1. DAVID C KLONOFF, MD Medical Director Dorothy L. and James E. Frank Diabetes Research Institute of Mills-Peninsula Health Services Clinical Professor of Medicine, UCSF

3. AUGUST 13, 2005 KEYSTONE RESORT GLUCOSESENSORS IN ACHIEVING TARGET A1C

4. San Francisco

5. Mills Health Center San Mateo, California

6. Spring, 1999 Vol. 1, No. 1 ISSN 1520-9156

7. A SENSOR IS A DEVICE THAT DETECTS OR SENSES A SIGNAL AND CAN MEASURE GLUCOSE INTERMITTENTLY IN BLOOD OR CONTINUOUSLY IN ISF DEFINITION

8. Three Waves of Technology in Diabetes Monitoring Three Waves of Technology in Diabetes Monitoring (1)UrineTesting (2) Intermittent Intermittent Blood Glucose Testing (3)ContinuousGlucoseMonitoring

9. INTERMITTENT BLOOD GLUCOSE SENSORS IN ACHIEVING TARGET A1C Improves control in T1DM and insulin-treated T2DM Generally does not improve control in T2DM on diet or OHAs Prevents severe hypos in all pts Works best if pts know to respond CURRENT STATUS

10. ASSOCIATION BETWEEN FREQUENCY OF SMBG TESTING AND A1c IN T1DM A1c = 5.99 + 5.32 / ([number of glucose tests per day] + 1.39) Davidson et al. Diabetes 2004; 53 (Suppl 2): A101 n=378 0 2 4 6 8 10 12 SMBG Tests per Day A1c (%) 10 9.5 9 8.5 8 7.5 7 6.5 6 5.5 5 378 T1DM INSULIN PUMP USERS

11. SMBG FREQUENCY CORRELATES WITH A1C ADJUSTED FOR DEMOGRAPHIC VARIABLES For full adherence  A1C = 1.0% in T1 DM 0.6% in T2 DM P <.0001 No r values calculatedKarter et al. Am J Med 2001: 111:1-924,312 Kaiser Northern Calif adults (95% T2 / 5% T1) A1c (%)

12. SMBG FREQUENCY CORRELATES WITH A1C ADJUSTED FOR DEMOGRAPHIC VARIABLES For full adherence  A1C = 1.0% in T1 DM 0.6% in T2 DM P <.0001 No r values calculatedKarter et al. Am J Med 2001: 111:1-924,312 Kaiser Northern Calif adults (95% T2 / 5% T1) For each additional SMBG per day - A1c fell by 0.3% A1c (%)

13. July 2005 ● Volume 22 ● Pages 200-206 SELFMONITORING OF BLOOD GLUCOSE IN NON-INSULIN-TREATED DIABETIC PATIENTS: A LONGITUDINAL EVALUATION OF ITS IMPACT ON METABOLIC CONTROL M. Franciosi, F. Pellegrini, G. De Berardis, M. Belfiglio, B. Di Nardo, S. Greenfield, S. H. Kaplan, M. C. E. Rossi, M. Sacco, G. Tognoni, M. Valentini and A. Nicolucci for The QuED Study Group quality of care and outcomes in Type 2 diabetes 1896 T2DM non-insulin-treated patients followed for 3 years Freq of SMBG did not predict better control but did predict fewer hypoglycemic episodes

14. THE DiGEMtrial PROTOCOL A 12-MONTH RCT IN T2DM TO DETERMINE THE EFFECT OF 3 STRATEGIES OF SMBG ON CONTROL 450 T2DM PATIENTS ON OHAs OR DIET 450 T2DM PATIENTS ON OHAs OR DIET CONTROL Rx: Q 3 MO A1c WITH NP INTERPRETATION CONTROL Rx: Q 3 MO A1c WITH NP INTERPRETATION SMBG WITH ADJUSTMENTS IN Rx PER NP ONLY SMBG WITH ADJUSTMENTS IN Rx PER NP ONLY SMBG WITH ADJUSTMENTS IN Rx PER SUBJECT OR NP SMBG WITH ADJUSTMENTS IN Rx PER SUBJECT OR NP STUDY TO REPORT IN 2007 STUDY TO REPORT IN 2007 1 2 3 BMC Fam Pract 6: 25; 2005

15. CONTINUOUS GLUCOSE SENSORS IN ACHIEVING TARGET A1C Provides around-the-clock info on absolute BG values and trends Five products now approved and two are being evaluated by the FDA Greater accuracy needed Reimbursement is inconsistent CURRENT STATUS

16. Purpose Technologies Target Populations Accuracy Clinical Indications Outcomes Future Trends CONTINUOUS GLUCOSE MONITORING OUTLINE

17. Purpose Technologies Target Populations Accuracy Clinical Indications Outcomes Future Trends CONTINUOUS GLUCOSE MONITORING OUTLINE

18. PURPOSE OF CONTINUOUS GLUCOSE MONITORING To obtain maximal information about shifting blood glucose levels throughout the day to make the best treatment decisions

19. Purpose Technologies Target Populations Accuracy Clinical Indications Outcomes Future Trends CONTINUOUS GLUCOSE MONITORING OUTLINE

20. APPROVED PRODUCTS IN US & EUROPE Continuous Glucose Monitoring System Gold (CGMS Gold) Guardian Europe only) Guardian RT * (Europe only) GlucoWatch ® G2 Biographer Europe only) GlucoDay * (Europe only) CONTINUOUS GLUCOSE MEASUREMENT DEVICES

21. CONTINUOUS GLUCOSE MONITORING SYSTEM GOLD (CGMS GOLD)

22. SENSERTER GLUCOSE SENSOR SENSOR COM-STATION TO DOWNLOAD DATA MONITOR CGMS GOLD - CONTINUOUS GLUCOSE MONITORING SYSTEM

23. MEDTRONIC MINIMED GUARDIAN AND GUARDIAN RT

25. Sensor Transmitter Monitor Alarm (50 db) MEDTRONIC MINIMED GUARDIAN COMPONENTS

26. GLUCOWATCH ® G2 BIOGRAPHER

27. TIMEGLUCOSETREND

28. MENARINI GLUCODAY

29. CONTINUOUS GLUCOSE MONITOR ITALY

30. ABBOTT LABORATORIES FREESTYLE NAVIGATOR

31. Abbott Laboratories FreeStyle Navigator™ Continuous Glucose Monitor FEATURES 1 Enzyme-tipped SC catheter 2 Wireless transmission to monitor up to 10 ft away 3 Reads Q 1 min in real time 4 Sensor lasts 3 days

32. Attach Sensor Mount to Skin Press to Insert Sensor Data is Transmitted to Receiver DEPLOYMENT OF THE NAVIGATOR 1 2 3 4 Attach Transmitter to Sensor Mount 3

33. DEXCOM SHORT-TERM CONTINUOUS GLUCOSE MONITORING SYSTEM (STS)

35. Purpose Technologies Target Populations Accuracy Clinical Indications Outcomes Problems CONTINUOUS GLUCOSE MONITORING OUTLINE

36. RELATIVE ABSOLUTE DIFFERENCE (RAD) = I EXPERIMENTAL BG – REFERENCE BG I 1 REFERENCE BG 100 x A TOOL FOR DETERMINING ACCURACY IN AN EXPERIMENTAL BLOOD GLUCOSE MONITOR RAD IS EXPRESSED AS A PERCENTAGE

37. ACCURACY STUDIES BY DIRECNET RAD of CGMS 19% & 12% RAD of CGMS Gold 11% & 12% RAD of GW2B 16% DirecNet: Diabetes Technol Ther 2005 ; 7:109-114 200 children with T1DM in an outpatient setting 91 and 89 children with T1DM in a CRC setting DirecNet: Diabetes Technol Ther 2003 ; 5: 781-789 and 791-800 CONTINUOUS GLUCOSE MONITORING

38. INTERNATIONAL ORGANIZATION FOR STANDARDIZATION (ISO) CRITERIA A TOOL FOR DETERMINING ACCURACY IN AN EXPERIMENTAL BLOOD GLUCOSE MONITOR Ref BG > 75 mg/dl: Sensor BG +/- 20% Ref BG < 75 mg/dl: Sensor BG +/- 15 mg/dl Data expressed as % of pairs meeting above criteria

39. One Touch Ultra CGMS Gold GW2B % of Values Meeting ISO Criteria Reference Glucose Values (mg/dl) ISO ACCURACY OF CONTINUOUS BG MONITORS DirecNet: Diabetes Technol Ther 2003; 5: 781-789 and 791-800

41. Similar Mean BGs: 188 mg/dl 183 mg/dl Mean noc BG: 199 mg/dl 174 mg/dl ? ↑ specificity low BG ? ↓ specificity low BG Similar BG / A1c ratios: 23 mg/dl per 1% A1c 19/mg/dl per 1% A1c 2-hr PP ∆BG PM: - 2-hr PP ∆BG PM: + Compliance (72h): 10% Compliance Median: 70h EIGHT-POINT TESTING ADVANTAGES EIGHT-POINT TESTING VS CGMS TO EVALUATE CONTROL IN T1DM CGMS MONITOR ADVANTAGES JCEM 2005; 90: 3387-3391 Children with T1DM n = 200

42. Purpose Technologies Target Populations Accuracy Clinical Indications Outcomes Future Trends CONTINUOUS GLUCOSE MONITORING OUTLINE

43. Assess impact of an adjustment in therapy to improve control Achieve tighter control without causing hypoglycemia ( e.g. peds DM, GDM, ICU) Diagnose / prevent hypoglycemia during sleep or hypoglycemia unawareness Quantify the response in clinical trials SITUATIONS REQUIRING DETAILED INFO ABOUT GLUCOSE FLUCTUATIONS CLINICAL INDICATIONS TO USE CGM

44. Type or dose of mealtime insulin Type or dose of basal insulin Treatment of High or Low BG Insulin: Glucose ratio for High BGs Insulin: CH 2 O ratio at mealtime Carbohydrate composition of diet Discount in short-acting ins for exercise HS regimen because of dawn phenom Target pre- or post- prandial BG Refer to Ψ to improve adherence ELEMENTS OF THERAPY THAT CAN BE ADJUSTED WITH CGM

45. (#1 of 8) Increase dose of mealtime insulin (#1 of 8) (#1 of 9) Type of basal insulin. (#1 of 9) Treatment of High or Low BG Insulin: Glucose ratio for High BGs Insulin: CH 2 O ratio at mealtime Carbohydrate composition of diet Discount in short-acting ins for exercise HS regimen because of dawn phenom Target pre- or post- prandial BG Refer to Ψ to improve adherence ELEMENTS OF THERAPY THAT CAN BE ADJUSTED WITH CGM Sabbah et al: Diabetes 2000; 49 (Suppl 1): A393 Kaufman et al: Diabetes Care 2001; 24: 2430-2434 I Type

46. Purpose Technologies Target Populations Accuracy Clinical Indications Outcomes Future Trends CONTINUOUS GLUCOSE MONITORING OUTLINE

47. Six RCT’s: two showed SS ↓ in A1c, three showed NSS ↓ in A1c and one showed no ↓ in A1c but did show a SS ↓ in duration of hypo episodes Five nonrandomized uncontrolled trials: all five showed a SS ↓ in A1c One nonrandomized uncontrolled trial using ↓ and ↑ excursions as an endpoint showed reduced excursions of both OUTCOMES TRIALS OF CGM: STUDY DESIGNS AND ENDPOINTS

48. Glucose Range (mg/dl) Time Spent (hrs/day) BLINDED TESTING REAL TIME ACCESS IMPROVED BG CONTROL WITH REAL TIME CONTINUOUS GLUCOSE MONITORING USING AN IMPLANTED SENSOR 10 8 6 4 2 0 BLINDED TESTING vs REAL TIME ACCESS Time spent Hypoglycemic (< 55 mg/dl) Decreased 47% Time spent Hyperglycemic (> 241 mg/dl ) Decreased 25% 40 - 55 56 - 80 81 – 140 141 – 240 241 - 400 Diabetes Care. 2004;27:734-8

49. SUMMARY 20 T1DM subjects at Stanford and Barbara Davis Center wore 1-2 GlucoWatch GW2Bs 240 total alarms in 24 hours (180 during sleep) for: a) BG ≤ 70 mg/dl b) expected hypo within 20 min c) BG ≥ 300 mg/dl Subjects awoke to: 29% of individual alarms 66% of alarm events 100% of true hypo events DirecNet: Diabetes Technol Ther June 2005 ; 7:440-447

50. SUMMARY 20 T1DM subjects at Stanford and Barbara Davis Center wore 1-2 GlucoWatch GW2Bs 240 total alarms in 24 hours (180 during sleep) for: a) BG ≤ 70 mg/dl b) expected hypo within 20 min c) BG ≥ 300 mg/dl Subjects awoke to: 29% of individual alarms 66% of alarm events 100% of true hypo events DirecNet: Diabetes Technol Ther June 2005 ; 7:440-447

51. Purpose Technologies Target Populations Accuracy Clinical Indications Outcomes Future Trends CONTINUOUS GLUCOSE MONITORING OUTLINE

52. CONTINUOUS REAL TIME SENSOR TRANSMITTER COMBINED MONITOR AND INSULIN PUMP MEDTRONIC MINIMED PARADIGM SENSOR AUGMENTED SYSTEM

53. Diabetes Technol Ther 2002; 4: 305-312 SUTURES MONITOR SENSOR CABLE

54. J Feline Med Surg 2005; 7: 53-62

60. CONTINUOUS GLUCOSE MONITORING MEANS MORE BLOOD GLUCOSE DATA

61. CONTINUOUS GLUCOSE SENSORS IN ACHIEVING TARGET A1C Provides maximal information for making treatment decisions Multiple methods are effective Technology will be a routine part of intensive treatment regimens In the future a continuous sensor will control an artificial pancreas CONCLUSIONS