1. Current And Emerging Technologies In Insulin Pumps & Continuous Monitors May 8, 2008 John Walsh, PA, CDE jwalsh@diabetesnet.com (619) 497-0900 Advanced Metabolic Care + Research 700 West El Norte Pkwy Escondido, CA 92126 (760) 743-1431

2. Highlights Background Smart Pumps and Features Pump Control Tips DIA and BOB Super Bolus Continuous Monitors and Tips Wrap Up

3. EDIC Study Findings Lower Glucose Prevents Heart Attacks & Early Death After the DCCT ended in 1993, the EDIC Study has followed these participants. Over 11 years, A1c levels in intensive and conventional control groups have been identical at 7.9% (was ~7.4% and ~9.1%). However, heart attacks and strokes have been twice as high (98 vs 46) in the original conventional versus intensive group, even though A1c levels have been identical since the DCCT trial ended. 1. EDIC Study Group presentation at 2005 ADA, K.M. Venkat Narayan: Clinical Diabetes 24:88-89, 2006

4. EDIC Study Findings Lower Glucose Temporarily Reduces Nerve Damage The tight control group also experienced half as much neuropathy BUT, as shown in figure, improved control in the past delays progression but offers no long-term protection Also, an A1c of 7.9% does not stop progression of nerve damage (or CVD) Take Home: Improve control and KEEP it there! Diabetes Care, Vol 29, No. 2, pp. 340-344 Avg A1c = 7.9%

5. Goal: A Healthy, Saner Life With Less Glucose Exposure And Variability The DCCT proved that exposure to high blood glucose was damaging. New emphasis is on glucose variability. Glucose Exposure = Glucose Variability (Swing) = A1c or average BG from meter SD* from PC or meter

6. Current Pump Reality Pumps provide only modest improvements in A1c levels over MDI: About 0.6% lower (mid to upper 8% range) Avg. A1c of 8.5% is well above goal of less than 7% or 6.5% But glucose levels ARE more stable with less insulin needed per day

7. Smart Pump Features

8. Smart Pump Features – Overview  Automatic carb and correction calculations based on: Carb and correction factors Glucose targets DIA avoids insulin stacking Carb and correction boluses adjusted for BOB for accuracy and safety  Personal carb database  Correction bolus shown as % of TDD  Direct glucose entry and detailed glucose history  Reminders, alerts, weekly schedule, temp basal rates, etc.

9. Deltec Cozmo Features: # Pumps HypoManager1 Weekly Schedule1 Missed Meal Bolus1 Bolus Not Completed1 Disconnect Bolus1 Basal Test1 Meal Maker with CozFoods4 Therapy Effectiveness2 BG Variability (SD)1

10. Meter/CGM Improve BG History Pump + Meter – direct BG entry Deltec Cozmo + Freestyle CoZmonitor Omnipod + Freestyle Paradigm + Lifescan (US)/Bayer (Eur) Pump + Cont Mon – no direct BG entry Medtronic x22 + Paradigm RT Future Pump + Meter/Monitor Combos Animas pump + Lifescan meter Cozmo + Abbott Navigator Animas & Omnipod + Dexcom AccuChek pump + meter

11. Disconnect Bolus Disconnect up to 2 hrs for sports, sauna, sex, etc. Useful for “Mini-vacations” User estimates time off and pump gives up to 50% of missed basal as bolus Alarm reminds user to re-connect On reconnecting, pump shows missed basal and offers to supply the missing amount

12. Weekly Schedule User’s profile changes automatically for specific days of the week Allows 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 college, shift work, weekends, exercise, or other regular variation in schedule

13. Pump As Carb Counter  Pump or external controller contains user-selected food list for accurate carb counting for Easy carb calculations More accurate boluses  Available in Animas 2020, Deltec Cozmo, Omnipod PDM, and Spirit PDA

14. Carb Bolus Varieties Regular Taken immediately – for most meals Extended / square wave Extended over time – gastroparesis Combo / dual wave Some now, some later – bean burrito, some pastas and pizzas, Symlin

15. Helpful Aids And Alerts Carb or insulin recommendation for each BG Bolus-not-completed alert Missed meal bolus alert Check after high or low BG 10 extra units for basal when reservoir reads zero Easier analysis with TDD and basal/bolus balance Overview of basal/bolus balance and correction bolus Not available in all pumps

16. Getting The Big Picture Therapy Effectiveness – A summary of glucose and insulin history

17. Therapy Effectiveness Scorecard  Screen 1: Average BG (over 2 to 30 days) BG tests per day BG standard deviation (SD)  Screen 2: Carbs per day TDD  % correction boluses  % carb boluses  % basal rates Largely available in Paradigm pumps as well

18. Therapy Scorecard Screen 1 14 Day Average: BG 146 mg/dl Tests 3.5/day Std Dev 53 mg/dl Overall control Adequacy of testing BG variability – aim for less than 65 mg/dl or less than half of average BG Monitor control, testing frequency, glucose variability

19. 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 diet? Guides therapy – A1c, lows, etc Carb bolus % Correction less than 8% of TDD? Basal at least 40 to 45% of TDD? Monitors carb intake, TDD, basal/carb bolus balance, correction bolus%

20. Check Correction Bolus %  If correction boluses make up more than 8% of the TDD (and lows are NOT a problem):  Move half of the excess units above 8% into basal rates or carb boluses  Raise the basal rates  Lower the carb factor  Or stop skipping carb boluses

21. 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 add to basals or carb boluses Over 8%

22. Therapy Effectiveness Guides TDD – Raise for frequent highs or high A1c Lower for frequent lows or for frequent lows and highs Basal/Bolus Balance – about 50% of TDD Correction Factor = ~ carb factor X 4.4 (mg/dl), carb factor / 4 (mmol) Correction Bolus % – if over 8% of TDD, move excess into basals or carb boluses Average BG – < 160 when checking before & after meals, < 140 when checking mainly before meals Standard Deviation – Keep less than 1/2 of avg BG or below 65 mg/dl

23. Pump Control Tips

24. High BGs? Keep The Usual Suspects In Mind I ate too much Bad infusion set or site Inaccurate carb counts Missed or late boluses Bad insulin Stress hormone rebound Empty refrigerator syndrome Stress, pain, steroid meds

25. Bad Infusion Set Or Site If you have “unexplained” highs: How often do they happen? Do they correct only when you replace your infusion set? If you answer yes: Always use tape to anchor the infusion line Consider changing to a different infusion set The right infusion set and good site technique prevents headaches and improves your A1c

26. Tape The Tubing!!! Put 1” tape on the infusion line to stop Teflon tugs Tape the tubing down to stop movement of Teflon catheter under the skin Stops “unexplained highs” caused when insulin leaks back to surface Less skin irritation Prevents pull outs Lose tape not insulin! No anchor!

27. Tape The Tubing!!! Lose tape not insulin! Photo courtesy of kerri@sixuntilme.com

28. Use Sterile Technique For Site Prep 30% of people are constant staph carriers and 25% are intermittent. MRSA is now common. Prevent infections: Wash hands Sterilize skin with IV Prep Place bio-occlusive IV3000 over site Insert infusion set through IV 3000 Steps for staph carriers: Use antiseptic soap all over body once every 1-2 weeks Occasionally, apply bacitracin ointment to inside of nose

29. Pump Settings That Affect Control

30. Important Pump Settings TDD – adjust when having frequent lows or highs Basal % – basal/bolus balance, secure sleep Basal rate variation – large variation not physiologic Carb factor – postmeal control Carb factor variation – may indicate basal problem Correction factor – lower high BGs safely DIA – bolus accuracy, HypoManager

31. CDA1 Study Carb Factors From Cozmo CDA Study  Note how actual carb factors are distributed in blue  They are NOT bell-shaped!!!  People prefer “magic” numbers – 7, 10, 15, and 20 (grs/unit) – for their carb factors  A normal, bell-shaped, physiologic distribution is shown in green  MANY “magic” carb factors are inaccurate 7 10 115 20

32. Carb Factors From CDA1 Sudy  Graph shows carb factor versus TDD for 200 pumps with better control (avg BG < 209 mg/dl)  Note a break in relationship (red line) near a TDD of 40 u/day or carb factor of 10  Suggests that people are hesitant to lower carb factors below 10

33. CDA1 Carb Rule #s Compared To PI The average carb factors in the blue boxes are those used in pumps with better control where the avg BG was 209 mg/dl or less. TDDs are shown in the tan box on the left. 450-475 475-625 Carb Rule #s

34. CDA1 Basal/Bolus Balance  As TDD rises, basal percentage falls slightly from 51.7% at a TDD of 20 u to 49.4% at 40 u and 48.3% at 80 u  Basals vary widely – 27% to 83% of TDD  Many basal rates do not appear to be accurate  If correction bolus excess is distributed evenly into basals and carb boluses, “real” basal rates would average over 50% of TDD

35. Walsh-Roberts Rules For Optimum Readings Starting TDD = (TDD X 0.9) + (wt [lbs]/4* X 0.9) ** 2 Keep Basal/Bolus Balance near 50/50 Basal test – rise/fall less than 30 mg/dl (1.7 mmol) over 8 hrs 500 Rule for Carb Factor 2000 Rule for Correction Factor (110 Rule for mmol) Set DIA at 4 to 6 hrs Keep correction boluses less than 8% of TDD * or kg/1.8 ** If current TDD less than wt/4 with good control, TDD = current TDD X 0.90 J Walsh and R Roberts: Pumping Insulin, 2006

36. Delay Eating When BG Is High Glucose exposure is reduced when high readings are allowed to fall before eating. Remember: Test early Don’t forget to eat on time Don’t forget you bolused

37. Duration Of Insulin Action (DIA) How long a bolus lowers your glucose Bolus On Board (BOB) Bolus insulin still active from previous boluses

38. Problem Most Carbs Are Faster Than “Rapid” Insulin % bolus activity remaining From Pumping Insulin Take Home:Bolus 15 to 30 minutes before meals Use extended and combo boluses sparingly Time over which most meals affect the BG An hour later, half of most meal’s glucose rise has occurred, but 80% of rapid insulin activity remains

39. Typical Carb Digestion Times Food Digestion Time water 0 m fruit/veg juice 5-20 m fruit/veg salad 20-40 m melons/oranges 30 m apples/pears 40 m broccoli/caulif 45 m raw carots/beets 50 m potatoes/yams 60 m cornmeal/oats 90 m Food Digestion Time fish 30-60 m milk/cot cheese 90 m legumes/beans 120 m egg 45 m chicken 1.5-2 hr seeds/nuts 2.5-3 hr beef/lamb 3-4 hr cheese 4-5 hr Take Home: Choose combo foods to lengthen carb digestion time

40. Best Bolus Timing For Carbs Figure shows rapid insulin injected 0, 30, or 60 min before a meal Normal glucose and insulin profiles shown in the shaded areas DO NOT bolus an hour ahead of your meals!!!

41. Accurate DIA Prevents Lows Accurate DIA Time Accurate BOB Accurate Boluses Accurate HypoManager Prevents Lows

42. A short DIA hides true BOB level and its glucose- lowering activity Causes “unexplained” lows Leads to incorrect adjustments in basal rates, carb factors, and correction factors Or user starts to ignore “smart” pump’s advice Set DIA based on real insulin action time. Do not modify DIA time to fix a control problem. Short DIAs Hide Bolus Insulin Activity

43. Duration Of Insulin Action (DIA) 4 hrs 6 hrs 2 hrs 0 Accurate boluses require an accurate DIA Glucose-lowering Activity DIA times shorter than 4 to 7 hrs will hide BOB and its glucose lowering activity

44. Large Doses, Longer Duration  Large doses (0.3 u/kg or 30 u for 220 lb. person) of “rapid” insulin in 18 non-diabetic, obese people show significant activity beyond 4 hours.  Medium doses (0.2 u/kg or 10 u for 110 lb. person) show similar results. Large doses may lengthen DIA Apidra product handout, Rev. April 2004a

45. Dose Size May Affect Duration Of Action For a 154 lb or 70 kg person: 0.05 u/kg= 3.5 u 0.1 u/kg = 7 u 0.2 u/kg = 14 u 0.3 u/kg = 21 u Woodworth et al. Diabetes. 1993;42(Suppl. 1):54A

46. But Studies Routinely Underestimate DIA  To measure pharmacodynamics, glucose clamp studies are done in healthy individuals  SQ doses from 0.05 to 0.3 u/kg  But injected insulin ALSO SUPPRESSES normal basal release from the pancreas (grey area in figure)  Unmeasured basal suppression makes smaller boluses appear to have a shorter DIA  When basal suppression is accounted for, true DIA times become longer

47. Recommended DIA Times A DIA of 4 to 6 hrs gives best estimate for residual bolus activity A longer DIA is a safer DIA 4 hr Linear 4 hr Curvilinear From Pumping Insulin, 4th ed., adapted fom Mudaliar et al: Diabetes Care, 22: 1501, 1999

48. DIA Time Selection Current limited research suggests that DIA times are NOT different between children and adults Immediate factors can change insulin action time: Shorter with activity and exercise Shorter in hot weather Longer with fat in diet Do not change DIA time for temporary factors

49. DIA Tips If pump often suggests boluses that are too small, do not shorten the DIA– it is rarely NOT problem Instead, ask what is causing the highs and where more insulin is needed – in basal rates, in carb boluses, or both DO NOT shorten the DIA for occasional activity. Instead: lower boluses or basals ahead of time for planned activities or eat more carbs or lower basals for unplanned activities Basal rates that are too low make the DIA appear SHORT!

50. How Different Pumps Handle DIA Differences In DIA Calculations DIA Type % Of DIA Measured Default DIA My Preferred DIA Time Increment For DIA Animas 2020 Curvilinear100%4 hrs4.5 to 6 hrs30 min Deltec Cozmo Linear100%3 hrs4 to 5.25 hrs15 min Insulet Omnipod Linear100%4 hrs4 to 5.5 hrs30 min Paradigm 522/722 Curvilinear95%6 hrs5 to 6 hrs60 min

51. Bolus On Board (BOB) Glucose-lowering activity that remains from recent boluses An accurate BOB Prevents insulin stacking Improves bolus accuracy Reveals current carb or insulin deficit Basal insulin is NOT measured by BOB! aka: insulin on board, active insulin, unused insulin* * Introduced as Unused Insulin in 1st ed of Pumping Insulin (1989)

52. BOB Prevents Insulin Stacking Bedtime BG = 173 Is there an insulin or a carb deficit? 6 pm8 pm10 pm12 am Dinner Dessert Correction Bedtime BG = 173 mg/dl

53. BOB Is Present In 65% Of Boluses CDA1 Study Results Of 201,538 boluses, 64.8% were given within 4.5 hrs of a previous bolus An accurate DIA shows that BOB is present for MOST boluses Take Home: insulin stacking is a common threat 4.5 hrs

54. Blind Boluses Hide BOB  In 2005, only 28,969 of 117,711 carb boluses given by 541 pumps across the US were accompanied by a BG value.  6 of 7 carb boluses are blind – given with no BG  With no BG, BOB cannot be accounted for by the pump in most carb boluses 85.8% blind boluses

55. Before giving a bolus, check your BOB (via BG). Do not give blind boluses.

56. BOB Is BOB If BOB is present, it doesn’t matter how it got there. Safety requires that BOB be subtracted from BOTH carb and correction boluses to avoid hypoglycemia. BOB is measured only when a BG is entered into pump!

57. How Different Pumps Handle BOB What’s In BOB And What Is It Applied Against? BOB Includes This Type Of Bolus BOB Is Subtracted From This Type Of Bolus CarbCorrectionCarbCorrection Animas 2020Yes No*Yes Deltec CozmoYes Insulet OmnipodNoYesNoYes Medtronic ParadigmYes NoYes * Except when BG is below target BG

58. Different Pump Bolus Recommendations BOB = 3.0 u and 30 gr. of carb will be eaten at these glucose levels Carb factor = 1u / 10 gr Corr. Factor = 1 u / 40 mg/dl over 100 Target BG = 100 TDD = ~50 u units mg/dl Omnipod cannot be determined here - it counts only correction bolus insulin as BOB Bolus recommended by each pump when:

59. Recommended Bolus Errors Can Be Corrected 3.0U 30 gr 160 3U 1.5U 4.5U A Paradigm user can scroll down 3 times to see active insulin, then adjust dose: 3 + 1.5 - - 4.5 - = 0 u bolus 30

60. HypoManager Shows current insulin OR carb deficit

61. HypoManager Compares BOB to correction bolus need: When BOB is smaller –> all pumps recommend a correction bolus When BOB is larger –> Cozmo recommends eating carbs A very helpful feature: Shows current carb OR insulin deficit Reduces overeating when BG is low Warns when carbs may be needed later even though current BG is OK or high.

62. HypoManager Helps TREAT lows Encourage users to test when low The BG reading triggers what should be an accurate recommendation for carb intake to treat that low Prevents ETRS – “Empty The Refrigerator Syndrome” Don’t use with Symlin, ?gastroparesis

63. Continuous Monitors

64. CGM Benefits Increased sense of security Immediate feedback – look and learn Control with safety Worth out of pocket cost for many Reimbursement gradually catching on

65. Continuous Monitor A continuous monitor (OR frequent meter checks) can assist optimum energy flow Optimum BG range for energy flow

66. Plus Insulin Pump With full BG record, basals and boluses can be adjusted to provide optimum fuel flow Optimum BG range

67. 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 Accuracy Data gaps Insurance coverage Occ cell phone and other interference

68. Continuous Monitor Tips

69. CGM: Look And Learn Excess night basal or bedtime bolus Breakfast bolus too small or too late Lunch bolus too small or afternoon basal too low

70. No Two Points Are Created Equal! Lower Risk Going Up Higher Risk Going Down Level of a BG’s risk depends on its trend

71. Turnaround Time A Glucose in Motion Stays in Motion

72. Don’t Stack Insulin

73. Stay Between The Lines As readings improve, bring the upper glucose target alert line down

74. Continuous Monitoring Tips Be patient, have realistic expectations Don’t panic when 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

75. Comparison Of Two Continuous Monitors The Dexcom STS 3 Day & Paradigm RT continuous monitors were worn at the same time by one person with Type 1 diabetes. With low alert at 80 mg/dl and high alert at 160 mg/dl, 262 readings from Ultra meter performed over 33 days. Ultra tests done: As soon as either monitor’s low or high alert sounded When values between the monitors disagreed And at routine intervals, including calibrations Screens show same 3 hr time period (0 to 400 mg/dl), Ultra reading was 73 mg/dl.

76. Glycensit TM Analysis Simultaneous comparison vs 262 Ultra readings over 33 days 1.Blue dotted lines = ISO meter standard 2.Yellow area = 95% of all data points 3.Red lines = min and max deviation by star points Ideally, all readings would fall between the blue dotted lines A B http://tomcatbackup.esat.kuleuven.be/GLYCENSIT/

77. Which Monitor Alerted First? 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% as ties. Monitor A was first to arlert for readings above 160 mg/dl 68% of the time, B was first 5% of the time, with 27% as ties.

78. More On Monitor 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 (not shown): Median ARD = 17% Clark error grid  A: 70%  B: 28%  C and D: 3%

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