Insulin Regimens: Hitting Glycemia Targets

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1 Insulin Regimens: Hitting Glycemia Targets Grant Kelley MD March 1 st, 2018

2 Faculty Disclosure: Financial relationships with commercial interests None

3 Overview Mortality and Morbidity Insulin and Insulin analogs. Target Glucose Four steps to calculate insulin regimen 1. Total Daily Dose (TDD) 2. Basal Insulin 3. Nutritional Insulin 4. Correction Insulin New SQ Insulin Order Set Cases 70 kg DM2 outpatient Glyburide and Januvia with A1c kg DM2 outpatient 90U 70/30 am and 45U 70/30 hs with A1c kg DM2 outpatient 80U Lantus and Metformin with A1c10 70kg DM1 outpatient 21L and sliding scale with meals with A1c7 60kg DM1 insulin pump basal unconscious after CVA.

4 Diabetes Type 1 Type 2 Onset Sudden Gradual Age Onset Children/Adolescent Adult Body Habitus Thin/Normal Obese Ketoacidosis Risk Common Rare Autoantibody Usually present Absent Endogenous Insulin Low or absent Normal, decreased, increased Genetic concordance identical twins 50% 90% Prevalence 10% 90% Treatment Insulin Oral agents and Insulin 1) Basal Insulin Absolute Requirement in DM1 2) Stop Oral Agents in DM2

5 Morbidity and Mortality and Hypoglycemia Increase in inpatient mortality risk: mg/dl adjusted odds ratio (OR) 1.62 <40 mg/dl adjusted odds ratio (OR) 2.05 Increase LOS cw >70mg/dL group: mg/dl 1.51 fold <40 mg/dl 2.33 fold Diabetes Med. 12:e445-8, 2012

6 Morbidity and Hyperglycemia 1. Fluid and electrolyte abnormalities secondary to osmotic diuresis 2. Decreased WBC function 3. Delayed gastric emptying 4. Increased surgical complications including: Glc > 220 mg/dl - relative risk postop nosocomial infection 5.7 fold. Glc mg/dl - relative odds of wound infection to Glc >253 mg/dl - relative odds of wound infection to LOS with fluctuating (glucose <60 or >250 mg/dl) vs control (glucose mg/dl).

Insulin Signaling http://www.cellsignal.

7 Insulin Signaling

8 Hyperglycemia and Poor Hospital Outcome Metabolic stress response stress hormones and peptides Glucose Insulin Reactive O2 species Immune dysfunction Infection dissemination FFA Ketones Lactate Cellular injury/apoptosis Inflammation Tissue damage Altered tissue wound repair Clement et al, Diabetes Care 27: , 2004 Prolonged hospital stay Disability / Death Transcription factors Secondary mediators

Target St Joseph s Hospital 121-170 (80-200) mg/dl Outpatient Fasting 80-130 mg/dl -SICU/MICU 140-200.

9 Target St Joseph s Hospital (80-200) mg/dl Outpatient Fasting mg/dl -SICU/MICU Ann Intern Med 154: , Intensive Insulin Therapy in Hospitalized Patients: A Systemic Review. Ann Intern Med 154: , Standards of Medical Care in Diabetes DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY

10 INSULINS

INSULIN HISTORICAL PERSPECTIVE Discovery: 1921-22: Banting, Best, Macleod,

Macleod Nobel Prize in Physiology or Medicine:.

$1969: Dorothy Hodgkin Nobel Prize tertiary structure X-Ray diffraction.$

11 INSULIN HISTORICAL PERSPECTIVE Discovery: : Banting, Best, Macleod, Campbell, and Fletcher discovered insulin Nobel Prizes: 1923: Banting and Macleod Nobel Prize in Physiology or Medicine:. 1958: Frederick Sanger Nobel Prize sequencing insulin. 1969: Dorothy Hodgkin Nobel Prize tertiary structure X-Ray diffraction. 1977: Rosalyn Yalow Nobel Prize radioimmunoassay for insulin Davidson, Clinical Diabetes Mellitus; Kahn and Weir Joslin's Diabetes Mellitus

Insulin Beef and Pork Insulin: -1920s - 1980s insulin purified from beef or pork pancreata 1L insulin from pig pancreata shown Human

Human Insulin Analogs: -2000s recombinant DNA technology -development of human insulin analogs.

12 Insulin Beef and Pork Insulin: -1920s s insulin purified from beef or pork pancreata 1L insulin from pig pancreata shown Human Recombinant Insulin: -1980s recombinant DNA technology -produce human insulin in Saccharomyces cerevisiae or E coli. Human Insulin Analogs: -2000s recombinant DNA technology -development of human insulin analogs. -engineered to alter pharmacokinetics absorption from subcutaneous tissue binding to proteins. classroom.sdmesa.net/eschmid/lab7-biol210.htm

13 (Lantus) (Levemir) Degludec (Triceba) Des-B30 De Glu (deleted Glu) +16C diacid dec (hexadecanedioic acid added)

Regular (1921-22) human, crystalline zinc insulins. Insulin preparations NPH (neutral protamine Hagedorn; 1936) protamine complex to delay absorption.

15 Regular ( ) human, crystalline zinc insulins. Insulin preparations NPH (neutral protamine Hagedorn; 1936) protamine complex to delay absorption. Rapid acting analogs: aspart (Novolog), glulisine (Apidra) and lispro (Humalog) modified to decrease heximer and dimer formation. Long acting analogs: glargine (Lantus, Toujeo 300U/mL, Basaglar), detemir (Levemir) and degludec (Tiseba) modified to slow absorption kinectics: -glargine, degludec soluble at ph 4.0 but precipitates at physiologic ph upon SC injection. -detemir: binds albumin through its engineered fatty acid moiety. Mixtures: e.g. Humulin 70/30, Humalog 75/25

16 Insulin Profiles Toujeo (U300 glargine) Basaglar (glargine) Triseba (degludec )

17 Insulin Profiles: Best Insulin to Cover Glucose 1. Basal 2. Nutritional 3. Correction Insulin Effect NPH Detemir (Levemir) Glargine (Lantus) Regular Lispro (Humalog) Aspart (Novolog) Glulisine (Apidra) Inhaled insulin Time (hours) Society of Hospital Medicine

18 Insulin Profiles: Stacking Insulin given before a previous dose is gone will stack onto the previous dose Insulin Effect Time (hours) Society of Hospital Medicine

19 Insulin Profiles Avoid Mixtures In Hospital: 70/30; 75/25

20 INSULIN REGIMEN: TOTAL DAILY DOSE (TDD)

21 Basal Bolus Insulin Regimen Basal Insulin: Insulin to cover glucose produced by the liver/kidneys Bolus Insulin: Nutritional + Correction Nutritional: insulin to cover meal carbs. Correction: insulin to correct blood glucose to target.

22 Basal, Bolus, and Correction Insulin 400 Glucose and Insulin Profiles Breakfast Lunch Dinner Basal Insulin Nutritional Insulin Correction Insulin Glucose (mg/dl)

23 Physiologic Insulin Secretion: Basal/Bolus Concept Insulin (µu/ml) Nutritional (Prandial) Insulin Basal Insulin Breakfast Lunch Supper Glucose (mg/dl) Nutritional Glucose Basal Glucose A.M. P.M. Time of Day The 50/50 Rule

24 Four Steps to Calculate Basal Bolus Insulin Using Total Daily Dose 1. TDD (total daily dose): Daily insulin requirement. 2. Basal (~50% TDD): Insulin to cover glucose produced by the liver/kidneys. 3. Nutritional (~50% TDD): Insulin to cover meal carbs. 4. Correction (TDD dependent): Insulin to correct blood glucose to target.

25 Step 1) Calculate Total Daily Dose (TDD) 1) Preadmission Insulin: add insulin per day = TDD (best indication) beware of high doses of basal insulin (110 U Lantus no bolus) 2) Weight Based: Frail: Average: Resistant: U/kg/day (eg. thin, new DM1) (50kg=15U) U/kg/day (eg. new DM2) (70kg=35U) U/kg/day (eg. Obese DM2) (100kg=70U) 3) Insulin drip-based: add last 20h = TDD (careful with high rates) average rate last 4 hours x 20 = TDD ***Best educated guess use all available info! ***Average nondiabetic TDD ~30U.

26 Step 2) Calculate Basal Insulin 50/50 rule Basal insulin is ~ 50% of TDD. eg. TDD=36U/day then basal ~ 18U Lantus. Long acting insulin: Glargine (Lantus) (once a day) Detemir (Levemir) (once-twice a day) NPH (twice a day)

27 Advanced Calculation: Nutritional Calculate Nutritional Insulin Insulin Carbohydrate Ratio = 500 rule ~500/TDD = g Carb per U of insulin. e.g. TDD=180U/day 500/180 = 2.8 so 1U insulin required per 2.8 g Carb 60g Carbohydrate average ADA meal 60/2.8~20U Using Insulin, John Walsh et al, Torrey Pines Press

28 Step 3) Calculate Nutritional Insulin 50/50 rule Nutritional insulin is ~ 50% of TDD divided between 3 meals. eg. TDD=36U/day ~ 18/3=6U/meal. Rapid or Short acting insulin: Glulisine (Apidra) Aspart (Novolog) Lispro (Humalog) Regular (Novolin, Humulin)

29 Step 4) Calculate Correction Insulin Insulin required to correct hyperglycemia to target. Use Rapid or Short acting insulin. Dependent on sensitivity or TDD. Target Frail TDD<40 1U/50 Average U/ U/50 Obese >120 4U/ >420 MD

30 Advanced Calculation: Correction Step 4) Correction Insulin Sensitivity = 1800 rule ~1800/TDD = mg/dl glc change per U insulin. e.g. TDD=180U/day 1800/180=10 so 1U insulin will drop glc 10mg/dl. To correct 300mg/dl / 10 = 30U Using Insulin, John Walsh et al, Torrey Pines Press

31 Grid Nutritional and Correction Insulin (Bolus)

32 Ordering SQ Insulin NEW SQ Insulin order set

33 Medication Section of New SC Insulin Order Set

34 Medication Section of New SC Insulin Order Set

35 MAR: SC Insulin Order Target

36 Daily Adjustments Monitor glucose levels daily Consideration for changing sensitivity Steroids Improving condition (sepsis, etc.) Increase or decrease TDD by 10-20% TDD 36 x 1.2 ~ 42 TDD 36 x 0.8 ~ 28

37 Daily Adjustments Evaluate Glucose Measurements: basal: fasting changes reflect basal insulin. -if fasting hs to am need more long-acting insulin. -if fasting hs to am need less long-acting insulin. -if fasting hs to am good. bolus (nutrition + correction): next premeal should correct to target.

38 Review Patient Glycemia and Insulin Administration

39 Review Patient Glycemia and Insulin Administration

40 DISCHARGE TOOLS

41 Add Nutritional Scale to AVS

42 Nutritional Scale Added to AVS

43 CASES

44 Case 1: Four Step Calculation 70 kg DM2 outpatient Glyburide and Januvia with A1c 7 1. TDD: 2. Basal: 3. Nutritional: 4. Correction: (no hm ins) or (0.3U/kg=21U) 10U Lantus 3U Humalog ac Built into order set The patient is made NPO and POC Glc have been mg/dL. How should the insulin dosing be changed?

45 Medication Section of New SC Insulin Order Set X 10 Units Lantus X

46 Case 2: Four Step Calculation 140 kg DM2 outpatient 90U 70/30 am and 45U 70/30 hs with A1c 8 1. TDD: 2. Basal: 3. Nutritional: 4. Correction: 108U (135Ux.8) or (0.7U/kg=98U) 54U Lantus 18U Humalog ac Built into order set The patient is made NPO and POC Glc have been mg/dL. How should the insulin dosing be changed?

47 X 54 Units Lantus X

48 Case 3: Four Step Calculation 100 kg DM2 outpatient 80U Lantus and Metformin with A1c10 1. TDD: 64U (80Ux.8) or (0.7U/kg=70U) 2. Basal: 32U Lantus 3. Nutritional: 10U Humalog ac 4. Correction: Built into order set

49 X 32 Units Lantus X

50 Case 3 part b: Four Step Calculation 100 kg DM2 outpatient 80U Lantus and Metformin with A1c10 1. TDD: 64U (80Ux.8) or (0.7U/kg=70U) 2. Basal: 32U Lantus 3. Nutritional: 10U Humalog ac 4. Correction: Built into order set POC Glc range from mg/dl. What would you do? 1. TDD: 64x1.2=76; 64x1.1=70 2. Basal: 38U Lantus 3. Nutritional: 12U Humalog ac 4. Correction: Built into order set

51 X 38 Units Lantus X

52 Case 4: Four Step Calculation 70kg DM1 outpatient 21L and sliding scale with meals with A1c7 1. TDD: 2. Basal: 3. Nutritional: 4. Correction: 40U (21b+21nutr) or (0.5U/kg=35U) 18U Lantus 6U Humalog ac Built into order set The patient is made NPO, how should the insulin dosing be changed? Should a patient with DM1 ever not get basal insulin? Patients with DM1 absolutely require insulin or they will develop DKA.

53 X 18 Units Lantus X

54 Case 4 part b: Four Step Calculation 70kg DM1 outpatient 21L and sliding scale with meals with A1c7 1. TDD: 2. Basal: 3. Nutritional: 4. Correction: 40U (21b+21nutr) or (0.5U/kg=35U) 18U Lantus 6U Humalog ac Built into order set POC between and steroids tapered. What would you do? 1. TDD: 2. Basal: 3. Nutritional: 4. Correction: 36x0.8=28; 36x0.9=32 15U Lantus 5U Humalog ac Built into order set

55 X 15 Units Lantus X

56 Case 5: Four Step Calculation 60kg DM1 insulin pump basal 12 basal and 4 nutritional with A1c8 and unconscious after CVA 1. TDD: 24U (12+12) or (0.4U/kg=24U) 2. Basal: 12U Lantus 3. Nutritional: 4U Humalog ac 4. Correction: Built into order set

57 X 12 Units Lantus X

58 Summary Hyperglycemia and Hypoglycemia associated with increased morbidity, mortality, and LOS Four Steps to Calculate Basal Bolus Insulin 1. TDD (calculate: preadmission insulin, weight based, insulin gtt) 2. Basal (~50% TDD) 3. Nutritional (~50% TDD: 60g carb meal) 4. Correction (calculation intrinsic to Order Set)

Insulin Prior Authorization with optional Quantity Limit Program Summary

Insulin Prior Authorization with optional Quantity Limit Program Summary 1-13,16-19, 20 FDA LABELED INDICATIONS Rapid-Acting Insulins Humalog (insulin lispro) NovoLog (insulin aspart) Apidra (insulin glulisine)