1. Healthcare Across Borders - September 2003 Current And Emerging Technologies In Insulin Pumps And Continuous Monitors John Walsh, P.A., C.D.E. North County Endocrine 700 West El Norte Pkwy Escondido, CA 92126 (760) 743-1431 The Diabetes Mall The Diabetes Mall www diabetesnet.com www diabetesnet.com (619) 497-0900 jwalsh@diabetesnet.com Children With Diabetes Toronto August 18, 2007

2. Healthcare Across Borders - September 2003 Highlights Smart Pump Capabilities Duration Of Insulin Action Bolus On Board (BOB) Continuous Monitors Continuous Monitor Tips Future Devices/Pumps Wrap Up

3. Healthcare Across Borders - September 2003 Winning With Technology 8 Type 1s set a new speed record in the 2007 RAAM team race, riding from Oceanside, CA, to Atlantic City in just over 5.5 days. They attribute their win to perseverance, reduced bonking using Navigator continuous monitors, and reliance on the ultimate energy hormone – insulin – delivered from Omnipod pumps.

4. Healthcare Across Borders - September 2003 Smart Pump Capabilities

5. Healthcare Across Borders - September 2003 Unique Pump Features Accu-Chek Spirit Boluses determined by BG not by BOB Accu-Chek meter software has Low BG Index that may help predict hypo unawareness Strong motor and delivery Animas 2020 High contrast color screen for easy viewing Smallest mainstream pump Smallest basal rate increment – 0.025 u

6. Healthcare Across Borders - September 2003 Unique Pump Features Insulet Omnipod No tubing for easy weari Automatic cannula insertion and priming Remote bolusing Medtronic Paradigm Built-in CGM eliminates one device Simple to operate Carelink online software

7. Healthcare Across Borders - September 2003 Carb Counter Pumps offer user-selected food lists to improve carb counting Easy carb calculation Improves bolus accuracy Available in Accu-Chek Spirit (#1000 on PDA) Animas 1250 (#500) Deltec Cozmo (#250) Insulet Omnipod (#1000 on PDM) Current Feature

8. Healthcare Across Borders - September 2003 Problem: Exposure And Variability One day’s BG results with usual meals and insulin. The DCCT proved that exposure to high blood glucose was damaging. New emphasis is on glucose variability. Exposure or Average = Variability or Swing = A1c or avg. BG from meter SD from PC or meter

9. Healthcare Across Borders - September 2003 Therapy Effectiveness Scorecard Screen 1 : Average BG BG tests per day BG standard deviation Screen 2: Carbs per day TDD % of TDD as correction boluses % of TDD as carb boluses of TDD as basal rates

10. Healthcare Across Borders - September 2003 Therapy Scorecard Screen 1 14 Day Average: BG 146 mg/dl Tests 3.5/day Std Dev 53 mg/dl Overall control Adequate testing BG variability – aim for less than half of avg BG Monitor control, testing frequency, and glucose variablility

11. Healthcare Across Borders - September 2003 Therapy Scorecard Screen 2 14 Day Average: Carbs 206 g TDD 48.58 u Meal 38.07% Corr 4.95% Basal 56.98% Boluses taken? Low carb? Guides therapy – A1c, lows, etc Carb bolus % Corrections less than 8% of TDD? Is basal at least 40-45% of TDD? Monitor carb intake, TDD, basal/carb bolus balance, and correction bolus %

12. Healthcare Across Borders - September 2003 Check Your Correction Boluses  If correction boluses are NOT less than 8% of TDD:  Raise basal rates,  Raise carb boluses, or  Stop skipping carb boluses  Move half of the excess units above 8% into basal rates or carb boluses, whichever is smaller, or into both if basals and carb boluses are balanced Note: Paradigm pumps give correction bolus % as a % of total bolus dose, not the TDD. Do not use this percentage here!

13. Healthcare Across Borders - September 2003 Example: Correction Boluses Over 8% 10 Day Average: Carbs 175 g TDD 54.1 u Meal 36% Corr 21% Basal 43% Move 1/3 to 1/2 of the overage to basals or carb boluses: 21% of 54.1 = 11.3 units, 8% of 54.1 = 4.3 units 11.3 u - 4.3 u = 7 units excess 1/3 to 1/2 of 7 u = 2.3 to 3.5 u to be added to basal rates or carb boluses Over 8%

14. Healthcare Across Borders - September 2003 Weekly Schedule The user’s basal profile changes automatically for specific days of the week Different basal patterns and missed meal bolus alerts for each day of the week No need to remember to change basal patterns or alerts Great for regular exercise, college classes, shift work, and other routine variations in schedule Current Feature

15. Healthcare Across Borders - September 2003 Disconnect Bolus Disconnect for up to 2 hours for sports, sauna, etc. User estimates time off pump Pump offers to give up to 50% of missed basal as disconnect bolus Alarm reminds user to re-connect at set time On reconnecting, pump determines basal missed and offers to supply the missing basal amount Current Feature

16. Healthcare Across Borders - September 2003 Duration Of Insulin Action (DIA) How long a bolus lowers the blood sugar and Bolus On Board (BOB) Bolus insulin still active from previous boluses

17. Healthcare Across Borders - September 2003 Duration Of Insulin Action (DIA) 4 hrs 6 hrs 2 hrs 0 Accurate boluses require an accurate DIA. Glucose-lowering Activity Current Feature

18. Healthcare Across Borders - September 2003 A Short DIA Time May SEEM OK Pumpers and clinicians often set the DIA too short because: Recommended boluses do not bring high BGs down (ie, basal rates or carb bolus are too low) Shortening the DIA seems easier or safer than raising basal rates or lowering the carb factor. The default DIA is too short and never gets reset A low basal rate hides the true bolus activity

19. Healthcare Across Borders - September 2003 A short DIA hides the true BOB and its glucose- lowering activity. Hiding bolus activity makes boluses excessive and may cause basal rates to be lowered inappropriately Set your DIA to your insulin’s action time. Do not modify the DIA based on control problems. A Short DIA Can Cause Problems

20. Healthcare Across Borders - September 2003 A Comparison Of Linear And Curvilinear DIAs Set the DIA for a linear pump 30 minutes shorter to get results close to that of a curvilinear pump. A Deltec or Omnipod pump set at 4.5 hrs is equivalent to a Medtronic or Animas pump set at 5 hrs. Hrs Units of insulin activity left Curvilinear DIA = 5 hrs Linear DIA = 4.5 hrs

21. Healthcare Across Borders - September 2003 Recommended DIA Times From Pumping Insulin, 4th ed., adapted fom Mudaliar et al: Diabetes Care, 22: 1501, 1999 Set DIA to 4 hrs or more to calculate BOB and bolus doses accurately Linear Curvilinear

22. Healthcare Across Borders - September 2003 Blind Boluses Also Hide BOB Only 32.5% of 204,005 boluses from over 500 Cozmo pumps used across the US were accompanied by a BG value. 2/3 of boluses are given without a BG test Only 1 of every 7 boluses had both carbs and a BG Data in preparation for publication 67.5% blind boluses

23. Healthcare Across Borders - September 2003 Bolus On Board (BOB) The glucose-lowering activity that remains from recent boluses An accurate BOB calculation Prevents insulin stacking Improves bolus accuracy Reveals current carb or insulin deficit Your BOB can be determined only after a BG has been entered into pump! aka: insulin on board, active insulin, unused insulin* * Introduced as Unused Insulin in 1st ed of Pumping Insulin (1989)

24. Healthcare Across Borders - September 2003 BOB Prevents Insulin Stacking With a bedtime BG of 173, is there an insulin deficit or a carb deficit? 6 pm8 pm10 pm12 am Dinner Dessert Correction Bedtime BG = 173 mg/dl Insulin stacking is common for anyone who gives frequent boluses!

25. Healthcare Across Borders - September 2003 Hypo Manager Do you eat carbs or take insulin? 1 BG = 173 mg/dl (9.6 mmol) Bolus on board = 0.4 u Correction bolus: 1.2 u Insulin deficit = - 0.8 u Give 0.8 u now? Y or N 2 BG = 173 mg/dl (9.6 mmol) Bolus on board = 4.6 u Correction bolus: 1.2 u Insulin excess = 3.4 u You may need: 37 grams of carb later to prevent a low BG Only after a BG has been entered can a pump determine whether carbs or insulin are needed Helps prevent & treat hypoglycemia and avoid over-treatment Current Feature

26. Healthcare Across Borders - September 2003 Recommended Boluses Differ Between Pumps Does Your Pump Subtract BOB From Carb Boluses? Whenever BOB is greater than correction need, recommended boluses may be excessive for Paradigm and Omnipod pumps, or Animas pump when BG is above target 3.0U 45 gr 160 3.0U 1.0U 3.0U Excess BOB is subtracted from correction bolus, but NOT carb bolus 3 u + 1 u – 3 u - = 1 u bolus

27. Healthcare Across Borders - September 2003 Recommended Boluses Differ Between Pumps Carb factor = 1u / 10 gr Corr. Factor = 1 u / 40 mg/dl (2.2 mmol) over 100 mg/dl (5.6 mmol) Target BG = 100 mg/dl TDD = ~50 u units BG in mg/dl Bolus recommendations from different pump for various BGs when BOB = 3.0 u and 30 grams of carb will be eaten

28. Healthcare Across Borders - September 2003 Helpful Features Often Go Unused Reminders, alerts Entry of BG results Carb counting aids Temporary basal rates Alternate and temporary basal patterns Tracking and use of BOB Review of glucose history and insulin use Use features that can improve your control!

29. Healthcare Across Borders - September 2003 Helpful Reminders And Alerts Chech BG after a bolus after a low after a high Bolus at certain times Warn if bolus was not given for a particular meal * Warn if bolus was not completed * When to change infusion set Low reservoir (ie, 20, 10, 5 and 0 units, with extra 10 “hidden” units for basal delivery)* Current Feature * in Cozmo pump

30. Healthcare Across Borders - September 2003 Looking At History Helps Pump & Meter for direct BG entry Deltec Cozmo + Freestyle CoZmonitor Omnipod + Freestyle Paradigm + BD Logic Pump & Cont Mon, no direct BG entry Medtronic 5/722 + Paradigm RT Future Pumps & Cont Mons Abbott Navigator + Deltec Cozmo, or Insulet Omnipod Animas + Lifescan AccuChek Current Feature

31. Healthcare Across Borders - September 2003 Continuous Monitors

32. Healthcare Across Borders - September 2003 Old Tools

33. Healthcare Across Borders - September 2003 The Value of Frequent Testing Breakfast 100 (5.6) 200 (11) 400 (22) 300 (17) DinnerLunchBed 4 opportunities 1 opportunity to intervene 288 opportunities

34. Healthcare Across Borders - September 2003 Continuous Monitors Reduce Exposure & Variability 15 users with implanted Dexcom continuous monitors blind to glucose readout for 50 days, then open readout for the next 44 days. hrs/day More normal BGs - 65 min + 32 min + 250 min -13 min -160 min Fewer lows Fewer highs

35. Healthcare Across Borders - September 2003 Continuous Monitoring Benefits Lots more info Alarms to prevent lows & highs Security in knowing where the BG is and where it is going Trends shown by graph, arrows, or predictors Limitations Less accuracy Data gaps Minimal insurance coverage in U.S. Occ. cell phone, microwave, other interference

36. Healthcare Across Borders - September 2003 Continuus Monitor Components 1.Sensor through the skin 2.Radio transmitter on sensor 3.Receiver display BG readings every 1-5 min Trend graphs for 1, 3, 9, 24 hrs showing where BG has been and is going Trend arrows High and low alarms 4.Software to download & analyze data

37. Healthcare Across Borders - September 2003 Dexcom STS FDA approved 3/27/06 for 18 and older 7 day sensor Readings every 5 min. 3-14 days of readings per sensor One high, two low alerts $475 + $60 for each 7 day sensor Transmitter: ~$250 every 6 mos Good analysis software Transmitter ~0.8 x 1.5”

38. Healthcare Across Borders - September 2003 Medtronic Paradigm RT No closed loop FDA approved: 4/13/06, now for 7 and older One high and one low alert, trend arrow Readings every 5 min. $1340 + $35 for each 3 day sensor Transmitter: ~$900 every 6 mos Transmitter ~1.1 x 1.4”

39. Healthcare Across Borders - September 2003 Freestyle Navigator FDA approval expected soon Good accuracy below 100 mg/dl Calibration requires 10 hrs, then 1-2 times per day for 1st two days Readings every 1-2 minutes with trend arrow (4 clicks to trend graphic) 5 day use High and low glucose alarms Rate of change alarm Likely to be used in Deltec Cozmo and Insulet Omnipod pumps Investigational Device.Limited by U.S. Law to Investigational Use

40. Healthcare Across Borders - September 2003 TRU  Directional Trend Arrows Glucose going down -1 to -2 (mg/dL)/min Glucose going up 1 to 2 (mg/dL)/min Glucose falling quickly < -2 (mg/dL)/min Fairly stable glucose -1 to 1 (mg/dL)/min (3.3 mmol/hr) Glucose rising quickly > 2 (mg/dL)/min

41. Healthcare Across Borders - September 2003 Trend Arrows Have Limits No trend arrow = BG change up to 60 mg/dl (3.3 mmol) / hr An hour later 159 mg/dl (8.8 mmol) Now 100 mg/dl (5.6 mmol) 41 mg/dl (2.3 mmol) With a bedtime BG of 300 (16.7 mmol) and a level trend arrow, the breakfast reading could be 0 or 750 mg/dl (0 to 41.7 mmol)! Large BG changes with no trend arrow Trend arrows lack accuracy!

42. Healthcare Across Borders - September 2003 200 150 0 50 100 24p68p1012a 250 300 Line Graphs Provide Better Trend Info Shortest Trend 1 Hr – Dexcom 2 Hr – Navigator 3 Hr – Paradigm Longest Trend 9 Hr – Dexcom 24 Hr – Navigator & Paradigm Target Zone – all Event Icons – Navigator

43. Healthcare Across Borders - September 2003 Easy Basal Testing 10 pm 2 am 8 am 120 mg/dl © Pumping Insulin, 2006 Overnight basal test Goal: green line

44. Healthcare Across Borders - September 2003 Easy Bolus Testing 6 pm 8 pm 10 pm 300 200 100 60 Carb bolus Correction bolus © Pumping Insulin, 2006 6 pm 8 pm 10 pm Goal: green line

45. Healthcare Across Borders - September 2003 Continuous Monitor Study

46. Healthcare Across Borders - September 2003 A Comparison Of Continuous Monitors The Dexcom STS 3 Day & Paradigm RT continuous monitors were available for this study A head to head comparison of monitors while worn by one person with Type 1 diabetes. Each monitor’s accuracy tested against Ultra readings Monitor screens above show glucoses over the same 3 hour time span (range of 0 to 400 mg/dl). Ultra reading at the time was 73 mg/dl compared to 93 and 122 mg/dl.

47. Healthcare Across Borders - September 2003 Glycensit TM Analysis Blue dotted lines = ISO standards Yellow area = where 95% of data points will fall Red lines = minimum and maximum deviation by star points Ideally, all readings would fall between the blue dotted lines -- this is the standard for today’s glucose meters A B http://tomcatbackup.esat.kuleuven.be/GLYCENSIT/

48. Healthcare Across Borders - September 2003 Monitor Accuracy Table shows how much each monitor’s glucose values differed from a simultaneous reading on the Ultra meter. 44.3% 31.7% 12.2% 4.2% 3.4% 1.5% 0.8% 1.9% 19.8% 23.7% 17.6% 13.7% 10.3% 5.3% 2.7% 6.9% 76.0% 19.8% 4.2% 43.5% 41.6% 14.9%

49. Healthcare Across Borders - September 2003 Which Monitor Alerted First? Accurate warning of low and high readings is desired. This table shows which monitor alerted at least 5 min earlier for true lows and highs. Monitor A was first to alert for readings below 80 mg/dl 76% of the time, B was first 3% of the time, with 21% ties. For detection of highs above 160, Monitor A was first 68% of the time, B was first 5% of the time, with 27% ties.

50. Healthcare Across Borders - September 2003 More On Accuracy 1 R L Weinstein et al: Diabetes Care, 30, 1125-1130, 2007 Navigator 5 day (shown in graph) 1 Median ARD = 9.3% Clark error grid A: 81.7% B: 16.7% C and D: 1.7% Dexcom 7-day (to FDA - not shown): Median ARD = 17% Clark error grid A: 70% B: 28% C and D: 3%

51. Healthcare Across Borders - September 2003 Continuous Monitors Today Readings have to be validated with a meter Not used by pump for dose calculations No warning when a reading is inaccurate Need daily calibration with fingerstick BGs Accuracy varies between devices and over time Otherwise wonderful

52. Healthcare Across Borders - September 2003 Future Devices And Pumps

53. Healthcare Across Borders - September 2003 Animas Debiotech Micropump Animas is one of several companies developing very small insulin pumps from Micro-Electro-Mechanical Systems or MEMS technology. Made from silicon, can be mass-produced at low cost

54. Healthcare Across Borders - September 2003 Valeritas H-Patch Pump Good introduction for Type 2s to basal/bolus therapy Automatic needle insertion Single basal available as 20, 30, or 40 units per day Button on pump delivers 2U per push

55. Healthcare Across Borders - September 2003 Pressure Pumps Pressure from small solenoid drives precise insulin delivery Eliminates need for motor and solid reservoir Insulin can be stored in a bladder to reduce size Two bladders with independent controls allow dual delivery Dual pumping for: Insulin + symlin Insulin + glucagon Or a micro pull/push interstitial glucose monitor

56. Healthcare Across Borders - September 2003 ExFactors For Activity Enter into pump: 1.Exercise intensity (1-7 scale) 2.Exercise duration (15-480 min) 3.Current level of fitness for that activity (1-5 scale) Pump then shows carb intake or insulin reduction needed for the activity Future Pump Feature

57. Healthcare Across Borders - September 2003 Temporary Basal Reduction For Excess BOB A temporary basal reduction offsets excess BOB so it is not necessary to eat at bedtime. Future Pump Feature

58. Healthcare Across Borders - September 2003 Super Bolus For A High GI Meal Shift Basal To Bolus A Super Bolus shifts part of the next 2-4 hours of basal insulin into an immediate bolus. Gives a faster insulin effect for high GI and large carb meals with less risk of a low. Activated whenever user eats more than a selected quantity of carbs, such as 30 or 40 grams Future Pump Feature

59. Healthcare Across Borders - September 2003 Super Bolus For A Postmeal High Shift Basal To Bolus Enables a faster correction of highs with less risk of a low. Future Pump Feature

60. Healthcare Across Borders - September 2003 Automatic Basal/Bolus Testing A pump could automatically test: The TDD from Average blood sugar, stand. dev., frequency of lows % TDD used for corrections Basal/bolus balance Basal rates from Daytime when a meal is skipped (accounting for BOB) Overnight (accounting for BOB at bedtime) The carb factor from Premeal, 2 hr postmeal peak, normal in 4-5 hrs? The correction factor from High-to-normal in 4-5 hours? Current And Future Pump Feature

61. Healthcare Across Borders - September 2003 Pattern Analysis Pattern shows Inadequate or missed breakfast boluses or inadequate day basal rate Correction or carb boluses appear to be excessive at lunch Tests only when low in evenings Devices make sense of patterns in real time analyze history accurately much faster than MDs and RNs! Future Pump Feature

62. Healthcare Across Borders - September 2003 Insulin Lookback To find out if a low or high reading was caused by basals or boluses, a pump can compare: how much basal and how much bolus was active in the previous 5 hours Lows – usually caused by the larger insulin amount Highs – usually caused by the smaller insulin amount Future Pump Feature

63. Healthcare Across Borders - September 2003 Lookbacks # 1 BG = 47 at 1:00 am 5 hr. lookback: Boluses = 9.2 u Basal = 4.6 u

64. Healthcare Across Borders - September 2003 Lookbacks # 2 BG = 228 at 4:30 pm 5 hr. lookback: Boluses = 6.5 u Basal = 2.4 u

65. Healthcare Across Borders - September 2003 Delay Eating Alert Delay eating when BG is OK for high GI meal or a large # of carbs Future Pump Feature Allows insulin to start working before carbs begin to raise the blood sugar. Result: less glucose exposure Don’t forget to eat when pump alerts it is time!

66. Healthcare Across Borders - September 2003 Delay Eating Alert Delay eating when BG is high A lower glucose at the start of a meal reduces glucose exposure. Remember: Test early Don’t forget to eat on time Don’t forget the bolus was given Future Pump Feature

67. Healthcare Across Borders - September 2003 Continuous Monitor Tips

68. Healthcare Across Borders - September 2003 No Two Points Are Created Equal! Level of Risk Depends on Trend Going Up Lower Risk Going Down Higher Risk

69. Healthcare Across Borders - September 2003 Going Up: Consider Action! 187 8:43 AM 1 hr Bolus too small or too late

70. Healthcare Across Borders - September 2003 Watch For Peaking Out! 187 8:43 AM 1 hr Peak Wait!!

71. Healthcare Across Borders - September 2003 Wait and Watch! 1 hour And check BOB

72. Healthcare Across Borders - September 2003 Turnaround Time An Object in Motion Stays in Motion

73. Healthcare Across Borders - September 2003 Don’t Stack The Insulin

74. Healthcare Across Borders - September 2003 Look And Learn Breakfast bolus too small or too late Lunch bolus too small or afternoon basal too low Excess night basal or bedtime bolus

75. Healthcare Across Borders - September 2003 Stay Between The Lines As readings improve, lower the glucose for the upper alert

76. Healthcare Across Borders - September 2003 Continuous Monitoring Tips Be patient, have realistic expectations Don’t panic when your meter and sensor differ Expect some lag time Don’t react too quickly and stack your insulin Look at trends, not just individual values Rapid rises usually mean more insulin is needed Validate your readings with a meter

77. Healthcare Across Borders - September 2003 Wrap Up Pumps and continuous monitors offer technology improves control More flexibility and confidence, less hypoglycemia, less glucose exposure, less variability, and a healthier life Data easily analyzed with suggested improvements that guide user toward improved control through success Requires commitment, responsibility and training, but less work for everyone overall

78. Healthcare Across Borders - September 2003 Questions & Discussion