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Analogs as a Focus

ADA. Clinical Practice Recommendations. 2001.. Goals of Intensive Diabetes Management. Near-normal glycemiaHbA1c <6.5% to 7.0%Avoid short-term crisisHypoglycemiaHyperglycemiaDKAMinimize long-term complicationsImprove QOL. ACE/AACE Targets for Glycemic Control. HbA1c<6.5

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Analogs as a Focus

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    1. Analogs as a Focus Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

    2. Goals of Intensive Diabetes Management Near-normal glycemia HbA1c <6.5% to 7.0% Avoid short-term crisis Hypoglycemia Hyperglycemia DKA Minimize long-term complications Improve QOL

    3. ACE/AACE Targets for Glycemic Control HbA1c <6.5% Fasting/preprandial glucose <110 mg/dL Postprandial glucose <140 mg/dL

    4. Insulin The Most Powerful Agent We Have to Control Glucose

    5. The Discovery of Insulin (Toronto 1921)

    6. The Miracle of Insulin

    7. Comparison of Human Insulins/Analogs

    8. Ideal Basal/Bolus Insulin Absorption Pattern

    9. Rapid-acting Insulin Analogs: Medical Rationale Administration at mealtime Mimic physiologic insulin profile Improved postprandial glycemic control Lower risk of late hypoglycemia

    10. Primary Structure of Lys(B28), Pro(B29)–Insulin

    11. Primary Structure of Asp(B28)-Insulin

    12. Dissociation and Absorption of NovoLog®

    13. Insulin Aspart: Mean Serum Insulin Profiles During Euglycemic Clamp in Healthy Volunteers In a euglycemic clamp study,* insulin aspart was associated with less variability in time to maximum serum concentration and time to maximum glucose infusion rate than regular human insulin. *An experimental setting used to measure insulin action under conditions in which blood glucose levels are held constant by varying the rate of an intravenous glucose infusion. .In a euglycemic clamp study,* insulin aspart was associated with less variability in time to maximum serum concentration and time to maximum glucose infusion rate than regular human insulin. *An experimental setting used to measure insulin action under conditions in which blood glucose levels are held constant by varying the rate of an intravenous glucose infusion. .

    14. Glucose Area Under the Curve

    15. Insulin Aspart vs Human Regular: Glycemic Control

    16. Postprandial Blood Glucose Increment (Mean over the 3 Meals at 6 Months)

    17. Decreased Interindividual Variability in NovoLog® Values for Tmax

    18. Frequency of Minor* Hypoglycemia Observed by Level of Glycemic Control

    19. Reduced Reporting of Major Nocturnal Hypoglycemia

    20. Reduced Risk of Major Nocturnal Hypoglycemia Statistics for Relative Risk: Study 1, RR = 0.70 (0.47, 1.04 95% CI) (p=0.76) Study 2: RR = 0.50 (0.29, 0.86 95% CI) (p=0.13)Statistics for Relative Risk: Study 1, RR = 0.70 (0.47, 1.04 95% CI) (p=0.76) Study 2: RR = 0.50 (0.29, 0.86 95% CI) (p=0.13)

    21. Rapid-acting Insulin Analogs Provide Ideal Prandial Insulin Profile

    22. Short-acting Insulin Analogs: Lispro and Aspart Plasma Insulin Profiles

    23. Pharmacokinetic Comparison: NovoLog® vs Humalog®

    24. Insulin Aspart vs Buffered R vs Insulin Lispro in CSII Study The purpose of continuous subcutaneous insulin infusion (CSII) is to enable the administration of insulin to patients with diabetes in a pattern that closely mimics the normal physiological insulin secretion seen in non-diabetic individuals. CSII offers numerous advantages to patients with diabetes in terms of reduction in number of daily injections, hypoglycaemia risk, compliance and quality of life (meal schedules, travel and exercise). Soluble human insulin (buffered and non-buffered) is commonly used in CSII therapy, but the rapid onset of action of insulin aspart may make it a more suitable candidate for CSII therapy. This study was a multicentre, randomised parallel group study in which patients were assigned in 2:2:1 ratio (insulin aspart: buffered human insulin:insulin lispro) for 16 weeks in parallel groups. An open-label design was used as patients on the analogues were required to self-administer bolus doses immediately before meals, whereas those on human insulin administered it 30 minutes before meals. A 4-week run-in with buffered human insulin to achieve a pre-breakfast blood glucose of 80-120 mg/dl helped to determine approximate daily insulin requirements; after this, randomisation to the 3 groups was undertaken. Patients were transferred dose for dose from the buffered human insulin.The purpose of continuous subcutaneous insulin infusion (CSII) is to enable the administration of insulin to patients with diabetes in a pattern that closely mimics the normal physiological insulin secretion seen in non-diabetic individuals. CSII offers numerous advantages to patients with diabetes in terms of reduction in number of daily injections, hypoglycaemia risk, compliance and quality of life (meal schedules, travel and exercise). Soluble human insulin (buffered and non-buffered) is commonly used in CSII therapy, but the rapid onset of action of insulin aspart may make it a more suitable candidate for CSII therapy. This study was a multicentre, randomised parallel group study in which patients were assigned in 2:2:1 ratio (insulin aspart: buffered human insulin:insulin lispro) for 16 weeks in parallel groups. An open-label design was used as patients on the analogues were required to self-administer bolus doses immediately before meals, whereas those on human insulin administered it 30 minutes before meals. A 4-week run-in with buffered human insulin to achieve a pre-breakfast blood glucose of 80-120 mg/dl helped to determine approximate daily insulin requirements; after this, randomisation to the 3 groups was undertaken. Patients were transferred dose for dose from the buffered human insulin.

    25. Glycemic Control with CSII

    26. Self-monitored Blood Glucose in CSII

    27. Episodes/month/patient Symptomatic or Confirmed Hypoglycemia The risk of symptomatic or confirmed hypoglycaemia was 30% lower with insulin aspart than with either human insulin or insulin lispro.The risk of symptomatic or confirmed hypoglycaemia was 30% lower with insulin aspart than with either human insulin or insulin lispro.

    28. Insulin Aspart vs Buffered R vs Insulin Lispro in CSII Study: Pump Compatibility Subjects were instructed to replace their infusion sets and insulin at least every 48 hours. The graph shows the percentage of patients completing each of the study periods indicated without any clogging, blockage or other mechanical difficulties that resulted in the interruption of pump use. All three insulins appear to be acceptable in pump use, although there was a suggestion of more mechanical problems occurring with insulin lispro.Subjects were instructed to replace their infusion sets and insulin at least every 48 hours. The graph shows the percentage of patients completing each of the study periods indicated without any clogging, blockage or other mechanical difficulties that resulted in the interruption of pump use. All three insulins appear to be acceptable in pump use, although there was a suggestion of more mechanical problems occurring with insulin lispro.

    29. Long-acting Soluble Insulin Analogs: Medical Rationale Mimic basal physiological insulin profile Improved glycemic control More reproducible insulin delivery May be used in insulin pens

    30. Limitations of NPH, Lente, and Ultralente Do not mimic basal insulin profile Variable absorption Pronounced peaks Less than 24-hour duration of action Cause unpredictable hypoglycemia Major factor limiting insulin adjustments

    31. Primary Structure of Gly(A21), Arg(B31), Arg(B32)-Insulin

    32. Primary Structure of Lys(B29)-N-?-Tetradecanoyl, Des(B30)-Insulin

    33. Basis of Effect of Insulin Glargine Isoelectric point change Precipitates at neutral tissue pH Acid in solution; cannot be mixed with other insulins Retarded absorption rate Corresponding longer duration of action

    34. Insulin Glargine in Nondiabetic Subjects: Pharmacokinetics by Glucose Clamp

    35. Overall Summary: Glargine Insulin glargine has the following clinical benefits: Once-daily dosing because of its prolonged duration of action and smooth, peakless time-action profile Comparable or better glycemic control (FBG) Lower risk of nocturnal hypoglycemic events Safety profile similar to that of human insulin

    36. Basis of Effect of Acylated Insulin Analogs (Detemir) Bind to serum albumin Prolonged time in circulation Longer duration of action

    37. Use of a Serum Carrier Protein (eg, Albumin) to Extend Time of Action

    38. Insulin Detemir in Nondiabetic Subjects: Pharmacokinetics by Glucose Clamp

    39. Long-acting Insulin Analogs Provide Ideal Basal Insulin Profile

    40. Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs

    41. Receptor Binding Affinities

    42. Insulin Analogs Fulfilling the Promise of Recombinant DNA Technology: Better Basal Better Bolus Better Blood Glucose

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