1. Therapeutic Options Insulins

2. 1 Insulin Preparations ClassAgents Human insulinsRegular, NPH, lente, ultralente Insulin analoguesAspart, glulisine, lispro, glargine Premixed insulinsHuman 70/30, 50/50 Humalog mix 75/25 Novolog mix 70/30

3. 2 Human Insulin A-chain B-chain Zn ++ Self-aggregation in solution Monomers Dimers Hexamers 21 amino acids 30 amino acids

4. 3 Modified Human Insulin Regular InsulinShort acting Hexamers in Zn 2+ buffer Neutral Protamine Hagedorn (NPH) InsulinIntermediate acting Medium-sized crystals in protamine-Zn 2+ buffer Lente and Ultralente InsulinIntermediate and Large crystals in acetate-Zn 2+ bufferlong acting

5. 4 Profiles of Human Insulins 01 25346789 1011 12131415161718192021222324 Plasma insulin levels Regular 6–8 hours NPH 12–20 hours Ultralente 18–24 hours Hours

6. 5 Insulin Analogues Human Insulin Dimers and hexamers in solution A-chain B-chain Lys Pro Gly Arg Asp Lispro Limited self-aggregation Monomers in solution Aspart Limited self-aggregation Monomers in solution Glargine Soluble at low pH Precipitates at neutral (subcutaneous) pH Glu Glulisine Limited self-aggregation Monomers in solution Lys

7. 6 500 400 300 200 100 0 Insulin Aspart A Rapid-Acting Insulin Analogue Plasma Insulin Mudaliar SR et al. Diabetes Care. 1999;22:1501-1506 Insulin Action pmol/L 700 600 500 400 300 200 100 0 Minutes 01002003004005006000100200300400500600 Glusose infusion rate (mg/min ) Insulin aspart Regular insulin 20 Healthy Subjects, 10-h Euglycemic Clamp

8. 7 Insulin Lispro A Rapid-Acting Insulin Analogue Heinemann L et al. Diabet Med. 1996;13:625-629 Insulin lispro Regular insulin -60 -30 030 6090120150 180210240 Minutes mg/dL pmol/L 400 -60-30 0 306090120150 180210240 Meal and insulin Meal and insulin Plasma Insulin Plasma Glucose 10 Patients With Type 1 Diabetes Following a Meal 300 200 100 0 200 150 0 100

9. 8 04812162024 Insulin Action Profiles in Type 1 Diabetes Lepore M et al. Diabetes. 2000;49:2142-2148 Glucose infusion (mg/kg/min) 20 Patients 4321043210 Glargine NPH Ultralente Hours

10. 9 Action Profiles of Insulin Analogues 01 25346789 1011 12131415161718192021222324 Plasma insulin levels Regular 6–8 hours NPH 12–20 hours Ultralente 18–24 hours Hours Glargine 24 hours Aspart, glulisine, lispro 4–6 hours

11. 10 Human Insulins and Analogues Typical Times of Action Insulin Preparations Onset of ActionPeakDuration of Action Aspart, glulisine, lispro ~15 minutes1–2 hours4–6 hours Human regular30–60 minutes2–4 hours6–8 hours Human NPH, lente 2–4 hours4–10 hours12–20 hours Human ultralente 4–6 hours8–16 hours18–24 hours Glargine2–4 hoursFlat~24 hours

12. 11 Polonsky KS et al. N Engl J Med. 1988;318:1231-1239 0600 Time of day 20 40 60 80 100 BLD Normal Daily Plasma Insulin Profile B=breakfast; L=lunch; D=dinner 0800 1800 12002400  U/mL

13. 12 Time of day 20 40 60 80 100 BLD Evening Basal Insulin Bedtime NPH B=breakfast; L=lunch; D=dinner 0600 0800 1800 12002400 NPH Normal pattern  U/mL

14. 13 Starting Basal Insulin for Type 2 Diabetes Bedtime NPH Added to Diet Cusi K et al. Diabetes Care. 1995;18:843-851 300 200 0 080012001600 Time of day 2000240004000800 400 100 Diet only Bedtime NPH Plasma glucose (mg/dL) NPH 12 Patients Treated for 16 Weeks

15. 14 Starting Basal Insulin for Type 2 Diabetes Suppertime 70/30 Added to Glimepiride Riddle MC et al. Diabetes Care. 1998;21:1052-1057 0 100 150 200 250 300 * * 1216842024 Weeks Fasting Glucose 0 0 25 50 75 100 1216842024 *P<0.001 Insulin Dosage * * * * * * Placebo + insulin (N=73) Glimepiride + insulin titrated to FPG 140 mg/dL (N=72) mg/dL Units / day *P<0.001 FPG=fasting plasma glucose

16. 15 Time of day 20 40 60 80 100 BLD Split-Mixed Regimen Human Insulins B=breakfast; L=lunch; D=dinner 0600 0800 1800 12002400 NPH Regular NPH Regular Normal pattern  U/mL

17. 16 Split-Mixed Regimen NPH + Regular for Type 2 Diabetes Henry RR et al. Diabetes Care. 1993;16:21-31 200 400 100 300 0 0 200 600 1000 400 800 0600 180024001200 Time of day 0600 180024001200 Diet only Insulin 6 months Plasma GlucoseSerum Insulin BLD N + R mg/dL pmol/L BLD N + R B=breakfast; L=lunch; D=dinner

18. 17 Time of day 20 40 60 80 100 BLD Multiple Daily Injections Human Insulins B=breakfast; L=lunch; D=dinner 0600 0800 1800 12002400 Regular NPH Regular Normal pattern  U/mL Regular

19. 18 Multiple Daily Injections NPH + Regular for Type 2 Diabetes 0 300 250 200 150 100 50 0800120016002000240004000800 Time of day 0800120016002000240004000800 Plasma Glucose Serum Insulin R NRR 0 300 200 100 Baseline oral agents Insulin 8 weeksNormal mg/dL pmol/L BLDBLD R NRR Sn Lindström TH et al. Diabetes Care. 1992;15:27-34 B=breakfast; Sn=snack; L=lunch; D=dinner 10 Patients With Diabetes, 10 Normal Controls

20. 19 Multiple Daily Injections NPH + Regular or Aspart for Type 1 Diabetes Home PD et al. Diabetes Care. 1998;21:1904-1909 100 80 60 40 20 0 mU/L 06001200180024000600 Plasma Glucose Serum Insulin A A A N NPH + regular insulin B=breakfast; L=lunch; D=dinner B LD 250 200 150 mg/dL 14 12 10 8 6 mmol/L 16 Time of day Insulin aspart

21. 20 The Basal-Bolus Insulin Concept Basal insulin – Controls 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 postmeal – 10% to 20% of total daily insulin requirement at each meal For ideal insulin replacement therapy, each component should come from a different insulin with a specific profile

22. 21 0600 0800 1800 12002400 0600 Time of day 20 40 60 80 100 BLD Basal-Bolus Insulin Treatment With Insulin Analogues B=breakfast; L=lunch; D=dinner Glargine Lispro, glulisine, or aspart Normal pattern  U/mL

23. 22 Barriers to Using Insulin Patient resistance – Perceived significance of needing insulin – Fear of injections – Complexity of regimens – Pain, lipohypertrophy Physician resistance – Perceived cardiovascular risks – Lack of time and resources to supervise treatment Medical limitations of insulin treatment – Hypoglycemia – Weight gain

24. 23 Barriers to Using Insulin Attitudes of Patients With Type 1 and Type 2 Diabetes 0 20 40 60 80 100 % of patients High anxiety about injections Troubled by idea of more injections Avoid injections because of anxiety Troubled by idea of more injections Avoid injections because of anxiety All PatientsPatients With High Anxiety Zambanini A et al. Diabetes Res Clin Pract. 1999;46:239-246 14% 42% 28% 45% 70%

25. 24 Barriers to Insulin Therapy Cardiovascular Risk Is Not Supported by Trials 6- 14 Type 2 Diabetes in the UKPDS Risk of myocardial infarction Conventional treatment17.4 events/1000 pt-yr Intensive insulin14.7 events/1000 pt-yr ( P =0.052) Type 1 and 2 Diabetes in the DIGAMI Study Long-term survival after acute myocardial infarction Conventional treatment 44% mortality Intensive insulin33% mortality ( P =0.011) UKPDS Group. Lancet. 1998;352:837-853; Malmberg K. BMJ. 1997;314:1512-1515

26. 25 Barriers to Insulin Therapy Severe Hypoglycemia DCCT Research Group. Diabetes. 1997;46:271-286; UKPDS Group. Lancet. 1998;352:837-853 6- 14 Type 1 Diabetes in the DCCT Conventional insulin 35% of pts19 events/100 pt-yr A1C ~9%, 6.5 yr Intensive insulin65% of pts61 events/100 pt-yr A1C 7.2%, 6.5 yr Type 2 Diabetes in the UKPDS Intensive policy insulin37% of pts2.3% pts/yr A1C 7.0%, 10 yr

27. 26 Barriers to Insulin Therapy Weight Gain DCCT Research Group. Diabetes. 1997;46:271-286; DCCT Research Group. N Engl J Med. 1993;329:977-986; UKPDS Group. Lancet. 1998;352:837-853 Type 1 Diabetes in the DCCT Intensive insulin+ 10.1 lb more A1C 7.2%, 6.5 yrthan conventional insulin Type 2 Diabetes in the UKPDS Intensive insulin+ 8.8 lb more A1C 7.0%, 10 yr than diet treatment

28. 27 Insulin Injection Devices Insulin pens Faster and easier than syringes – Improve patient attitude and adherence – Have accurate dosing mechanisms, but inadequate mixing may be a problem

29. 28 Insulin Pumps Continuous subcutaneous insulin infusion (CSII) – External, programmable pump connected to an indwelling subcutaneous catheter to deliver rapid-acting insulin Intraperitoneal insulin infusion – Implanted, programmable pump with intraperitoneal catheter. Not available in the United States

30. 29 New Insulins in Clinical Development Long-acting insulin analogue – Insulin detemir – Acylated insulin analogue – Soluble, binds to albumin Rapid-acting insulin analogue – Insulin 1964 – Limited aggregation, like lispro and aspart – Rapid absorption from injection site Inhaled insulins – Aerodose , AERx , Exubera  – Liquid aerosol or particulate cloud – Delivered by portable devices Buccally absorbed insulin – Oralin  – Liquid aerosol – Delivered by portable device

31. 30 Subcutaneous insulin: 16 U regular + 31 U long-acting Inhaled insulin: 12 mg inhaled + 25 U ultralente Inhaled Insulin in Type 1 Diabetes Skyler JS et al. Lancet. 2001;357:331-335 10 Weeks A1C (%) 0 4812 73 Patients Taking Inhaled Insulin tid in Addition to Injected Long-Acting Insulin 9 8 7 6

32. 31 Δ A1C (%) (mean baseline, 8.7%) 2 BaselineWeek 8Week 12Week 4 Inhaled Insulin in Type 2 Diabetes Cefalu WT et al. Ann Intern Med. 2001;134:203-207 26 Patients With Subcutaneous Regular Replaced by Inhaled Insulin tid, in Addition to Long-Acting Insulin Baseline mean dose: 19 U regular + 51 U long-acting Week 12 mean dose: 15 mg inhaled + 36 U ultralente 1 0

33. 32 Inhaled Insulin in Type 2 Diabetes Weiss SR et al. Diabetes. 1999;48(suppl 1):A12 10 8 6 4 0 Baseline12 weeksBaseline12 weeks –2.3% P <0.001 2 A1C (%) Oral agents alone Oral + inhaled insulin 69 Patients With Inhaled Insulin tid Added to Sulfonylurea and/or Metformin

34. 33 11 A1C (%) Baseline60 days 90 days 30 days Buccally Absorbed Insulin in Type 2 Diabetes Schwartz S et al. Diabetes. 2001;50(suppl 2):A130 Oral insulin Placebo 33 Patients With Oral Insulin tid Added to Diet Change from baseline -1.7% Placebo-subtracted difference -2.2% 10 9 8 7

35. 34 Summary Insulin Therapy Replaces complete lack of insulin in type 1 diabetes Supplements progressive deficiency in type 2 diabetes Basal insulin added to oral agents can be used to start Full replacement requires a basal-bolus regimen Hypoglycemia and weight gain are the main medical risks New insulin analogues and injection devices facilitate use