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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 1 Human Insulin 21 amino acids A-chain B-chain 30 amino acids Monomers Dimers Zn++ Self-aggregation in solution Hexamers Zn++ 2 Modified Human Insulin Regular Insulin Hexamers in Zn2+ buffer Short acting Neutral Protamine Hagedorn (NPH) Insulin Intermediate acting Medium-sized crystals in protamine-Zn2+ buffer Lente and Ultralente Insulin Large crystals in acetate-Zn2+ buffer Intermediate and long acting 3 Profiles of Human Insulins Regular 6–8 hours NPH 12–20 hours Ultralente 18–24 hours Plasma insulin levels 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Hours 4 Insulin Analogues A-chain Human Insulin B-chain Dimers and hexamers in solution Aspart Asp Limited self-aggregation Monomers in solution Glu Lys Lys Pro Gly Glulisine Limited self-aggregation Monomers in solution Lispro Limited self-aggregation Monomers in solution Glargine Arg Arg Soluble at low pH Precipitates at neutral (subcutaneous) pH 5 Insulin Aspart A Rapid-Acting Insulin Analogue 20 Healthy Subjects, 10-h Euglycemic Clamp Plasma Insulin pmol/L Glusose infusion rate (mg/min) 500 400 300 Insulin aspart Regular insulin Insulin Action 700 600 500 400 300 200 200 100 100 0 0 100 200 300 400 500 600 0 0 100 200 300 400 500 600 Minutes Mudaliar SR et al. Diabetes Care. 1999;22:1501-1506 6 Insulin Lispro A Rapid-Acting Insulin Analogue 10 Patients With Type 1 Diabetes Following a Meal Regular insulin Insulin lispro pmol/L Plasma Insulin 400 mg/dL Meal and insulin 300 Plasma Glucose 200 150 Meal and insulin 200 100 100 0 -60 -30 0 30 60 90 120 150 180 210 240 0 -60 -30 0 30 60 90 120 150 180 210 240 Minutes Heinemann L et al. Diabet Med. 1996;13:625-629 7 Insulin Action Profiles in Type 1 Diabetes 20 Patients Glucose infusion 4 (mg/kg/min) Ultralente NPH 3 2 1 Glargine 0 0 4 8 12 16 20 24 Hours Lepore M et al. Diabetes. 2000;49:2142-2148 8 Action Profiles of Insulin Analogues Aspart, glulisine, lispro 4–6 hours Plasma insulin levels Regular 6–8 hours NPH 12–20 hours Ultralente 18–24 hours Glargine 24 hours 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Hours 9 Human Insulins and Analogues Typical Times of Action Insulin Preparations Onset of Action Peak Duration of Action Aspart, glulisine, lispro ~15 minutes 1–2 hours 4–6 hours Human regular 30–60 minutes 2–4 hours 6–8 hours Human NPH, lente 2–4 hours 4–10 hours 12–20 hours Human ultralente 4–6 hours 8–16 hours 18–24 hours Glargine 2–4 hours Flat ~24 hours 10 Normal Daily Plasma Insulin Profile U/mL 100 B L 0800 1200 D 80 60 40 20 0600 1800 2400 0600 Time of day B=breakfast; L=lunch; D=dinner Polonsky KS et al. N Engl J Med. 1988;318:1231-1239 11 Evening Basal Insulin Bedtime NPH U/mL 100 B L D 80 Normal pattern NPH 60 40 20 0600 0800 1200 1800 2400 0600 Time of day B=breakfast; L=lunch; D=dinner 12 Starting Basal Insulin for Type 2 Diabetes Bedtime 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 13 Starting Basal Insulin for Type 2 Diabetes Suppertime 70/30 Added to Glimepiride Placebo + insulin (N=73) Glimepiride + insulin titrated to FPG 140 mg/dL (N=72) mg/dL Fasting Glucose 300 * 250 * Insulin Dosage Units / 100 day 75 *P<0.001 200 * 25 0 4 8 12 16 20 24 * *P<0.001 100 0 * * 50 150 * * 0 4 8 12 16 20 24 Weeks FPG=fasting plasma glucose Riddle MC et al. Diabetes Care. 1998;21:1052-1057 14 Split-Mixed Regimen Human Insulins NPH Regular U/mL 100 B NPH Regular L D 80 Normal pattern 60 40 20 0600 0800 1200 1800 2400 0600 Time of day B=breakfast; L=lunch; D=dinner 15 Split-Mixed Regimen NPH + Regular for Type 2 Diabetes Diet only Insulin 6 months Plasma Glucose mg/dL 400 N+R Serum Insulin pmol/L N+R 1000 N + R N+R 800 300 600 200 400 100 200 0 0 0600 B 1200 L 1800 D 2400 0600 Time of day 0600 B 1200 L 1800 D 2400 0600 B=breakfast; L=lunch; D=dinner Henry RR et al. Diabetes Care. 1993;16:21-31 16 Multiple Daily Injections Human Insulins NPH Regular Regular U/mL 100 B L Regular NPH D 80 60 Normal pattern 40 20 0600 0800 1200 1800 2400 0600 Time of day B=breakfast; L=lunch; D=dinner 17 Multiple Daily Injections NPH + Regular for Type 2 Diabetes 10 Patients With Diabetes, 10 Normal Controls Baseline oral agents Normal Insulin 8 weeks Plasma Glucose R mg/dL R R Serum Insulin N R pmol/L 300 R R N 300 250 200 200 150 100 100 50 0 0800 1200 1600 2000 2400 B Sn L Sn D Sn 0400 0800 B=breakfast; Sn=snack; L=lunch; D=dinner Lindström TH et al. Diabetes Care. 1992;15:27-34 0 0800 1200 B Sn L 1600 2000 2400 0400 Sn D Sn 0800 Time of day 18 Multiple Daily Injections NPH + Regular or Aspart for Type 1 Diabetes mmol/L 16 mg/dL Plasma Glucose 14 12 10 250 200 8 6 150 Serum Insulin A mU/L 100 A A NPH + regular insulin Insulin aspart N 80 60 40 20 0 0600 B=breakfast; L=lunch; D=dinner 1200 B L Home PD et al. Diabetes Care. 1998;21:1904-1909 1800 D 2400 Time of day 0600 19 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 20 Basal-Bolus Insulin Treatment With Insulin Analogues Lispro, glulisine, or aspart U/mL 100 B L D 80 Glargine 60 40 Normal pattern 20 0600 0800 1200 1800 2400 0600 Time of day B=breakfast; L=lunch; D=dinner 21 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 22 Barriers to Using Insulin Attitudes of Patients With Type 1 and Type 2 Diabetes % of 100 patients All Patients Patients With High Anxiety 80 70% 60 42% 40 20 0 45% 28% 14% Avoid injections because of anxiety Troubled by idea of more injections High anxiety about injections Zambanini A et al. Diabetes Res Clin Pract. 1999;46:239-246 Avoid injections because of anxiety Troubled by idea of more injections 23 Barriers to Insulin Therapy Cardiovascular Risk Is Not Supported by Trials Type 2 Diabetes in the UKPDS Risk of myocardial infarction Conventional treatment Intensive insulin 17.4 events/1000 pt-yr 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 Intensive insulin 44% mortality 33% mortality (P=0.011) UKPDS Group. Lancet. 1998;352:837-853; Malmberg K. BMJ. 1997;314:1512-1515 24 Barriers to Insulin Therapy Severe Hypoglycemia Type 1 Diabetes in the DCCT Conventional insulin A1C ~9%, 6.5 yr 35% of pts 19 events/100 pt-yr Intensive insulin A1C 7.2%, 6.5 yr 65% of pts 61 events/100 pt-yr Type 2 Diabetes in the UKPDS Intensive policy insulin A1C 7.0%, 10 yr DCCT Research Group. Diabetes. 1997;46:271-286; UKPDS Group. Lancet. 1998;352:837-853 37% of pts 2.3% pts/yr 25 Barriers to Insulin Therapy Weight Gain Type 1 Diabetes in the DCCT Intensive insulin A1C 7.2%, 6.5 yr + 10.1 lb more than conventional insulin Type 2 Diabetes in the UKPDS Intensive insulin A1C 7.0%, 10 yr + 8.8 lb more 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 26 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 27 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 28 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 29 Inhaled Insulin in Type 1 Diabetes 73 Patients Taking Inhaled Insulin tid in Addition to Injected Long-Acting Insulin A1C (%) Subcutaneous insulin: 16 U regular + 31 U long-acting Inhaled insulin: 12 mg inhaled + 25 U ultralente 10 9 8 7 6 0 4 8 12 Weeks Skyler JS et al. Lancet. 2001;357:331-335 30 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 2 Δ A1C (%) (mean baseline, 8.7%) 1 0 -1 Baseline Cefalu WT et al. Ann Intern Med. 2001;134:203-207 Week 4 Week 8 Week 12 31 Inhaled Insulin in Type 2 Diabetes 69 Patients With Inhaled Insulin tid Added to Sulfonylurea and/or Metformin Oral agents alone A1C (%) Oral + inhaled insulin 10 –2.3% P<0.001 8 6 4 2 0 Baseline Weiss SR et al. Diabetes. 1999;48(suppl 1):A12 12 weeks Baseline 12 weeks 32 Buccally Absorbed Insulin in Type 2 Diabetes 33 Patients With Oral Insulin tid Added to Diet Change from baseline -1.7% Placebo-subtracted difference -2.2% A1C (%) 11 Oral insulin Placebo 10 9 8 7 Baseline 30 days Schwartz S et al. Diabetes. 2001;50(suppl 2):A130 60 days 90 days 33 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 34