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The action – pharmacological profiles

The action – pharmacological profiles. Tim Heise. Germany. Basal insulins: GIR profiles in patients with T1DM. Subject no: 222. Subject no: 224. Subject no: 228. 7. 7. 7. 6. 6. 6. NPH (0.4 U/kg). 5. 5. 5. 4. 4. 4. GIR (mg/kg/min). 3. 3. 3. 2. 2. 2. 1. 1. 1. 0. 0. 0.

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The action – pharmacological profiles

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  1. The action – pharmacological profiles Tim Heise Germany

  2. Basal insulins: GIR profiles in patients with T1DM Subject no: 222 Subject no: 224 Subject no: 228 7 7 7 6 6 6 NPH (0.4 U/kg) 5 5 5 4 4 4 GIR (mg/kg/min) 3 3 3 2 2 2 1 1 1 0 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Subject no: 211 Subject no: 213 Subject no: 217 7 7 7 6 6 6 5 5 5 IGlar (0.4 U/kg) 4 4 4 GIR (mg/kg/min) 3 3 3 2 2 2 1 1 1 0 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Subject no: 210 Subject no: 215 Subject no: 218 7 7 7 6 6 6 IDet (0.4 U/kg) 5 5 5 4 4 4 GIR (mg/kg/min) 3 3 3 2 2 2 1 1 1 0 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Elapsed time (hours) Elapsed time (hours) Elapsed time (hours) GIR, glucose infusion rate; IDet, insulin detemir; IGlar, insulnglargine Heise et al. Diabetes 2004;53:1614–20

  3. Basal insulins: GIR profiles in patients with T2DM 8 NPH IDet IGlar Glucose infusion rate (µmol/kg/min) 6 4 2 0 0 4 8 12 16 20 24 28 32 Time (hours post-dosing) Lucidi et al. Diabetes Care 2011;34:1312–14

  4. IDeg: Formation of multi-hexamers [Zn2+ ] Subcutaneous depot IDeg multi-hexamers Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers Monomers are absorbed from the depot into the circulation

  5. Objectives of developing insulin degludec • Ultra-long duration of action: • Control fasting blood glucose with one injection in all individuals • Flat time–action profile: • Lower risk of hypoglycaemia • Low day-to-day variability: • Less hypoglycaemia and hyperglycaemia

  6. Mathematical model: 24h insulin

  7. Mathematical model: 72h insulin

  8. Ultra-long action = Peakless insulin

  9. IDeg: Reaching steady state 10,000 9000 8000 7000 ITC IDeg (pmol/L) 6000 5000 4000 3000 2000 1000 0 192 0 24 72 48 96 120 144 168 Time (hours) ITC, insulin trough concentration Heise et al. ADA 2011; 37-P LB; Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)

  10. IDeg PK profile at steady state in T1DM 10000 IDeg (pmol/L) 1000 100 0 4 8 12 16 20 24 Time since last injection (hours) Jonassen et al. Diabetes 2010;59(Suppl. 1):0039-OR

  11. IDeg PD profile at steady state in T1DM 6 5 GIR (mg/kg/min) 4 3 2 1 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours) IDeg = 0.4 U/kg Heise et al. ADA 2011; 37-P LB; Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)

  12. IDeg: BG control over 42 hours in T1DM 11.1 Blood glucose level (mmol/L) 8.3 5.6 2.8 0.0 42 0 6 12 18 24 30 36 Time since injection (hours) IDeg = 0.6 U/kg Kurtzhals et al. ADA 2011; 32-LB; Kurtzhals et al. Diabetologia 2011;54(Suppl. 1):S426 (1049-P) (MoP + NN1250-1993)

  13. IDeg PD profiles in T2DM at steady state 0.8 U/kg 0.6 U/kg 0.4 U/kg Nosek et al. ADA 2011; 49-P LB; Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P) (NN1250-1987)

  14. IDeg in T2DM at steady state AUCGIR,0–12h AUCGIR,12–24h AUC, area under the curve Nosek et al. ADA 2011; 49-P LB; Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P) (NN1250-1987)

  15. Summary from steady-state trials In these trials, the glucose-lowering effect of IDeg • is flat and stable • is evenly distributed over a 24-hour period • lasts beyond 24 hours in all individuals studied

  16. PK/PD data and half-life for IDeg and IGlar Second treatment period 8 days First treatment period 8 days 7–21 days washout period Follow-up 7–21 days Screening 2–21 days IDeg 0.4, 0.6 or 0.8 U/kg IDeg 0.4, 0.6 or 0.8 U/kg n=66 IGlar 0.4, 0.6 or 0.8 U/kg IGlar 0.4, 0.6 or 0.8 U/kg • Inclusion criteria • T1DM 12 months • HbA1c 6.7–10.0% • BMI 18–28 kg/m2 • Age 18–65 years 42-hour euglycaemic clamp at steady state Clinical trial.gov identifier: NCT01114542 Heise et al. ADA 2011; 37-P LB; Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)

  17. Serum concentration and half-life of IDeg and IGlar IDeg 0.8 U/kg IGlar 0.8 U/kg Heise et al. ADA 2011; 37-P LB; Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)

  18. Distribution of glucose-lowering effect over 24 hours at steady state AUCGIR,t, total area under the glucose-infusion rate curve over 24 hours (in steady state) Heise et al. ADA 2011; 37-P LB; Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)

  19. Summary of half-life study Insulin degludec • Half-life of more than 25 hours(twice as long as that for IGlar) • More consistent and evenly distributed metabolic effect across a 24-hour dosing interval than IGlar Heise et al. ADA 2011; 37-P LB; Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)

  20. Objectives of developing IDeg • Duration of action: • Control fasting blood glucose with one injection in all individuals • Flat time–action profile: • Lower risk of hypoglycaemia • Day-to-day variability: • Less hypoglycaemia and hyperglycaemia

  21. Targeting fasting plasma glucose FPG(mmol/L) FPG(mg/dL) Average FPG 12.0 216 11.0 198 10.0 180 9.0 162 8.0 144 7.0 126 6.0 108 5.0 90 Target zone 4.0 72 3.0 54 2.0 36 Hypoglycaemia zone 1.0 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Day

  22. Targeting fasting plasma glucose FPG(mmol/L) FPG(mg/dL) Average FPG 12.0 216 11.0 198 10.0 180 9.0 162 8.0 144 7.0 126 6.0 108 5.0 90 Target zone 4.0 72 3.0 54 2.0 36 Hypoglycaemia zone 1.0 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Day

  23. Targeting fasting plasma glucose FPG(mmol/L) FPG(mg/dL) Average FPG 12.0 216 11.0 198 10.0 180 9.0 162 8.0 144 7.0 126 6.0 108 5.0 90 Target zone 4.0 72 3.0 54 2.0 36 Hypoglycaemia zone 1.0 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Day

  24. Targeting fasting plasma glucose FPG(mmol/L) FPG(mg/dL) Average FPG 12.0 216 11.0 198 10.0 180 9.0 162 8.0 144 7.0 126 6.0 108 5.0 90 Target zone 4.0 72 3.0 54 2.0 36 Hypoglycaemia zone 1.0 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Day

  25. Within-subject variability of IDeg and IGlar in T1DM Screening 2–21 days Follow-up 7–21 days IDeg OD (n=27) IGlar OD (n=27) 0 12 days 9 6 • Inclusion criteria • T1DM ≥12 months • HbA1c10.0% • BMI 18–28 kg/m2 • Age 18–65 years 24-hour euglycaemic clamp Clinical trial.gov identifier: NCT00961324 Heiseet al. Diabetes 2011;60(Suppl. 1):A263 (Abstract 960-P)

  26. Variability with IDeg and IGlar CV, coefficient of variation Heise et al. Diabetes 2011;60(Suppl. 1):A263; Heise et al. Diabetologia 2010;53(Suppl. 1):S387

  27. Within-subject variability over time IDeg Heise et al. Diabetes 2011;60(Suppl. 1):A263

  28. Within-subject variability over time IDeg IGlar Heise et al. Diabetes 2011;60(Suppl. 1):A263

  29. Summary of variability study Day-to-day variability of IDeg • Considerably (up to four times) lower than IGlar • Consistently low over the entire 24 hours(substantial increase in the variability of IGlar after 6–8 hours) Heise et al. Diabetes 2011;60(Suppl. 1):A263

  30. Overall conclusions Insulin degludec • flat and stable glucose-lowering effect, equally distributed over 24 hours • Half-life twice as long as that of IGlar • Variability considerably lower than that of IGlar • may facilitate titration to lower FPG targets • has the potential to lower the risk of both hypoglycaemia and hyperglycaemia

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