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The next step – clinical data on basal–bolus therapy

The next step – clinical data on basal–bolus therapy. Miles Fisher. UK. The benefits of early tight control: UKPDS 10-year post-trial follow-up. 1. 2. 2. Holman et al. N Engl J Med 2008;359:1577–89; UKPDS Study Group. Lancet 1998;352:837–53. UKPDS 1. ADVANCE 2. ACCORD 3. VADT 4.

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The next step – clinical data on basal–bolus therapy

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  1. The next step – clinical data on basal–bolus therapy Miles Fisher UK

  2. The benefits of early tight control:UKPDS 10-year post-trial follow-up 1 2 2 Holman et al. N Engl J Med 2008;359:1577–89; UKPDS Study Group. Lancet 1998;352:837–53

  3. UKPDS1 ADVANCE2 ACCORD3 VADT4 p<0.001vs. conventional HR 1.86 (1.42–2.40)p<0.001 p<0.001 p=0.01 5.0 4.6 3.8 4.0 3.0 Annualised rate of severe hypoglycaemia† (%) 1.8 1.8 2.0 1.5 1.4 1.0 0.7 0.7 0.4 0 Conv Gly Ins Std Int Std Int Std Int 7.9% HbA1c= 7.1% 7.2% 7.3% 6.5% 7.5% 6.4% 8.4% 6.9% Higher rate of severe hypoglycaemia with intensive glycaemic control* *Intensive glycaemic control was defined differently in these trials. †Hypoglycaemia requiring any assistance in glucose-lowering trials. Conv, conventional therapy; Gly, glibenclamide; HR, hazard ratio; Ins, insulin; Int, intensive therapy; Std, standard therapy 1. UKPDS Group. Lancet 1998;352:837–53; 2. Patel et al; ADVANCE. N Engl J Med 2008;358:2560–72; 3. Gerstein et al; ACCORD. N Engl J Med 2008;358:2545–59; 4. Duckworth et al. N Engl J Med 2009;360:129–39

  4. The physician’s dilemma: prognosis versus tolerability 1.2 120 Risk of retinopathy per 100 patient-years Severe hypoglycaemia per 100 patient-years 1.0 0.8 0.6 60 0.4 0.2 0.0 0 8.5 5.0 5.5 7.0 7.5 8.0 9.0 9.5 10.0 10.5 6.0 6.5 HbA1c (%) DCCT Research Group. N Engl J Med 1993;329:977

  5. Hypoglycaemia rates in basal–bolus therapy Insulin detemir NPH insulin Insulin glargine p<0.001 p<0.05 Basal+bolus T1DM Basal+bolus T1DM analogue vs. human insulin Basal+bolus T1DM paediatrics Basal+bolus T1DM 2-year study Basal+bolus T1DM crossover Basal+bolus T2DM

  6. Overall and nocturnal hypoglycaemia in type 2 diabetes Detemir pm p<0.02 p<0.01 p<0.001 p<0.001 p<0.05 p<0.05 Detemir twice daily 1.0 NPH pm 0.9 NPH twice daily 0.8 Glargine pm 0.7 0.6 Relative risk 0.5 0.4 0.3 0.2 0.1 0.0 24-hour Nocturnal 24-hour Nocturnal 24-hour Nocturnal Riddle 2003 24 weeks Hermansen 2006 24 weeks Philis-Tsimikas 2006 20 weeks

  7. Nocturnal hypoglycaemia • Approximately 30% of non-severe nocturnal hypoglycaemic events result in work absenteeism and lost productivity1 • Affects functioning the following day Adapted from Jauch-Chara et al. Best Pract Res Clin Endocrinol Metab 2010;24:801–15. 1Brod et al. Diabetes 2011;60(Suppl. 1):A329(1197-P);2Bendtson et al. Diabetologia 1992;35:898–903; 3Matyka et al.Arch Dis Child 1999;81:138–142;4Jauch-Chara et al.Diabetes Care 2007;30:2040–5; 5King et al. Diabetes Care 1998;21:341–5; 6Schmid et al.Diabet Med 2008;25:232–5; 7Veneman et al.Diabetes 1993;42:1233–7; 8Fanelli et al. Diabetes 1998;47:1920–7

  8. Phase 2: basal–bolus trial in T1DMStudy design IDeg OD + IAsp (n=59) Patients with type 1 diabetes n=118 IGlar OD + IAsp (n=59) 0 16 weeks • Inclusion criteria • T1DM ≥12 months • Treated continuously with insulin (any regimen) • HbA1c 7–11% • BMI no restriction • Age 18–75 years Randomised 1:1 Open label IAsp, insulin aspart; IDeg, insulin degludec; IGlar, insulin glargine; OD, once daily Birkeland et al. Diabetes Care 2011;34:661–5

  9. Change in HbA1c Treatment difference: non-inferior Birkeland et al. Diabetes Care 2011;34:661–5

  10. Change in fasting plasma glucose IGlar OD (n=59) IDeg OD (n=59) p=NS Birkeland et al. Diabetes Care 2011;34:661–5

  11. Hypoglycaemia classification Suspected hypoglycaemia or routine PG measurement Patient able to treat self? Yes No PG <3.1 mmol/L* No Yes Not classified as trial hypoglycaemia Confirmed hypoglycaemia Severe hypoglycaemia Minor hypoglycaemia *With or without symptoms A nocturnal episode is any confirmed episode with time of onset between 23:00 and 05.59 am

  12. Hypoglycaemia: confirmed episodes IDeg OD (n=59) IGlar OD (n=59) 1200 28% risk reduction RR: 0.72 p=0.051 1000 Number of events 800 600 400 200 0 0 4 8 12 16 Time (weeks) Mean cumulative function Birkeland et al. Diabetes Care 2011;34:661–5

  13. Hypoglycaemia: nocturnal episodes IDeg OD (n=59) IGlar OD (n=59) 200 150 Number of events 58% risk reduction RR: 0.42 p=0.0007 100 50 0 0 4 8 12 16 Time (weeks) Mean cumulative function Birkeland et al. Diabetes Care 2011;34:661–5

  14. Phase 3 studies

  15. IDeg OD + IAsp (n=472) IGlar OD + IAsp (n=157) 52 weeks 0 Phase 3: basal–bolus in T1DMStudy design Patients with type 1 diabetes n=629 • Inclusion criteria • T1DM ≥12 months • Previously treated with any basal–bolus regimen ≥12 months • HbA1c≤10% • BMI≤35 kg/m2 • Age ≥18 years Randomised 3:1 (IDeg:IGlar)Open label Russell-Jones et al. Diabetologia 2011;54(Suppl. 1):S425 (1045-P); Heller et al. Diabetes 2011;60(Suppl. 1):A19 (70-OR) (NN1250-3583)

  16. HbA1c over time IDeg + IAsp (n=472) IGlar + IAsp (n=157) Treatment difference: non-inferior 0.0 FAS; LOCF Comparisons: estimates adjusted for multiple covariates FAS, full analysis set; LOCF, last observation carried forward Russell-Jones et al. Diabetologia 2011;54(Suppl. 1):S425 (1045-P); Heller et al. Diabetes 2011;60(Suppl. 1):A19 (70-OR) (NN1250-3583)

  17. Fasting plasma glucose over time IDeg + IAsp (n=472) IGlar + IAsp (n=157) 0 FAS; LOCF; p=NS Comparisons: estimates adjusted for multiple covariates Russell-Jones et al. Diabetologia 2011;54(Suppl. 1):S425 (1045-P); Heller et al. Diabetes 2011;60(Suppl. 1):A19 (70-OR) (NN1250-3583)

  18. Confirmed hypoglycaemia RR:1.07 p=NS IDeg + IAsp (n=472) IGlar + IAsp (n=154) SAS Comparisons: estimates adjusted for multiple covariates RR, relative risk; SAS, safety analysis set Russell-Jones et al. Diabetologia 2011;54(Suppl. 1):S425 (1045-P); Heller et al. Diabetes 2011;60(Suppl. 1):A19 (70-OR) (NN1250-3583)

  19. Nocturnal hypoglycaemia 25% risk reduction RR:0.75 p<0.05 IDeg + IAsp (n=472) IGlar + IAsp (n=154) 6.0 5.4 4.8 4.2 3.6 Confirmed nocturnal hypoglycaemia (number of events per patient) 3.0 2.4 1.8 1.2 0.6 0.0 0 4 8 12 16 20 24 26 32 36 40 44 48 52 SAS Comparisons: estimates adjusted for multiple covariates Time (weeks) Russell-Jones et al. Diabetologia 2011;54(Suppl. 1):S425 (1045-P); Heller et al. Diabetes 2011;60(Suppl. 1):A19 (70-OR) (NN1250-3583)

  20. Phase 3: basal–bolus in T2DM intensification/optimisation 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 • T2DM ≥6 months • Previously treated with any insulin regimen ≥3 months ± OADs • HbA1c 7–10% • BMI≤35 kg/m2 • Age ≥18 years 0 52 weeks Randomised 3:1 (IDeg:IGlar) Open label Hollander et al. Diabetologia 2011;54(Suppl. 1):S421 (1035-P); Garber et al. Diabetes 2011;60(Suppl. 1):A20 (74-OR) (NN1250-3582)

  21. 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):A20 (74-OR) (NN1250-3582)

  22. Confirmed hypoglycaemia 18% risk reduction RR:0.82 p=0.036 IDeg OD + IAsp (n=753) IGlar OD + IAsp (n=251) SAS 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):A20 (74-OR) (NN1250-3582)

  23. Nocturnal hypoglycaemia 25% rate reduction RR:0.75 p=0.04 IDeg OD + IAsp (n=753) IGlar OD + IAsp (n=251) SAS 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):A20 (74-OR) (NN1250-3582)

  24. Pre-specified meta-analysis of hypoglycaemia

  25. Hypoglycaemia results consistent with BEGIN™ pre-specified meta-analyses Nocturnal hypoglycaemia (all IDeg vs. IGlar studies, T1DM and T2DM) Trial (weeks) BEGIN™ BB T1 (52) BEGIN™ Flex T1 (26) BEGIN™ BB T2 (52) BEGIN™ Once Long (52) BEGIN™ Low Vol (26) BEGIN™ Once Asia (26) BEGIN™ Flex T2 (26) 26% risk reduction Meta-analysis 0.0 0.5 1.0 1.5 2.0 Favours IDeg Favours IGlar The meta-analyses were pre-specified as part of the BEGIN™ phase 3a trials for insulin degludec Garber et al. ADA 2011;74-OR (NN1250-3582)

  26. Reduction in confirmed hypoglycaemia withdegludec(all IDeg vs. IGlar studies) Nocturnal 26%* T1 and T2 36%* T2 basal only Overall 9%* T1 and T2 17%* T2 basal only *statistically significant improvement Hypoglycaemia results consistent with BEGIN™ pre-specified meta-analyses The meta-analyses were pre-specified as part of the BEGIN™ phase 3a trials for insulin degludec Garber et al. ADA 2011;74-OR (NN1250-3582) Reference: http://www.novonordisk.com/images/investors/investor_presentations/2011/CMD2011/04_Diabetes_treatment_tomorrow_CMD2011.pdf

  27. Maintenanceperiod(16 weeks+) Hypoglycaemia results consistent with BEGIN™ pre-specified meta-analyses 200 180 160 140 120 100 80 60 40 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (weeks) The meta-analyses were pre-specified as part of the BEGIN™ phase 3a trials for insulin degludec Garber et al. ADA 2011;74-OR (NN1250-3582) Reference: http://www.novonordisk.com/images/investors/investor_presentations/2011/CMD2011/04_Diabetes_treatment_tomorrow_CMD2011.pdf

  28. Reduction in confirmed hypoglycaemia withdegludec (all IDeg vs. IGlar studies,maintenance period) Nocturnal 32%* T1 and T2 49%* T2 basal only Overall 16%* T1 and T2 28%* T2 basal only *statistically significant improvement Hypoglycaemia results consistent with BEGIN™ pre-specified meta-analyses The meta-analyses were pre-specified as part of the BEGIN™ phase 3a trials for insulin degludec Garber et al. ADA 2011;74-OR (NN1250-3582) Reference: http://www.novonordisk.com/images/investors/investor_presentations/2011/CMD2011/04_Diabetes_treatment_tomorrow_CMD2011.pdf

  29. Conclusion • Tight diabetes control is associated with a reduced risk for long-term complications – but is also associated with increased risk of hypoglycaemia • Nocturnal hypoglycaemia not only affects the well-being of people with diabetes; in addition, it results in work absenteeism and lost productivity • Insulin degludec has been documented through several studies to lead to less risk of hypoglycaemia, especially less nocturnal hypoglycaemia, in both type 1 and type 2 diabetes compared with insulin glargine

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