Insulin degludec (4) – Tresiba®

a) Adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with at least two blood glucose-lowering medicinal products (excluding insulin) do not adequately control blood glucose levels

• An additional benefit is not proven.
• Overall, the additional benefit of insulin degludec compared with the appropriate comparator therapy for this patient group is not proven.
• mortality
  • For the endpoint of all-cause mortality, neither the meta-analysis nor the extension study showed a statistically significant difference between the treatment arms.
• Morbidity – Cardiovascular events (MACE)
  • For the composite endpoint of major adverse cardiovascular events (MACE), including the individual components ‘cardiovascular death’ and ‘non-fatal stroke’, no statistically significant difference between the treatment arms was observed in either the meta-analysis or the extension study.
  • For the endpoint ‘acute coronary syndrome’, the extension study showed a statistically significant disadvantage for insulin degludec in combination with metformin. In the meta-analysis, the effect is not statistically significant.
• Morbidity – Health status (the ‘daily life’ and ‘mental health’ domains of the TRIM-D)
  • Patients’ health status was assessed using the ‘daily life’ and ‘mental health’ domains of the TRIM-D. This endpoint was not recorded in the extension study. The meta-analysis showed no statistically significant difference between the treatment arms for this endpoint.
• Health-related quality of life – SF-36 – physical composite score (PCS) and mental composite score (MCS)
  • For the MCS, the meta-analysis and the extension study revealed no statistically significant differences between the treatment arms.
  • The additional benefit of insulin degludec over insulin glargine, in each case in combination with metformin, is not proven for the quality of life category.
• Side effects – serious adverse events (SAEs)
  • For the SUE endpoint, no statistically significant difference between the treatment arms was observed in either the meta-analysis or the extension study.
• Side effects – Therapy discontinuation due to AEs and renal impairment
  • For the endpoints of therapy discontinuation due to AEs and renal impairment, no statistically significant differences between the treatment groups were observed in either the meta-analysis or the extension study.
• Side effects – non-severe symptomatic, confirmed hypoglycaemia
  • An additional benefit of insulin degludec over insulin glargine, in each case in combination with metformin, is not proven for the quality of life category.
• Side effects – Severe hypoglycaemia
  • For the endpoint of severe hypoglycaemia (SAE), no statistically significant differences between the treatment groups were observed in either the meta-analysis or the extension study.
• Side effects – Specific AEs (vomiting and depression)
  • For the endpoint of vomiting (PT), the meta-analysis shows no statistically significant difference between the treatment arms. In the extension study, however, a statistically significant advantage was observed for this endpoint in favour of insulin degludec.
  • For the endpoint of depression (PT), the meta-analysis showed no statistically significant effect between the treatment arms. In the extension study, however, a statistically significant difference was observed for this endpoint, with a disadvantage for insulin degludec.
• Overall assessment
  • For the benefit assessment of insulin degludec in combination with metformin for the treatment of adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with at least two blood glucose-lowering medicinal products (excluding insulin, in this case metformin) do not adequately control blood glucose, the studies NN1250-3587 and NN1250-3672, each lasting 26 weeks, as well as the 52-week study NN1250-3579 with the extension study 3579Ext (a further 52 weeks).
  • The studies compared the administration of insulin degludec with that of insulin glargine, in each case in combination with metformin.
  • For the patient population relevant to the assessment, both in the meta-analysis and in the extension study, no benefits were observed in the endpoint categories of mortality and health-related quality of life, nor for the endpoints of cardiovascular events (the combined endpoint MACE, including the individual components ‘cardiovascular death’ and ‘non-fatal stroke’) and health status (TRIM-D) in the morbidity category, no advantages were observed for insulin degludec over the control. Similarly, in the ‘side effects’ category, for the endpoints SAE, therapy discontinuation due to AEs, hypoglycaemia and renal dysfunction, the results of the meta-analysis and the extension study do not indicate any positive effects for insulin degludec compared with the control.
  • Statistically significant differences were observed only in the extension study, in each case to the disadvantage of insulin degludec compared with insulin glargine for the endpoint acute coronary syndrome in the morbidity category and for side effects in the PT depression category. On the other hand, for the ‘vomiting’ sub-trajectory (PT) among side effects in the extension study, there was a statistically significant difference in favour of insulin degludec. In the meta-analysis, no statistically significant differences were found for these endpoints between the treatment arms.
  • Overall, the potential for bias is assessed as high for all endpoints recorded in the extension study. Consequently, the positive or negative effects observed in this study cannot be interpreted without reservation.
  • On balance, the additional benefit of insulin degludec is not proven in this patient group compared with the appropriate comparator therapy.

b) Adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with insulin (with or without another blood glucose-lowering medicinal product) do not adequately control blood glucose

• The additional benefit is not proven.
• On balance, the additional benefit of insulin degludec compared with the appropriate comparator therapy for this patient group is not proven.
• mortality
  • No statistically significant difference was observed between the treatment arms for the endpoint of all-cause mortality.
• Morbidity – Cardiovascular events (MACE)
  • For the endpoint of major adverse cardiovascular events (MACE) and its constituent components – cardiovascular death, non-fatal stroke and acute coronary syndrome – there was no statistically significant difference between the treatment arms.
• Morbidity – Health status (the ‘daily life’ and ‘mental health’ domains of the TRIM-D)
  • Patients’ health status was assessed using the ‘daily life’ and ‘mental health’ domains of the TRIM-D. In the main study NN1250-3582, no statistically significant difference was observed between the treatment arms in either domain. This endpoint was not assessed in the extension study.
• Health-related quality of life – SF-36 – physical composite score (PCS) and mental composite score (MCS)
  • In the main study NN1250-3582, there were no statistically significant differences between the treatment arms for either the MCS or the PCS. This endpoint was not assessed in the extension study.
• Side effects – Serious adverse events (SAE)
  • For the SAE endpoint, no statistically significant difference between the treatment arms was observed in either the main study or the extension study.
• Side effects – Therapy discontinuation due to AEs and renal impairment
  • For the endpoints of therapy discontinuation due to AEs and renal impairment, no statistically significant differences between the treatment groups were observed in either the main study or the extension study.
• Side effects – Non-severe symptomatic, confirmed hypoglycaemia
  • For non-severe symptomatic, confirmed hypoglycaemia – defined as a plasma glucose level < 56 mg/dl – there was no statistically significant difference between the treatment arms in either the main study or the extension study.
• Side effects – Severe hypoglycaemia
  • For the endpoint of severe hypoglycaemia (SAE), no statistically significant differences were observed between the treatment groups in either the main study or the extension study.
• Overall assessment
  • For the re-assessment of the benefits of insulin degludec in adult patients with type 2 diabetes mellitus who do not achieve adequate glycaemic control despite diet, exercise and treatment with insulin (with or without another blood glucose-lowering medicinal product), the two-arm, open-label phase-III study NN1250-3582, with a treatment duration of 52 weeks, and the associated extension study NN1250-3667 (a further 26 weeks) are used. The study compared insulin degludec with insulin glargine, each in combination with insulin aspart, with or without OADs.
  • Data are available on various endpoints across the categories of mortality, morbidity, health-related quality of life and side effects. No statistically significant differences were observed between the treatment arms for the endpoints assessed. On this basis, neither positive nor negative effects of insulin degludec compared with insulin glargin can be inferred.
  • Overall, the additional benefit of insulin degludec is not proven in this patient group compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.