1. Basal Bolus: The Strategy for Managing All Diabetes Paul Davidson, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia Presented in San Antonio, May 3, 2003

2. ACE/AACE Targets for Glycemic Control A1C <6.5 % Fasting/preprandial glucose <110 mg/dL Postprandial glucose <140 mg/dL ACE/AACE Consensus Conference; August 2001; Washington, DC.

3. Type 2 Diabetes: A Progressive Disease Over time, patients will need insulin to be controlled to target most

4. MIMICKING NATURE WITH INSULIN THERAPY All persons need both basal and mealtime insulin control to control glucose 6- 19 (endogenous or exogenous)

5. Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine or Detemir Aspart or Lispro (U/mL) Plasma insulin (  U/mL) Aspart or Lispro Aspart or Lispro 25 50 75

6. Starting Multiple Dosage Insulin (MDI) Starting insulin dose is based on weight —0.25 x wt in lb Basal dose (glargine/detemir) —50% of starting dose at bedtime Bolus dose (aspart/lispro) —16% of starting dose at each meal —CIR 12 Correction bolus —(BG-Target)/CF

7. Correction Bolus An estimate of how much glucose will be lowered by 1 unit of rapid-acting insulin This value is the correction factor (CF) Use the 1700 rule to estimate the CF CF = 1700 divided by the total daily dose (TDD) (Current BG - Target BG) / CF = Bolus

8. Alternatives to MDI Simpler regimen Premixed BID (DM 2 only) Insulin pump

9. Variable Basal Rate: CSII Program 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal infusion Bolus Plasma insulin(U/mL) Plasma insulin (  U/mL) 25 50 75 CSII=continuous subcutaneous insulin infusion.

10. Glycemic Control with CSII NovoLog® Human insulin Humalog® 7.0 7.2 7.8 8.0 HbA 1c (%) 7.6 7.4 BaselineWeek 8Week 12Week 16 0 Bode, Diabetes 2001 ; 50(S2):A106 Type 1 Diabetes

11. NovoLog®Buffered RegularHumalog® 80 100 120 140 160 180 200 220 Blood Glucose (mg/dl) * * * Bedtime2 AM Before and 90 min. after breakfast Before and 90 min. after lunch Before and 90 min. after dinner Type 1 Diabetes Bode, Diabetes 2001 ; 50(S2):A106 Insulin for CSII Mean SBGM

12. Symptomatic or Confirmed Hypoglycemia Episodes/month/patient 0 2 4 6 8 10 12 Insulin aspartHuman insulinInsulin lispro P<0.05 30% relative reduction Bode et al. Diabetes Care. March 2002.

13. 0 10 20 30 40 50 Insulin aspart Buffered human insulin Insulin lispro Patients with trouble-free use (%) Insulin aspart versus buffered R versus insulin lispro in CSII study: pump compatibility Data on file (study ANA 2024)

14. DM 1 CSII Patient: Lispro to Aspart Lispro Average = 140 SD = 118 Aspart Average = 118 SD = 73 Glucose (mg/dL) LisproAspart

15. DM 1 CSII Patient: Lispro to Aspart Lispro Average = 140 SD = 118 Aspart Average = 118 SD = 73 Glucose (mg/dL) LisproAspart

16. CSII Usage in Type 2 Patients: Atlanta Diabetes Experience 7.19 7.57 9.2 5.00 6.00 7.00 8.00 9.00 10.00 Baseline6 months18 months P=0.026P=0.040 N=11 Mean A1C (%) Davidson et al. Diabetologica. 1999;42(suppl 1):796.

18. Glycemic Control in Type 2 DM: CSII vs MDI in 127 Patients A1C 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.4 CSIIMDI Baseline End of study (24 wk) Raskin et al. Diabetes. 2001;50(suppl 2):A128.

19. CSII vs MDI in DM 2 Patients Raskin et al. Diabetes 2001;50 Suppl 2:A128

20. 6600 8700 11,400 15,000 20,000 26,500 35,000 43,000 60,000 81,000 120,000 157,000 200,000 0 50,000 100,000 150,000 200,000 250,000 '90'91'92'93'94'95'96'97'98'99'00'01'02 US Pump Usage: Total Patients Using Insulin Pumps Total no. of patients

21. Current Pump Therapy Indications Need to normalize BG —A1C  6.5% —Glycemic excursions Hypoglycemia New onset type 1 DM Pregnancy and diabetes

22. STATISTICAL ESTIMATES FOR CSII PARAMETERS: CARBOHYDRATE-TO-INSULIN RATIO (CIR, 2.8 Rule); CORRECTION FACTOR (CF,1700 Rule); BASAL INSULIN Paul C Davidson, Harry R Hebblewhite, Bruce W Bode, R Dennis Steed, N Spencer Welch, Patricia L Richardson, and Joseph A Johnson Atlanta, GA, USA Diabetes Technology & Therapeutics 2003 How to Prime a Pump

23. Prescription for insulin therapy includes: Basal Insulin (BI) Carbohydrate-to-Insulin Ratio (CIR) Correction Factor (CF) Data from well-controlled pump patients Analyzed for optimum parameters Resulting formulae The Accurate Insulin Management (AIM) formulae. AIM INTRODUCTION

24. Materials and Methods Target Group (TG) of 182 patients with A1C <7% Not-to-Target Group (NTG) of 214 Determine individuals slopes of: Basal versus total daily dose of insulin (TDD) Correction factor (CF) versus 1/TDD TDD versus body weight (BW) CIR versus BW/TDD Median of all slopes in the TG was used for each formula.

25. Sampling Results P<.01 P<.03 P<.01

26. AIM Starting Total Dose of Insulin TDDstart = 0.24 * BW#

27. Basal Insulin = 0.48 * TDD

28. CARBOHYDRATE TO INSULIN RATIO CIR = 2.8 * BW# / TDD

29. Correction Factor The 1700 Rule CF = 1708 / TDD n = 179

30. RESULTS

31. AIM FORMULAE and Slopes

32. 125 100 75 50 25 Correction Factor 25 20 15 12 10 9 8 7 6 5 Carbohydrate to Insulin Ratio CF Curve AIM Nomogram Davidson et al Diab Tech Ther 2003 Vol 5 No 2 ( CIR = 2.8 Wt / TDD ) ( CF = 1700 / TDD ) Intial Dosing: Plot BW and 25 CIR for BI Plot BW and 12 CIR for TDD Plot BW and TDDfor CIR Plot TDD and CF curve for CF Follow-up Dosing: Change CF as above Change CIR by 20% toward CIR AIM 4 3 2

33. Initial Visit Type 1 Diabetes Starting CSII Poorly controlled on QID insulin —10 units lispro tid and 28 units glargine hs —Mean BG 189, A1c 9 Weight 210 #

34. 125 100 75 50 25 Correction Factor 25 20 15 12 10 9 8 7 6 5 Carbohydrate to Insulin Ratio CF Curve AIM Nomogram Davidson et al Diab Tech Ther 2003 Vol 5 No 2 ( CIR = 2.8 Wt / TDD ) ( CF = 1700 / TDD ) Intial Dosing: Plot BW and 25 CIR for BI Plot BW and 12 CIR for TDD Plot BW and TDDfor CIR Plot TDD and CF curve for CF Follow-up Dosing: Change CF as above Change CIR by 20% toward CIR AIM 4 3 2 BI 24 units

35. 125 100 75 50 25 Correction Factor 25 20 15 12 10 9 8 7 6 5 Carbohydrate to Insulin Ratio CF Curve AIM Nomogram Davidson et al Diab Tech Ther 2003 Vol 5 No 2 ( CIR = 2.8 Wt / TDD ) ( CF = 1700 / TDD ) Intial Dosing: Plot BW and 25 CIR for BI Plot BW and 12 CIR for TDD Plot BW and TDDfor CIR Plot TDD and CF curve for CF Follow-up Dosing: Change CF as above Change CIR by 20% toward CIR AIM 4 3 2 TDD 50 units CF 35 CIR BI 24 units

36. Follow-up One Month Later Weight 210# 4.5 BG’s per day Average BG 158 Current basal 1.2 u/hr (28.8 u/d) TDD from pump 64 units

37. 125 100 75 50 25 Correction Factor 25 20 15 12 10 9 8 7 6 5 Carbohydrate to Insulin Ratio CF Curve AIM Nomogram Davidson et al Diab Tech Ther 2003 Vol 5 No 2 ( CIR = 2.8 Wt / TDD ) ( CF = 1700 / TDD ) Intial Dosing: Plot BW and 25 CIR for BI Plot BW and 12 CIR for TDD Plot BW and TDDfor CIR Plot TDD and CF curve for CF Follow-up Dosing: Change CF as above Change CIR by 20% toward CIR AIM 4 3 2 CIR New CIR Old TDD Current CF New 25 CF Old 35 Basal AIM TDD/2=32

38. AIM Study 21 Patients HbA1c>8 Competent Self- Monitoring Pump Veterans Bi-Weekly Fax and Phone Follow-Up Three Month Study Davidson et al Diabetes Technology & Therapeutics 2003 180 160 140 120 P<0.0001

39. PumpMaster A Combined Database Collector and Patient-Treatment Advisor for Interactive Use by Practitioners

40. Pumpmaster Day divided into five periods —Sleep, dawn, am, pm, evening BG monitored initially for each period —Mean and SD Variation of mean from target —Correction formula used to quantify average insulin need for each period —Summed for day Program suggests change in insulin for each period balancing change in basal against CIR —Simulates best controlled patients in database

41. Input Form, Screen 1

42. Input Form, Screen 2

43. In development (Patent Pending) Has shown that it lowers HbA1c Will advise the pump therapist Will advise the pump wearing diabetic Will encourage more pump prescribing Will facilitate progress to target control Can be programmed into PDA or pump Overview of PumpMaster

44. Because of the similar bolus-basal nature of glargine/detemir plus rapid acting insulin to pump therapy the AIM program is also applicable to MDI programs. The AIM formulae are designed to: Recommend an estimated initial TDD which can be used in the other formulae. Promote treatment of follow up patients to target by balanced incremental adjustments. Basal insulin may be given as glargine or detemir. Bolus insulin is given as rapid acting insulin. AIM Nomogram for MDI: Background

45. If HbA 1c Not to Goal i.e. 6.5% SMBG —frequency —recording —memory meter Diet —accurate CHO counting —appropriate CHO/insulin bolusing Infusion site areas Overtreatment of low BG Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2

46. If HbA 1c Not to Goal i.e. 6.5% SMBG —frequency —recording —memory meter Diet —accurate CHO counting —appropriate CHO/insulin bolusing Infusion site areas Overtreatment of low BG Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2

47. Improvement in HbA 1c with Increased BG Testing

48. If HbA 1c Not to Goal i.e. 6.5% SMBG —frequency —recording —memory meter Diet —accurate CHO counting —appropriate CHO/insulin bolusing Infusion site areas Overtreatment of low BG Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2

49. Correction of Hypoglycemia with Glucose 100-BG X 0.2 Grams BeforeAfter Richardson Diabetes 1999 50:A200 100-BG X 0.15 Grams

50. If A1c Not at Goal and No Reason Identified Place on a continuous glucose monitoring system —CGMS —GlucoWatch —TheraSense

51. Summary Insulin is the only powerful agent we have to control diabetes When used in a basal/bolus format, near- normoglycemia can be achieved Newer insulins, new insulin delivery devices, and developing glucose sensors with better algorithms for linking them are revolutionizing the care of diabetes

52. Conclusion For the Responsible, Informed Physician Like Yourself Intensive Therapy is the ONLY Way to Treat Patients with Diabetes

53. Questions For a copy or viewing of these slides, contact: www.adaendo.com Address correspondence to: Paul C. Davidson, M.D. Atlanta Diabetes Associates 77 Collier Road, Suite 2080 Atlanta, GA 30309 email: paul_c_davidson@msn.com