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Degludec poster and oral presentations at ADA 2011

Degludec poster and oral presentations at ADA 2011

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Degludec poster and oral presentations at ADA 2011

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  1. Degludec poster and oral presentations at ADA 2011

  2. ADA 2011 Degludec abstracts

  3. Clinical pharmacology

  4. ADA 2011 Degludec abstracts

  5. The pharmacodynamic variability of insulin degludec is consistently lower than insulin glargine over 24 hours at steady-state T Heise, L Hermanski, L Nosek, A Feldmann, S Rasmussen, H Haahr Heise et al. ADA 2011; 960-P (NN1250-1991)

  6. Background Individual day-to-day variability in AUCGIR,0-24h IDeg IGlar 1200 1000 180 160 140 Individual CV (%) 120 100 80 60 40 20 0 1 4 7 10 13 16 19 22 25 27 Patients listed in increasing order of individual CV Heise et al. Diabetologia 2010; 53 (Suppl. 1):S387 CV: within-subject coefficient of variation (%) AUC: area under the curve AUCGIR,0-24h: total glucose-lowering effect Heise et al. ADA 2011; 960-P (NN1250-1991)

  7. Study design IDeg OD (n=27) Patients with type 1 diabetes (n=54) IGlar OD (n=27) 12 days 0 9 6 • Inclusion criteria • Type 1 diabetes ≥12 months • Multiple daily insulin injections or CSII for ≥12 months • Daily basal insulin ≥0.2 U/kg/day • Total daily insulin <1.2 U/kg/day • HbA1C 10.0% • BMI 18.0–28.0 kg/m2 • Age 18–65 years 24h euglycaemic clamp Dosing: IDeg/IGlar 0.4U/kg Aim: estimate the day-to-day variability in glucose-lowering effect in consecutive 2h intervals during a 24h dosing interval OD: once-daily CSII: continuous subcutaneous insulin infusion Heise et al. ADA 2011; 960-P (NN1250-1991)

  8. GIR variability Clamp 1 (Day 6) Clamp 2 (Day 9) IGlar IDeg Clamp 3 (Day 12) 8.0 8.0 6.0 6.0 4.0 4.0 GIR (mg/(kg*min) GIR (mg/(kg*min) 2.0 2.0 0.0 0.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time (hours) Time (hours) Individual clamp profiles representative for the mean variability in glucose-lowering effect (AUCGIR,0-24h) (Mean CV: IDeg 31% and IGlar 62%) PD: pharmacodynamic Heise et al. ADA 2011; 960-P (NN1250-1991)

  9. Within-subject variability over time IDeg IGlar Heise et al. ADA 2011; 960-P (NN1250-1991)

  10. Within-subject variation GIRmax: maximum glucose-lowering effect Heise et al. ADA 2011; 960-P (NN1250-1991)

  11. Conclusions • The primary analysis of this trial showed a four-times lower day-to-day variability in glucose-lowering effect (AUCGIR,0-24h) for insulin degludec as compared to insulin glargine. • This post-hoc analysis shows that the day-to-day variability in glucose-lowering effect is significantly lower with insulin degludec than insulin glargine over the entire 24 hours. • With insulin degludec, day-to-day variability is consistently low over the entire 24 hours, whereas the variability of insulin glargine increases substantially 6–8 hours after dosing, reaching a maximum at 14–16 hours post-dosing. • This consistently low day-to-day variability with insulin degludec should facilitate insulin titration to lower FPG targets than achievable with insulin glargine, and contribute to the lower risk of hypoglycemia observed with insulin degludec in clinical trials. Heise et al. ADA 2011; 960-P (NN1250-1991)

  12. Insulin degludec has a 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 Heise et al. ADA 2011; 37-P LB (NN1250-1993)

  13. 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 42h euglycaemic clamp at steady-state CSII: continuous subcutaneous insulin infusion Heise et al. ADA 2011; 37-P LB (NN1250-1993)

  14. 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) Heise et al. ADA 2011; 37-P LB (NN1250-1993)

  15. Distribution and consistency of glucose-lowering effect GIR: glucose infusion rate AUCFGIR,total: total area under the GIR curve over a 24h dosing interval at steady-state Heise et al. ADA 2011; 37-P LB (NN1250-1993)

  16. Serum concentration of IDeg and IGlar IDeg 0.8U/kg 0.6U/kg 0.4U/kg LLoQ IGlar 0.8U/kg 0.6U/kg 0.4U/kg LLoQ LLoQ: lower limit of quantification Heise et al. ADA 2011; 37-P LB (NN1250-1993)

  17. Terminal half-life of IDeg and IGlar Data are harmonic means Heise et al. ADA 2011; 37-P LB (NN1250-1993)

  18. Conclusions • Insulin degludec 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 insulin degludec than for insulin glargine. • The glucose-lowering effect is more consistent and evenly distributed across a 24h dosing interval for insulin degludec than for insulin glargine. Heise et al. ADA 2011; 37-P LB (NN1250-1993)

  19. Multi-hexamer formation is the underlying mechanism behind the ultra-long glucose-lowering effect of insulin degludec P Kurtzhals, T Heise, HM Strauss, SG Bøttcher, C Granhall, H Haahr, Ib Jonassen Kurtzhals et al. ADA 2011; 32-P LB (MoA + 1993)

  20. 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. ADA 2011; 32-P LB (MoA + 1993)

  21. TEM • Elongated IDeg structures were seen under conditions resembling sc physiological conditions (no phenol). • These elongated IDeg structures were not observed in the presence of phenol (inset). sc: subcutaneous Kurtzhals et al. ADA 2011; 32-P LB (MoA + 1993)

  22. Proposed steps from injection to absorption IDeg di-hexamers Injected formulation – Phenol IDeg multi-hexamers Subcutaneous depot formation – Zn2+ IDeg monomers Absorption Phenol Zn2+ Kurtzhals et al. ADA 2011; 32-P LB (MoA + 1993)

  23. Pharmacodynamic effect of IDeg Individual patient profile Mean profile 200 Blood glucose level (mg/dL) 150 100 50 0 42 0 6 12 18 24 30 36 Time since injection (hours) IDeg = 0.6U/kg Kurtzhals et al. ADA 2011; 32-P LB (MoA + 1993)

  24. Conclusion • Following injection, insulin degludec forms a depot of soluble and stable multi-hexamers in the subcutaneous tissue. • The gradual separation of insulin degludec monomers from the multi-hexamers results in a slow and continuous delivery of insulin degludec from the subcutaneous injection site into the circulation, leading to an ultra-long glucose-lowering effect beyond 40h. Kurtzhals et al. ADA 2011; 32-P LB (MoA + 1993)

  25. 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. ADA 2011; 49-P LB (NN1250-1987)

  26. 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 • 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 26h euglycaemic clamp at steady-state Nosek et al. ADA 2011; 49-P LB (NN1250-1987)

  27. Mean GIR profiles at steady-state 0.8U/kg 0.6U/kg 0.4U/kg Data are arithmetic means GIR: glucose infusion rate AUCx-y: area under the curve for a specified time interval after injection AUCtotal: total area under the curve over a 24h dosing interval at steady-state Nosek et al. ADA 2011; 49-P LB (NN1250-1987)

  28. Mean glucose level profiles at steady-state 0.8U/kg 0.6U/kg 0.4U/kg 130 120 110 Glucose level (mg/dL) 100 90 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (hours) Nosek et al. ADA 2011; 49-P LB (NN1250-1987)

  29. Terminal half-life of IDeg Data are harmonic means Nosek et al. ADA 2011; 49-P LB (NN1250-1987)

  30. Conclusions These results show that at steady-state: • Insulin degludec has a flat and stable glucose-lowering effect. The glucose-lowering effect of insulin degludec 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 insulin degludec has a duration of action beyond 26h in patients with type 2 diabetes. Nosek et al. ADA 2011; 49-P LB (NN1250-1987)

  31. Response to induced hypoglycemia in type 1 diabetes: insulin degludec elicits an enhanced counter-regulatory hormone response compared with insulin glargine T Pieber, S Korsatko, G Köhler, S Deller, G Bock, S Zahiragic, J Mader, C Roepstorff, S Rasmussen, H Haahr, S Heller Pieber et al. ADA 2011; 498-P (NN1250-3538)

  32. Study design Day 5 IDeg OD (n=14) Hypoglycemia induction Recovery Run-in IGlar OD (n=14) Last dose (3x regular dose) 00:00 06:00 07:00 Variable timing 0 5 days Patients with type 1 diabetes (n=28) GIR PG=100 mg/dL 60 min 120 min PG=70 mg/dL 30 min PG=63 mg/dL 15 min PG=nadir Hypoglycaemic response assessments At PG = 81, 72, 63, 54 mg/dL and nadir At 0, 60, and 120 min after PG reached 70mg/dL Variable glucose infusion rate (GIR) Constant GIR (5.5mg/kg/min) Pieber et al. ADA 2011; 498-P (NN1250-3538)

  33. Development of hypoglycaemia IDeg OD (n=14) IGlar OD (n=14) Rate of PG decline (81 mg/dL to nadir) Treatment ratio (IDeg/IGlar for slope): 1.02, p=0.84 100 PG (mg/dL) 81 72 63 60 54 50 Nadir 40 Individual PG at nadir Treatment ratio (IDeg/IGlar): 1.03, p=0.12 60 80 0 100 -40 -20 120 20 40 t, PG decline (min)† †PG level of 81 mg/dL has been set to time=0 on the x axis to reflect the analysis of rate of PG decline Pieber et al. ADA 2011; 498-P (NN1250-3538)

  34. Counter-regulatory hormone response Growth hormone Cortisol 12 140 IDeg OD (n=14) IGlar OD (n=14) 10 130 8 ng/mL ng/mL 6 120 4 110 2 100 100 81 72 63 54 Nadir 100 81 72 63 54 Nadir Plasma glucose (mg/dL) Plasma glucose (mg/dL) Epinephrine 140 120 pg/mL 100 80 60 40 20 100 81 72 63 54 Nadir Plasma glucose (mg/dL) Pieber et al. ADA 2011; 498-P (NN1250-3538)

  35. 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=63 mg/dL (30 min) Data are estimated treatment ratios (IDeg/IGlar) with [95% CI] Pieber et al. ADA 2011; 498-P (NN1250-3538)

  36. Conclusions • A solid counter-regulatory hormone response was seen when hypoglycemia was induced by insulin degludec. • Less glucose was required to alleviate hypoglycemia induced by insulin degludec than insulin glargine. • There was some indication of a greater counter-regulatory hormone response with insulin degludec compared with insulin glargine. Pieber et al. ADA 2011; 498-P (NN1250-3538)

  37. Ultra-long-acting insulin degludec: two different formulations (U100 and U200) are bioequivalent and show similar pharmacodynamics S Korsatko, S Deller, S Zahiragic, J Mader, K Neubauer, C Adrian, H Thomsen, H Haahr, T Pieber Korsatko et al. ADA 2011; 2349-PO (NN1250-3678)

  38. Study design IDeg OD U100 Patients with type 1 diabetes (n=33) IGlar OD U200 0 8 days 26-hour euglycemic glucose clamp procedure was performed on day 8 Dosing: IDeg U100 = 0.4U/kg IDeg U200 = 0.4U/kg Korsatko et al. ADA 2011; 2349-PO (NN1250-3678)

  39. Glucose infusion rates Korsatko et al. ADA 2011; 2349-PO (NN1250-3678)

  40. Bioequivalence †means derived from ANOVA model with treatment and period as fixed effects and subject as random effect Korsatko et al. ADA 2011; 2349-PO (NN1250-3678)

  41. Conclusions • Insulin degludec U100 and U200 demonstrated a good safety and tolerability profile. • Insulin degludec U100 and U200 formulations were bioequivalent and had similar pharmacodynamics at steady-state. • Insulin degludec U100 and U200 could be used interchangeably in clinical practice. Korsatko et al. ADA 2011; 2349-PO (NN1250-3678)

  42. Basal-bolus

  43. ADA 2011 Degludec abstracts

  44. Insulin degludec improves long-term glycemic control with less nocturnal hypoglycemia compared with insulin glargine: 1-year results from a randomized basal-bolus trial in patients with type 2 diabetes(BEGIN™: BB T2)A Garber*, A King, AM Ocampo Francisco,L Endahl, P Hollander Clinicaltrials.gov identifier: NCT00972283 *Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX Garber et al. ADA 2011; 74-OR (NN1250-3582)

  45. Study design IDeg OD*+ IAsp + met ± pio (n=755) Patients with advanced type 2 diabetes (n=1006) IGlar OD§+ 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 Randomized 3:1 (IDeg:IGlar) Open label *Dosed with eveningmeal §Dosed any time of day but same time every day (as per label) met: metformin pio: pioglitazone IAsp: insulin aspart IDeg: insulin degludec IGlar: insulin glargine Garber et al. ADA 2011; 74-OR (NN1250-3582)

  46. Titration algorithm: IDeg and IGlar aMean of 3 consecutive days’ measurementsbUnless there is obvious explanation for the low value, such as a missed meal Garber et al. ADA 2011; 74-OR (NN1250-3582)

  47. Subject disposition 1440 Screened 434Failed screening criteria 1006 Randomized 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 randomization Garber et al. ADA 2011; 74-OR (NN1250-3582)

  48. Baseline characteristics Values are mean (±SD) unless otherwise stated aCalculated, not measured Garber et al. ADA 2011; 74-OR (NN1250-3582)

  49. 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 Garber et al. ADA 2011; 74-OR (NN1250-3582)

  50. Fasting plasma glucose over time IDeg OD + IAsp (n=744) IGlar OD + IAsp (n=248) Treatment difference: –5.22, p=NS 0 FAS; LOCF Comparisons: Estimates adjusted for multiple covariates Garber et al. ADA 2011; 74-OR (NN1250-3582)