1. Inpatient Diabetes Treatment Goals, Strategies, Safety Amish A. Dangodara, MD, FACP Professor of Medicine Internal Medicine, Hospitalist Program University of California, Irvine School of Medicine 2015

2. Disclosures None

3. Learning Objectives Review physiology of glucose regulation Describe the duration of action of various types of insulin Distinguish differences between nutritional, correctional, and basal insulin treatment strategies Describe appropriate action for NPO patients Describe appropriate prevention and treatment of hypoglycemia

4. Glucose Regulation Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program 1 2 3 4 1 2 2 3

5. Incretin Pathway Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

6. GLP-1 Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

7. DPP4 DPP4 is an intrinsic membrane glycoprotein (serine exopeptidase) expressed on the surface of most cell types. antigenic enzyme that cleaves X-proline dipeptides from the N-terminus of polypeptides immune regulation, signal transduction, and apoptosis suppressor in the development of cancer and tumors Rapidly degrades incretins (GLP-1) Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

8. Normal GI Response to Meal Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program Intestinal GLP-1 Release GLP-1 [9-36] Inactive GLP-1 [7-36] Active DPP-4 Rapid Inactivation (>80%) Mixed Meal GLP-1 actions to control glucose: Inhibits glucagon secretion Inhibits hepatic gluconeogenesis Augments glucose-induced insulin secretion Slows gastric emptying Promotes satiety Additional features of GLP-1 based treatment: Restores beta-cell function Increases insulin synthesis Promotes beta-cell differentiation Drucker, DJ. Diabetes Care. 2003; 26: 2929-2940.

9. Normal Glucose Response to Meal Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

10. Normal GI Response to Meal Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program Incretins increase insulin release from Beta cells in pancreas

11. Normal Pancreas Response to Meal Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

12. Diabetes, Type II Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

13. Incretin Effect in Diabetes Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

14. GLP-1 Effect in Diabetes Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

15. Pancreas Response in Diabetes Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program NGT - normal glucose tolerance T2DM - Type 2 Diabetes Mellitus

16. Diabetic Therapies Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program Na-glucose transport (SGLT); blocks glucose reabsorption in kidney Prevents digestion of carbohydrates Slows gastric emptying Reduce gluconeogenesis and increase insulin sensitivity Decrease insulin resistance Increase insulin secretion Binds FFA to increase insulin secretion Exogenous insulin Increase insulin secretion Pancreatic Beta cells Multiple effects  GLP-1 Decrease insulin resistance

17. Case 63 yo M admitted with (L) foot ulcer/cellulitis, not responding to outpatient Abx. Weight 100 Kg. He is NPO for LE angiogram. PMHx: PVD s/p (L) distal tibial artery bypass, DM II, CRI Meds: 70/30 insulin 70 units in AM, 30 units in PM, Metformin 1000 mg BID (takes after breakfast & bedtime) Labs: HgbA1c=11.4, glucose 325, BUN 20, creatinine 0.9 In addition to holding Metformin, what should you do with insulin? A.Hold 70/30 and start regular insulin sliding scale q4h B.Reduce 70/30 to 35 units in AM and 15 units in PM C.Change 70/30 to Lantus 25 units/d & use corrective insulin scale q4h D.Change 70/30 to Lantus 50 units/d & use corrective insulin scale q6h E.Continue home dose of insulin Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

18. What’s Wrong With Sliding Scale Alone? GlucoseUnits 180 - 2002 201 - 2504 251 - 3006 301 - 3508 351 - 40010 >40012 Corrective Insulin Dose 185 223 264 241 2 4 6 ? Time q4 h Insulin Level Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

19. What’s Wrong With Using Home Dose To Estimate Insulin Dose? HomeHospital Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

20. Insulin Strategy: Goal Glucose = 140-180 Hypoglycemia Cortisol, Epinepherine, Glucagon, Glycogenolysis 180 126 80 0 Fasting Euglycemia Nutrition, Glycogenolysis, Insulin Post-prandial Hyperglycemia Insulin, GLP-1, Incretins Severe Hyperglycemia Insulin resistance or DM Basal Therapy Nutritional Therapy Corrective Therapy Hypoglycemia Tx Sliding Scale Insulin Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

21. Some Endogenous Insulin Activity Hypoglycemia Cortisol, Epinepherine, Glucagon, Glycogenolysis 180 126 80 0 Fasting Euglycemia Nutrition, Glycogenolysis, Insulin Post-prandial Hyperglycemia Insulin, GLP-1, Incretins Severe Hyperglycemia Insulin resistance or DM Basal Insulin Nutritional Insulin Corrective Insulin Hypoglycemia Tx Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

22. Types of Nutrition Bolus: meal or bolus TFContinuous: TF or TPN Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

23. Inpatient Diabetes Treatment Basal-Bolus Nutritional insulin: Basal insulin for fasting & nutritional insulin for meals BreakfastLunchDinner Glucose Time 18:0012:008:0021:00 Nutritional Insulin Analog Long-acting Basal Insulin Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

24. Inpatient Diabetes Treatment Basal-Continuous Nutritional insulin: Basal insulin for fasting & nutritional insulin for meals Glucose Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program Time 16:0012:008:0020:00 4:0024:00 Long-acting Basal Insulin Nutritional Insulin Long-acting Basal glucose Continuous nutrition Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

25. Inpatient Diabetes Treatment Basal-Continuous Nutritional insulin: Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186. Basal insulin for fasting & nutritional insulin for meals Glucose Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program Long-acting Time 16:0012:008:0020:00 4:0024:00 Nutritional Insulin Basal Insulin Short-acting Basal glucose Continuous nutrition

26. Which Insulin Is Best For What Strategy? Basal: GFR<30-50 -Lantus q24h q24h -Levemir q12h q24h -NPH q8h q12h Nutritional (Bolus): -Analog qAC qAC -Regular qAC qAC Nutritional (Continuous): -Regular q4h q6h -Analog q4h q6h Corrective and/or NPO: -Same as nutritional! Analog Insulins: (Lispro) (Glulisine) (Aspart) (Glargine) Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

27. Basal-Nutritional Strategy  D/C all home diabetic therapy  Estimate initial Total Daily Dose (TDD):  TDD = Weight (Kg) x 0.3 units/d for DM I or non-diabetic hyperglycemia  TDD = Weight (Kg) x 0.4 units/d for controlled DM II (FBS<200)  TDD = Weight (Kg) x 0.5 units/d for uncontrolled DM II  Correct for renal clearance (adjusted TDD):  GFR >50%, no change in TDD  GFR <50%, reduce initial estimated TDD by 50%  Basal-Bolus (Nutritional) dosing:  Basal dose = 50% adjusted TDD (not needed if endogenous insulin ok)  Nutritional dose = 50% adjusted TDD  Bolus dose per meal = (Nutritional Dose)/(meals/d) Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

28. Basal-Nutritional Strategy Adjust dose after 24 hours:  If zero events of hypoglycemia in past 24h and glucose >180:  Increase adjusted TDD by up to 20%  If one or more events hypoglycemia in past 24h:  Decrease adjusted TDD by 20% and consider holding nutritional insulin  Evaluate nutrition intake  Assess for nutrition-insulin mismatch  Assess for improving insulin resistance as acute illness improves  Assess for worsening renal function Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

29. RaBBIT-2 Trial Corrective insulin sliding scale vs basal-bolus insulin trial:  Schedule qAC & qHS if eating or q4 hrs if NPO or q6 hrs if NPO with GFR < 30 using short-acting insulin: aspart, glulisine, humalog, regular Insulin sensitive/Type 1: Glucose at treatment goal = 0 units 141 - 180 = 2 units 181 - 220 = 4 units 221 - 260 = 6 units 261 - 300 = 8 units 301 - 350 = 10 units 351 - 400 = 12 units >400 = 14 units Usual treatment/Type 2: Glucose at treatment goal = 0 units 141 - 180 = 4 units 181 - 220 = 6 units 221 - 260 = 8 units 261 - 300 = 10 units 301 - 350 = 12 units 351 - 400 = 14 units >400 = 16 units Insulin resistant: Glucose at treatment goal = 0 units 141 - 180 = 6 units 181 - 220 = 8 units 221 - 260 = 10 units 261 - 300 = 12 units 301 - 350 = 14 units 351 - 400 = 16 units >400 = 18 units Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186. Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

30. Mean Blood Glucose Levels During Insulin Tx Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

31. Treatment success –BG target of < 140 mg/dL was achieved in 66% of patients on Basal-Bolus (Lantus® + Apidra®) and 38% regular insulin (SSI) Treatment failure –One out of 5 patients using SSI remained with BG >240 mg/dL and switched to Basal-Bolus (Lantus® + Apidra®) Basal–Bolus Insulin Outcomes Days of Therapy Blood Glucose (mg/dL) 100 120 140 160 180 200 220 240 Admit 1 2 3 4 1 2 3 4 5 6 7 Sliding-Scale Insulin Delivery LANTUS ® + APIDRA ® 260 280 300 Sliding-Scale Insulin Basal-Bolus 66% 38% 0% 25% 50% 75% 100% Patients with BG <140 mg/dL, % Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

32. Hypoglycemia Basal Bolus Group: –1,005 BG readings –Two patients (3%) had BG < 60 mg/dL –Four BG readings (0.4%) < 60 mg/dL –No BG < 40 mg/dL Regular ISS: –1,021 BG readings –Two patients (3%) had BG < 60 mg/dL –Two BG readings (0.2%) < 60 mg/dL –No BG < 40 mg/dL None of the episodes of hypoglycemia in either group were associated with adverse outcomes Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program Umpierrez GE et al. [RaBBIT-2 Trial] Diabetes Care, 2007; 30: 2181-2186.

33. NPO - Hold Nutritional Insulin Hypoglycemia Cortisol, Epinepherine, Glucagon, Glycogenolysis 180 126 80 0 Fasting Euglycemia Nutrition, Glycogenolysis, Insulin Post-prandial Hyperglycemia Insulin, GLP-1, Incretins Severe Hyperglycemia Insulin resistance or DM Basal Insulin Nutritional Insulin Corrective Insulin Hypoglycemia Tx Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

34. NPO (No Nutrition) Treatment  Hold nutritional insulin  Continue basal insulin (reduce to 0.15 – 0.25 units/Kg/day)  Continue corrective insulin  If no other carbohydrate (CHO) source:  Start D5 (+/- saline) @ minimum 100 mL/h or D10 (+/- saline) @ minimum 50 mL/h  Equivalent to 17 KCal/h or 408 Kcal/d  Order prn hypoglycemia therapy Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

35. Inpatient Diabetes Safety Hypoglycemia:  Definition <80 :  Glucose lower than desired treatment goal  Clinically insignificant: Glucose 60 - 80  Associated with either mild or no symptoms of hypoglycemia  This level can be occasionally tolerated  Clinically significant: <60  Confirm with serum blood test  Glucose 40 - 60, usually associated with significant symptoms of hypoglycemia, including confusion and lethargy; avoid if possible  Glucose <40, associated with lethargy, coma, possible permanent parkinsonian dementia with extrapyramidal symptoms, and increased mortality; goal would be to avoid 100% of the time Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

36. Inpatient Diabetes Safety Hypoglycemia Treatment:  Clinically stable:  Glucose 40 - 80, give meal first, then recheck q15 minutes until >70  Give D50 IVP or glucagon if unable to take PO, start D5 or D10 until >70  Reduce nutritional insulin dose and corrective sliding scale dose by 20+ %  Clinically significant:  Glucose <40, give D50 IVP and start D5 or D10-IVF  Hold all diabetic medications.  Once >70, use insulin sensitive corrective sliding scale @ >200  If corrective scale needed >2 times/24h, restart basal insulin at lower dose Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

37. Basal-Bolus (Basal-Nutritional) Strategy  Remember this!:  Inpatient goal: glucose 140 - 180  I, II, rII = 0.3, 0.4, 0.5 (DM I, II, resistant II, use 0.3, 0.4, 0.5 units/Kg/d as TDD)  GFR <50, adjustment 50% reduction of TDD  50/50 basal to nutritional (50% TDD = Basal, 50% TDD = nutritional)  D5 @100 mL/h or D10 @ 50 mL/h if no nutrition source  Forget this:  Insulin sliding scale  Estimating inpatient requirement based on home therapy  Using last 24h IV insulin dose to estimate SQ insulin dose Amish A Dangodara, MD, University of California, Irvine School of Medicine, Hospitalist Program

38. Questions?