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Therapeutic Options Insulins

Therapeutic Options Insulins. Insulin Preparations. Class Agents Human insulins Regular, NPH, lente, ultralente Insulin analogues Aspart, glulisine, lispro, glargine Premixed insulins Human 70/30, 50/50 Humalog mix 75/25 Novolog mix 70/30. Human Insulin. 21 amino acids. A-chain.

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Therapeutic Options Insulins

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  1. Therapeutic OptionsInsulins

  2. Insulin Preparations Class Agents Human insulins Regular, NPH, lente, ultralente Insulin analogues Aspart, glulisine, lispro, glargine Premixed insulins Human 70/30, 50/50 Humalog mix 75/25 Novolog mix 70/30

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

  4. Modified Human Insulin Regular InsulinShort acting Hexamers in Zn2+ buffer Neutral Protamine Hagedorn (NPH) InsulinIntermediate acting Medium-sized crystals in protamine-Zn2+ buffer Lente and Ultralente InsulinIntermediate andLarge crystals in acetate-Zn2+ buffer long acting

  5. Profiles of Human Insulins 2 3 4 5 6 7 8 9 12 13 14 15 16 17 18 19 20 21 22 23 24 0 1 10 11 Regular 6–8 hours Plasma insulin levels NPH 12–20 hours Ultralente 18–24 hours Hours

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

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

  8. Insulin LisproA Rapid-Acting Insulin Analogue 10 Patients With Type 1 Diabetes Following a Meal Regular insulin Insulin lispro Plasma Insulin pmol/L Plasma Glucose mg/dL 200 400 Meal and insulin Meal and insulin 300 150 200 100 100 0 0 -60 -30 0 30 60 90 120 150 180 210 240 -60 -30 0 30 60 90 120 150 180 210 240 Minutes Heinemann L et al. Diabet Med. 1996;13:625-629

  9. Insulin Action Profiles in Type 1 Diabetes 20 Patients 4 3 2 1 0 Glucose infusion (mg/kg/min) Ultralente NPH Glargine 0 4 8 12 16 20 24 Hours Lepore M et al. Diabetes. 2000;49:2142-2148

  10. Action Profiles of Insulin Analogues 2 3 4 5 6 7 8 9 12 13 14 15 16 17 18 19 20 21 22 23 24 0 1 10 11 Aspart, glulisine, lispro 4–6 hours Regular 6–8 hours Plasma insulin levels NPH 12–20 hours Ultralente 18–24 hours Glargine 24 hours Hours

  11. Human Insulins and AnaloguesTypical Times of Action

  12. Normal Daily Plasma Insulin Profile U/mL 100 B L D 80 60 40 20 1200 2400 1800 0800 0600 0600 Time of day B=breakfast; L=lunch; D=dinner Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

  13. Evening Basal InsulinBedtime NPH 1200 2400 0600 1800 0800 0600 U/mL 100 B L D Normal pattern 80 NPH 60 40 20 Time of day B=breakfast; L=lunch; D=dinner

  14. Starting Basal Insulin for Type 2 DiabetesBedtime NPH Added to Diet 12 Patients Treated for 16 Weeks Plasma glucose (mg/dL) 400 Diet only Bedtime NPH 300 NPH 200 100 0 0800 1200 1600 2000 2400 0400 0800 Time of day Cusi K et al. Diabetes Care. 1995;18:843-851

  15. Starting Basal Insulin for Type 2 DiabetesSuppertime 70/30 Added to Glimepiride Placebo + insulin (N=73) Glimepiride + insulin titrated to FPG 140 mg/dL (N=72) Fasting Glucose Insulin Dosage mg/dL Units /day 100 300 * * 250 * * * 75 *P<0.001 * * * 200 50 150 25 *P<0.001 100 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Weeks FPG=fasting plasma glucose Riddle MC et al. Diabetes Care. 1998;21:1052-1057

  16. Split-Mixed RegimenHuman Insulins 1200 2400 1800 0800 0600 0600 NPH Regular NPH Regular U/mL 100 B L D 80 Normal pattern 60 40 20 Time of day B=breakfast; L=lunch; D=dinner

  17. Split-Mixed RegimenNPH + Regular for Type 2 Diabetes Diet only Insulin 6 months Plasma Glucose Serum Insulin pmol/L mg/dL N + R N + R N + R N + R 1000 400 800 300 600 200 400 100 200 0 0 0600 1200 1800 2400 0600 0600 1200 1800 2400 0600 B L D B L D Time of day B=breakfast; L=lunch; D=dinner Henry RR et al. Diabetes Care. 1993;16:21-31

  18. Multiple Daily InjectionsHuman Insulins 0800 0600 1200 2400 0600 1800 NPH Regular Regular Regular NPH U/mL 100 B L D 80 60 Normal pattern 40 20 Time of day B=breakfast; L=lunch; D=dinner

  19. Multiple Daily InjectionsNPH + Regular for Type 2 Diabetes 10 Patients With Diabetes, 10 Normal Controls Baseline oral agents Normal Insulin 8 weeks Plasma Glucose Serum Insulin R R N R R N R R mg/dL pmol/L 300 300 250 200 200 150 100 100 50 0 0 0800 1200 1600 2000 2400 0400 0800 0800 1200 1600 2000 2400 0400 0800 B Sn L Sn D Sn B Sn L Sn D Sn Time of day B=breakfast; Sn=snack; L=lunch; D=dinner Lindström TH et al. Diabetes Care. 1992;15:27-34

  20. Multiple Daily InjectionsNPH + Regular or Aspart for Type 1 Diabetes 16 Plasma Glucose mg/dL mmol/L 14 250 12 10 200 8 150 6 Serum Insulin NPH + regular insulin A N A A mU/L 100 Insulin aspart 80 60 40 20 0 0600 1200 1800 2400 0600 B L D B=breakfast; L=lunch; D=dinner Time of day Home PD et al. Diabetes Care. 1998;21:1904-1909

  21. 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. Basal-Bolus Insulin TreatmentWith Insulin Analogues 0600 1800 0800 0600 1200 2400 Lispro, glulisine, or aspart U/mL 100 Glargine B L D 80 60 Normal pattern 40 20 Time of day B=breakfast; L=lunch; D=dinner

  23. 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 Barriers to Using Insulin

  24. Barriers to Using InsulinAttitudes of PatientsWith Type 1 and Type 2 Diabetes All Patients Patients With High Anxiety 100 % of patients 80 70% 60 45% 42% 40 28% 14% 20 0 Avoidinjectionsbecause of anxiety Troubledby ideaof moreinjections High anxietyabout injections Avoidinjectionsbecause of anxiety Troubledby ideaof moreinjections Zambanini A et al. Diabetes Res Clin Pract. 1999;46:239-246

  25. Barriers to Insulin TherapyCardiovascular Risk Is Not Supported by Trials Type 2 Diabetes in the UKPDS Risk of myocardial infarction Conventional treatment 17.4 events/1000 pt-yr Intensive insulin 14.7 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 insulin 33% mortality (P=0.011) UKPDS Group. Lancet. 1998;352:837-853; Malmberg K. BMJ. 1997;314:1512-1515 6-14

  26. Barriers to Insulin TherapySevere Hypoglycemia Type 1 Diabetes in the DCCT Conventional insulin 35% of pts 19 events/100 pt-yr A1C ~9%, 6.5 yr Intensive insulin 65% of pts 61 events/100 pt-yr A1C 7.2%, 6.5 yr Type 2 Diabetes in the UKPDS Intensive policy insulin 37% of pts 2.3% pts/yr A1C 7.0%, 10 yr DCCT Research Group. Diabetes. 1997;46:271-286; UKPDS Group. Lancet. 1998;352:837-853 6-14

  27. Barriers to Insulin TherapyWeight Gain Type 1 Diabetes in the DCCT Intensive insulin + 10.1 lb more A1C 7.2%, 6.5 yr than conventional insulin Type 2 Diabetes in the UKPDS Intensive insulin + 8.8 lb more A1C 7.0%, 10 yr than diet treatment 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

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

  29. 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. 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. Inhaled Insulin in Type 1 Diabetes 73 Patients Taking Inhaled Insulin tid in Addition to Injected Long-Acting Insulin Subcutaneous insulin: 16 U regular + 31 U long-acting A1C (%) 10 Inhaled insulin: 12 mg inhaled + 25 U ultralente 9 8 7 6 0 4 8 12 Weeks Skyler JS et al. Lancet. 2001;357:331-335

  32. Inhaled Insulin in Type 2 Diabetes 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 Δ A1C (%)(mean baseline, 8.7%) 2 1 0 -1 Baseline Week 4 Week 8 Week 12 Cefalu WT et al. Ann Intern Med. 2001;134:203-207

  33. Inhaled Insulin in Type 2 Diabetes 69 Patients With Inhaled Insulin tid Added to Sulfonylurea and/or Metformin Oral agents alone Oral + inhaled insulin A1C (%) 10 –2.3% P<0.001 8 6 4 2 0 Baseline 12 weeks Baseline 12 weeks Weiss SR et al. Diabetes. 1999;48(suppl 1):A12

  34. Buccally Absorbed Insulin in Type 2 Diabetes 33 Patients With Oral Insulin tid Added to DietChange from baseline -1.7%Placebo-subtracted difference -2.2% A1C (%) 11 Oral insulin Placebo 10 9 8 7 Baseline 30 days 60 days 90 days Schwartz S et al. Diabetes. 2001;50(suppl 2):A130

  35. SummaryInsulin 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

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