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Degludec posters and oral presentation at EASD 2011

Degludec posters and oral presentation at EASD 2011. EASD 2011 Degludec abstracts. EASD 2011 Degludec abstracts. Clinical pharmacology. EASD 2011 Degludec abstracts. EASD 2011 Degludec abstracts.

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Degludec posters and oral presentation at EASD 2011

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  1. Degludec posters and oral presentation at EASD 2011

  2. EASD 2011 Degludec abstracts

  3. EASD 2011 Degludec abstracts

  4. Clinical pharmacology

  5. EASD 2011 Degludec abstracts

  6. EASD 2011 Degludec abstracts

  7. A higher counter‑regulatory hormone response is seen with insulin degludec than insulin glargine in response to induced hypoglycaemia in type 1 diabetes S Heller, T Pieber, S Korsatko, G Köhler, S Deller, G Bock, S Zahiragic, J Mader, C Roepstorff, S Rasmussen, H Haahr Clinical trial.gov identifier: NCT01002768 Heller et al. Diabetologia 2011;54(Suppl. 1):S261 (640-P); Pieber et al. Diabetes 2011;60(Suppl 1):A138 (498-P) (NN1250-3538)

  8. Study design Day 5 IDeg Hypoglycaemia induction Recovery Run-in IGlar Last dose (3x regular dose) 00:00 06:00 07:00 Variable timing 0 5 days Patients with type 1 diabetes GIR PG=5.5mmol/L 60 min 120 min PG=3.9mmol/L 30 min PG=3.5mmol/L 15 min PG=nadir Hypoglycaemic response assessments At PG = 4.5, 4, 3.5, 3 mmol/L and nadir At 0, 60, and 120 min after PG reached 3.9mmol/L Variable glucose infusion rate (GIR) Constant GIR (5.5mg/kg/min) Heller et al. Diabetologia 2011;54(Suppl. 1):S261 (640-P); Pieber et al. Diabetes 2011;60(Suppl 1):A138 (498-P) (NN1250-3538)

  9. Development of hypoglycaemia IDeg OD (n=14) IGlar OD (n=14) Rate of PG decline (4.5mmol/L to nadir) Treatment ratio (IDeg/IGlar for slope): 1.02, p=0.84 5.5 PG (mmol/L) 4.5 4.0 3.5 3.3 3.0 2.7 Nadir 2.2 Individual PG at nadir Treatment ratio (IDeg/IGlar): 1.03, p=0.12 60 80 -40 -20 0 100 120 20 40 t, PG decline (min)† †PG level of 4.5mmol/L has been set to time=0 on the x axis to reflect the analysis of rate of PG decline Heller et al. Diabetologia 2011;54(Suppl. 1):S261 (640-P); Pieber et al. Diabetes 2011;60(Suppl 1):A138 (498-P) (NN1250-3538)

  10. Counter-regulatory hormone response Growth hormone Cortisol 12 140 10 ng/mL 130 8 ng/mL 6 120 IDeg OD (n=14) IGlar OD (n=14) 4 110 2 100 5.5 4.5 4.0 3.5 3.0 Nadir 5.5 4.5 4.0 3.5 3.0 Nadir Plasma glucose (mmol/L) Plasma glucose (mmol/L) Epinephrine 140 pg/mL 120 100 80 60 40 20 5.5 4.5 4.0 3.5 3.0 Nadir Plasma glucose (mmol/L) Heller et al. Diabetologia 2011;54(Suppl. 1):S261 (640-P); Pieber et al. Diabetes 2011;60(Suppl 1):A138 (498-P) (NN1250-3538)

  11. Glucose infusion rate over time 3 0.55 p<0.01 IDeg OD (n=14) IGlar OD (n=14) 0.71 p=0.02 2 GIR (mg/kg*min) 0.62 p=0.08 1 0.43 p=0.11 0 Baseline (last 30 min) Nadir (15 min) Recovery PG=3.5 mmol/L (30 min) Data are estimated treatment ratios (IDeg/IGlar) Heller et al. Diabetologia 2011;54(Suppl. 1):S261 (640-P); Pieber et al. Diabetes 2011;60(Suppl 1):A138 (498-P) (NN1250-3538)

  12. Conclusions • A solid counter-regulatory hormone response was seen when hypoglycaemia was induced by IDeg. • Less glucose was required to alleviate hypoglycaemia induced by IDeg than IGlar. • There was some indication of a greater counter-regulatory hormone response with IDeg compared with IGlar. Heller et al. Diabetologia 2011;54(Suppl. 1):S261 (640-P); Pieber et al. Diabetes 2011;60(Suppl 1):A138 (498-P) (NN1250-3538)

  13. Ultra-long-acting insulin degludec: bioequivalence and similar pharmacodynamics shown for two different formulations (U100 and U200) S Korsatko, S Deller, S Zahiragic, J Mader, K Neubauer, C Adrian, H Thomsen, H Haahr, T Pieber Korsatko et al. Diabetologia 2011;54(Suppl. 1):S427 (1051-P); Diabetes 2011;60(Suppl 1):A624 (2349-PO) (NN1250-3678)

  14. Study design IDeg OD U100 Patients with type 1 diabetes (n=33) IDeg OD U200 0 8 days 26-hour euglycaemic glucose clamp procedure was performed on day 8 Dosing: IDeg U100 = 0.4U/kg IDeg U200 = 0.4U/kg Korsatko et al. Diabetologia 2011;54(Suppl. 1):S427 (1051-P); Diabetes 2011;60(Suppl 1):A624 (2349-PO) (NN1250-3678)

  15. Glucose infusion rates Korsatko et al. Diabetologia 2011;54(Suppl. 1):S427 (1051-P); Diabetes 2011;60(Suppl 1):A624 (2349-PO) (NN1250-3678)

  16. Bioequivalence Korsatko et al. Diabetologia 2011;54(Suppl. 1):S427 (1051-P); Diabetes 2011;60(Suppl 1):A624 (2349-PO) (NN1250-3678)

  17. Conclusions • IDeg U100 and U200 are bioequivalent (post-hoc analysis) and have similar total glucose lowering effect • Based on these data, IDeg U100 and U200 could be used interchangeably in clinical practice Korsatko et al. Diabetologia 2011;54(Suppl. 1):S427 (1051-P); Diabetes 2011;60(Suppl 1):A624 (2349-PO) (NN1250-3678)

  18. Insulin degludec: two-fold longer half-life and a more consistent pharmacokinetic profile than insulin glargine T Heise, U Hövelmann, L Nosek, SG Bøttcher, C Granhall, H Haahr Clinical trial.gov identifier: NCT01114542 Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P); ADA 2011;37-LB (NN1250-1993)

  19. Study design 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 0.8U/kg IDeg 0.4, 0.6 or 0.8U/kg n=66 IGlar 0.4, 0.6 or 0.8U/kg IGlar 0.4, 0.6 or 0.8U/kg • Inclusion criteria • Type 1 diabetes 12 months • Multiple daily insulin injections or CSII for 12 months • Total daily insulin <1.2U/kg/day • Daily basal insulin ≥0.2U/kg/day • HbA1c 6.7–10.0% • BMI 18–28 kg/m2 • Age 18–65 years Euglycaemic clamps at steady-state CSII: continuous subcutaneous insulin infusion Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P); ADA 2011;37-LB (NN1250-1993)

  20. Distribution and consistency of exposure 200 AUCT (pmol·h·l-1·10-3) 160 120 80 40 0 0 0.2 0.4 0.6 0.8 Dose (U/kg) AUCFGIR,T: total area under the GIR curve over a 24h dosing interval at steady-state Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P); ADA 2011;37-LB (NN1250-1993)

  21. Distribution and consistency of glucose-lowering effect GIR: glucose infusion rate Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P); ADA 2011;37-LB (NN1250-1993)

  22. Serum concentration of IDeg and IGlar IDeg 0.8U/kg IDeg 0.6U/kg IDeg 0.4U/kg LLOQ IGlar 0.8U/kg IGlar 0.6U/kg IGlar 0.4U/kg LLOQ Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P); ADA 2011;37-LB (NN1250-1993) LLOQ=lower limit of quantification (20pmol/L); samples were collected until 120 hours for both IDeg and IGlar.

  23. Terminal half-life of IDeg and IGlar Data are harmonic means Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P); ADA 2011;37-LB (NN1250-1993)

  24. Conclusions • IDeg has a half-life of more than 25h, which is twice as long as that for insulin glargine. • Pharmacokinetic exposure is more consistent and evenly distributed across a 24h dosing interval for IDeg than for IGlar. • The glucose-lowering effect is more consistent and evenly distributed across a 24h dosing interval for IDeg than for IGlar. Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P); ADA 2011;37-LB (NN1250-1993)

  25. Multi-hexamer formation is the underlying basis for the ultra-long glucose-lowering effect of insulin degludec P Kurtzhals, T Heise, HM Strauss, SG Bøttcher, C Granhall, H Haahr, I Jonassen Clinical trial.gov identifier: NCT01002768 Kurtzhals et al. Diabetologia 2011;54(Suppl. 1):S426 (1049-P); ADA 2011;42-LB (MoP + NN1250-1993)

  26. Study design Pharmacodynamic effect Transmission electron microscopy Treatment period 8 days • IDeg samples (2.5mg/mL) in a preparation containing five zinc ions per insulin monomer were placed on formvar-coated copper grids • Samples were stained with a 2.5% (m/V) uranyl acetate solution • Samples were examined with a FEI Morgagni 268 microscope at 80kV Patients with type 1 diabetes (n=66) IDeg OD 0.4, 0.6 or 0.8U/kg 42h euglycaemic clamp at steady-state Kurtzhals et al. Diabetologia 2011;54(Suppl. 1):S426 (1049-P); ADA 2011;42-LB (MoP + NN1250-1993)

  27. IDeg Multi-hexamers Main picture shows elongated IDeg structures in absence of phenol; inset (white box)shows absence of elongated IDeg structures in presence of phenol. Kurtzhals et al. Diabetologia 2011;54(Suppl. 1):S426 (1049-P); ADA 2011;42-LB (MoP + NN1250-1993)

  28. Proposed steps from injection to absorption IDeg di-hexamers Injected formulation – Phenol IDeg multi-hexamers Subcutaneous depot formation – Zn2+ IDeg monomers Absorption Kurtzhals et al. Diabetologia 2011;54(Suppl. 1):S426 (1049-P); ADA 2011;42-LB (MoP + NN1250-1993)

  29. Pharmacodynamic effect of IDeg 11.1 Individual patient profile Mean profile 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 = 0.6U/kg Kurtzhals et al. Diabetologia 2011;54(Suppl. 1):S426 (1049-P); ADA 2011;42-LB (MoP + NN1250-1993)

  30. Conclusion • Following injection, IDeg forms a depot of soluble and stable multi-hexamers in the subcutaneous tissue. • The gradual separation of IDeg monomers from the multi-hexamers results in a slow and continuous delivery of IDeg from the subcutaneous injection site into the circulation, leading to an ultra-long glucose-lowering effect beyond 40h. Kurtzhals et al. Diabetologia 2011;54(Suppl. 1):S426 (1049-P); ADA 2011;42-LB (MoP + NN1250-1993)

  31. Ultra-long pharmacokinetic properties of insulin degludec in adults with type 1 diabetes is preserved in children and adolescents after single-dose administration T Danne, T Biester, S Blaesig, R Kerstin, B Aschemier, O Kordonouri, C Granhall, G Søndergaard, AMO Francisco, H Haahr Clinical trial.gov identifier: NCT01030926 Danne et al. Diabetologia 2011;54(Suppl. 1):S425 (1047-P) (NN1250-1995)

  32. Study design Second treatment period First treatment period 7–21 days washout period Follow-up 7–21 days Screening 2–21 days IDeg 0.4U/kg IDeg 0.4U/kg IGlar 0.4U/kg IGlar 0.4U/kg • Inclusion criteria • Type 1 diabetes 12 months • Multiple daily insulin injections or CSII for 12 months • Total daily insulin 0.6–1.2 U/kg/day • HbA1c ≤10.0% • BMI • Children 15.0–20.0 kg/m2 • Adolescents 18.0–28.0 kg/m2 • Adults ≤30.0 kg/m2 • Age 6–65 years Danne et al. Diabetologia 2011;54(Suppl. 1):S425 (1047-P) (NN1250-1995)

  33. Mean Insulin Profiles 100 Children Adolescents Adults IDeg serum concentration (% of maximum) 10 1 0.1 0 20 30 40 10 50 60 70 Time since injection (hours) Danne et al. Diabetologia 2011;54(Suppl. 1):S425 (1047-P) (NN1250-1995)

  34. Pharmacokinetics Danne et al. Diabetologia 2011;54(Suppl. 1):S425 (1047-P) (NN1250-1995)

  35. Conclusions • The ultra-long pharmacokinetic profile of IDeg observed in adults is preserved in children and adolescents with type 1 diabetes. • Extent of exposure to IDeg was greater for adolescents than adults, and tended to be greater for children than adults; however, this is unlikely to have any clinical implications. As with other insulin products, IDeg should always be dosed according to individual needs. • IDeg is well tolerated in children, adolescents and adults. • Paediatric studies investigating the potential clinical benefits of this ultra-long-acting basal insulin appear warranted. Danne et al. Diabetologia 2011;54(Suppl. 1):S425 (1047-P) (NN1250-1995)

  36. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect L Nosek, T Heise, SG Bøttcher, H Hastrup, H Haahr Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P); ADA 2011;49-LB (NN1250-1987)

  37. Study design Second treatment period 6 days First treatment period 6 days Follow-up 7–21 days Screening 2–21 days 13–21 days washout period IDeg 0.4, 0.6 or 0.8U/kg IDeg 0.4, 0.6 or 0.8U/kg n=49 Euglycaemic clamp at steady-state • Inclusion criteria • Type 2 diabetes 12 months • Treated with insulin 3 months • HbA1c 10.0% • Fasting C-peptide <1.0 nmol/L • BMI 35 kg/m2 • Age 18–70 years Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P); ADA 2011;49-LB (NN1250-1987)

  38. Mean GIR profiles at steady-state 0.8U/kg 0.6U/kg 0.4U/kg Data are arithmetic means Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P); ADA 2011;49-LB (NN1250-1987)

  39. Mean glucose level profiles at steady-state 0.8U/kg 0.6U/kg 0.4U/kg 7.0 6.5 6.0 Glucose level (mmol/L) 5.5 5.0 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (hours) Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P); ADA 2011;49-LB (NN1250-1987)

  40. Terminal half-life of IDeg Data are harmonic means Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P); ADA 2011;49-LB (NN1250-1987)

  41. Conclusions • These results show that at steady-state: • IDeg has a flat and stable glucose-lowering effect. • The glucose-lowering effect of IDeg is consistent and evenly distributed over the 24h period. • Blood glucose remained at the clamp target level until end of the clamp and end of action was not reached in any patient. • These results confirm that IDeg has a duration of action beyond 26h in patients with type 2 diabetes. Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P); ADA 2011;49-LB (NN1250-1987)

  42. Basal–bolus

  43. EASD 2011 Degludec abstracts

  44. EASD 2011 Degludec abstracts

  45. Basal–bolus therapy with insulin degludec improves long-term glycaemic control with fewer nocturnal hypoglycaemic events compared with insulin glargine in people with type 2 diabetes P Hollander, A King, AMO Francisco, L Endahl, A Garber Hollander et al. Diabetologia 2011;54(Suppl. 1):S421 (1035-P); Garber et al. Diabetes 2011;60(Suppl 1):A203 (74-OR) (NN1250-3582)

  46. Study design IDeg + IAsp + met ± pio (n=755) Patients with advanced type 2 diabetes (n=1006) IGlar + IAsp + met ± pio (n=251) • Inclusion criteria • Type 2 diabetes ≥6 months • Previously treated with any • insulin regimen ≥3 months • ± OADs • HbA1c 7–10% • BMI ≤40 kg/m2 • Age ≥18 years 0 52 weeks Randomised 3:1 (IDeg:IGlar) Open label met: metformin pio: pioglitazone Hollander et al. Diabetologia 2011;54(Suppl. 1):S421 (1035-P); Garber et al. Diabetes 2011;60(Suppl 1):A203 (74-OR) (NN1250-3582)

  47. Titration algorithm: IDeg and IGlar aMean of 3 consecutive days’ measurementsbWithout obvious explanation Bolus dose titrated at investigator discretion Hollander et al. Diabetologia 2011;54(Suppl. 1):S421 (1035-P); Garber et al. Diabetes 2011;60(Suppl 1):A203 (74-OR) (NN1250-3582)

  48. Subject disposition Screened 1440 Failed screening criteria 434 Randomised 1006 IDeg OD + IAsp 755 IGlar OD + IAsp 251 Withdrawals 137 (18%) Adverse event 31 (4%) Non-compliance 23 (3%) Ineffective therapy 3 (0.4%) Other 80 (11%) Withdrawals 40 (16%) Adverse event 9 (4%) Non-compliance 12 (5%) Ineffective therapy 0 (0%) Other 19 (8%) Completers 618 (82%) Completers 211 (84%) 3:1 randomisation Hollander et al. Diabetologia 2011;54(Suppl. 1):S421 (1035-P); Garber et al. Diabetes 2011;60(Suppl 1):A203 (74-OR) (NN1250-3582)

  49. Baseline characteristics Values are mean (±SD) unless otherwise stated aCalculated, not measured Hollander et al. Diabetologia 2011;54(Suppl. 1):S421 (1035-P); Garber et al. Diabetes 2011;60(Suppl 1):A203 (74-OR) (NN1250-3582)

  50. HbA1c over time IDeg OD + IAsp (n=744) IGlar OD + IAsp (n=248) Treatment difference: Non-inferior 0.0 FAS; LOCF Comparisons: Estimates adjusted for multiple covariates Hollander et al. Diabetologia 2011;54(Suppl. 1):S421 (1035-P); Garber et al. Diabetes 2011;60(Suppl 1):A203 (74-OR) (NN1250-3582)

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