1. Basics of Continuous Subcutaneous Insulin Infusion Therapy Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Website: www.endocrinology-online.com

2. Overview History of insulin pumps Benefits of improved glycemic control Advantages of insulin pump therapy Indications for pump therapy Beginning insulin pump therapy (basal and bolus dosing) Carbohydrate Counting Hypoglycemia and hyperglycemia prevention Conclusions

3. History of Pumps

4. Best and Banting

5. Evolution of Diabetes Management Technologies Discovery of Insulin Urine Test Strips Glucose Sensors Artificial Pancreas 19991978 19211900s 1977 Urine Tasting 1776 BG Meters Insulin Pump Therapy

6. First Insulin Pump (early 1970s)

7. Early Insulin Pumps

8. AutoSyringe AS*6c 1979-1980

9. Lilly Betatron 1983

10. Present Day Insulin Pumps

11. U.S. Pump Usage Total Patients Using Insulin Pumps

12. 60% How Diabetes Specialists Treat Their Own Type 1 Diabetes AADE Membership n=229 Industry estimates at time of survey (9/98); Graff: Diabetes Educator 2000; 46:460-467 6% General Type 1 Population* 52% Injections Pump Therapy Color Key: n=293 ADA Membership

13. Benefits of Improved Glycemic Control

14. Potential Chronic Complications of Elevated HbA1c CONTROL Foot Ulcers Foot Ulcers Angina Angina Heart Attack Heart Attack Coronary Bypass Coronary Bypass Surgery Surgery Stroke Stroke Blindness Blindness Amputation Amputation Dialysis Dialysis Kidney Kidney Transplant Transplant Microalbuminuria Microalbuminuria Mild Retinopathy Mild Retinopathy Mild Neuropathy Mild Neuropathy Albuminuria Albuminuria Macular Edema Macular Edema Proliferative Proliferative Retinopathy Retinopathy Peridontal Disease Peridontal Disease Impotence Impotence Gastroparesis Gastroparesis Depression Depression RISK GoodPoor

15. DCCT Microvascular Risk Reduction With Intensive Treatment Data from the Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986. Reduction in ComplicationRelative Risk Retinopathy63% Nephropathy54% Neuropathy60%

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

17. Additional Benefits of Improving Glycemic Control Decreased macrovascular changes –Insulin is NOT atherogenic Improved wound healing Decreased infections Improved post infarct survival Minimization of oxidative damage

18. Treatment Strategies for Diabetes: Are Patients Achieving Good Control? Controlled Uncontrolled Hypertension Hyperlipidemia Glycemic control 59% 41% Harris MI et al. Diabetes Care. 2000;23:754 BP <140/90 mm Hg LDL-C <130 mg/dL A1C <7.0 59% 41% 58% 42%

19. A1C’s in Clinical Practice ~30% of type 2 insulin users have A1C <8% Harmel et al. 7.0 8.0 9.5 A1C (%) 6.0 7.5 8.5 10.0 6.5 5.5 Upper limit of normal range 6 AACE/ACE: recommended target <6.5 ADA: recommended target <7 9.0 ~20 to >40% have A1C > 9.5% NHANES/BRFSS; Harmel et al.; NCQA 2000 ~40 to >50% have A1C > 8% NHANES/BRFSS; Harmel et al. ADA. Diabetes Care 2003; 26(S1):S33-S50 ACE Consensus Conference on Guidelines for Glycemic Control. Endocrine Practice, 2002 HEDIS 2000. Washington: National Committee for Quality Assurance, 1999 State of Managed Care Quality. National Committee for Quality Assurance, 2000

20. Advantages of CSII

21. The Goal of Insulin Therapy: Attempt to Mimic Normal Pancreatic Function Schade, Skyler, Santiago, Rizza, “Intensive Insulin Therapy,” 1993, p. 131.

22. Twice-daily Split-mixed Regimens Regular NPH BSLHS Insulin Effect B 6-23

23. BSLHSB lispro Glargine Insulin Effect Basal Bolus Regimen with Glargine and Lispro 6-56

24. Continuous Subcutaneous Insulin Infusion BSLHSB Insulin Effect Bolus Basal

25. Pharmacokinetics of CSII vs MDI Uses only immediate acting insulin –More predictable absorption Uses one injection site –Reduces variations in absorption Eliminates most of the subcutaneous insulin depot Closest match with physiologic needs * Lauritzen: Diabetologia 1983; 24:326-9

26. Advantages of Pump Therapy Improved blood glucose control –Improved AIC’s –Decreased hypoglycemia and hyperglycemia – Delay in incidence and progression of complications Precise dosage delivery Improved control for pre-conception and pregnancy Management of dawn phenomenon Increased flexibility in lifestyle Improved control during exercise Improved gastroparesis management

27. Population: Comparison of glycemic control in 58 patients while on MDI x 3yrs and subsequent CSII x 3yrs Methods: Retrospective, observational cohort study of patients with Type 1 diabetes Trial Evidence: CSII versus MDI use in routine clinical practice Mean HbA1c% 10 9 8 7 6 MDI CSII MDI HbA1c >8.0% Entire Cohort MDI HbA1c >9.0% 8.4 9.2 10.0 8.4 8.2 7.7 P=0.0006 P=0.001 Bell and Ovalle, Endocr Pract 2000;6:357-60

28. Improved Control and Less Variability With Pump Therapy Time (Day) 12:00 a.m. 6:00 a.m. 12:00 p.m. 6:00 p.m. 12:00 a.m. 0 50 100 150 200 250 300 350 400 Glucose (mg/dl) Time (Day) 12:00 a.m. 6:00 a.m. 12:00 p.m. 6:00 p.m. 12:00 a.m. 0 50 100 150 200 250 300 350 400 Glucose (mg/dl) Finger Stick Sensor Finger Stick Sensor Pump Therapy Multiple Daily Injections

29. Improved Control: Decreased Hypoglycemia Bode et al: Diabetes Care 1996; 19:324-7 Episodes per 100 pt yrs N=55

30. Benefits of Decreased Hypoglycemia Reduced risk of diabetic encephalopathy Reduced risk of accidents and death Improved hypoglycemia awareness

31. Improved Hypoglycemia Awareness Meticulous glycemic control reduced hypoglycemia events from 20 to 2 per month in this study of 21 patients Glycemic thresholds for hypoglycemia symptoms normalized in all groups Partial recovery of the counterregulatory response Fanelli: Diabetes 1997;46: 1172-1181

32. 15 7 0 2 4 6 8 10 12 14 16 Pre-CSIIPost-CSII Diabetic Ketoacidosis (episodes / 100 pt years) Bode, BW, Diabetes Care 19:324-7, 1996.

33. Improved Health Status with CSII Association for Insulin Pump Therapy, Diabetes 1991:40:#1807 N=886 Self-Reported Data

34. Advantages of Pump Therapy in Pregnancy Mimics normal physiology Decreases glucose excursions Reduces hypoglycemia Provides insulin regimen individualization Improves management of morning sickness Increase lifestyle flexibility Jornsay, DL. CSII Therapy During Pregnancy. Diabetes Spectrum 11:1998: 26-32.

35. Children Recent studies show benefits for under 12 years of age Prevention and reduction of night-time hypoglycemia Ability to accommodate variable appetites and eating patterns Effective and safe with parental education/control/supervision Buckingham, B; Kaufman, F; ADA 61 st Scientific Sessions, 2001

36. Pump Therapy in Type 2 diabetes Reduces glucose toxicity Decreases insulin resistance Restores sensitivity to oral agents and diet Often can result in reduced total daily insulin needs Ilkova et al., Diabetes Care 1997, vol 20: p 1353. Glaser,1985; Garvey, 1985; Scarlett,1997 Must meet same criteria as Type 1

37. Challenges of Pump Therapy Learning curve Risk of DKA Possible weight gain Frequent monitoring required Potential site infections Inconvenience in wearing pump Education and follow-up required Cost

38. Cost and Insurance A pump typically lists for close to $5000. Pump supplies average $1,200 to $1,600 per year! Many insurance companies cover all or most of this cost.

39. Choosing a Pump... Ease of use Clinical features Safety features Customer service Cost of pump Insurance coverage Physician/CDE preference Bolus options Number of basal programs Training and education Insulin delivery system Patient age Patient lifestyle Cosmetic issues Some things to consider……

40. Indications for Pump Therapy

41. Criteria for Selection of a Pump Candidate Clinical Indications: Inadequate glucose control OR HbA 1c >7.0% with MDI regimen Hypoglycemia unawareness Recurrent hypoglycemia Dawn phenomenon Preconception and pregnancy Gastroparesis or other complications Post-renal transplant

42. Patient Success Characteristics: Motivated Realistic expectations Ability to manage diabetes—MDI, frequent SMBG and interpretation of results Uses carbohydrate counting effectively Family support Financial resources Psychological and emotional stability Intellectual, physical, and technical ability to use the pump

43. Contraindications to Pump Therapy Insufficient motivation to: Perform frequent (4+ daily) SBGM tests Learn and practice CHO counting Initially document activities of daily living Adjust to recommended medical therapy

44. Current Continuation Rate Continuous Subcutaneous Insulin Infusion (CSII) N = 165 Average Duration = 3.6 years Average Discontinuation <1%/yr Bode, et al.: Diabetes 1998; 47 (Suppl 1): 392.

45. Beginning Insulin Pump Therapy

46. Basal Rate of Insulin Mimics fasting insulin secretion of a normal pancreas Continuous flow of insulin Replaces the intermediate or long acting insulin of MDI regimen Adjust to match metabolic need for insulin under fasting conditions

47. Bolus Insulin Simulates mealtime insulin secretion of normal pancreas Programmed for delivery by patient Replaces short acting insulin of MDI regimen Is given as needed by patient premeal or to correct for hyperglycemia

48. Pump Therapy Insulin Doses Basal rate = 40 – 50% TDD Bolus totals = 50 – 60% TDD American Diabetes Association, Intensive Diabetes Management. 2 nd ed. Alexandria, VA: 1998. Bode, BW. The Insulin Pump Therapy Book: Insights From the Experts. Sylmar, CA: MiniMed Technologies; 1995: 49-56, 85-93. Remember: Always Individualize!

49. ~50% Basal* Total Daily Dose (~70-75% of prior insulin regimen TDD) ~50% Bolus* Usually divided into 3 premeal doses (depending on number and size of meals) *Range: 40 to 60% Pre-Pump Dose Establishing Starting Basal and Bolus Doses

50. Total Daily Dose (75% pre-pump dose) Example: TDD (Total Daily Dose) = ~27 u/24 hrs 27 u x.75 = 20.25 u TDD If pre-pump dose of fast acting is >70% /24 hrs, may need further reduction. Note: If pre-pump dose of fast acting is >70% /24 hrs, may need further reduction. Bode, BW. The Insulin Pump Therapy Book: Insights From the Experts. Sylmar, CA: MiniMed Technologies, 1995: 49-56, 85-93.

51. Basal Rate Calculation: 40 – 50% TDD 40 – 50 % of TDD ÷ 24 hours = u/hr Example: TDD = 48 u x 0.4 = 19.2 = 0.8 u/hr 24 24 American Diabetes Association, Intensive Diabetes Management. 2 nd ed. Alexandria, VA: 1998. Bode, BW. The Insulin Pump Therapy Book: Insights From the Experts. Sylmar, CA: MiniMed Technologies; 1995: 49-56, 85-93.

52. Basal Rate Calculation May need to use 60% or higher of the TDD for insulin resistance: Teens Type 2 Dawn phenomenon

53. Which basal rate to start with?? Most clinicians prefer to initiate a conservative basal rate. It’s always better if the patient’s blood glucose values run slightly higher than too low during pump initiation. It’s easier to increase a basal rate gradually by 0.1 u/hr.

54. Fine Tuning: Basal Rate Monitor BG pre-meal, post-meal, bedtime, 12am, and 2-4am We assess basal insulin by fasting and premeal BG’s Test fasting BG with skipped meals Adjust nighttime basal based on 2-4am and pre-breakfast BG Usually adjust basal by 0.1 u/hr to avoid over-correction

58. Bolus Insulin

59. Bolus Dose Insulin Premeal boluses: –Taken before meals –Covers mealtime carbohydrate intake – Prevents postprandial hyperglycemia Correction or supplementation boluses: –Used to Correct and treat hyperglycemia –May be given alone between meals for hyperglycemia –May be given to supplement already scheduled insulin to cover premeal hyperglycemia

60. Calculation of Premeal Bolus Doses Methods 1.Use the patient’s pre-pump insulin-to carb ratio 2.Formula: 500 Rule 3.Weight based Method * Bode et al: Diabetes Care 1994: 19: 324-7

61. Determination of Insulin to Carb Ratio: Method 1 EXAMPLE: Pre-pump 1 unit of insulin: 15 gm carb Note: 1 unit: 15 gm is often a “safe” starting point for most patients...

62. Determination of Insulin to Carb Ratio: Method 2 Use the 500 Rule: Divide 500 by TDD= 1 unit insulin to ___ gm CHO as bolus EXAMPLE: 500 ÷ 34 u= 15 Bolus ratio is 1 u insulin : 15 gm CHO

63. Weight (lb)Insulin u: CHO gm * 100-1091: 16 110-1291: 15 130-1391: 14 140-1491: 13 150-1691: 12 170-1791: 11 180-1891: 10 190-1991: 9 200+1: 8 Determination of Insulin to Carb Ratio: Method 3 *Walsh, Pumping Insulin, 2 nd ed. Weight Based Method

64. Extended Bolus Option Equally divides, or “spreads” one bolus amount over a specific number of hours Use for: long meals (parties or holidays) high fat meals (pizza) delayed digestion (gastroparesis)

65. Normal vs. Extended Bolus Extended Bolus Normal Bolus Time Insulin

66. Split or Dual Wave Bolus Option Patient divides bolus into 2 separate bolus amounts Use for continuous snacking, high fat meals or snacks : Initial bolus: 30–50% of total bolus Second bolus: –Set an Extended Bolus OR –Bolus remainder 2 to 4 hours later

67. Split or Dual Wave Bolus Time Insulin First Phase Insulin Secretion Second Phase Insulin Secretion

68. Dual Wave Bolus vs. Standard Bolus after High Fat Meal

69. Pump Therapy Initiation Insulin: Carb Bolus Tips Use pre-pump MDI insulin-to-CHO ratio for boluses, if has been successful Try to keep CHO amount consistent at meals (consume same amount of CHO for each breakfast, each lunch, etc.) Avoid excessive protein, high fat content meals, alcohol, and foods not usually consumed

70. Carbohydrate Counting

71. What Is Carbohydrate Counting? Simple meal planning method... Preferred meal planning approach used in the DCCT Widely used throughout Europe Result of advances in diabetes management and is research-based

72. Why Count Carbs? It works Increases flexibility in food choices and the amounts of foods consumed Easy to understand Well-accepted

73. Macronutrient Conversion to Blood Glucose

74. Glucose Elevations per Carbohydrate Grams Each gram of carbohydrate raises glucose by 3-4 mg/dl Blood Glucose Increase (mg/dl) Carbohydrate grams ingested

75. Carbohydrate Counting Benefits Allows for variation in appetite and preferences Increases variety of food choices Can be used to match insulin bolus doses to food intake

76. Carb Counting and Insulin Bolusing Sample Meal 1 c. orange juice 30 g 2 slices toast 30 g ½ c. oatmeal 15 g 1 soft-cooked egg 1 tsp margarine Coffee & 1 T cream _____________________ Total CHO: 75 g Insulin bolus: 5 units Sample Meal 2 slices wheat bread 30 g 2 oz. turkey breast Lettuce leaf, tomato slice 1 tsp mayonnaise 6-8 3-ring pretzels 15 g 2 small choc cookies 15 g Diet soda, 16 oz__________ Total CHO: 60 g Insulin bolus: 4 units Insulin-to-Carb Ratio EXAMPLE: 1 unit insulin: 15 grams CHO

77. Fine Tuning: Meal Bolus Doses Adjust bolus based on post-meal BGs Carbohydrate counting or pre-determined meal portion Individualize insulin to carbohydrate dose or insulin to premeal dose

79. Correction Boluses

80. Correction Bolus Insulin To be taken to correct for hyperglycemia Based on insulin sensitivity factor Goal is for correction bolus to lower blood glucose to within 30 to 50 mg/dl of target value

81. Insulin Sensitivity Factor 1 unit of insulin will  blood glucose by: mg/dl Regular: 1500 Rule Humalog: 1800 Rule 1500 or 1800 divided by TDD= amount of blood glucose lowered by 1 unit insulin Use to  high blood glucose

82. Insulin Sensitivity Factor EXAMPLE TDD is 34 units 1500 Rule: 1500 ÷ 34 = 44 1 unit of Regular  bg 44 mg/dl 1800 Rule: 1800 ÷ 34 = 53 1 unit of Humalog  bg 53 mg/dl

84. Unused Insulin Rule Lispro is gone in approx. 3 – 4 hrs Decrease bolus 30% each hour: 1 st hour = 70% remaining 2 nd hour = 40% remaining 3 rd hour = 10% remaining 4 th hour = 0% remaining Walsh. PA. Roberts. R Pumping Insulin. 3rd ed. San Diego, Calif: Torrey Pines Press; 2000

85. Preventing Hypoglycemia

86. Check BG 4-6 times per day Carry glucose tablets Have Glucagon Kit available

87. Preventing Hypoglycemia Test before driving and ideally 1 hour later (target: over 100 mg/dl) Perform two SMBG 30 minutes apart prior to bedtime (confirming rising or falling BG) When drinking alcohol, perform SMBG hourly With exercise, perform SMBG pre- and post-exercise If hypoglycemia episodes persist, raise target glucose levels

88. Hypoglycemia Treatment Guidelines The Rule of 15 If BG is 70 mg/dl or below –Treat with 15 grams of carbohydrates (glucose tabs) –Check BG in 15 minutes, and if not above 70 mg/dl, repeat treatment Glucagon Current emergency kit readily available and knowledgeable person trained to administer

89. Preventing Hyperglycemia and DKA

90. Monitor BG 4-6 times per day Use Correction Boluses when appropriate Change infusion set every 2-3 days

91. Hyperglycemia Treatment Guidelines The Key to Preventing DKA 1st BG over 250 mg/dl: Take a correction bolus via pump, check again in 1 hour 2nd BG over 250 mg/dl: Take correction bolus by syringe and change infusion set, review pump, check BG again in 1 hour Call physician immediately if nausea and vomiting and/or ketones are present

92. Follow-Up: The Patient’s Role Every Day Check BG 4-6 times a day, and always before bed Follow hypoglycemia guidelines Follow hyperglycemia guidelines Every 3 months Visit healthcare provider - even if feeling well Review log book and pump settings with physician/CDE Get a HbA1c Every month Review DKA prevention Check BG - 3am (overnight) - 1 and/or 2-hour post-meal BG for all meals on a given day

93. Conclusion Pump Therapy is becoming widely recognized as the best way to treat insulin requiring diabetes It is now considered standard of care in appropriate patients Pump Therapy is not difficult to implement in a medical practice When implantable continuous glucose sensors are perfected and become readily available; pumps will become an even greater tool

94. Implantable Pumps: Coming Soon? Continuous intraperitoneal insulin delivery – provides physiologic insulin absorption Negative pressure insulin reservoir –special U-400 insulin refilled every 2 to 3 months Small, programmer communicates with the pump using RF telemetry. In the US implantable insulin pumps are investigational only

95. Consider Pump Therapy… Poor HbA1c’s Frequent hypoglycemia Dawn phenomenon Pediatrics Pregnancy Gastroparesis Hectic Lifestyle Shift Work Insulin Requiring Type 2’s?