Insulin degludec (3) – Tresiba®

• Clinical trials
  • The study submitted by the pharmaceutical manufacturer is an open-label, multicentre, parallel-group, actively controlled Phase III trial.

a) Treatment of type 1 diabetes mellitus in adolescents and children aged 1 year and over

• Additional benefit from insulin degludec for the treatment of type 1 diabetes mellitus in adolescents and children aged 1 year and over is not proven.
• For insulin degludec in the treatment of type 1 diabetes mellitus in adolescents and children aged 1 year and over, the additional benefit compared with the appropriate comparator therapy, human insulin, is not proven on the basis of the criteria set out in Section 5(7) of the AM-NutzenV.
• mortality
  • Overall mortality
  • In the study, no deaths occurred in either the insulin degludec or the insulin detemir arm, neither after 26 weeks nor after 52 weeks.
  • No additional benefit of insulin degludec compared with the appropriate comparator therapy is proven for overall survival.
• Morbidity – Change in HbA1c level (%) from baseline to week 26 or 52
  • The endpoint ‘change in HbA1c level (%) from baseline to week 26 or 52’ is a long-term marker of average blood glucose levels over the preceding 8–12 weeks.
  • For the endpoint ‘change in HbA1c level from baseline to week 26 or 52’, no statistically significant difference was observed between the treatment groups, with a difference in baseline HbA1c levels of 0.2, which remained largely constant throughout the study (mean difference at 26 weeks: 0.15 [-0.03; 0.32]; at 52 weeks: -0.01 [-0.20; 0.19]).
  • An additional benefit of insulin degludec compared with the appropriate comparator therapy is not proven for this endpoint.
  • Overall, therefore, for the endpoint category of morbidity – in particular for the cardiovascular and cerebrovascular complications that are generally decisive for the prognosis in type 1 diabetes mellitus – there is no additional benefit of insulin degludec compared with the appropriate comparator therapy, human insulin.
• Morbidity – Change in BMI
  • During the course of the NN1250-3561 study, an increase in BMI was observed in both the insulin degludec and insulin detemir arms.
  • A statistically significant difference in BMI change was observed between the treatment arms at the end of the study (mean difference at 26 weeks: 0.30, 95% CI [0.08; 1.52]; p = 0.008; at 52 weeks: 0.60, 95% CI [0.34; 0.86]; p < 0.001].
  • However, the significance or impact of BMI over the long term, particularly with regard to cardiovascular safety, remains unclear.
• quality of life
  • Health-related quality of life is a patient-relevant endpoint in the context of benefit assessment.
  • Data on health-related quality of life were not collected in the NN1250-3561 study.
  • An additional benefit of insulin degludec compared with the appropriate comparator therapy (human insulin) is therefore not proven for this endpoint.
• Side effects – Serious adverse events (SAEs)
  • No statistically significant difference was observed between the treatment groups for the SAE endpoint (26 weeks: RR = 1.10 [0.50; 2.42), p = 0.877; 52 weeks: RR = 1.13 [0.60; 2.15), p = 0.762).
  • There was an indication at 26 weeks and proof at 52 weeks of an effect modification by the characteristic of sex for the SAE endpoint: for boys, there was no statistically significant difference between the treatment groups at either week 26 or week 52. In contrast, a statistically significant result was observed in girls at 52 weeks, to the detriment of insulin degludec (boys: RR 0.44 [0.18; 1.09), p = 0.072; girls: RR = 5.92 [1.37; 25.59), p = 0.006; interaction: 0.003).
  • In the overall population, it is not proven that insulin degludec causes greater or minor harm with regard to the SAE endpoint.
• Side effects – discontinuation due to AEs
  • For the endpoint ‘discontinuation due to AE’, there was no statistically significant difference between the treatment groups (26 weeks: RR 0.20 [0.01; 4.16], p = 0.170; 52 weeks: RR 0.14 [0.01; 2.76], p = 0.087).
  • There is not enough proof that insulin degludec causes greater or minor harm compared with the appropriate comparator therapy, human insulin, for the endpoint ‘discontinuation due to AEs’.
• Side effects – symptomatic hypoglycaemia
  • For symptomatic hypoglycaemia with a plasma glucose cut-off value of ≤ 56 mg/dl, no statistically significant difference was observed between the treatment arms at either 26 weeks or 52 weeks (26 weeks: RR = 1.02 [0.96; 1.08], p = 0.669; 52 weeks: RR = 1.02 [0.97; 1.08], p = 0.461).
  • Similarly, for symptomatic hypoglycaemia with a plasma glucose cut-off value of ≤ 70 mg/dl, no statistically significant difference was observed between the treatment arms at either 26 weeks or 52 weeks (26 weeks: RR = 1.03 [0.96; 1.11], p = 0.497; 52 weeks: RR = 1.02 [0.97; 1.09], p = 0.497).
  • It is not proven that insulin degludec is more or less harmful than the appropriate comparator therapy, human insulin, with regard to the endpoint of symptomatic hypoglycaemia.
• Side effects – severe hypoglycaemia
  • There was no statistically significant difference between the treatment groups for the endpoint of severe hypoglycaemia (26 weeks: RR = 1.38 [0.77; 2.49], p = 0.246; 52 weeks: RR = 1.22 [0.75; 1.98], p = 0.301).
  • It is not proven that insulin degludec causes greater or minor harm compared with the appropriate comparator therapy, human insulin, for the endpoint of severe hypoglycaemia.
• Side effects – ketoacidosis (PT)
  • No statistically significant difference was observed between the treatment groups for the endpoint of ketoacidosis (26 weeks: RR n/a, p > 0.999; 52 weeks: RR = 5.03 [0.24; 103.99], p = 0.169).
  • Insulin degludec is not proven to be more or less harmful than the appropriate comparator therapy, human insulin, for the endpoint of ketoacidosis.
• Side effects – symptomatic hyperglycaemia
  • For the endpoint of symptomatic hyperglycaemia (plasma glucose level >250 mg/dl), there was no statistically significant difference between the treatment groups (26 weeks: RR 1.00 [0.86; 1.16], p > 0.999; 52 weeks: RR = 1.03 [0.91; 1.16], p = 0.683).
  • Overall, for the endpoint of symptomatic hyperglycaemia, the additional benefit of insulin degludec in adolescents and children aged 1 year and over with type 1 diabetes mellitus is not proven.
• Overall review
  • In the overall review of side effects, there is no proof that insulin degludec causes greater or minor harm compared with the appropriate comparator therapy, human insulin.
• Conclusion
  • Long-term data on insulin degludec relating to patient-relevant endpoints and its general safety profile are not yet available.
  • These are urgently required due to the chronic nature of type 1 diabetes mellitus and the resulting long-term treatment of patients.

b) Treatment of type 2 diabetes mellitus in adolescents and children aged 1 year and over as monotherapy

• An additional benefit of insulin degludec for the treatment of type 2 diabetes mellitus in adolescents and children aged 1 year and over as monotherapy is not proven compared with the appropriate comparator therapy, human insulin.
• No study or data were submitted that would have been suitable for assessing the additional benefit of insulin degludec for the treatment of type 2 diabetes mellitus in adolescents and children aged 1 year and over as monotherapy compared with the appropriate comparator therapy (human insulin).

c) Treatment of type 2 diabetes mellitus in adolescents and children aged 1 year and over in combination with other antidiabetic agents

• The additional benefit of insulin degludec for the treatment of type 2 diabetes mellitus in adolescents and children aged 1 year and over in combination with other antidiabetic agents compared with the appropriate comparator therapy of human insulin plus metformin, or human insulin alone where metformin is not suitable according to the SmPC, is not proven.
• As already stated under b), no study or data were submitted that would allow an assessment of the additional benefit of insulin degludec for the treatment of type 2 diabetes mellitus in adolescents and children aged 1 year and over in combination with other antidiabetic agents, compared with the appropriate comparator therapy (human insulin plus metformin, or human insulin alone where appropriate).

Courtesy translation only, please refer to the German original.