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Intensive Insulin Therapy Advances in MDI and CSII

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

  2. 0 12 24 Hours Goals of Intensive Insulin Therapy • Maintain near-normal glycemia • Avoid short-term crisis • Minimize long-term complications • Improve the quality of life

  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. Physiological Serum Insulin Secretion Profile 75 Breakfast Lunch Dinner 50 Plasma insulin (µU/mL) 25 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

  5. Rapid-acting Insulin Analogs Provide Ideal Prandial Insulin Profile Breakfast Lunch Dinner Aspart Aspart Aspart or or or Lispro Lispro Lispro Plasma insulin 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

  6. Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs Breakfast Lunch Dinner Aspart Aspart Aspart or or or Lispro Lispro Lispro Plasma insulin Glargine or Detemir 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

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

  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. 79% of DM 1 Patients Preferred the InDuo Combined Pen/Meter Device 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. Example: Current BG: 220 mg/dL Ideal BG: 100 mg/dL Glucose CF: 50 mg/dL Correction Bolus Formula Current BG - Ideal BG Glucose Correction Factor 220 - 100 = 2.4 U 50

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

  20. Variable Basal Rate: CSII Program Breakfast Lunch Dinner Bolus Bolus Bolus Plasma insulin Basal infusion 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

  21. Photograph reproduced with permission of manufacturer.

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

  23. Insulin Aspart CSII vs Insulin Aspart/Glargine MDI • 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 IAsp CSII IAsp + Gar MDI IAsp + Gar MDI IAsp CSII Run-in (1 week) Period 1 (5 weeks) Period 2 (5 weeks) Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438.

  24. 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 200 CSII (n=93) MDI (n=91) 180 160 Self-monitored BG (mg/dL) 140 120 100 BL 3 AM BB AB AL BD AD Midnight Mean ± 2 SEM Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438.

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

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

  28. Aspart (CSII) vs Aspart/Insulin Glargine (MDI): Serum Fructosamine P=0.0001 400 n=97 300 means ± 2 SEM 200 Fructosamine (mol/L) 100 0 CSII MDI 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. –2 0 16 weeks weeks weeks 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 Screening Buffered regular human insulin (Velosulin®) Insulin lispro Bode B, et al. Diabetes Care. 2002;25:439-444.

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

  35. SMBG in CSII 220 NovoLog® Buffered regular Humalog® 200 180 * 160 Blood glucose (mg/dL) * * 140 120 Type 1 diabetes 100 80 Before and90 minutesafter lunch Before and90 minutes after breakfast Before and90 minutesafter dinner Bedtime 2 AM Bode B. Diabetes. 2001;50(suppl 2):A106.

  36. Pharmacokinetic Comparison: Aspart vs Lispro 350 Aspart 300 Lispro 250 200 Free insulin (pmol/L) 150 100 50 0 13 8 9 10 11 12 7 Time (h) Hedman CA, et al. Diabetes Care. 2001;24:1120-1121.

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

  38. Long-term Heat Stability of Insulin Aspart in Infusion Pumps • In vitro 6-day stabilitystudy under conditions of simulated CSII pump use (37°Cwith constant shaking) • 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 MiniMed (506) pumps Disetronic H-Tron plus V100 700 600 500 400 Concentration (nM) 300 200 100 0 Day 05°C Day 2 Day 6 Lawton S, et al. Diabetes. 52 (Suppl 1) 2003, Abstract 450.

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

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

  41. CSII vs MDI in DM 2 Patients CSII MDI Less pain Fewer social limitations Preference Advocacy Less hassle Less life interference General satisfaction Flexibility Convenience Less burden -5 0 5 10 15 20 25 30 35 Change in scores (raw units) from baseline to endpoint 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. Current Continuation Rate: Continuous Subcutaneous Insulin Infusion (CSII) Continued 97% Discontinued 3% N=165. Average duration=3.6 years. Average discontinuation <1%/y. 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. 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 Pump Therapy 6 5 Meal bolus 4 Units 3 2 1 Basal rate 12 AM 12 PM 12 AM Time of day