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

ADA. Clinical Practice Recommendations 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

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.

Insulin The Most Powerful Agent We Have to Control Glucose

Fred Banting ( ) Charles H. Best ( ) John J.R. McLeod ( ) James B. Collip ( ) Marjorie (?-?) The Discovery of Insulin (Toronto 1921)

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

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 h Ultralente2-4 hUnpredictable h Lispro/aspart 5-15 min1-2 h 4-6 h Glargine1-2 hFlat~24 h

4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Plasma insulin Ideal Basal/Bolus Insulin Absorption Pattern

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

GlyThrGluPheTyrProLysThr GlyThrGluPheTyrLysProThr Insulin Lispro Primary Structure of Lys(B28), Pro(B29)–Insulin

GlyThrGluPheTyrProLysThr GlyThrGluPheTyrAspLysThr Insulin Aspart Primary Structure of Asp(B28)-Insulin

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

Serum insulin (pmol/L) 0.2 U/kg SQ Time (h) 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

Glucose Area Under the Curve None Regular Aspart

Home PD, et al. Diabetes Care. 1998;21: BreakfastLunchDinnerNPH mU/L :0012:00 18:0024:0006:00 Serum insulin 10 mmol/L Plasma glucose mg/dL Insulin aspart Human regular Insulin Aspart vs Human Regular: Glycemic Control

Prandial increment is the increase in blood glucose from premeal to 90 minutes postmeal European trial North American trial Increment (mmol/L) 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)

NovoLog ® Regular human insulin 100 Study 1Study 2Study 3Study 4      Outliers Median   Data from: Home. Eur J Clin Pharmacol. 1999;55: Heinemann. Diabet Med. 1996;13: Mudaliar. Diabetes Care. 1999;22: Heinemann. Diabetes Care. 1998;21: Healthy Volunteers Decreased Interindividual Variability in NovoLog ® Values for T max T max ( min )

Frequency of events: HbA 1c (%) NovoLog ® Regular insulin NovoLog ® Regular insulin per year 0-10 per year 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

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

Reduced Risk of Major Nocturnal Hypoglycemia 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.

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

Meal SC injection Time (min) Regular Lispro Time (min) Plasma insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13: Mudaliar SR, et al. Diabetes Care. 1999;22: Regular Aspart Short-acting Insulin Analogs: Lispro and Aspart Plasma Insulin Profiles

Pharmacokinetic Comparison: NovoLog ® vs Humalog ® NovoLog ® Humalog ® Free insulin (pmol/L) Time (h) Hedman CA, et al. Diabetes Care. 2001;24:

Insulin Aspart vs Buffered R vs Insulin Lispro in CSII Study Bode B, et al. Diabetes Care. 2002;25: 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

Glycemic Control with CSII NovoLog ® Human insulin Humalog ® HbA 1c (%) BaselineWeek 8Week 12Week 16 0 Bode B. Diabetes. 2001;50(S2):A106. Type 1 Diabetes

Self-monitored Blood Glucose in CSII NovoLog ® Buffered regularHumalog ® 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.

Episodes/month/patient Insulin aspartHuman insulinInsulin lispro P<0.05 Symptomatic or Confirmed Hypoglycemia 30% relative reduction Bode B, et al. Diabetes Care. 2002;25:

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.

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

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

ThrPheTyrProLysThr Insulin B-chain Glargine ThrPheTyrProLysThrArg AsnLeu Glu Tyr Cys Gly AsnLeuGluTyrCysAsn Insulin A-chain Glargine Primary Structure of Gly(A21), Arg(B31), Arg(B32)-Insulin

GlyThrGluPheTyrProLysThr GlyThrGluPheTyrProLysThr Insulin Detemir (CH 2 ) 4 NH CO R Primary Structure of Lys(B29)-N-  -Tetradecanoyl, Des(B30)-Insulin

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

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

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

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

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

Brunner GA, et al. Exp Clin Endocrinol Diabetes. 2000;108: Elapsed time (min) Detemir - high Detemir - low Placebo Glucose infusion rate (mg/kg/min) Insulin Detemir in Nondiabetic Subjects: Pharmacokinetics by Glucose Clamp

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

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

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

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