Empagliflozin / Linagliptin (1) – Glyxambi®

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 and/or a sulphonylurea and empagliflozin or linagliptin) do not adequately control blood glucose

• For adult patients with type 2 diabetes mellitus in whom diet and exercise, together with treatment with at least two blood glucose-lowering medicinal products (excluding insulin; in this case, metformin and/or a sulphonylurea and empagliflozin or linagliptin) do not adequately control blood glucose levels, the additional benefit is not proven.
• The pharmaceutical manufacturer did not submit any studies that would have been suitable for assessing the additional benefit of empagliflozin/linagliptin compared with the appropriate comparator therapy.
• Instead of presenting randomised controlled trials for a direct comparison with the appropriate comparator therapy, the pharmaceutical manufacturer describes in its dossier the placebo-controlled Phase III trials 1275.9 and 1275.10 for empagliflozin/linagliptin, as well as the respective cardiovascular outcome trials for the individual substances (CARMELINA and CAROLINA for linagliptin and EMPA-REG OUTCOME for empagliflozin).
• However, the studies mentioned are not relevant to the assessment of the additional benefit of empagliflozin/linagliptin.
• Firstly, in the marketing authorisation studies 1275.9 and 1275.10, empagliflozin/linagliptin is not compared with the appropriate comparator therapy.
• Secondly, the cardiovascular outcome studies CARMELINA, CAROLINA and EMPA-REG OUTCOME each examine only the individual substances linagliptin or empagliflozin.
• Consequently, these additional studies do not provide any relevant results for the fixed-dose combination of empagliflozin/linagliptin under consideration.
• For indirect comparisons, the pharmaceutical manufacturer first identifies the marketing authorisation-relevant studies 1275.9 and 1275.10, which are relevant to the authorisation process, involving the fixed-dose combination of empagliflozin and linagliptin to be assessed, together with metformin, compared with linagliptin and metformin or empagliflozin and metformin.
• As no studies were found using the bridge comparators linagliptin and metformin or empagliflozin and metformin in comparison with the appropriate comparator therapy of human insulin and metformin, the pharmaceutical manufacturer has decided not to carry out an indirect comparison.
• Studies 1275.9 and 1275.10 are therefore not used for the benefit assessment, as they do not contain suitable data to allow a direct comparison of empagliflozin/linagliptin with the appropriate comparator therapy.
• Nor do the cardiovascular outcome studies of the individual substances provide suitable data for the benefit assessment of the present fixed-dose combination of empagliflozin/linagliptin, as the fixed-dose combination was not investigated.
• No relevant studies with a bridging comparator were identified for an indirect comparison that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.
• Overall, there are no adequate studies or indirect comparisons available for the benefit assessment of empagliflozin/linagliptin.
• Summary of the assessment
  • As part of the benefit assessment, the pharmaceutical manufacturer, in the absence of both direct comparative studies of empagliflozin/linagliptin against the appropriate comparator therapy and studies that would allow for an indirect comparison, the results of the existing authorisation studies for empagliflozin/linagliptin and the cardiovascular outcome studies of the individual substances empagliflozin and linagliptin.
  • These studies are not suitable for benefit assessment of empagliflozin/linagliptin, as they do not allow for a comparison between the fixed-dose combination under assessment and the appropriate comparator therapy specified by the G-BA.
  • Overall, there are no adequate studies available for the benefit assessment of empagliflozin/linagliptin.
  • Additional benefit is therefore not proven.

Courtesy translation only, please refer to the German original.