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

2. ADA. Clinical Practice Recommendations. 2001. Goals of Intensive Diabetes Management Near-normal glycemia —HbA 1c <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 HbA 1c <6.5% Fasting/preprandial glucose<110 mg/dL Postprandial glucose<140 mg/dL ACE/AACE Consensus Conference. Washington, DC. August 2001.

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

5. Fred Banting (1891-1941) Charles H. Best (1899-1978) John J.R. McLeod (1876-1935) James B. Collip (1892-1965) Marjorie (?-?) The Discovery of Insulin (Toronto 1921)

6. Patient J.L., December 15, 1922 February 15, 1923 The Miracle of Insulin

7. Comparison of Human Insulins/Analogs Insulin Onset ofDuration of Preparations Action Peak Action Regular30-60 min2-4 h 6-10 h NPH/lente1-2 h4-8 h 10-20 h Ultralente2-4 hUnpredictable 16-20 h Lispro/aspart 5-15 min1-2 h 4-6 h Glargine1-2 hFlat~24 h

8. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Plasma insulin 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. GlyThrGluPheTyrProLysThr GlyThrGluPheTyrLysProThr 23 24 25 26 27 28 29 30 Insulin Lispro Primary Structure of Lys(B28), Pro(B29)–Insulin

11. GlyThrGluPheTyrProLysThr GlyThrGluPheTyrAspLysThr 23 24 25 26 27 28 29 30 Insulin Aspart Primary Structure of Asp(B28)-Insulin

12. Dissociation and Absorption of NovoLog ® Insulin aspart (NovoLog ® ) Regular human insulin Peak time=80-120 min Peak time=40-50 min Capillary membrane Subcutaneous tissue

13. 800 700 600 500 400 300 200 100 0 Serum insulin (pmol/L) 0.2 U/kg SQ Time (h) 0246810 Insulin aspart Regular insulin Heinemann L, et al. Diabetes Care. 1998;21:1910. Insulin Aspart: Mean Serum Insulin Profiles During Euglycemic Clamp in Healthy Volunteers

14. Glucose Area Under the Curve None Regular Aspart

15. Home PD, et al. Diabetes Care. 1998;21:1904-1909. BreakfastLunchDinnerNPH mU/L 80 60 40 20 010006:0012:00 18:0024:0006:00 Serum insulin 10 mmol/L 16 14 12 8 618 Plasma glucose 250 200 150300mg/dL Insulin aspart Human regular Insulin Aspart vs Human Regular: Glycemic Control

16. Prandial increment is the increase in blood glucose from premeal to 90 minutes postmeal European trial North American trial Increment (mmol/L) 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 P<0.001 NovoLog ® Regular human insulin Raskin P, et al. Diabetes Care. 2000;23:583. Home PD, et al. Diabet Med. 2000;17:762. Postprandial Blood Glucose Increment (Mean over the 3 Meals at 6 Months)

17. NovoLog ® Regular human insulin 100 Study 1Study 2Study 3Study 4    0 200 300 400 500   Outliers Median   Data from: Home. Eur J Clin Pharmacol. 1999;55:199-203. Heinemann. Diabet Med. 1996;13:683-684. Mudaliar. Diabetes Care. 1999;22:1501-1506. Heinemann. Diabetes Care. 1998;21:1910-1914. Healthy Volunteers Decreased Interindividual Variability in NovoLog ® Values for T max T max ( min )

18. Frequency of events: 7.9 7.8 7.7 7.6 0 HbA 1c (%) NovoLog ® Regular insulin NovoLog ® Regular insulin 8.0 8.1 8.2 0 per year 0-10 per year 10-30 per year >30 per year Type 1 Diabetes *Symptoms or blood glucose <45 mg/dL. Data on file, Novo Nordisk. Studies 035/EU, 036/US. Study 035/EUStudy 036/US Frequency of Minor* Hypoglycemia Observed by Level of Glycemic Control

19. NovoLog ® Regular human insulin 14 10 0 % Patients with Major Hypoglycemic Episodes Nighttime 4 12 Daytime 8 6 2 P<0.005NS Data on file, Novo Nordisk. Studies 035/EU, 036/US. Reduced Reporting of Major Nocturnal Hypoglycemia %

20. Reduced Risk of Major Nocturnal Hypoglycemia 0.7 0.5 Relative Risk NovoLog Compared with Regular Human Insulin NovoLog ® Human Insulin (No. of Patients with Events) Home 8% (54/707) 11% (39/358) Raskin 4% (24/596) 8% (23/286) Study 035/EU Study 036/US Data on file, Novo Nordisk. Studies 035/EU, 036/US.

21. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Plasma insulin lispro lispro lispro Aspart Aspart Aspart or Rapid-acting Insulin Analogs Provide Ideal Prandial Insulin Profile

22. 400 350 300 250 200 150 100 Meal SC injection 50 0 03060 Time (min) 90120180210150240 Regular Lispro 500 450 400 350 300 250 150 50 200 100 0 050100 Time (min) 150200300250 Plasma insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625-629. Mudaliar SR, et al. Diabetes Care. 1999;22:1501-1506. Regular Aspart Short-acting Insulin Analogs: Lispro and Aspart Plasma Insulin Profiles

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

24. Insulin Aspart vs Buffered R vs Insulin Lispro in CSII Study Bode B, et al. Diabetes Care. 2002;25:439-444. Insulin aspart Buffered regular human insulin (Velosulin ® ) Screening Insulin lispro -2 weeks16 weeks0 weeks 146 patients in the USA; 2-25 years with type 1 diabetes; 7%  HbA 1c  9%; previously treated with CSII for 3 months

25. 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 B. Diabetes. 2001;50(S2):A106. Type 1 Diabetes

26. Self-monitored Blood Glucose in CSII 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 *P<0.01 vs buffered regular insulin. Bode B. Diabetes. 2001;50(S2):A106.

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

28. 0 10 20 30 40 50 Insulin aspart Buffered human insulin Insulin lispro Patients with trouble-free use (%) Insulin Aspart vs Buffered R vs Insulin Lispro in CSII Study: Pump Compatibility Data on file, Novo Nordisk. Study ANA 2024.

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. ThrPheTyrProLysThr 25 26 27 28 29 30 Insulin B-chain Glargine ThrPheTyrProLysThrArg AsnLeu Glu Tyr Cys Gly AsnLeuGluTyrCysAsn 16 17 18 19 20 21 Insulin A-chain Glargine Primary Structure of Gly(A21), Arg(B31), Arg(B32)-Insulin

32. GlyThrGluPheTyrProLysThr GlyThrGluPheTyrProLysThr 23 24 25 26 27 28 29 30 Insulin Detemir (CH 2 ) 4 NH CO R 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. 0 0 1 2 3 4 5 6 24681012141618202224262830 NPH Glargine Placebo 0.4 U/kg Time (h) Glucose infusion rates (mg/kg/min) Linkeschowa R, et al. Diabetes.1999;48(suppl 1):A97. 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. Injection site Hormone Blood Carrier protein Carrier protein Hormone hormone Carrier protein Tissue Receptor hormone Use of a Serum Carrier Protein (eg, Albumin) to Extend Time of Action

38. Brunner GA, et al. Exp Clin Endocrinol Diabetes. 2000;108:100-105. Elapsed time (min) 0.0 0.5 1.0 1.5 2.0 -10010030050070090011001300 1500 Detemir - high Detemir - low Placebo Glucose infusion rate (mg/kg/min) Insulin Detemir in Nondiabetic Subjects: Pharmacokinetics by Glucose Clamp

39. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine or detemir Plasma insulin Long-acting Insulin Analogs Provide Ideal Basal Insulin Profile

40. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine or detemir lispro lispro lispro Aspart Aspart Aspart or Plasma insulin Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs

41. Insulin Receptor Affinity (%)IGF-1 Receptor Affinity (%) CellsSolubilized CellsSolubilizedReceptors Relative to human insulinRelative to human insulin Receptor Binding Affinities Human insulin100100100100 Insulin aspart92926981 Insulin lispro102 ND 142156 Insulin glargine ND 86 ND 641 ND = not determined.

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