Insulin degludec / Liraglutid (1) – Xultophy®

• Clinical trials
  • To assess the additional benefit, the pharmaceutical manufacturer submitted the randomised controlled trial DUAL I (including the extension).

a) Insulin degludec/liraglutide in combination with oral antidiabetic agents for the treatment of type 2 diabetes mellitus, where combination therapy with oral antidiabetic agents is insufficient to control blood glucose levels

• For the combination of insulin degludec/liraglutide with oral antidiabetic agents for the treatment of type 2 diabetes mellitus, where combination therapy with oral antidiabetic agents is insufficient to control blood glucose levels, the additional benefit compared with the appropriate comparator therapy (metformin plus human insulin or human insulin alone, where metformin is not suitable according to the SmPC or is not sufficiently effective in combination with human insulin) has not been proven.
• The additional benefit of insulin degludec in combination with oral antidiabetic agents for the treatment of type 2 diabetes mellitus, where combination therapy with oral antidiabetic agents is insufficient to control blood glucose levels, is therefore not proven.
• However, the majority of patients (83%) had previously been treated with metformin monotherapy alone and therefore do not correspond to the target population under consideration here, which is defined by inadequate blood glucose control whilst on a combination of oral antidiabetic agents.
• Only 17% of patients in both arms of the DUAL I study were inadequately treated with combination therapy consisting of metformin and pioglitazone.
• However, due to the exclusion of glitazones from prescribing guidelines (AM Guideline, Annex III) for the treatment of type 2 diabetes mellitus, data on patients receiving pioglitazone therapy are not relevant for the benefit assessment.
• Consequently, the patient population of the DUAL I study as a whole does not correspond to the target population for this research question.
• Furthermore, the DUAL I study is not suitable for assessing the additional benefit of insulin degludec/liraglutide in combination with oral antidiabetic agents for the treatment of type 2 diabetes mellitus, where combination therapy with oral antidiabetics is insufficient for blood glucose control, as the appropriate comparator therapy (metformin plus human insulin, or human insulin alone where appropriate, if metformin is not suitable according to the SmPC or is not sufficiently effective in combination with human insulin) was not adequately implemented.

b1) Insulin degludec/liraglutide in combination with oral antidiabetic agents for the treatment of type 2 diabetes mellitus, where these oral antidiabetic agents in combination with basal insulin are insufficient for blood glucose control: in combination with metformin

• For insulin degludec/liraglutide in combination with oral antidiabetic agents for the treatment of type 2 diabetes mellitus, where metformin in combination with basal insulin is insufficient for blood glucose control (statutory health insurance), an additional benefit is not proven.
• An additional benefit is not proven for insulin degludec/liraglutide compared with human insulin, where appropriate in combination with metformin, for patients with type 2 diabetes mellitus when metformin in combination with basal insulin is insufficient for blood glucose control.
• The DUAL II study enrolled adult patients with type 2 diabetes mellitus and inadequate blood glucose control (defined as 7.5% ≤ HbA1c ≤ 10%) despite treatment with a stable dose of basal insulin in combination with one or two oral antidiabetic agents (metformin ± sulphonylurea or glinide).
• Furthermore, the DUAL II study is not suitable for assessing the additional benefit of insulin degludec/liraglutide in combination with metformin when metformin combined with basal insulin is insufficient for blood glucose control, as the appropriate comparator therapy – human insulin plus metformin where necessary – was not adequately implemented in the study.
• In the insulin comparison arm, patients were not given human insulin as the insulin component, but rather the insulin analogue insulin degludec.
• However, the pharmaceutical manufacturer has not demonstrated the transferability of the results from insulin degludec to the appropriate comparator therapy, human insulin.
• The DUAL V study enrolled adult patients with type 2 diabetes mellitus and inadequate blood glucose control (defined as 7.0% ≤ HbA1c ≤ 10%) despite treatment with insulin glargine in combination with metformin.
• The patient population studied in the DUAL V trial had inadequate blood glucose control despite treatment with insulin glargine in combination with metformin.
• Due to the shortcomings described, particularly in view of the lack of opportunities for individualised treatment optimisation and the treatment targets—which are too stringent and do not comply with clinical guidelines—the study is considered unsuitable for demonstrating the additional benefit of insulin degludec/ liraglutide over the appropriate comparator therapy (human insulin plus metformin where appropriate).

b2) Insulin degludec/liraglutide in combination with oral antidiabetics for the treatment of type 2 diabetes mellitus, where these oral antidiabetics, in combination with basal insulin, are insufficient for blood glucose control: in combination with oral antidiabetics (excluding metformin)

• For combination therapy with insulin degludec/liraglutide and oral antidiabetic agents other than metformin, where these oral antidiabetic agents, in combination with basal insulin, are insufficient to control blood glucose levels, the additional benefit is not proven.
• No study has been submitted to assess the additional benefit of treatment with insulin degludec/liraglutide in combination with oral antidiabetics other than metformin – where these oral antidiabetics, in combination with basal insulin, are insufficient to control blood glucose levels – compared with the appropriate comparator therapy (human insulin plus metformin where appropriate).

Courtesy translation only, please refer to the German original.