Dapagliflozin / Metformin (1) – Xigduo®

• Clinical trials
  • To demonstrate the additional benefit of dapagliflozin in combination with metformin compared with the appropriate comparator therapy (sulfonylurea [glibenclamide or glimepiride] with metformin), the manufacturer submitted study D1690C00004, which investigated the combination of dapagliflozin/metformin in comparison with glipizide/metformin.
  • The pharmaceutical manufacturer submitted three placebo-controlled studies to demonstrate an additional benefit of Dapagliflozin/Metformin in combination with insulin (D1690C00006, as well as pooled data from studies D1690C00018 and D1690C00019).

a) Combination therapy with metformin, where metformin at the maximum tolerated dose, together with diet and exercise, does not adequately control blood glucose

• For the combination of dapagliflozin and metformin, where metformin monotherapy, together with diet and exercise, does not adequately control blood glucose, the additional benefit is not proven.
• In its assessment of the methodological shortcomings described in the data submitted for this patient group, the G-BA concludes that no additional benefit has been established for dapagliflozin in combination with metformin compared with the appropriate comparator therapy, sulphonylurea (glibenclamide, glimepiride) with metformin or compared with glipizide in combination with metformin.
• According to the Austrian summary of product characteristics for glipizide, the dose is generally increased gradually by 2.5 mg or 5 mg. A larger dose increase from 10 mg to 20 mg, as chosen in the study, is therefore only possible in individual cases.
• Furthermore, in the intervention arm, dapagliflozin was not used in accordance with the marketing authorisation.
• The approach taken in study D1690C00004 is therefore, on the whole, inadequate, as, in the dapagliflozin arm, titration was carried out despite the lack of marketing authorisation and, in some cases, a dose that was too low was selected, whilst in the glipizide arm, titration did not take place in accordance with the titration increments of 2.5 mg or 5 mg generally specified in the summary of product characteristics (SmPC), but instead involved a sudden, extremely rapid dose increase of 10 mg (to 20 mg), which is therefore not appropriate for the majority of eligible patients as per the SmPC.
• It cannot be ruled out that the rapid escalation of antidiabetic therapy, as carried out for glipizide in this study, led to a distortion of the results, in particular to hypoglycaemia, to the detriment of the sulphonylurea, whereas for dapagliflozin, contrary to the SmPC, a gradual dose escalation was carried out.

b) Combination therapy with other blood glucose-lowering medicinal products other than insulin, where blood glucose is not adequately controlled with metformin and these medicinal products in conjunction with diet and exercise

• For the combination of dapagliflozin/metformin with other blood glucose-lowering medicinal products (other than insulin), where blood glucose is not adequately controlled with metformin and these medicinal products in conjunction with diet and exercise, the additional benefit is not proven.
• No study has been submitted to assess the additional benefit of a treatment consisting of dapagliflozin in combination with metformin and other blood glucose-lowering medicinal products (other than insulin), where blood glucose is not adequately controlled with metformin and these medicinal products in combination with diet and exercise, compared with the appropriate comparator therapy (human insulin + metformin or human insulin alone).

c) Combination therapy with insulin, where blood glucose is not adequately controlled with metformin and insulin, together with diet and exercise

• For combination therapy with dapagliflozin and metformin plus insulin, where blood glucose is not adequately controlled with metformin and insulin in conjunction with diet and exercise, the additional benefit is not proven.
• In its summary assessment of the methodological shortcomings described in the data submitted for this patient group, the G-BA concludes that, for dapagliflozin/metformin in combination with insulin offers no additional benefit compared with the appropriate comparator therapy of metformin plus human insulin or human insulin alone.
• All three studies were based on the requirement for patients to continue their previous insulin treatment unchanged; modifications to insulin therapy (change of insulin type or treatment regimen, individual dose adjustments) were not permitted.
• Due to the lack of opportunities for optimisation, the studies are not suitable for drawing conclusions regarding the additional benefit of dapagliflozin in combination with insulin compared with the appropriate comparator therapy.
• To avoid hypoglycaemia and hyperglycaemia, antidiabetic therapy is optimised even in the event of minor fluctuations in blood glucose levels. Consequently, the studies presented do not allow for a comparison with realistic treatment decisions.

Courtesy translation only, please refer to the German original.