Birmingham England • Population: • Control: 353 diabetic patients with myocardial infarction through retrospective analysis treated with ‘standard care’ • Treatment: 64 diabetic patients with myocardial infarction prospectively assigned to insulin regimen

  26. Gwilt et al • Insulin Regimen • 1 unit per hour if FSG 0-144 mg/dl • 2 units per hour if FSG 144-216 mg/dl • 4 units per hour if FSG 216-432 mg/dl • if > 432 mg/dl rate adjusted to the “needs of the patient” • Glucose Monitoring: Duration of insulin drip and protocol for changing rate not clearly specified

  27. Gwilt et al

  28. Gwilt et al • Study concerns: • (1) pre-thrombolytics • (2) retrospective controls vs prospective treatment • (3) low dose protocol • (4) infusion rate change unclear (glucose targets?) • (5) duration of infusion not clear • (6) baseline characteristics unclear • (7) small numbers

  29. Gwilt et al • Conclusions: • There is no difference in mortality or complications after MI in diabetics when comparing insulin infusion with ‘standard care’.

  30. Effect of intravenous infusion of insulin in diabetics with acute myocardial infarction British Medical Journal Clark et al

  31. Clark et al • Objective: To determine if IV insulin reduces mortality in diabetic patients after MI • Location: Dundee, England • Endpoints: Mortality (in-hospital) and Cardiac arrhythmias requiring treatment • Population: • Control: 33 diabetics with AMI between April 1982 and April 1983 • Treatment: 29 diabetics with AMI between April 1982 and April 1983

  32. Control Patients on diet or oral therapy continued on therapy unless poorly controlled then to multi dos insulin Patients on insulin were continued with subcutaneous insulin before meals Treatment Patients receive continuous iv insulin for four days with goal to maintain blood glucose between (72-126 mg/dl). Then patients returned to previous diabetes therapy. Clark et al

  33. Clark et al

  34. Clark et al

  35. Clark et al • Study Strength • (1) similar baseline characteristics • (2) well defined insulin protocol • (3) stated glucose goals • (4) intention to treat analysis

  36. Clark et al • Study concerns • (1) small numbers • (2) not randomized (bias) • (3) not blinded (bias) • (4) performed prior to thrombolytics

  37. Clark et al • Conclusion: Insulin-glucose infusion significantly decreased in-hospital mortality and arrhythmias after MI in diabetics. Previous study concerns make applicability questionable.

  38. DIGAMI Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction Malmberg et al

  39. DIGAMI • Objective: Test how insulin-glucose infusion followed by multidose insulin treatment in diabetic patients with acute myocardial infarction affected mortality • Location: 19 Coronary Care Units in Sweden • Population: Diabetic Patients or Patients with elevated glucose and AMI • Randomization: 306 patients to receive treatment with insulin-glucose infusion followed by multidose subcutaneous insulin for >3 months and 314 patients to conventional therapy

  40. DIGAMI • Inclusion criteria: • (1) Suspected MI within 24 hours (at least two of the following): • (a) chest pain for at least 15 minutes • (b) 2 CK/CK-MB values above normal after 10-16 hours after symptoms or 2 LDH values above normal 48-72 hours after symptoms • (c) new q waves in at least 2 of 12 leads • (2) Blood glucose >11 mmol/liter (198 mg/dl) with or without previously known diabetes

  41. DIGAMI • Exclusion criteria: • (1) inability to participate for reasons due to health • (2) refusal to participate • (3) residence outside hospital area • (4) enrollment in other studies

  42. DIGAMI

  43. Risk Characterization: Patients deemed high risk if > 2 of the below are present (1) Age > 70 (2) Previous MI (3) History of CHF (4) Current Treatment with Digitalis Predefined Strata (1) no insulin, low risk (2) no insulin, high risk (3) insulin, low risk (4) insulin, high risk DIGAMI

  44. DIGAMI: Predefined Strata

  45. DIGAMI: Infusion protocol • Protocol Used by the Coronary Care Unit Nurses for the Insulin-Glucose Infusions • INFUSION: 500 ml 5% glucose with 80 IU of soluble insulin (~1IU / 6 ml) • Start with 30 ml/h. Check blood glucose after 1 h. Adjust infusion rate according to the protocol and aim for a blood glucose level of 7-10 mmol/liter (126-180md/dl). Check FSG 1 h after change and otherwise every 2 h. If the initial decrease in blood glucose exceeds 30%, the infusion rate should be left unchanged if blood glucose is >11 mmol/liter (198 mg/dl) and reduced by 6 ml/h if blood glucose is within the targeted range of 7-10.9 mmol/liter (126-196 mg/dl). • If FSG stable and <10.9mmol/l (196 mg/dl) after 10pm reduce infusion by 50%

  46. DIGAMI: Infusion protocol • Sliding Scale Insulin Regimen • > 15 mmol/l (270 mg/dl): Give 8 IU insulin iv and increase infusion rate by 6ml/h • 11 - 14.9 mmol/l (198-268): Increase rate by 3 ml/h • 7 to 10.9 mmol/l (126-196): No change • 4 to 6.9 mmol/l (72-124): Decrease rate by 6 ml/h • < 4 mmol/l (<72): Stop infusion for 15 minutes. Test FSG q 15 minutes until > & mmol/l. If symptomatic, give 20 ml of 30% glucose i.v. Then restart infusion with a rate decreased by 6 ml/h when FSG > 7 mmol/l.

  47. DIGAMI: Insulin treatment • Treatment Group: Infusion continued until normoglycemia was obtained and always >24 hours. Then converted to sub q insulin as short acting before meals and intermediate acting at bedtime. • Control Group:Received insulin when “ it was deemed clinically indicated”

  48. DIGAMI: AMI treatment • Streptokinase (if not contraindicated) administered to all patients presenting within 6 hours of symptoms and having >1 mm ST elevation in the limb leads or >2 mm ST elevation in the chest leads or new left bundle branch block. Streptokinase use at ~50%. • Beta-blockers as i.v. and oral metoprolol administered to >70% of patients. • Heparin administered to 17%. • Aspirin given to ‘almost all’ (> 80% discharged on ASA).

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