Intensive Insulin Therapy

1. Intensive Insulin Therapy Robert E. Jones, MD, FACP, FACE Professor of Medicine University of Utah School of Medicine

2. Objectives • Define intensive insulin therapy • Explore the basis of insulin therapeutics: • Insulin dosing (just where did the “Rule of 1700” come from and how does it relate to my patients?) • Insulin kinetics • Discover how to modify a mathematically crafted (and otherwise perfect) insulin regimen to match the needs of our patients • Understand that nothing is perfect

3. Intensive Insulin Therapy

4. Physiologic Insulin Therapy Bolus insulin Basal insulin Insulin Effect D B L HS Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193

5. Biological Actions Of Insulin • Glucose lowering • Anabolic properties • Storage of lipids, protein, carbohydrate • Anti-catabolic properties • Mitogenic properties • Growth factor • Promote endothelial function • Anti-inflammatory

6. Endogenous insulin Regular NPH B L D HS B Basic Insulin Regimen: Split-Mixed Regimen or Premix

7. BASAL INSULIN Suppress hepatic glucose production (overnight and intermeal) Prevent catabolism (lipid and protein) Ketosis Unregulated amino acid release Reduce glucolipotoxicity BOLUS INSULIN Meal-associated CHO disposal Storage of nutrients Help suppress inter-meal hepatic glucose production Basal vs Bolus Insulin

8. The Mathematics

9. The Systems • Accurate Insulin Management • Rule of 1700 • CIR • Body Weight Only • Assumes insulin requirements are predicted only on the basis of weight • 400/500 Rule • CIR = 400-500/TDD Davidson PC et al. Endocr Pract 14:1095-1101 (2008)

10. Accurate Insulin Management • Combines 1700 Rule and Rule of 3 • 1500 Rule (Davidson, 1983) • Refined as 1700 Rule • CF = 1700/TDD • Rule of 3 (Steed, 1998) • CIR = 3 * BWlb/TDD Davidson PC et al. Endocr Pract 14:1095-1101 (2008)

11. Regression Models Davidson PC et al. Endocr Pract 14:1095-1101 (2008)

12. Regression Models Davidson PC et al. Endocr Pract 14:1095-1101 (2008)

13. Regression Models Davidson PC et al. Endocr Pract 14:1095-1101 (2008)

14. Regression Models Davidson PC et al. Endocr Pract 14:1095-1101 (2008)

15. Regression Models Davidson PC et al. Endocr Pract 14:1095-1101 (2008)

16. AIM Equations • When insulin requirements are known: • CF = 1700/TDD • Glucose lowering per unit of insulin • CIR = 2.8 * BWlb/TDD • G rams CHO covered per unit of insulin • Basal = 0.47 * TDD • When insulin requirements are NOT known • TDD = 0.24 * BWlb Davidson PC et al. Endocr Pract 14:1095-1101 (2008)

17. Simple Equations • TDD = Basal + Bolus (50:50) • CF = 1700/TDD • CIR = 0.33 * CF UDPRs, 2008 IHC Diabetes Care Model, 2010

18. Comparisons 25 year old 150 lb woman who requires 30 U/day

19. Comparisons 25 year old 150 lb woman who requires 50 U/day

20. Comparisons 45 year old 200 lb man who requires 110 U/day

21. Comparison Conclusions • Equations assume everyone is average • There is a wide variability that defines “average” • Basal insulin requirements • No significant differences • Bolus requirements • The “Simple Method” seems to under estimate CIR in more insulin-sensitive patients

22. Insulin Kinetics

23. 110 90 70 Glucose (mg/dL) 50 Euglycemic Hyperinsulinemic Clamp Because HGO is suppressed and glucose levels are clamped, the rate of exogenous glucose infusion must equal the rate of tissue glucose uptake. HGO is effectively suppressed (in normals) and an exogenous glucose infusion is started to maintain target glucose levels. Labeled glucose may be used to completely assess endogenous glucose production. An IV bolus of insulin is given at time 0 followed by a constant infusion of 1 mU/min/kg or 40 mU/min/m2. Yields insulin levels of ~ 70 U/mL. 80 48 36 Glucose Infusion Rate (mol/minkg) 40 24 Insulin (U/mL) 12 0 0 60 80 Time (min)

24. Aspart, Lispro, Glulisine (4–5 hr) Glargine (~24 hr) Analog Insulin Profiles Regular (6–10 hr) NPH (10–20 hr) Plasma Insulin Levels Detemir ~18-24hr 2 4 6 8 12 14 16 18 20 22 24 0 10 Time (hr) Rosenstock J. Clin Cornerstone. 2001;4:50-61.

25. What Can Influence Insulin Kinetics?

26. Effect of Dose (Lispro) (PK) Obese 50 U Healthy 10 U Obese 30 U Obese 10 U Gagnon-Auger M et al. Diabetes Care. E-pub Sept 14, 2010.

27. Effect of Dose (Lispro) (PD) Healthy 10 U Obese 30 U Obese 50 U Obese 10 U Gagnon-Auger M et al. Diabetes Care. E-pub Sept 14, 2010.

28. Effect of Dose (Detemir) Detemir 1.6 U/kg 0.2 U/kg 0.8 U/kg 0.4 U/kg NPH 0.3 IU/kg 0.1 U/kg Plank J et al. Diabetes Care 28:1107-1112 (2005).

29. Aspart 1,2 70/30 NovoLog Mix 3 -60 0 60 120 180 240 300 360 420 480 540 Effect of Premixing on Rapid-Acting Analog Properties Tmax 49-53 min Tmax 2.4 hours Plasma Insulin Levels Time (min) 1. Hedman CA et al. Diabetes Care 2001;24:1120-1121 2. Home PD et al. Eur J Clin Pharm 1999;55:199-201 3. Novo Nordisk, data on file

30. 4.0 3.0 2.0 1.0 0 24 20 16 12 8 4 0 PEN DOWN MIX mg/Kg/min µmol/Kg/min PEN UP 0 1 2 3 4 5 6 7 8 9 Time (hours) Effect of Insulin Suspensions on GIR 90 80 70 5.0 4.5 4.0 Plasma Glucose mmol/l mg/dl Glucose Infusion Rate 0.3 U/Kg NPH s.c. Lepore M. et al., unpublished data

31. What Else Can Influence Insulin Kinetics? • Site of injection • Local blood flow • Exercise • Obesity • Inherent variability • Absentmindedness • Effect of food

32. Effect of Food Or Think Outside the Box... Mondo Mama’s Pizza Mondo Mama’s Pizza

33. Effect of Food Or Think Outside the Box... DUAL WAVE BOLUS Mondo Mama’s Pizza Mondo Mama’s Pizza

34. Effect of Food Or Think Outside the Box... Mondo Mama’s Pizza Mondo Mama’s Pizza RAA + RHI (50/50 Mix)

35. Difficult Questions That Were Not Asked • When do you split the basal insulin? • NPH • Detemir • Glargine • How do you time a bolus in relationship to eating?

36. Cases

37. Case #1 45 year old man is seen with complaints of polyuria and polydipsia of several weeks duration. He has had an associated 30 lb weight loss. He weighs 250 pounds. Lab results: RBS 397 mg/dl; A1C 12.6%; Na+ 133 mEq/l; CO2 19 mEq/L What does he have and how would you treat him?

38. Case #1 • The practice of medicine is an art…but we base our decisions on science (and experience) • Oral agents? • Insulin? • Premix • Basal only • Basal-bolus

39. Case #2 56 year old woman returns for follow up. She has had diabetes for 10 years and has intermittently struggled with her glucose control (A1C range 6.4 -8.8%). Her current A1C is 8.9% and her fasting glucose (SMBG) is 210 mg/dL. She is presently taking metformin 1500 mg/d, glyburide 15 mg/d; sitagliptin 100 mg/d, exenatide 10 mcg BID How would you alter her therapy? If you chose insulin, how would you start it?

40. Case 2 Metformin Basal Insulin Secretogogue Insulin Effect HS B L D

41. Case 3 A 25 year old woman is sent to you because her glucose control is poor (A1C 9.7%). She really wants to improve her control, but doesn’t know how, and, by the way, she is recently married. She is currently on 25 IU glargine per day and 5 to 15 IU aspart given before meals. She tests her glucose levels 3-4 times a day.

43. Florentine Arch

44. Severe insulin reactions per 100 patient-yr 0 20 40 60 80 100 120 62 DCCT Type 1 diabetes 110 SDIS 2.3 UKPDS Type 2 diabetes 3 VA CSDM 7.8 VA IIIP Adapted with permission from McCall A. In: Leahy J, Cefalu W eds. Insulin Therapy. New York, NY:Marcel Dekker, Inc.; 2002:193 Hypoglycemia

45. 8 7 Glargine NPH Weight v Delta A1CStudies with Type 2 Diabetes 2 Detemir 7 1. Yki-Jarvinen Diabetes Care 2000;23:1131 2. Rosenstock Diabetes Care 2001;24:631 3. Riddle Diabetes Care 2003;26: 3079 4. Fritsche Ann Int Med 2003;138: 952 5.Raslova Diab Res Clin Pract 2004;66:193 6. Haak Diab Obes Clin Pract 2005;7:56 3 3 1.5 9 9 4 Reduction in A1C (%) 1 8 4 1 1 2 5 5 0.5 2 2 6 6 7. Study 1530 8. Study 1337 9. Study 1373; Rosenstock, 2006 0 1 2 3 4 Weight Gain (kg)