1. New Insulins and Insulin Delivery Systems Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

2. Methods For Managing Persons with Diabetes Take Diabetes out of the equation. Control glucose!!!

3. Undiagnosed diabetes ~5.2 million Prevalence of Glycemic Abnormalities in the United States Additional 25 -35 million with Prediabetes Diagnosed type 2 diabetes ~12 million Diagnosed type 1 diabetes ~1.0 million Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm; Harris MI. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK; 1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001 US Population: 275 Million in 2000 3

4. Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2001;24(Suppl 1):S5-S20. FPG 126 mg/dL 100 mg/dL 7.0 mmol/L 5.6 mmol/L Prediabetes Normal 2-Hour PG on OGTT 200 mg/dL 140 mg/dL 11.1mmol/L 7.8mmol/L Diabetes Mellitus Impaired Glucose Tolerance Normal Diabetes Mellitus Diagnostic Criteria Associated with Glucose Abnormalities

5. Relative Risk of Progression of Diabetes Complications (DCCT) DCCT Research Group, N Engl J Med 1993, 329:977-986. RELATIVE RISK Mean A1C

6. l Gain of 15.3 years of complication free living compared to conventional therapy l Gain of 5.1 years of life compared to conventional therapy Lifetime Benefits of Intensive Therapy (DCCT) DCCT Study Group, JAMA 1996, 276:1409-1415.

7. Effect of A1C On Complications in the UKPDS Study A1C Stratton IM et al. BMJ 2000;321:405 0 10 20 30 40 50 60 Myocardial InfarctionMicrovasc Disease 5.5% 6.5% 7.5% 8.5% 9.5% 10.5%

8. Lessons from the DCCT and UKPDS: Sustained Intensification of Therapy is Difficult DCCT EDIC (Type 1) UKPDS (Type 2), Insulin Group DCCT/EDIC Research Group. New Engl J Med 2000; 342:381-389 Steffes M et al. Diabetes 2001; 50 (suppl 2):A63 UK Prospective Diabetes Study Group (UKPDS) 33 Lancet 1998; 352:837-853 4 6 8 10 9.0 8.1 7.3 7.9 06.5+ 4+ 6 yrs DCCT EDIC 0 6 7 8 0246810 yrs A1C (%) Normal Baseline A1C (%)

9. Specific Goals in Management of Diabetes l Fasting < 110 mg/dL l Post-meal < 140 mg/dL l A1C < 6.5% l Blood Pressure < 130/80 l LDL 45 mg/dL l Triglycerides < 150 mg/dL

10. Primary Objectives of Effective Management A1C % SBP mm Hg LDL mg/dL 455055 6065 70 75 808590 9 Diagnosis 8 7 130 100 145 140 Patient Age Reduction of both micro- and macro- vascular event rates …by 75%! lGæde P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393.

11. Mortality of DM Patients Undergoing CABG Furnary et al J Thorac Cardiovasc Surg 2003;123:1007-21

12. P=0.000 9 P=0.026 BG<110 110<BG<150 BG>150 Surgical ICU Mortality Effect of Average BG Van den Berghe et al (Crit Care Med 2003; 31:359-366)

13. Hyperglycemia and Hospital Mortality 1826 consecutive ICU patients 10/99 thru 4/02, Stamford CT Krinsley JS: Mayo Clin Proc 78: 1471-1478, 2003

14. Glucose Goals in Type 2 Diabetes Fasting < 110 mg/dL Post-meal < 140 mg/dL A1C < 6.5%

15. Glucose Goals in Type 1 Diabetes Fasting and Premeal 70 - 140 mg/dL Post-meal < 160 mg/dL A1C < 6.5%

16. Glucose Goals in Hospital l 80 – 110 mg/dl in Surgical ICU patients l 80 - 140 mg/dl premeal and < 180 mg/dl postmeal in other Surgical and Medical Patients l 70 – 100 mg/dl in Pregnancy

17. Insulin The most powerful agent we have to control glucose

18. Patient J.L., December 15, 1922 February 15, 1923 The Miracle of Insulin

19. 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

20. Options in Insulin Therapy for Type 1 Diabetes l Current –Multiple injections –Insulin pump (CSII) l Future –Implant (artificial pancreas) –Transplant (pancreas; islet cells)

21. Type 2 Diabetes … A Progressive Disease Over time, most patients will need insulin to control glucose

22. Multiple factors may drive progressive decline of  -cell function  -cell (genetic background) Hyperglycaemia (glucose toxicity) Protein glycation Amyloid deposition Insulin resistance “lipotoxicity” elevated FFA,TG

23. Approach to Combination Oral Therapy Intensifying of Oral Therapies metformin &/or glitazone + sulfonylurea/repaglinide &/or glucosidase inh sulfonylurea/repaglinide &/or glucosidase inh + metformin &/or glitazone Continue FPG < 120 mg/dl A1C < 6.5%FPG > 120 mg/dl A1C >6.5% Add Insulin

24. Comparison of Human Insulins / Analogues Insulin Onset ofDuration of preparations action Peak action Regular30–60 min2–4 h6–10 h Lispro/aspart5–15 min1–2 h 4–6 h NPH/Lente1–2 h4–8 h10–20 h Ultralente2–4 hUnpredictable16–20 h Glargine1–2 hFlat~24 h

25. Dissociation & Absorption of Aspart / Lispro Insulin Aspart or Lispro Regular Human Insulin Peak Time = 80-120 min Peak Time = 40-50 min Capillary Membrane Subcutaneous Tissue

26. 400 350 300 250 200 150 100 Meal SC injection 50 0 03060 Time (min) 90120180210150240 Regular Lispro 500 450 400 350 300 250 150 50 200 100 0 050100 Time (min) 150200300250 Plasma insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625–629; Mudaliar, et al. Diabetes Care. 1999;22:1501–1506. Short-Acting Insulin Analogs Lispro and Aspart Plasma Insulin Profiles Regular Aspart

27. Lepore, et al. Diabetes. 1999;48(suppl 1):A97. 6 5 4 3 2 1 0 010 Time (h) after SC injection End of observation period 2030 Glargine NPH Glucose utilization rate (mg/kg/h) Glargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose Clamp

28. 4:00 25 50 75 8:0012:0016:0020:0024:004:00 BreakfastLunchDinner Plasma insulin (U/ml) Plasma insulin ( µ U/ml) Time 8:00 Physiological Serum Insulin Secretion Profile

29. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine Lispro Lispro Lispro Aspart Aspart Aspart or Plasma insulin Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs

30. The Basal/Bolus Insulin Concept l Basal insulin –Suppresses glucose production between meals and overnight –40% to 50% of daily needs l Bolus insulin (mealtime) –Limits hyperglycemia after meals –Immediate rise and sharp peak at 1 hour –10% to 20% of total daily insulin requirement at each meal

31. Insulin Therapy in Type 2 Diabetes Indications l Significant hyperglycemia at presentation l Hyperglycemia on maximal doses of oral agents l Decompensation –Acute injury, stress, infection, myocardial ischemia –Severe hyperglycemia with ketonemia and/or ketonuria –Uncontrolled weight loss –Use of diabetogenic medications (eg, corticosteroids) l Surgery l Pregnancy

32. Starting With Basal Insulin in DM 2 Advantages l 1 injection with no mixing l Insulin pens for increased acceptance l Slow, safe, and simple titration l Low dosage l Effective improvement in glycemic control l Limited weight gain 6-37

33. Treat to Target Study: Glargine vs NPH Added to Oral Therapy of Type 2 Diabetes l Type 2 DM on 1 or 2 oral agents (SU, MET, TZD) l Age 30 to 70 l BMI 26 to 40 l A1C 7.5 to 10% and FPG > 140 mg/dL l Anti GAD negative l Willing to enter a 24 week randomized, open labeled study Riddle et al, Diabetes June 2002, Abstract 457-p

34. Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA l Add 10 units Basal insulin at bedtime (NPH or Glargine) l Continue current oral agents l Titrate insulin weekly to fasting BG < 100 mg/dL - if 100-120 mg/dL, increase 2 units - if 120-140 mg/dL, increase 4 units - if 140-180 mg/dL, increase 6 units - if >180 mg/dL, increase 8 units

35. Treatment to Target Study; A1C Decrease

36. Treatment to Target Study: % at Goal l 57% of patients in both groups reached A1C  7% l At wk 24, mean insulin glargine dose was higher than mean NPH insulin dose: Insulin glargine NPH insulin 48.8 IU/day 42.4 IU/day, P<0.001 Rosenstock J, Riddle M, HOE901/4002 Study Group. Diabetes 2002;51(suppl 2):A482. Abstract 1982-PO Results

37. Treat to Target Study: Glargine vs NPH Added to Oral Therapy of Type 2 Diabetes l Nocturnal Hypoglycemia reduced by 40% in the Glargine group (532 events) vs NPH group (886 events) Riddle et al, Diabetes June 2002, Abstract 457-p

38. Morning vs Bedtime Insulin Baseline: 9.1  1.0 Morning Glargine Bedtime Glargine Bedtime NPH -2 0 A1C Change From Baseline (%) –1.24 –0.96 –0.84 P<0.001 P=0.008 Adapted from Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952

39. Starting with Bolus Insulin l 16 obese Type 2 patients on NPH or Human 70/30 insulin twice daily randomized to: Insulin aspart premeal with metformin and rosiglitazone NPH or Human 70/30 twice daily l Insulin titrated to 90 to 126 mg/dl at 1.5 hr post meal in the aspart group and premeal in the conventional group with goal A1C <7% Diabetes Care 2003

40. Insulin Aspart Premeal with Metformin and Rosiglitazone vs Conventional Insulin A1C% N =16 0.42 units/kg 3 kg weight gain 0.67 units/kg 1 kg weight gain P = 0.03

41. Advancing Basal/Bolus Insulin l Indicated when FBG acceptable but –A1C > 7% or > 6.5% and/or –SMBG before dinner > 140 mg/dL l Insulin options –To glargine or NPH, add mealtime aspart / lispro –To suppertime 70/30, add morning 70/30 –Consider insulin pump therapy l Oral agent options –Usually stop sulfonylurea –Continue metformin for weight control –Continue glitazone for glycemic stability?

42. Novo Nordisk devices in diabetes care First pen (NovoPen 1) launched in 1985 Committed to developing one new insulin administration system per year.

43. Lilly Insulin Pens

44. Prefilled Syringe with Flexible Dosing

45. 82% of DNEs Preferred FlexPen ® Source: Diabetes Nurse Educators In-Depth Study—Reactions to FlexPen. NovoLog ® FlexPen ® ®

46. Novo Innolet ® Large push button with low resistance Large-scale numbers 1 unit increments Support shoulder Maximum dose 50 units Clear & uncomplicated dial, dials forward and back Contains 300 units Novolin ® 70/30, NPH, or R Audible clicks NovoFine ® disposable needle Needle storage compartment

47. Starting MDI l Starting insulin dose is based on weight 0.2 x wgt. in lbs. or 0.45 x wgt. in kg l Bolus dose (aspart/lispro) = 20% of starting dose at each meal l Basal dose (glargine/NPH) = 40% of starting dose at bedtime

48. Starting MDI in 180 lb person l Starting dose = 0.2 x wgt. in lbs. 0.2 x 180 lbs. = 36 units l Bolus dose = 20% of starting dose at each meal 20% of 36 units = 7 units ac (tid) l Basal dose = 40% of starting dose at bedtime 40% of 36 units = 14 units at HS

49. Individually determined CIR = (2.8 x wgt in lbs) / TDD Anywhere from 5 to 25 g CHO is covered by 1 unit of insulin Estimating the Carbohydrate to Insulin Ratio (CIR)

50. Correction Bolus (Supplement) l Must determine how much glucose is lowered by 1 unit of short- or rapid-acting insulin l This number is known as the correction factor (CF) l Use the 1700 rule to estimate the CF l 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

51. 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

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

53. Human Insulin Time-action Patterns Time (h) Baseline level Regular insulin Premix 70/30 SC injection Normal insulin secretion at mealtime NPH insulin Change in serum insulin

54. A More Physiologic Insulin Time (h) SC injection Baseline Level Normal insulin secretion at mealtime NPH insulin NovoLog  NovoLog  Mix 70/30 Change in serum insulin

55. Analog Mix 70/30: Serum Insulin Levels in Type 2 Diabetes BreakfastLunch 0 6:00 PM 10:00 PM 8:00 AM 6:00 PM 1:00 PM Dinner C max Serum insulin (mU/L) 100 Time 80 40 20 60 * * NovoLog ® Mix 70/30 70/30 Premix McSorley. Clin Ther. 2002;24(4):530-539. * P<0.05.

56. Analog Mix 70/30 vs 75/25 vs 70/30 Premix: Serum Insulin Levels in Type 2 Diabetes Lispro Mix 75/25 70/30 Premix Aspart Mix 70/30 0 12345 0 80 Time (h) Serum insulin (mU/L) 60 40 20 Hermansen. Diabetes Care. 2002;25(5):883-888.

57. Aspart Mix 70/30: Serum Glucose Levels in Type 2 Diabetes Aspart Mix 70/30 70/30 Premix DinnerBreakfastLunch *Glucose excursions 0-4 h, P<0.05. McSorley. Clin Ther. 2002;24(4):530-539.

58. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal infusion Bolus Plasma insulin Variable Basal Rate: CSII Program

59. Photograph reproduced with permission of manufacturer.

60. Pump Infusion Sets

61. CSII vs MDI in 100 DM 1 Patients Bode, et al. Diabetes 52,(Suppl 1), 2003 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)

62. n=63 in each treatment 0 500 1000 1500 2000 2500 3000 CSII MDI p = 0.0027 Novo Nordisk, data on file (Study 2155/US) Aspart (CSII) vs Aspart/Insulin glargine (MDI) Glucose Exposure During CGMS Measurement of AUC (glu) ≥80 mg/dL during the 48-hour continuous glucose monitoring period † AUC glu (mg hr/dL ) †

63. 6 6.5 7 7.5 8 8.5 9 Baseline4 weeks8 weeks12 weeks16 weeks Glargine (n=16) CSII (n=14) CSII vs. MDI with Glargine in Children (Preliminary Data) Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192. A1c

64. CSII vs MDI in Children – Preliminary Data Safety and Preference Safety Severe hypoglycemic episodes MDI: 4 CSII: 2 No cases of DKA Preference (at 16 weeks) All 12 CSII subjects remained on CSII 12 of 14 MDI subjects switched to CSII Boland et al., Diabetes 2003, 52:S1, A45, 192-OR

65. CSII vs MDI with NPH in 127 DM 2 Patients 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.4 CSIIMDI Baseline End of study (24 weeks) Raskin et al. Diabetes Care Sept 2003 A1C (%)

66. 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

67. Current Pump Therapy Indications l Diagnosed with diabetes (even new onset DM 1) l Need to normalize blood glucose (BG) –A1C > 6.5% –Glycemic excursions l Hypoglycemia

68. l Monitoring –A1C = 8.3 - (0.21 x BG per day) l Recording 7.4 vs 7.8 l Diet practiced –CHO: 7.2 –Fixed: 7.5 –WAG: 8.0 l Insulin type (Aspart) CSII Factors Affecting A1C Bode et al. Diabetes 1999;48 Suppl 1:264 Bode et al. Diabetes Care 2002;25 439

69. Total Daily Dose = 0.23 x Wgt. In lbs. Basal Dose = 0.47 x Total Daily Dose CIR = (2.8 x Wgt in lbs) / TDD (Anywhere from 5 to 25 g CHO is covered by 1 unit of insulin) Correction Factor = 1700 / TDD Target = 100 mg/dl Pump Formulas Davidson et al: Diabetes Tech & Therap. April 2003

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

71. Bolus: Source of Errors l “Inability” to count carbs correctly – Lack of knowledge, skill – Lack of time – Too much work l Incorrect use of SMBG number l Incorrect math in calculation l “WAG” estimations

72. Most common bolusing errors l Under-estimation of carbohydrates consumed (CHO bolus) l Over-correction of post-prandial elevations (CF bolus) – Remaining unused, active insulin – Stacking of boluses

73. The Major Problems ♦ Up until now we have not taken the active insulin issue into consideration ♦ The math involved with this has become too complicated, and it would be impossible to accurately calculate the active insulin without assistance

74. Smart Insulin Pumps

75. l Monitor sends BG value to pump via radio waves : No transcribing error l Enter carbohydrate intake into pump l “Bolus Wizard” calculates suggested dose Paradigm Link ™ Paradigm 512 ™ ) ) ) ) ) ) ) ) ) ) ) ) ) Bolus Wizard Calculator : meter-entered

76. For This System To Work ♦ It is critical the target, basal doses, the correction doses, and the 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.

77. Do Smart Pumps Enable Others To Go To CSII? l YES l All patients with diabetes not at goal are candidates for Insulin Pump Therapy - Type 1 any age - Type 2 - Diabetes in Pregnancy

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

79. If A1C Not to Goal and No Reason Identified l Place on a continuous glucose monitoring system (CGMS by Medtronic Minimed, Glucowatch by Cygnus) to determine the cause

80. CGMS

81. CGMS Sensor

82. GLUCOSE MONITORING SYSTEMS - Telemetry l “Real time” glucose readings l Wireless communication from sensor to monitor l High and low glucose alarms l FDA panel pending Consumer Product

83. GlucoWatch ® Biographer

84. FreeStyle Navigator TheraSense Continuous Glucose Monitor Patient Inserted Sensor “On demand” glucose and trend arrow User-configurable Low Glucose and High Glucose Alarms Projected alarms give advance warning of glucose excursions Integrated FreeStyle blood glucose meter (3) BG calibrations for each 3-day sensor Wireless sensor-to-Meter path (10 foot operating range)

85. FreeStyle Navigator TheraSense Continuous Glucose Monitor –Designed to monitor interstitial fluid and provide continuous glucose readings –Patient-attached adhesive section includes sensor, and wireless transmitter –Designed to be self-inserted every three days and provide patients with glucose for use in managing therapy

86. The DexCom Continuous Glucose Sensor System l l Sensor –7 x 1 cm –Cylindrical –7 cc –Battery –Microprocessor –Antenna l l Receiver –Pager-Like Receiver with Graphical Display

87. Implantable Pump l Average HbA 1c 7.1% l Hypoglycemic events reduce to 4 episodes per 100 pt-years

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

89. Predicted Times l Glucose Sensors - Alarm sensor (72 hr) early 2004 - Replace fingersticks mid late 2005 l Semi-Closed loop 2006 – 2007 l Implantable 2007-2008

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

91. Billing l Get paid for what you do l Use your codes and negotiate for coverage l Detailed visit: 99214 l Prolonged visit with contact plus above: 99354 or 99355 (insulin start or pump start) l Prolonged visit w/o contact plus above: 99358 or 59 (faxes, phone calls, emails)

92. Billing l Bill faxes as prolong visits with out contact or negotiate a separate charge l Bill meter download: 99091 l Bill CGMS: 95250 l Bill immediate A1C: 83036

93. Questions l For a copy or viewing of these slides, contact l WWW.adaendo.com WWW.adaendo.com