1. Diabetes Technology and Insulin Therapy Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

2. Case 1: New Onset Diabetes 45-year-old male lawyer presents with “polys” and weight loss Sees internist who recommends metformin (blood glucose 500, urine ketones small, BMI 26) The lawyer does some internet reading and seeks a second opinion from diabetes specialist who was a high school classmate he has not seen for 27 years

3. Case 1: New Onset Diabetes What type of diabetes does he have? a)Type 1 b)Type 1.5 c)LADA d)Type 2 e)a, b or c

4. Case 1: New Onset Diabetes (cont’d) What is your best diagnostic tests to determine the type of diabetes? a)Islet cell antibody panel (ICA, anti-GAD) b)Serum C-peptide c)Genetic Typing d)Other tests?

5. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1997;350:1288-1293. Shimada A et al. Ann N Y Acad Sci. 2003;1005:378-386. LADA: Detection and Impact of GAD Antibodies GAD: Glutamic acid decarboxylase Other antibodies —ICA, IA2, insulin autoantibodies 7% of the patients screened in the Treat to Target Study had GAD antibodies 95% of patients in the UKPDS who were anti-GAD or anti-ICA required insulin within 6 years

6. Progression of Type 1 Diabetes Adapted from: Atkinson. Lancet. 2002;358:221-229. Age (y) Precipitating Event Beta cell mass Genetic predisposition Normal insulin release Glucose normal Overt diabetes No C-peptide present Progressive loss of insulin release C-peptide present Antibody

7. 1999 – 2001 National Health Survey Estimates Projected to 2002, Centers for Disease Control and Prevention, National Diabetes Fact Sheet. Age Group Number Diabetes: New Cases Diagnosed Annually in the US

8. Case 1: New Onset Diabetes Sees me the following AM (BG 514, urine ketones small) I concur with him that he has type 1 diabetes and metformin is not the treatment, insulin is What is your initial treatment? a)IV insulin b)Basal/bolus therapy with MDI c)Premixed d)Insulin pump therapy

9. Options in Insulin Therapy for Type 1 Diabetes Current —Multiple injections —Insulin pump (CSII)

10. Case 1: New Onset Diabetes (cont’d) He asks about insulin pump therapy instead of multiple injections I hospitalize him and tell him I will get back to him the following AM

11. DCCT Absolute Risk of Retinopathy: Conventional vs Intensive Insulin Therapy At the same A1C level, intensive insulin therapy provides a greater risk reduction of the development of retinopathy DCCT Research Group. Diabetes. 1995;44:968–983. Conventional Therapy Intensive Therapy 0 4 8 12 16 20 24 123456789 0 Mean A1C 10% 9% 8% 7% Rate per 100 per 100patient-years Time during (y) Time during study (y) 0 4 8 12 16 20 24 1234567890 Mean A1C 8% 7% 6% 11% 9% Development of Retinopathy

12. Does Intensive Diabetes Therapy Preserve Beta Cell Function? Adapted from: DCCT Study Group: Ann Intern Med. 1998;128:517-523. 0123456 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years Post Enrollment Number of evaluated patients in each treatment group Intensive Conventional 0 13180533282108 15063322230165 Conventional therapy Intensive therapy Patient probability of maintaining C-peptide > 2.0

13. The Physiological Insulin Profile Adapted from Polonsky, et al. 1988. 10 20 30 Insulin (mU/L) 0 40 50 60 70 Short-lived, rapidly generated prandial insulin peaks Low, steady, basal insulin profile Normal free insulin levels from genuine data (mean) 060009001200150018002100240003000600 BreakfastLunchDinner

14. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine or Detemir Plasma insulin Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs Aspart, Lispro or Glulisine

15. Insulin Predictability of Basal Insulin NPH Glargine Detemir Pumps 46% 59% 27% Gold Standard Intrasubject Variability Lepore M, et al. Diabetes. 2000;49:2142-2148. Heise TC, et al. Diabetes. 2003;52(suppl 1):A121.

16. Glargine NPH sc insulin N=20 T1DM Mean ± SEM Time (hours) Ultralente CSII Glucose mg/dl Lepore M, et al. Diabetes. 2000;49:2142-2148. Duration of Effectiveness 220 200 180 160 140 120 04812162024

17. Insulin Treatment in Type 2 Diabetes Basal Treatment (NPH, Glargine, or Detemir) Start 10U and titrate; will need ~0.5U/kg; will lower A1C 1.5 to 2 points Bolus Treatment Premeal Start at 3-5U premeal and titrate; will lower A1C 2 plus points Premixed Therapy Start at 5U BID and titrate; will need ~0.8U/kg; will lower A1C 2 plus points Basal Bolus Therapy

18. Case 1: New Onset Diabetes If you decided on MDI, how do you determine his starting doses of insulin? a)Based on trial and error b)Based on BMI c)Based on weight d)Let the CDE decide

19. Starting Basal/Bolus Therapy Starting insulin dose is based on weight —0.2 x wgt. in lbs. or 0.5 x wgt. in kg Bolus dose (aspart/lispro) = 20% of starting dose at each meal Basal dose (glargine/NPH) = 40% of starting dose at bedtime

20. Starting MDI in 180-lb Person Starting dose = 0.2 x 180 lb —0.2 x 180 = 36 units Bolus dose = 20% of starting dose at each meal —20% of 36 units = 7 units ac (tid) Basal dose = 40% of starting dose at bedtime —40% of 36 units = 14 units at HS

21. Correction Bolus (Supplement) Must determine how much glucose is lowered by 1 unit of short- or rapid-acting insulin This number is known as the correction factor (CF) Use the 1700 rule to estimate the CF CF = 1700 divided by the total daily dose (TDD) —Ex: if TDD = 36 units, then CF = 1700/36 = ~50 —Meaning 1 unit will lower the BG ~50 mg/dl

22. Correction Bolus Formula Example: —Current BG:220 mg/dl —Ideal BG: 100 mg/dl —Glucose Correction Factor:50 mg/dl Current BG - Ideal BG Glucose Correction Factor 220 – 100 50 =2.4u

23. Insulin Pens The first insulin pen was developed by NovoNordisk in 1926 but not launched until 1985. Since then, numerous pens, both disposable and reusable, have been developed adding to accuracy in dosing and convenience to insulin injection therapy. Disposable Lilly Pen Novo Reusable Pen with disposable cartridge Disposable NovoNordisk Pen Aventis Reusable Pen with disposable cartridge

24. Options to MDI A Simpler Regimen Insulin Pump Premixed BID (DM 2 only)

25. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal infusion Bolus Plasma insulin Variable Basal Rate: CSII Program

26. Summary: The Benefits of CSII in Mimicking Normal Physiology Nocturnal variability —Covering the dawn phenomenon Exercise-related changes —Reducing basal insulin to normalize glucose Normal eating patterns —Multiple boluses; dual bolus Complex carbohydrates and dietary fat —Covering delayed carbohydrate absorption

27. Metabolic Advantages with CSII Improved glycemic control Better pharmacokinetic delivery of insulin —Less hypoglycemia than NPH based therapy —Less insulin required Improved quality of life

28. DCCT. Diabetes Care. 1995;18:361-376. Insulin Delivery Therapy at End of DCCT Pump 42% MDI 56% Unknown 2%

29. Insulin aspart (CSII) vs insulin aspart / glargine (MDI) Run-in (1 week) Period 1 (5 weeks) Period 2 (5 weeks) IAsp CSII IAsp + Glarg MDI CSII vs MDI with Glargine in Adults Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438. 100 patients with type 1 on CSII at entry A1C <9% Efficacy: A1C, fructosamine, 8-point BG profile, glucose exposure (CGMS) Safety: frequency of hypoglycemia, AEs

30. CSII vs MDI in 100 DM 1 Patients Bode BW, et al. Diabetes. 2003;52(suppl 1). Abstract 438. Mean ± 2 SEM 200 160 140 120 100 180 Self-monitored BG (mg/dL) BBAB BL ALBDADMidnight 3 AM CSII (n=93) MDI (n=91)

31. CSII vs MDI with Glargine in Children Subjects at baseline Age: 8-19 yr (mean 12.7 ± 2.7) Type 1 DM > 1 yr duration Standard insulin therapy (2-3 injections/day) CSII (aspart) n=16 MDI (aspart/glargine) n=16 16 Week treatment period Injection therapy Randomized, Parallel-group, 16 week study Doyle EA, et al. Diabetes Care 2004; 27: 1554

32. 16 Week Comparison of MDI using Glargine versus CSII: Children Doyle EA, et al. Diabetes Care 2004; 27: 1554 P < 0.05 P <.001 CSII MDI

33. CSII versus MDI in Type 2 Diabetes 14 Center Randomized Parallel Group Study Dose adjustmen t Maintenance period Week 0 Week 8 Week 24 Insulin aspart in CSII (n = 66) Insulin aspart/NPH in MDI (n = 61) Screen: DM 2 >2 years On insulin >6 months A1C > 7.5%; Stop OHA Raskin et al. Diabetes Care 26(9): 2598-2603, 2003 Target FBG 80-120

34. CSII versus MDI in Type 2 Diabetes 14 Center Randomized Parallel Group Study l A1C Raskin et al. Diabetes Care 26(9): 2598-2603, 2003

35. Change in scores (raw units) from baseline to endpoint -505101520253035 Convenience Less burden Less hassle Advocacy Preference General satisfaction Flexibility Less life interference Less pain Fewer social limitations MDICSII CSII vs MDI in DM 2 Patients Testa et al. Diabetes. 2001;50(suppl 2):1781.

36. CSII vs MDI in Older Adults with Type 2 DM 2 Center Randomized Parallel Group Study Dose adjustment Week 0 Week 52 Insulin lispro in CSII (n = 48) Insulin lispro/glargine in MDI (n = 50) Screen: DM 2 On insulin Age > 60yo Stop OHA Herman W et al, Poster 504-P, ADA 2005

37. CSII vs MDI in Older Adults with Type 2 DM 2 Center Randomized Parallel Group Study A1C

38. Case 1: New Onset Diabetes I see patient in the AM and tell him that 8 out of 10 patients polled yesterday would have started CSII at onset if offered the choice Dr. Pozzilli, an expert in DM 1 prevention, also recommended CSII at onset if it was him or a close relative Patient opted for CSII

39. Case 1: New Onset Diabetes on CSII: A1C Results A1C

40. Case 1: New Onset Diabetes on CSII Patient extremely satisfied with his care C-peptide 0.9 to 0.8 at 1 year, 0.5 to 0.7 at 3 years Does not understand why everyone is not on CSII with optimal control

41. Current Pump Therapy Indications Need to normalize blood glucose (BG) —A1C > 6.5% —Glycemic excursions Hypoglycemia or hypoglycemia unawareness Need for a flexible insulin regimen

42. US Pump Usage: Total Patients Using Insulin Pumps Industry estimates

43. N = 165 Average duration = 3.6 years Average discontinuation <1%/y Continued 97% Discontinued 3% Current Continuation Rate: Continuous Subcutaneous Insulin Infusion (CSII) Bode BW, et al. Diabetes. 1998;47(suppl 1):392.

44. Photograph reproduced with permission of manufacturer. Smart Insulin Pumps

45. Smart Pumps Bolus Calculator: Meter-Entered Monitor sends BG value to pump or patient dials in BG value Enter carbohydrate intake into pump “Bolus Calculator” calculates suggested dose Paradigm Link ™ Paradigm 512 ™ ) ) ) ) ) ) ) ) ) ) ) ) )

46. Calculator: On Carb Units: Grams Carb Ratios: 10 BG Units: mg/dl Sensitivity: 40 BG Target: 80-100 Active Insulin Time: 5 hours Bolus Calculator Set Up Screen

47. Pump Infusion Sets: Perpendicular vs Oblique Perpendicular (Sof-set™, Quick-set™, Ultraflex™) —Easier insertion —Prone to kink Oblique (Silhouette™, Tender™, Comfort™) —More difficult insertion —Less kinking

48. Disposable Patch Pumps

49. CSII: Factors Affecting A1C Monitoring —A1C = 8.3 - (0.21 x BG per day) Bode BW, et al. Diabetes. 1999;48(suppl 1):264. Bode BW, et al. Diabetes Care. 2002;25:439.

50. Increased SMBG Testing Frequency Lowers A1C Atlanta Diabetes Associates study: 378 patients sorted from a database of 591 Pumps=MM 511 or earlier BG Target=100 C peptide <0.1

51. CSII: Factors Affecting A1C (cont’d) Monitoring —A1C = 8.3 - (0.21 x BG per day) Recording 7.4 vs 7.8 Diet practiced —CHO: 7.2 —Fixed: 7.5 —WAG: 8.0 Insulin type (aspart, glulisine ) Bode BW, et al. Diabetes.1999;48(suppl 1):264. Bode BW, et al. Diabetes Care. 2002;25:439.

52. Pump Formulas For Adults Total Daily Dose of Insulin (TDD) —Weight (kg) x 0.5 Carbohydrate / Insulin Ratio (CIR) — CIR in grams = 6 x Body Weight (kg) / TDD Correction Factor (CF) — CF = 1700 / TDD Basal Insulin — Basal = 0.48 x TDD Davidson et al. Diabetes Tech Therap. April 2003.

53. Initial Adult Dosage: Calculations Starting doses —Based on pre-pump total daily dose (TDD) Reduce TDD by 25% to 30% for pump TDD —Calculated based on weight 0.5 x weight in kg (0.24 x wgt in lbs) Bode BW, et al. Diabetes. 1999;48(suppl 1):84. Bell D, Ovalle F. Endocr Pract. 2000;6:357-360. Crawford LM. Endocr Pract. 2000;6:239-243.

54. Target BG Ranges for CSII Normal awareness to hypoglycemia —Preprandial 70 - 140 mg/dL —Postprandial <160 mg/dL Individually set for each patient Bode BW. Medical Management of Type 1 Diabetes. 4th ed. ADA; 2004. Fanelli CG, et al. Diabetologia. 1994;37:1265-1276. Jovanovich L. Am J Obstet Gynecol. 1991;164:103-111.

55. Target BG Ranges for CSII Hypoglycemic unawareness —Preprandial:100 - 160 mg/dL Pregnant —Preprandial:60 - 90 mg/dL —1 hr postprandial:<120 mg/dL Individually set for each patient Bode BW. Medical Management of Type 1 Diabetes. 4th ed. ADA;2004. Fanelli CG, et al. Diabetologia. 1994;37:1265-1276. Jovanovich L. Am J Obstet Gynecol. 1991;164:103-111.

56. Initial Adult Dosage: Calculations Basal rate —45% to 50% of pump TDD —Divide total basal by 24 hours to decide on hourly basal —Start with only 1 basal rate —See how it goes before adding basals

57. Basal Dose Adjustment Overnight Rule of 30: —Check BG Bedtime 12 AM 3 AM 6 AM —Adjust overnight basal if readings vary >30 mg/dL

58. Basal Dose Adjustment Overnight Adults often need an increase in basal rate in the “dawn” hours (4 AM to 9 AM ) Children often need an increase in basal rate earlier starting at 10 PM to 2 AM

59. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal infusion Bolus Variable Basal Rate: Adults Plasma insulin

60. BreakfastLunchDinner Basal infusion Bolus Variable Basal Rate: Children Plasma insulin Time 4:0016:0020:0024:004:00 8:00 12:008:00

61. Basal Dose Adjustment Daytime Rule of 30: —Check BG Before usual mealtime Skip meal Every 2 hrs (for 6 hrs) —Adjust daytime basal if readings vary >30 mg/dL

62. Bolus Dose Calculations Meal (food) Bolus Method 1 —Test BG before meal —Give predetermined insulin dose for predetermined CHO content —Test BG after meal —Goal <60 mg/dl rise postmeal or <160 mg/dL

63. Estimating the Carbohydrate to Insulin Ratio (CIR) Individually determined —CIR = (2.8 x wgt in lbs) ÷ TDD or —CIR = (6 x wgt in kg) ÷ TDD —Anywhere from 5 to 25 g CHO is covered by 1 unit of insulin Davidson et al. Diabetes Tech Therap. April 2003.

64. Pump Follow-up Procedures Monitor, record, and report glucoses —Premeal and postmeal —Overnight (periodically) Contact as needed —Phone, fax, e-mail Office visits —First infusion set change —1-2 weeks later with RD, RN, or MD and PRN —Quarterly visits once stable Bode BW. Medical Management of Type 1 Diabetes. 4th ed. ADA; 2004.

65. Adapted from Fredrickson L, et al. Optimal Pumping: A Guide to Good Health with Diabetes. Medtronic MiniMed, Inc.; 1998. Plotnick L, et al. Diabetes Care. 2003;26:1142-1146. Avoiding DKA BG is greater than 250 mg/dL: —Take correction dose —Check for ketones —Recheck in 60 minutes If coming down, leave alone If not, take a shot and change the site There is no increase in DKA occurrence with pumps

66. Adapted from Fredrickson L, et al. Optimal Pumping: A Guide to Good Health with Diabetes. Medtronic MiniMed, Inc.; 1998. Avoiding Hypoglycemia Frequent blood glucose monitoring Occasional 3 AM checks Consider readjusting glycemic goals for hypoglycemic unawareness Bolus frequency —Utilize Bolus Wizard calculator —Utilize technology to avoid over bolus

67. If A1C Is Not at Goal SMBG frequency and recording Diet practiced —Do they know what they are eating? —Do they bolus for all food and snacks? Infusion site areas —Are they in areas of lipohypertrophy? Other factors: —Fear of low BG —Overtreatment of low BG Must look at:

68. If on Smart Pumps and Not at Goal Postmeal too high —Lower CIR (Carb-to-Insulin Ratio) All BGs too high —Lower target and/or change CF (ISF) Fasting or premeal too high —Increase basal

69. Do Smart Pumps Enable Others to Go to CSII? YES All patients with diabetes not at goal are candidates for Insulin Pump Therapy —Type 1 any age —Type 2 —Diabetes in pregnancy

70. For This System to Work It is critical that the target, basal doses, correction doses, and carbohydrate ratios are accurate Understanding how to match carbohydrate amounts with insulin is critical If the target is set too high (>110 mg/dL), glucoses will run too high. Normal target is 100 mg/dL and for pregnancy 80 mg/dL is safe

71. If A1C Is Not at Goal and No Reason Identified Place on a continuous glucose monitoring system

72. Continuous Monitoring Systems Cygnus Glucowatch Menarini GlucoDay Medtronic MiniMed CGMS Guardian DexCom Pendragon Medical Abbott Navigator

73. Missed Postprandial Hyperglycemia With Fingersticks 0 50 100 150 200 250 300 350 400 12:00 AM4:00 AM8:00 AM12:00 PM4:00 PM8:00 PM Time Glucose Concentration (mg/dL)

74. Missed Postprandial Hyperglycemia With Fingersticks

75. External Open-Loop Patients are expected to make immediate therapy adjustments based upon real-time continuous glucose readings displayed every 5 minutes and by viewing a graph with 3-hour and 24-hour glucose trends.* *Not yet approved by the FDA or European Health Authorities Sensor-Augmented Insulin Pump System

76. Sensor Augmented Pump* —Receives sensor glucose values every 5 minutes —Receives meter value to automatically calibrate sensor —Displays current glucose value, trend graph, hypo and hyper glycemia alerts Sensor BG Meter BG Download Sensor, Meter, & Pump Data Download Sensor, Meter, & Pump Data only in office Dummy Pump

77. Run-in (1 week) Period 1 (12 weeks) Period 2 (12 weeks) Sensor CSII CSII Sensor CSII CSII Sensor Augmented Pump Therapy A Pilot Study 20 patients with type 1 on CSII for at least 1 year A1C >6.5%; SMBG ≥4 per day Efficacy: A1C (mean and % <7), BG mean, glucose exposure (CGMS) Safety: frequency of hypoglycemia, AEs

78. Case 1: J.B is a 50 yo teacher with DM 1 since age 14, on CSII for 18 years, A1C 8.1. Has Hypoglycemia Unawareness with need for secondary help by wife once a month. Enters a real-time open loop sensor augmented pump trial

79. Breakfast 5U Lunch 3U 2 Glucose Tabs 2.8U Supper 5U Case 1: JB, 50 yo male, DM 1 age 14, TDD 38, Basal 0.7, ICR 1:12, Target 100; CF 42

80. Breakfast 63g; Took 5.1U No bolus Lunch 60 g; 5USupper Out ?50g 4U 7.4U Another Day

81. Case 1 JB Modal Day Graph

82. Case 2: MB. is a 49 yo mother with DM 1 since age 21, on CSII for 22 years, with A1C 8.1. Labile BG values on 4.6 tests/day. Works part-time. History of low BG spells needing help. Enters a real-time open loop sensor augmented pump trial

83. Case 2: MB, 49 yo female, History of Labile BG and Lows Basal 1.2 U/h TDD = 47 U 2 U per Carb Basal 61% 4 U 0 U 2 Carb O U 1 Carb O U 2 Carb 2 U

84. Case 4: MB, 49 yo female, History of Labile BG and Lows Changes made: 1.Decreased Basal by 1.0 U/h 2.Increased CIR to 2.2 U per Carb 3.A1C dropped to 7.3% at 3 months

85. Case 5 16-year-old girl with T1DM for 7 years16-year-old girl with T1DM for 7 years HbA1c: 9.1%HbA1c: 9.1% Problems: Too low breakfast dose; Increased meal carb on 10/24

86. Why the Majority Reached Goal They wore it 90% of the time They were long term patients in my practice on CSII for years They looked at it 10 to 20 times per day They made changes with my help by looking at trends and patterns

87. CSII versus Sensor Augmented CSII (7 Center Study) Download via CareLink Week 0 Week 13 Week 26 CSII (715 model) ~70 Sensor Augmented CSII ~70 Screen: DM 1 on CSII A1C > 7.5%; SMBG ≥ 4 per day Age 12-80 Week 52 Efficacy: A1C (mean and % <7), BG mean, glucose exposure (CGMS) Safety: frequency of hypoglycemia, AEs Efficacy: A1C (mean and % <7), BG mean, glucose exposure (CGMS) Safety: frequency of hypoglycemia, AEs Efficacy: A1C (mean and % <7), BG mean, glucose exposure (CGMS) Safety: frequency of hypoglycemia, AEs Week 2

88. Vision Toward the Artificial Pancreas *This product concept not yet submitted to the FDA for commercialization. Implanted Closed-Loop External Closed-Loop

89. Predicted Times Glucose Sensors —Alarm sensor (72 hr) 2004 —Guardian RT (72 hr) 2005 —Replace fingersticks 2006 Semi-closed loop 2007-2008 Implantable 2007-2008

90. Summary Insulin remains the most powerful agent we have to control diabetes When used appropriately in a basal/bolus format, near-normal glycemia can be achieved Newer insulins and insulin delivery devices along with glucose sensors will revolutionize our care of diabetes

91. Questions For a copy or viewing of these slides, go to: www.adaendo.com