1. Intensive Insulin Therapy Advances in MDI and CSII Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

2. Goals of Intensive Insulin Therapy Maintain near-normal glycemia Avoid short-term crisis Minimize long-term complications Improve the quality of life 01224 Hours

3. The Basal/Bolus Insulin Concept Basal insulin —Suppresses glucose production between meals and overnight —40% to 50% of daily needs Bolus insulin (mealtime) —Limits hyperglycemia after meals —Immediate rise and sharp peak at 1 hour —10% to 20% of total daily insulin requirement at each meal

4. 4:00 25 50 75 8:0012:0016:0020:0024:004:00 BreakfastLunchDinner Plasma insulin (U/mL) Plasma insulin ( µ U/mL) Time 8:00 Physiological Serum Insulin Secretion Profile

5. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Plasma insulin LisproLisproLispro AspartAspartAspart or Rapid-acting Insulin Analogs Provide Ideal Prandial Insulin Profile

6. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine or Detemir Plasma insulin Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs LisproLisproLispro AspartAspartAspart or

7. Advancing Basal/Bolus Insulin in Type 2 Diabetes Indicated when FBG acceptable but —A1C >7% or >6.5% and/or —SMBG before dinner >130 mg/dL Insulin options —To basal insulin, add mealtime aspart/lispro —To supper time 70/30, add morning 70/30 —Consider insulin pump therapy

8. Insulin Pens First pen launched in 1985 —Committed to developing one new insulin administration system per year Photograph reproduced with permission of manufacturer.

9. Insulin Pens Photograph reproduced with permission of manufacturer.

10. Prefilled Syringe with Flexible Dosing Photograph reproduced with permission of manufacturer.

11. Pen Preference Study 83% of DM Patients Preferred FlexPen ® ® ® Asakura T. Diabetes 52,(Suppl 1), 2003 Abstract 437. n = 58

12. Combined Insulin Pen and Meter Feature Combined insulin doser and blood glucose monitor Photograph reproduced with permission of manufacturer.

13. Combined Insulin Pen and Meter Feature Remembers amount of insulin delivered and time since last dose Benefit Helps people inject the right amount of insulin at the right time Photograph reproduced with permission of manufacturer.

14. Combined Pen/Meter Device 79% of DM 1 Patients Preferred the InDuo n = 125 Bode B et al. Diabetes 52,(Suppl 1), 2003 Abstract 440.

15. Starting MDI Starting insulin dose is based on weight —0.2 x weight in lb or 0.45 x weight in kg Bolus dose (aspart/lispro)=20% of starting dose at each meal Basal dose (glargine/NPH)=40% of starting dose at bedtime

16. Starting MDI in 180-lb person Starting dose = 0.2 x weight in lb —0.2 x 180 lb = 36 U Bolus dose = 20% of starting dose at each meal —20% of 36 U = 7 U AC (TID) Basal dose = 40% of starting dose at bedtime —40% of 36 U = 14 U HS

17. Correction Bolus Must determine how much glucose is lowered by 1 U of short- or rapid- acting insulin This number is known as the correction factor (CF) Use the 1700 rule to estimate the CF CF=1700 divided by the total daily dose (TDD); example: if TDD=36 U, then CF=1700/36=  50, meaning 1 U will lower the BG  50 mg/dL

18. Correction Bolus Formula Example: —Current BG:220 mg/dL —Ideal BG: 100 mg/dL —Glucose CF: 50 mg/dL Current BG - Ideal BG Glucose Correction Factor 220 - 100 50 = 2.4 U

19. Options to MDI A simpler regimen Insulin pump Premixed BID (DM 2 only)

20. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal infusion Bolus Plasma insulin Variable Basal Rate: CSII Program

21. Photograph reproduced with permission of manufacturer.

22. Pump Infusion Sets Photograph reproduced with permission of manufacturer.

23. Open-label, randomized, crossover, 2-arm study of 10-week duration Comparison of insulin aspart CSII vs insulin aspart/glargine MDI Subjects: n=100, type 1 patients on CSII at entry, A1C <9% Assessments —Efficacy: A1C, fructosamine, 8-point BG profile, glucose exposure (CGMS) —Safety: frequency of hypoglycemia, AEs Run-in (1 week)Period 1 (5 weeks)Period 2 (5 weeks) IAsp CSII IAsp + Gar MDI Insulin Aspart CSII vs Insulin Aspart/Glargine MDI Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438.

24. Treatment Sequence CSII to MDIMDI to CSIIAll Subjects Subjects treated50 100 Age (y) 41.7  11.144.2  11.043.0  11.1 BMI (kg/m 2 ) 27.1  4.126.7  4.026.9  4.0 A1C at screening (%) 7.5  0.87.4  0.87.5  0.8 Duration of diabetes (y) 19.7  11.323.9  12.321.8  11.9 Daily insulin dose 42.3  17.9 (n=45) 41.6  16.1 (n=50) 41.9  16.9 (n=95) Basal 21.1  8.122.6  10.721.9  9.2 Bolus 22.7  13.819.3  8.720.9  11.4 Characteristics of Enrolled Population Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438.

25. Aspart (CSII) vs Aspart/Insulin Glargine (MDI): 8-Point Blood Glucose Profiles Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438. Mean ± 2 SEM 200 160 140 120 100 180 Self- monitored BG (mg/dL) BBAB BL ALBDADMidnight 3 AM CSII (n=93) MDI (n=91)

26. n=63 in each treatment 0 500 1000 1500 2000 2500 3000 CSII MDI P=0.0027 *Measurement of AUC (glu) ≥80 mg/dL during the 48-hour continuous glucose monitoring period. Aspart (CSII) vs Aspart/Insulin Glargine (MDI): Glucose Exposure During CGMS* AUC glu (mgh/dL) Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438.

27. Aspart (CSII) vs Aspart/Insulin Glargine (MDI): Rate of Hypoglycemia Episodes/subject/5 weeks 12 10 8 6 4 2 0 TotalDaytimeNocturnal P=0.0039 P<0.0001 P=0.0006 CSII MDI Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438.

28. Aspart (CSII) vs Aspart/Insulin Glargine (MDI): Serum Fructosamine n=97 CSII MDI 0 100 200 300 400 means ± 2 SEM Fructosamine (  mol/L) P=0.0001 Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438.

29. CSII vs. MDI with Glargine in Children (Randomized, Prospective) 60 DM 1 patients age 8-18, duration >1 year, A1C 6.5-11% Naïve to glargine and pump Treatment —CSII with insulin aspart —MDI with insulin aspart and glargine Primary outcome A1C Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192.

30. CSII vs. MDI with Glargine in Children (Randomized, Prospective) Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192.

31. Metabolic Advantages with CSII Improved glycemic control Better pharmacokinetic delivery of insulin —Less hypoglycemia —Less insulin required Improved quality of life

32. CSII: Factors Affecting A1C Monitoring —A1C=8.3% - (0.21 x BG per day) Recording 7.4 vs 7.8 Diet practiced —CHO: 7.2 —Fixed: 7.5 —WAG: 8.0 Insulin type (aspart) Bode B, et al. Diabetes. 1999;48(suppl 1):264. Bode B, et al. Diabetes Care. 2002;25:439.

33. Insulin Aspart vs Buffered R vs Insulin Lispro in CSII Study 146 patients in the US; 2 to 25 years with type 1 diabetes; 7%  A1C  9%; previously treated with CSII for 3 months Insulin aspart Buffered regular human insulin (Velosulin ® ) Screening Insulin lispro –2016 weeks Bode B, et al. Diabetes Care. 2002;25:439-444.

34. Glycemic Control with CSII NovoLog ® Human insulin Humalog ® 7.0 7.2 7.8 8.0 A1C (%) 7.6 7.4 BaselineWeek 8Week 12Week 16 0 Type 1 diabetes Bode B. Diabetes. 2001;50(suppl 2):A106.

35. SMBG in CSII NovoLog ® Buffered regularHumalog ® 80 100 120 140 160 180 200 220 Blood glucose (mg/dL) * * * Bedtime2 AM Before and 90 minutes after breakfast Before and 90 minutes after lunch Before and 90 minutes after dinner Type 1 diabetes Bode B. Diabetes. 2001;50(suppl 2):A106.

36. Pharmacokinetic Comparison: Aspart vs Lispro 300 350 250 200 150 100 50 0 7 89101112 13 Aspart Lispro Free insulin (pmol/L) Time (h) Hedman CA, et al. Diabetes Care. 2001;24:1120-1121.

37. Symptomatic or Confirmed Hypoglycemia Episodes/mo/patient 0 2 4 6 8 10 12 Insulin aspartHuman insulinInsulin lispro P<0.05 30% Relative Reduction Bode B, et al. Diabetes Care. 2002;25:439-444.

38. Concentration (nM) 100 600 500 400 300 200 0 700 Day 0 5°C Day 2Day 6 MiniMed (506) pumps Disetronic H-Tron plus V100 In vitro 6-day stability study under conditions of simulated CSII pump use (37°C with constant shaking) Lawton S, et al. Diabetes. 52 (Suppl 1) 2003, Abstract 450. Long-term Heat Stability of Insulin Aspart in Infusion Pumps Antimicrobial effectiveness and particulate matter were within USP requirements after 6 days Stable pH during the 6 days Physicochemical integrity of insulin aspart was retained

39. Lispro Average=140 SD=118 Aspart Average=118 SD=73 DM 1 CSII Patient: Lispro to Aspart

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

41. Change in scores (raw units) from baseline to endpoint -505101520253035 Convenience Less burden Less hassle Advocacy Preference General satisfaction Flexibility Less life interference Less pain Fewer social limitations MDICSII CSII vs MDI in DM 2 Patients Raskin et al. Diabetes. 2001;50(suppl 2):A128.

42. Case 3: DM 2 Poorly Controlled A 58-year-old woman presented with a 12-year history of poorly controlled, insulin-treated diabetes Ht 66", Wt 174 lb, BMI 28, C-peptide 2.1 A1C 10.4% on 165 U/d (70/30 BID) Added troglitazone, metformin, glimepiride to MDI insulin A1C range 7.7% to 12.6% over 3 years

43. Case 3: DM 2 Poorly Controlled Admitted twice for IV insulin and fasting with short-lived success (A1C to 7.6% but back up to 12.6%) Tried Weight Watchers ® and appetite suppressants; no help Decided to try CSII

44. Case 3: DM 2 on CSII, A1C Results A1C (%)

45. Case 3: DM 2 Poorly Controlled Patient loves the pump On 110 U/d consuming 2 meals only per day (1.4 U/kg or 0.6 U/lb) Also on rosiglitazone 4 mg/d

46. Normalization of Lifestyle Liberalization of diet—timing and amount Increased control with exercise Able to work shifts and through lunch Less hassle with travel—time zones Weight control Less anxiety in trying to keep on schedule

47. N=165. Average duration=3.6 years. Average discontinuation <1%/y. Continued 97% Discontinued 3% Current Continuation Rate: Continuous Subcutaneous Insulin Infusion (CSII) Bode BW, et al. Diabetes. 1998;47(suppl 1):392.

48. US Pump Usage: Total Patients Using Insulin Pumps

49. Current Pump Therapy Indications Diagnosed with diabetes (even new- onset DM type 1) Need to normalize blood glucose (BG) —A1C  7.0% —Glycemic excursions Hypoglycemia

50. Pump Therapy Basal rate Continuous flow of insulin Takes the place of NPH or glargine insulin Meal boluses Insulin needed premeal —Premeal BG —Carbohydrates in meal —Activity level Correction bolus for high BG Meal bolus 1 2 3 4 5 6 12 AM 12 PM 12 AM Time of day Basal rate Units

51. Initial Adult Dosage: Calculations Starting doses Based on prepump total daily dose (TDD), reduce TDD by 25% to 30% for pump TDD Calculated based on weight —0.24 x weight in lb (0.5 x weight in kg) Bode BW, et al. Diabetes. 1999;48(suppl 1):84. Bell D, Ovalle F. Endocr Pract. 2000;6:357-360. Crawford LM. Endocr Pract. 2000;6:239-243.

52. Initial Adult Dosage: Calculations Basal rate 45% to 50% of pump TDD Divide total basal by 24 hours to decide on hourly basal Start with only 1 basal rate See how it goes before adding basals

53. Estimating the Carbohydrate to Insulin Ratio (CIR) Individually determined —CIR=(2.8 x weight in lb)/TDD —Anywhere from 5 g to 25 g CHO is covered by 1 U of insulin

54. If A1C Is Not at Goal SMBG frequency and recording Diet practiced —Do they know what they are eating? —Do they bolus for all food and snacks? Infusion site areas —Are they in areas of lipohypertrophy? Other factors: —Fear of low BG —Overtreatment of low BG Must look at:

55. If A1C Is Not at Goal and No Reason Identified Place on a continuous glucose monitoring system CGMS by Medtronic MiniMed or GlucoWatch by Cygnus to determine the cause

56. Summary Insulin remains the most powerful agent we have to control diabetes When used appropriately in a basal/bolus format, near-normal glycemia can be achieved Newer insulins and insulin delivery devices, along with glucose sensors, will revolutionize our care of diabetes

57. Billing Get paid for what you do Use your codes and negotiate for coverage Detailed visit: 99214 Prolonged visit with contact plus above: 99354 or 99355 (insulin start or pump start) Prolonged visit without contact plus above: 99358 or 99359 (faxes, phone calls, e-mails)

58. Billing (cont’d) Bill faxes as prolonged visits without contact or negotiate a separate charge Bill meter download: 99091 Bill CGMS: 95250 Bill immediate A1C: 83036

59. Question and Answer Session For a copy of these slides go to: www.adaendo.com