1. Inpatient Glycemic Management: Time to shed our scales? Deric Morrison Oct. 2014

2. Objectives At the end of this presentation you will: 1.Understand the current guidelines for inpatient glycemic management. 2.Know the evidence that supports these guidelines. 3.Have an approach to managing inpatients with hyperglycemia.

3. A word about Type 1 DM ALWAYS NEED basal insulin. Options: o Intermediate (NPH) SQ insulin q8-24hours o Long-acting (glargine/detemir) SQ insulin q12-24h o Insulin pump basal rate o Intravenous Insulin Infusion

4. Why Do We Care? Both Hyper and Hypo -glycemia are associated with ↗ mortality and morbidity in- hospital. There has been little evidence to guide appropriate glycemic targets or glycemic management strategy in non-critically ill inpatients.

5. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Approximately 1/3 of in-patients have been found to have hyperglycemia Many have pre- existing diabetes prior to admission Hyperglycemia In-hospital Hyperglycemia is Common

6. What do you want to avoid In order of importance? o Severe hypoglycemic event o DKA o Symptomatic hypo/hyperglycemia o Persistent hyperglycemia Complications (association vs. causal) o The “ready for discharge - except requiring high doses of sliding scale insulin and has no long term diabetes management plan” syndrome

7. Why are sugars different in hospital? Higher o Stress/concomitant illness o Nutrition (TPN, tube feeds, IV dextrose) o Drugs (steroids) Lower o Nutrition (diet, portions, NPO) o Renal failure o Liver failure o Severe illness

8. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Hyperglycemia Decreased immune function, wound healing, increased oxidative stress Acute Illness Increased stress hormones, use of glucocorticoids, decreased level of activity Inzucchi SE. NEJM 2006;355;1903 Hyperglycemia and Acute Ilness

9. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Hyperglycemia Increases risks of postoperative infections and delirium Prolonged hospital stay, resource utilization Increased renal dysfunction and renal allograft rejection in transplant Adverse Effects of Hyperglycemia

10. Armamentarium Metformin Sulfonylureas (Glyburide, Gliclazide) Meglitinides (Repaglinide) Alpha glucosidase inhibitor (Acarbose) Incretins GLP-1 analogues (Exenatide, Liraglutide) DPP-4 inhibitors (Sita/Lina/Saxa – gliptin) Thiazolidinediones (Rosi/Pio – glitazone) SGLT2 inhibitors – cana (and other) gliflozin(s) Insulins

12. Insulins Which ones do you know?

14. Guidelines Canadian Diabetes Association – 2013 Endocrine Society – 2012 o Accompanied by Meta-Analysis American Diabetes Association – 2014 American College of Physicians – 2011 o Accompanied by Meta-Analysis

15. American College of Physicians Use of intensive insulin therapy for the management of glycemic control in Hospitalized patients: A CPG from the ACP: Feb. 2011. Intensive Insulin Therapy in Hospitalized Patients: A Systematic Review. Annals of Internal Medicine Feb. 2011. Organized into different clinical scenarios

16. Myocardial Infarction 3 Trials (fair); 2 Trials (poor) Target 4.0-11.0 mmol/L vs unspecified Target 7.0-11.0 mmol/L + insulin on discharge o Mortality reduction o RR 0.69 (CI 0.49 – 0.96) Overall, no mortality reduction

17. Stroke 2 Trials (fair); 2 Trials (poor) Overall, no mortality reduction

18. Perioperative Control 1 Trial (fair); 2 Trials (poor) Target 3.9 – 10.0 mmol/L vs unspecified No difference in health outcomes o Small studies o Low event rates

19. Infection Risk 9 Trials (fair); 7 Trials (poor) Sepsis o Reduction of sepsis with Intensive Insulin o RR 0.79 (CI 0.62 – 1.00) Pooled result of wound infection, UTI, pneumonia or combination o No significance o RR 0.68 (CI 0.36 – 1.30)

20. Effects of intensive insulin therapy on rates of infection in various inpatient settings. We included inpatients in the MICU, SICU, and perioperative settings as well as patients with stroke or acute brain injury. Kansagara D et al. Ann Intern Med 2011;154:268-282 ©2011 by American College of Physicians sepsis infx

21. General Medical Ward 0 Trials

22. ACP Recommendations deal with intensive insulin in ICU (this presentation does not). Highlights lack of evidence regarding other hospitalized patient populations.

23. Intensive insulin ~ <7.8 pre-meal, <10 random

25. This meta-analysis included observational studies (ACP did not) Main conclusion: Intensive Insulin may reduce risk of infection in non-critically ill patients (surgical) Low quality evidence Intensive insulin ~ <7.8 acMeal, <10 random

26. Travel Plans Now, that we’ve established we don’t really know where we should go… How do we get there?

27. Cases

28. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Patient TypeGlucose Target (mmol/L) Therapy of choice Non-critically illFasting 5-8 Random <10 Pre-hospital regimen OR basal-bolus- correction Critically ill8-10IV insulin infusion CABG intraop5.5-10IV insulin infusion Other periop5-10As appropriate CABG = coronary artery bypass graft; IV = intravenous; Intraop = intraoperative; periop = perioperative In-hospital Glycemic Targets

29. Targets (< 8 acMeal, < 10 Random) Editorial No evidence for these targets in hospital (Outpatient targets) Reasonable place to start Safety first Conservative dosing, avoid catastrophic hypos Glucoses slightly above targets may be acceptable Try to maintain close to target Symptomatic or severe hyperglycemia should prompt action REASSESS targets and treatments daily

30. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 1.Provided that their medical conditions, dietary intake, and glycemic control are acceptable, people with diabetes should be maintained on their pre- hospitalization oral anti-hyperglycemic agents or insulin regimens [Grade D, Consensus] Recommendation 1

33. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Use BASAL + BOLUS + CORRECTION In-hospital circumstances may warrant temporarily holding other antihyperglycemic medications (eg. renal or hepatic impairment) Insulin = treatment of choice BASAL + BOLUS + CORRECTION Insulin BOLUS + CORRECTION BASAL BreakfastLunchDinner

34. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association In the absence of routine insulin, sliding scale insulin regimen (bolus insulin on a prn basis) is purely reactive rather than proactive and allows for hyperglycemia to occur before responding BG (mmol/L)Bolus insulin (U) <4Call MD 4.1 – 10.00 10.1 – 13.02 13.1 – 16.04 16.1 – 19.06 >19.0Call MD Queale WS. et al. Arch Int Med 1997;157 Sliding Scale Alone is Inefficient

35. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 4.0 10.0 BreakfastLunchDinnerBedtime BG (mmol/L)Bolus insulin (U) < 4Call MD 4.1 – 10.00 10.1 – 13.02 13.1 – 16.04 16.1 – 19.06 > 19.0Call MD 6.0 Bolus insulin QID 14.0 6.0 16.5 3.0 Sliding Scale alone What do you do? +4 U 0 U +6 U QID: four times daily; SSI: sliding-scale insulin; BG: blood glucose Sliding Scale Insulin Alone Results in Variable Glucose Control BG (mmol/L)

36. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association BASAL + BOLUS + CORRECTION Results in Smoother Glycemic Control 4.0 10.0 BreakfastLunchDinnerBedtime BG (mmol/L)Bolus insulin (U) < 4Call MD 4.1 – 10.00 10.1 – 13.02 13.1 – 16.04 16.1 – 19.06 > 19.0Call MD 6.0 12.0 6.0 Correctional Insulin AC meals What do you do? 6+2 U 6+0 U 6U What do you do? 6+0 U 6.0 ROUTINE Bolus insulin Basal insulin 6U 18 U Routine Basal

37. Rabbit -2 Trial Medicine At 2 American Academic Hospitals Open label, randomized study 130 insulin naïve non-surgical inpatients, known history of diabetes and initial BG 7.8 – 22.2. OHAs stopped, randomized to SSI or basal- bolus with glargine + glulisine. Admission BG = 12.7, A1c = 8.8%

38. Scheduled Dose

39. Sliding scale

40. Sliding scale/Supplemental doses 7.8 – 10 >22.2 14.4 – 16.7

41. Comment on doses Scheduled routine dosing o 0.4 – 0.5 Units/kg/day o 50% glargine, 50% glulisine o E.g. 70 kg person 30-35 Units/day ~15 Units glargine ~5/5/5 Units glulisine o Conservative?

43. RABBIT 2 Results 10 13.3 5.6

44. Rabbit 2 Surgery 2011 Similar to Rabbit trial, similar glycemic results.

45. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association * * ŧ ŧ † † RABBIT 2RABBIT 2 Surgery Adapted from: Umpierrez GE, et al. Diabetes Care 2007;30:2181-86. Adapted from: Umpierrez GE, et al. Diabetes Care 2011;34:256-61. Basal-Bolus (BBI) Regimen Achieves Better Control than Sliding Scale (SSI) Alone Blood glucose (mmol/L) ¶ ¶ ¶ * * * Admit 12345678910 Duration of treatment (days) 5.6 6.7 7.8 8.9 10.0 11.1 12.2 13.3 *p < 0.01; ¶ p < 0.05. ¶ SSI BBI 1 Randomi -zation 23456789 Duration of treatment (days) 6.7 7.8 8.9 10.0 11.1 13.3 *p < 0.001, ŧp = 0.02, †p = 0.01 SSI BBI

46. RABBIT 2 Results End point: o Target BG <7.8; o 66% in Basal/Bolus, 38% SSI No differences in hospital stay or hypoglycemia

47. Basal Plus Trial Umpierrez GE, et al. Randomized Study Comparing a Basal Bolus With a Basal Plus Correction Insulin Regimen for the Hospital Management of Medical and Surgical patients With Type 2 Diabetes: Basal Plus Trial. Diabetes Care. 2013 Feb 22. [Epub ahead of print].Randomized Study Comparing a Basal Bolus With a Basal Plus Correction Insulin Regimen for the Hospital Management of Medical and Surgical patients With Type 2 Diabetes: Basal Plus Trial.

48. Basal Plus Multicentre, 375 DM2 patients Home regimen: diet, oral agents, or low dose insulin, randomized 2:2:1 1.Basal-Bolus-Correction [glargine-glulisine] 2.Basal Plus (sliding scale) [glar-glu] 3.Sliding Scale (alone) [regular]

49. Basal-Bolus-Correction

50. Basal Plus

51. Sliding Scale – Added to Basal bolus or Plus (glulisine) OR alone SSI (R)

52. Insulin adjustment Basically increase insulin by 10% if mildly high, 20% if high. Reduce by 20% if low.

54. Basal Plus Trial Treatment Failure (mean glucose or 2 consecutive > 13.3) o Basal Bolus 0, Basal Plus 2%, SSI 19% Hypoglycemia o Less than 3.8 Significantly less in SSI o Less than 3.3 Trend to less in SSI o Less than 2.2 1 event each in basal bolus and basal plus, 0 in SSI

55. Basal Plus Trial Conclusions DM2 patients who are not on high doses of insulin can be managed by a Basal Plus (SSI) routine Basal Plus controls hyperglycemia = Basal Bolus, and better than a SSI with Insulin R Concern about hypoglycemia risk in basal bolus/basal plus. o Assumption is risk is low and outweighed by risks of hyperglycemia with SSI Evidence?

56. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association CONTINUE pre-hospital diabetes regimen if appropriate, otherwise … USE insulin as the treatment of choice DO NOT use sliding scale insulin alone DO use BASAL + BOLUS + CORRECTION insulin regimen AVOID hypoglycemia 2013 In-hospital Management Checklist

57. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Recommendation 2 2.For hospitalized patients with diabetes treated with insulin, a proactive approach that includes basal, bolus, and correction (supplemental) insulin, along with pattern management, should be used to reduce adverse events and improve glycemic control, instead of the reactive sliding-scale insulin approach that uses only short- or rapid-acting insulin [Grade B, Level 2]

58. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 3.For the majority of non critically ill patients treated with insulin, pre-meal BG targets should be 5.0 to 8.0 mmol/L in conjunction with random BG values <10.0 mmol/L, as long as these targets can be safely achieved [Grade D, consensus] 4.For most medical/surgical critically ill patients with hyperglycemia, a continuous IV insulin infusion should be used to maintain glucose levels between 8.0-10.0 mmol/L [Grade D, consensus] 2013 Recommendations 3 and 4

59. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 5.To maintain intraoperative glycemic levels between 5.5-10.0 mmol/L for patients with diabetes undergoing CABG, a continuous IV insulin infusion protocol administered by trained staff, [Grade C, Level 3] should be used 6.Perioperative glycemic levels should be maintained between 5.0-10.0 mmol/L for most other surgical situations, with appropriate protocol and trained staff to ensure safe and effective implementation of therapy and to minimize the likelihood of hypoglycemia [Grade D, Consensus] 2013 Recommendations 5 and 6

60. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 7.In hospitalized patients, hypoglycemia should be avoided: –Protocols for hypoglycemia avoidance, recognition and management should be implemented with nurse –initiated treatment, including glucagon for severe hypoglycemia when IV access is not readily available [Grade D, consensus] –Patients at risk of hypoglycemia should have ready access to an appropriate source of glucose (oral or IV) at all times, particularly when NPO or during diagnostic procedures [Grade D, Consensus] 2013 Recommendation 7

64. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 8.Healthcare professional education, insulin protocols and order sets may be used to improve adherence to optimal insulin use and glycemic control [Grade C, Level 3] 9.Measures to assess, monitor, and improve glycemic control within the inpatient setting should be implemented, as well as diabetes-specific discharge planning [Grade D, Consensus] 2013 Recommendation 8 and 9

65. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association CONTINUE pre-hospital diabetes regimen if appropriate, otherwise … USE insulin as the treatment of choice DO NOT use sliding scale insulin alone DO use BASAL + BOLUS + CORRECTION insulin regimen AVOID hypoglycemia 2013 In-hospital Management Checklist

66. Question 55 yr old person with Type 2 DM on oral agents (metformin and gliclazide) who will be NPO for an indefinite period of time. What are your options for in hospital treatment?

67. DM2: NPO on Gliclazide and Metformin

68. What do you want to avoid In order of importance? o Severe hypoglycemic event o DKA o Symptomatic hypo/hyperglycemia o Persistent hyperglycemia o The “ready for discharge except requiring high doses of sliding scale insulin and has no long term diabetes management plan” syndrome Hold Oral agents when NPO

69. Insulin Strategies Basal Bolus o Scheduled bolus inappropriate if NPO o Risk of hypoglycemia Basal Plus (SSI) o Reasonable Basal dose ~0.1-0.25 U/kg (half of a total estimated daily dose of ~0.2-0.5 U/kg) SSI alone o Reasonable – IF TEMPORARY If very concerned about hypoglycemia, can use gentle DOSE FINDING sliding scale. REASSESS in 12-24 hours consider basal insulin

70. If Not NPO - Insulin Basal Bolus o Reasonable Total daily dose ~0.2-0.5 U/kg/day o 50% Basal o 50% Bolus (divided by 3 to be given at 3 meals) I would use gentle sliding scale option to start, but reassess often Basal Plus (SSI) o Reasonable 50% of total daily dose as basal ~0.1-0.25 U/kg/day Consider more aggressive sliding scale option Sliding Scale Alone o Only if high concern for hypoglycemia o If requires sliding scale doses in first ~12 hours strongly reconsider strategy

71. If Not NPO – Oral agents Discontinue Metformin if: o Liver failure o Heart Failure o Renal Failure o Radiocontrast dye o Acidosis Usually discontinue gliclazide (sulfonylurea) re: hypoglycemia o Consider re-instituting if no hypoglycemia and clinically stable o Renal/liver/cardiac function stable o Not expected to be NPO o Want to try transitioning off insulin before d/c

72. Rational Sliding Scale Reassess DAILY! o If no or very few sliding scale doses sugars are <10 and no change required. o If sliding scale is being used blood sugars are >10 i.e. add OHA, add Basal, premix or MDI insulin Unless expect insulin requirements to decrease Ac BreakfastAc LunchAc Supperqhs 13 – 4 Units11 – 2 Units17 – 8 Units13 – 4 Units 10 – 0 Units15 – 6 Units

73. Rational Sliding Scale Reassess DAILY! o In addition to assessing need for DM mgmt plan assess scale If constantly increasing and very high sugar then consider tightening scale If there are BGs <6 reassess scale o Risk of hypos – consider loosening If there are BGs less than 4 decrease insulin o Scale, scheduled, OHAs or a combination acBreakfastacLunchacSupperBedtime 9 – 0 Units12 – 2 Units14 – 4 Units18 – 8 Units 13 – 4 Units16 – 8 Units

74. Consider DM1 made NPO Home insulin lispro 6/6/8 U and glargine 20 U Options? o IV insulin infusion = “Right” answer o Glargine (usual, slight decrease, slight increase?) + scale if sugars stable/easy to manage o Can stabilize with IV insulin infusion then when stable transition to basal insulin based on requirements E.g. add up 24 hour insulin requirement and deliver slightly less as basal SQ + corrective scale for highs (remember may be insulin sensitive if requirements are low) Bottom line – DO NOT interrupt insulin delivery! o Sliding scale only is WRONG!

75. Approach to Hospitalized Patient with severe insulin resistance J Clin Endocrinol Metab Sept 2011

76. Causes of insulin resistance in hospitalized patients Stress response Obesity Electrolyte disturbance: low K/Ca/Mg or high Ca Feeds Fatty emulsion eg. Propofol Steroids/Tacrolimus/Sirolimus Anesthetic Agents: volatile agents Hormonal agents: octreotide, leuprolide, bicalutamide Hormonal disorders: Cushing’s Syndrome, Acromegaly, Hyperaldosteronism, Pheochromocytoma

77. Approach to Patient Rule-out pseudo-resistance o Check IV bag, tubing, IV site Review medications Assess for concurrent diseases Check electrolytes Check if dextrose is used Assess feeds

78. Case 62 Male DM2 on 30/70 20 scB, 30acS at home. Liver transplant NPO on TPN Sliding scale post op o 2 U for 10, 4 for 13, 6 for 16… Ac BreakfastAc LunchAc Supperqhs 18 – 6 Units17 – 4 Units23– 10 Units19– 8 Units 14– 4 Units24– 10 Units21 – 10 Units

79. If patient receiving SC o Consider change to IV insulin infusion o SC insulin may be poorly absorbed due to edema poor perfusion etc

81. Feeds/TPN May consider adding regular insulin to TPN bag o Will decrease risk of hypoglycemia if TPN held o Max dose 50% of daily requirement of insulin Change feed to enteral feeds Decrease or hold TPN with consultation Decrease Intralipid o Changing from FFA infusion to soybean fat

82. Transition from IV to SC Patient on and staying on continuous feeds? IV insulin 3-5 U/hr over last 24 hours

83. Patient on and staying on continuous feeds Requirement for Basal and Supplemental Insulin o Estimates 24hr insulin requirements from the IV infusion (eg. units/hr x 24 hrs) o Options: 1/3 dose as NPH q8h ½ dose as glargine or detemir q12h Full dose as glargine or detemir q24h

84. Overlap IV with SC for 3 hrs; sorter if glucose falls < 5.5 mmol/L Change BG checks to q4h once IV is off Add fast acting analog or regular insulin q4h Reassess and adjust

85. Transition from IV to SC Currently on continuous feeds with plans to stop and advance diet? On 3-5U/hr IV

86. Currently on continuous feeds with plans to stop and advance diet Requirement for Basal, Bolus and Supplemental insulin o Stop feeds while continuing with the IV infusion o After 4-5 hrs estimate basal requirements New rate while off feeds eg. 2 units/hr ~24hr req 48 units o Options Give entire basal dose as once daily glargine or detemir or use split dosing half in the morning, half at HS Use NPH: 2/3 ACB and 1/3 evening or 50:50 split

87. Estimate requirement for meals o Give fast acting analog or regular using a CHO ratio with meals, if previous ratio unknown start with 1:15; if resistant use 1:7  1:5 o Use fixed dose approx 50% of basal insulin dose divided for each meal (units of basal/3 = units for each meal) o If limited intake may need small doses with adjustment as intake improves Overlap IV insulin Blood glucose checks AC meals and HS, consider 3 AM checks

88. Transition from IV to SC Currently on continuous feeds with plan for intermittent or overnight feeds? On 3-5U/hr IV

89. Currently on continuous feeds with plan for intermittent or overnight feeds Scheduled overnight feeds o Calculate 24hr requirements as previously o At initiation of feeds: administer NPH in the evening with additional 5-10 units of fast acting analog or regular insulin o Check BG at 3AM and at the end of the feeds o Adjust as required o If patient eating during the day assess BG levels and treat if required

90. If bolus feeds o Add fast acting insulin at the time of planned feeds o Base dose on CHO count and use a ratio or fixed dose insulin

91. Steroids May need additional insulin NPH may be used in the AM when steroids are given and adjusted as the dose of steroids is tapered Meal time insulin may also need to be increased for 4 – 8 hrs after the steroid is given Multiple doses of dex have a long T 1/2

92. Take Home Messages Safety first o Avoid lows and significant highs o Consider whether to continue or stop orals Insulin Strategy o Basal +/- Bolus o Almost never should use Sliding scale alone Reassess and adjust Plan for discharge o When medically stable consider Taper insulin/re-introduce orals Plan for discharge on insulin with appropriate education and follow up