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

3. American Diabetes Association. Facts and Figures. Available at: http://www.diabetes.org/ada/facts.asp. Accessed January 18, 2000. Diagnosed Type 1 Diabetes 0.5 – 1.0 Million Diagnosed Type 2 Diabetes 10.3 Million Undiagnosed Diabetes 5.4 Million Prevalence of Diabetes in the US 3

4. ADA: Clinical Practice Recommendations. 2001. Goals of Intensive Diabetes Management l Near-normal glycemia –HbA1c less than 6.5 to 7.0% l Avoid short-term crisis –Hypoglycemia –Hyperglycemia –DKA l Minimize long-term complications l Improve QOL

5. ACE / AACE Targets for Glycemic Control HbA 1c < 6.5 % Fasting/preprandial glucose< 110 mg/dL Postprandial glucose< 140 mg/dL ACE / AACE Consensus Conference, Washington DC August 2001

6. Type 2 Diabetes: Two Principal Defects Reaven GM. Physiol Rev. 1995;75:473-486 Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S; Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127. Insulin resistance  -cell dysfunction/ failure ± Environment± IGT Genes Type 2 diabetes Glucose Toxicity Glucose Toxicity

7. Role of Free Fatty Acids in Hyperglycemia Boden G. Proc Assoc Am Physicians. 1999;111:241-248. MUSCLE LIVER  FFA oxidation  Gluconeogenesis  Glucose utilization Hyperglycemia ADIPOSE TISSUE  Lipolysis  FFA mobilization Liver insulin resistance Adipose tissue insulin resistance Muscle insulin resistance

8. HbA 1c in the UKPDS

9. UKPDS:  -Cell Function for the Patients Remaining on Diet for 6 Years Years After Diagnosis  -Cell Function (%  ) Adapted from UKPDS Group. Diabetes. 1995; 44:1249-1258. N=376

10. 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

11. *Percent risk reduction per 0.9% decrease in HbA 1C ; UKPDS. Lancet. 1998;352:837-853. Lowering HbA 1C Reduces Risk of Complications Reduction in risk (%)* p=0.029 p=0.0099 p=0.052 p=0.015 p=0.000054 0 -10 -20 -30 -40 -50 -12 -25 -16 -34 -21 Any diabetes-related endpoint Microvascular endpoint MI Retinopathy Albuminuria at 12 years United Kingdom Prospective Diabetes Study (UKPDS)

12. UKPDS: Benefits of Glycemic Control in Type 2 Diabetes Risk reduction over 10 years Any diabetes-related endpoint12% P = 0.029 Microvascular endpoints25% P = 0.0099 Myocardial infarction16% P = 0.052 Cataract extraction24% P = 0.046 Retinopathy at 12 years21% P = 0.015 Microalbuminuria at 12 years33% P < 0.001 UKPDS 33. Lancet. 1998;352:837-853.

13. Metformin Prevents Heart Attacks and Reduces Deaths in Type 2 Diabetes Incidence (per 1,000 patient years) 39%  Reduction P=0.01 50%  Reduction P=0.02 Heart AttacksCoronary Deaths ConventionalMetformin Therapy ConventioalMetformin Therapy

14. Insulin Resistance and -Cell Dysfunction Produce Hyperglycemia in Type 2 Diabetes Pancreas Insulin Resistance Liver Hyperglycemia Islet -Cell Degranulation; Reduced Insulin Content Muscle Adipose Tissue Decreased Glucose Transport & Activity (expression) of GLUT4 Increased Lipolysis + - Reduced Plasma Insulin Increased Glucose Output -Cell Dysfunction Elevated Plasma FFA Courtesy of S. Smith, GlaxoSmithKline

15. Diabetes Prevention Program l 3234 obese patients with IGT l BMI average 34; A1C 5.9%, 55% Caucasion l 4 year study to compare diet and exercise to metformin, troglitazone or control l Troglitazone stopped at 8 months l Study ended after 3 years

16. Diabetes Prevention Program l 58% prevention with diet (low fat) and exercise (2.5 hours per week) l 31% prevention with metformin (more effective if < 60 years old and obese) l Troglitazone patients equal to metformin group at three years and equal to the diet and exercise group at 8 months.

17. Management of Type 2 DM Step Therapy l Diet l Exercise l Sulfonylurea or Metformin l Add Alternate Agent l Add hs NPH vs TZD l Switch to Mixed Insulin bid l Switch to Multiple Dose Insulin Utilitarian, Common Sense, Recommended Prone to Failure from Misscheduling and Mismanagement

18. Management of Type 2 DM Stumble Therapy l WAG Diet l Golf Cart Exercise l Sample of the Week Medication –Interrupted –Not Combined l Poor Understanding of Goals l Poor Monitoring HbA1c >8% (If Seen )

19. Consider A New Treatment Paradigm l Treatment designed to correct the dual impairments l Vigorous effort to meet glycemic targets l Simultaneous rather than sequential therapy l Combination therapy from the outset l Early step-wise titrations to meet glycemic targets

20. Goals in Management of Type 2 Diabetes l Fasting BG < 110 mg/dL l Post-meal < 140 mg/dL l HbA1c < 6.5% l Blood Pressure < 130/80 l LDL < 100 mg/dl l HDL > 45 mg/dl

21. Approach to Combination Oral Therapy

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

23. 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

24. 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

25. Limitations of NPH, Lente, and Ultralente l Do not mimic basal insulin profile –Variable absorption –Pronounced peaks –Less than 24-hour duration of action l Cause unpredictable hypoglycemia –Major factor limiting insulin adjustments –More weight gain

26. 15 10 15202530 1 5101520 Asp Gly Arg Extension Substitution Arg Insulin Glargine A New Long-Acting Insulin Analog l Modifications to human insulin chain –Substitution of glycine at position A21 –Addition of 2 arginines at position B30 l Gradual release from injection site l Peakless, long-lasting insulin profile

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. Glargine Plasma Glucose Time (hours) 220 200 180 160 140 120 12 11 10 9 8 7 04812162024 mg/dL mmol/L Lepore M, et al. Diabetes. 2000;49:2142–2148. n = 20 T1DM Mean ± SEM SC insulin NPH Ultralente CSII

29. Overall Summary: Glargine l Insulin glargine has the following clinical benefits –Once-daily dosing because of its prolonged duration of action and smooth, peakless time- action profile (23.5 hours on repeat injections) –Comparable or better glycemic control (FBG) –Lower risk of nocturnal hypoglycemic events –Safety profile similar to that of human insulin

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

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 l Renal or hepatic disease

32. Mimicking Nature The Basal/Bolus Insulin Concept 6-16

33. 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

34. Basal vs Mealtime Hyperglycemia in Diabetes Riddle. Diabetes Care. 1990;13:676-686. Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 18002400 Type 2 Diabetes 0600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal  AUC from normal basal >1875 mgm/dL. hr; Est HbA1 c >8.7%

35. When Basal Corrected Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 180024000600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 900 mgm/dL. hr; Est HbA1 c 7.2%

36. When Mealtime Hyperglycemia Corrected Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 180024000600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 1425 mgm/dL. hr; Est HbA1 c 7.9

37. When Both Basal & Mealtime Hyperglycemia Corrected Plasma Glucose (mg/dL) 200 100 0 06001200 Time of Day 180024000600 150 250 50 Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 225 mgm/dL. hr; Est HbA1 c 6.4%

38. MIMICKING NATURE WITH INSULIN THERAPY Over time, most patients will need both basal and mealtime insulin to control glucose 6-19

39. Starting With Basal Insulin 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

40. 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

41. Treat to Target Study: Glargine vs NPH Added to Oral Therapy of Type 2 Diabetes 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 140-160 mg/dL, increase 6 units - if 160-180 mg/dL, increase 8 units Riddle et al, Diabetes June 2002, Abstract 457-p

42. Treat to Target Study; A1C Decrease Riddle et al, Diabetes June 2002, Abstract 457-p

43. Treat to Target Study: Patients in Target (A1C < 7%) Riddle et al, Diabetes June 2002, Abstract 457-p

44. 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

45. Advancing Basal/Bolus Insulin l Indicated when FBG acceptable but –HbA1c > 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?

46. Case #1: DM 2 on SU with infection l 49 year old white male l DM 2 onset age 43, wt 180 lbs, Ht 70 inches l On glimepiride (Amaryl) 4 mg/day, HbA1c 7.3% (intolerant to metformin) l Infection in colostomy pouch (ulcerative colitis) glucose up to 300 mg/dL plus l SBGM 3 times per day

47. Case #1: DM 2 on SU with infection l Started on MDI; starting dose 0.2 x wgt. in lbs. l Wgt. 180 lbs which = 36 units l Bolus dose (lispro/aspart) = 20% of starting dose at each meal, which = 7 units ac (tid) l Basal dose (glargine) = 40% of starting dose at HS, which = 14 units at HS l Correction bolus = (BG - 100)/ SF, where SF = 1500/total daily dose = 1500/36 = 40

48. Correction Bolus Formula Example: –Current BG:220 mg/dl –Ideal BG: 100 mg/dl –Glucose Correction Factor: 40 mg/dl Current BG - Ideal BG Glucose Correction factor 220 - 100 40 =3.0u

49. Case #1: DM 2 on SU with infection l Started on MDI l Did well, average BG 138 mg/dL at 1 month and 117 mg/dL at 2 months post episode with HbA1c 6.1%

50. Strategies to Improve Glycemic Control: Type 2 Diabetes l Monitor glycemic targets – Fasting and postprandial glucose, HbA 1c l Self-monitoring of blood glucose is essential l Nutrition and activity are cornerstones of therapy l Combinations of pharmacologic agents are often necessary to achieve glycemic targets

51. Intensive Therapy for Type 1 Diabetes l Careful balance of food, activity, and insulin l Daily self-monitoring BG l Patient trained to vary insulin and food l Define target BG levels (individualized) l Frequent contact of patient and diabetes team l Monitoring HbA 1c l Basal / Bolus insulin regimen

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

53. 1.0 0.8 0.6 0 Insulin Time Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal

54. Injections 1.0 0.8 0.6 0 Insulin Time Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal

55. Injections 1.0 0.8 0.6 0 Insulin Time Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal

56. Injections 1.0 0.8 0.6 0 Insulin Time Multiple Injection Therapy Glargine & Short-Acting Insulin Pre-Meal

57. Case #2: DM 1 on MDI l 46 year old white male power line supervisor l DM 1 age 40 l On MDI: 10 u lispro pre-meal, 20 u NPH HS l HbA1c 7.4% l SMBG avg 124 mg/dL based on 1.9 tests/day (fasting 171 mg/dL, noon 105 mg/dL, pm 125 mg/dL, HS 75 mg/dL)

58. Case #2: DM 1 on MDI l Lantus (glargine) 20 u HS added in place of NPH l No change in behavior (diet, SMBG frequency) l Seen three months later (8-16-01) l HbA1c 6.3% l SMBG average 104 mg/dL (fasting BG 91 mg/dL, noon 126 mg/dL, pm 116 mg/dL, HS 126 mg/dL l NO HYPOGLYCEMIA l HAPPY

59. Insulin Pens

60. InDuo™ - Integration Feature l Combined insulin doser and blood glucose monitor

61. InDuo™ - Compact Size Feature l Compact, discreet design Benefit l Allows discreet testing and injecting anywhere, anytime

62. InDuo™ - Doser Remembers Feature l Remembers amount of insulin delivered and time since last dose Benefit l Helps people inject the right amount of insulin at the right time

63. Pump Therapy Basal & Bolus Short-Acting Insulin

64. l Combined with SMBG, physiologic insulin requirements can be achieved more closely l Flexibility in lifestyle

65. History of Pumps

67. PARADIGM PUMP Paradigm. Simple. Easy.

68. Metabolic Advantages with CSII l Improved glycemic control l Better pharmacokinetic delivery of insulin –Less hypoglycemia –Less insulin required l Improved quality of life

69. If HbA 1c 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:

70. Future of Diabetes Management

71. Improvements in Insulin & Delivery l Insulin analogs and inhaled insulin l External pumps l Internal pumps l Continuous glucose sensors l Closed-loop systems

72. Pulmonary Insulin

73. Oral Agents + Mealtime Inhaled Insulin Effect on HbA 1c *P <.001 Weiss, et al. Diabetes. 1999;48(suppl 1):A12. 10 9 8 7 5 Baseline (0) Follow-up (12) Oral Agents + Inhaled Insulin Oral Agents Alone Baseline (0) Follow-up (12)  2.3% * Weeks 6 HbA 1c (%) 6-55

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

75. MiniMed 2007 System Implantable Insulin Pump Placement

76. Long-Term Glucose Sensor

77. LONG TERM IMPLANTABLE SYSTEM Source: Medical Research Group, Inc. Human Clinical Trial

78. Combine Pump and Sensor Technology + LTSS => Long Term Sensor System (“Open Loop Control”) Using an RF Telemetry Link…...

79. Medtronic MiniMed’s Implantable Biomechanical Beta Cell

80. Today’s Reality Open-Loop Glucose Control Sensor # - 6347

81. Source: Medical Research Group, Inc. 50 100 150 200 250 300 350 400 16 Wed17 Thu18 Fri19 Sat20 Sun21 Mon22 Tue23 Wed August 2000 Glucose (mg/dL) LONG TERM IMPLANTABLE SYSTEM Automatic Glucose Regulation in a Fully Pancreatectomized Canine CLOSED LOOP CONTROL Manual Control Manual Control Automatic Control Begins Control Terminated

82. 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

83. Conclusion Intensive therapy is the best way to treat patients with diabetes

84. QUESTIONS l For a copy or viewing of these slides, contact l WWW.adaendo.com WWW.adaendo.com