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Mimicking Nature The Basal/Bolus Insulin Concept

Scheme of putative events at the injection site after subcutaneous injection of soluble human insulin. Mimicking Nature The Basal/Bolus Insulin Concept. 6-16. Over time, most patients will need both basal and mealtime insulin to control glucose. MIMICKING NATURE WITH INSULIN THERAPY. 6-19.

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Mimicking Nature The Basal/Bolus Insulin Concept

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  1. Scheme of putative events at the injection site after subcutaneous injection of soluble human insulin.

  2. Mimicking Nature The Basal/Bolus Insulin Concept 6-16

  3. Over time, most patients will need both basal and mealtime insulin to control glucose MIMICKING NATURE WITH INSULIN THERAPY 6-19

  4. MIMICKING NATURE WITH INSULIN THERAPYThe Basal/Bolus Insulin Concept • Basal Insulin • Suppresses glucose production between meals and overnight • Nearly constant levels • 50% of daily needs • Bolus Insulin (Mealtime or Prandial) • Limits hyperglycemia after meals • Immediate rise and sharp peak at 1 hour • 10% to 20% of total daily insulin requirement at each meal • Ideally, for insulin replacement therapy, each component should come from a different insulin with a specific profile 6-20

  5. BARRIERS TO INSULIN THERAPYPractical Limitations of Conventional Tactics • Complexity of Starting Insulin Therapy • Need to Mix and Inject Insulins • Limitations of Insulin Preparations 6-21

  6. INSULIN TACTICS Comparison of Human Insulins and Analogues Insulin Onset of Duration ofPreparations Action Peak Action Lispro/Aspart 5-15 minutes 1-2 hours 4-6 hours Human Regular 30-60 minutes 2-4 hours 6-10 hours Human NPH/Lente 1-2 hours 4-8 hours 10-20 hours HumanUltralente 2-4 hours Unpredictable 16-20 hours Glargine 1-2 hours Flat ~24 hours The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only. 6-22

  7. INSULIN TACTICS Twice-daily Split-mixed Regimens Regular NPH Insulin Effect B L S HS B 6-23

  8. INSULIN TACTICS Multiple Daily Injections (MDI)NPH + Regular NPH at AM and HS + Regular AC NPH at HS + Regular AC Regular Regular NPH NPH Insulin Effect Insulin Effect B L S HS B B L S HS B 6-24

  9. INSULIN TACTICSLimitations of Human Regular Insulin • Slow onset of action • Requires inconvenient administration: 20 to 40 minutes prior to meal • Risk of hypoglycemia if meal is further delayed • Mismatch with postprandial hyperglycemic peak • Long duration of activity • Up to 12 hours’ duration • Increased at higher dosages • Potential for late postprandial hypoglycemia 6-26

  10. INSULIN TACTICSShort-acting Analogues: Lispro and AspartClinical Features • Convenient administration immediately prior to meals • Faster onset of action • Limit postprandial hyperglycemic peaks • Shorter duration of activity • Reduce late postprandial hypoglycemia • Frequent late postprandial hyperglycemia • Need for basal insulin replacement revealed 6-27

  11. INSULIN TACTICSShort-acting Insulin Analogues: Lispro and AspartPlasma Insulin Profiles 400 500 Aspart Lispro 450 350 400 300 350 250 300 250 200 Plasma Insulin (pmol/L) Plasma Insulin (pmol/L) Regular 200 150 Human 150 Regular 100 100 Human 50 50 0 0 0 30 60 90 120 150 180 210 240 0 50 100 150 200 250 300 Time (min) Time (min) Meal SC injection Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506. 6-28

  12. Lispro Lispro NPH NPH Insulin Effect Insulin Effect B L S HS B B L S HS B INSULIN TACTICS Multiple Daily Injections (MDI)NPH + Mealtime Lispro NPH at AM and HS + Lispro AC NPH at HS + Lispro AC 6-29

  13. INSULIN TACTICS The Ideal Basal Insulin . . . • Mimics normal pancreatic basal insulin secretion • Long-lasting effect around 24 hours • Smooth, peakless profile • Reproducible and predictable effects • Reduced risk of nocturnal hypoglycemia • Once-daily administration for convenience 6-32

  14. INSULIN TACTICS Insulin GlargineA New Long-acting Insulin Analogue • Modifications to human insulin chain • Substitution of glycine at position A21 • Addition of 2 arginines at position B30 • Gradual release pattern from injection site • Peakless, long-lasting insulin profile Gly 1 Substitution 5 10 15 20 Asp 1 5 15 20 25 30 10 Extension Arg Arg 6-33

  15. INSULIN TACTICS Glargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose Clamp 6 5 4 NPH Glucose Utilization Rate (mg/kg/h) 3 2 Glargine 1 0 0 10 20 30 Time (h) After SC Injection End of observation period Lepore, et al. Diabetes. 1999;48(suppl 1):A97. 6-34

  16. INSULIN TACTICS Insulin GlargineSummary of Completed Trials • Glucose-insulin clamp studies of Glargine vs NPH • Smooth, continuous release from injection site • Longer duration of action with effect for about 24 hours • Peakless profile • Equivalent absorption rates at various injection sites • Clinical efficacy equivalent to NPH, with significantly less nocturnal hypoglycemia 6-35

  17. Overcoming ComplexitybyStarting With Basal Insulin 6-36

  18. INSULIN TACTICSStarting With Basal InsulinAdvantages • 1 injection with no mixing • Insulin pens for increased acceptance • Slow, safe, and simple titration • Low dosage • Limited weight gain • Effective improvement in glycemic control 6-37

  19. INSULIN TACTICSStarting With Basal InsulinBedtime NPH Added to Diet Diet only Bedtime NPH 400 300 200 Plasma Glucose (mg/dL) 100 0 0800 1200 1600 2000 2400 0400 0800 Time of Day Cusi & Cunningham. Diabetes Care. 1995;18:843-851. 6-38

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