Vildagliptin / Metformin (1) – Eucreas, Icandra, Zomarist®, Icandra®

• Clinical trials
  • In this randomised, double-blind, multicentre 104-week trial, an intervention involving vildagliptin in combination with metformin was compared with a combination of metformin and the sulphonylurea glimepiride in patients aged 18 to 73 years whose response to metformin monotherapy (at a maximum tolerated dose of 1500 mg metformin daily).
  • The LAF237AFR03 study was a 24-week, open-label, multicentre, randomised study.
  • This study is a randomised, open-label, single-centre, 32-week trial which investigated patients who were treatment-naïve for diabetes mellitus or who had received monotherapy with an oral antidiabetic agent (e.g. glimepiride 2 to 4 mg or metformin 500 to 1000 mg for less than 6 months).
  • A total of 45 patients aged between 30 and 80 years were enrolled in this randomised, open-label, single-centre 24-week study, a total of 45 patients aged between 30 and 80 years were enrolled who, according to the inclusion criterion, had ‘failed to achieve adequate blood glucose control despite metformin monotherapy at a stable, maximum or maximally tolerated dose’.
  • This study was a 24-week, placebo-controlled trial in which patients aged 18 to 80 years on a stable dose of insulin, with or without metformin (at least 1500 mg daily or a maximum tolerated dose) and inadequate glycaemic control.

a) Dual combination of vildagliptin and metformin in patients whose blood glucose has been discontinued despite monotherapy with the maximum tolerated dose of metformin alone

• For patients whose blood glucose levels are inadequately controlled despite monotherapy with the maximum tolerated doses of metformin, the additional benefit is not proven.
• Overall, for vildagliptin in a fixed-dose combination with metformin, where blood glucose is inadequately controlled despite monotherapy with the maximum tolerated dose of metformin, there is no additional benefit compared with the appropriate comparator therapy (glibenclamide or glimepiride in combination with metformin).
• Mortality and morbidity
  • Results on overall mortality and on cardiovascular or cerebrovascular events could only be derived from the data on adverse events (AEs) and were available for cardiovascular and cerebrovascular events, as well as for the combined endpoint of cardiovascular and cerebrovascular morbidity (CCV), only for the overall population, but not for the relevant patient population receiving a metformin dose of ≥ 1700 mg/day.
  • Consequently, there are no meaningful data available for the assessment of additional benefit across the endpoint categories of mortality and morbidity, particularly for the cardiovascular and cerebrovascular complications that are generally decisive for the prognosis in type 2 diabetes mellitus.
• quality of life
  • The data presented on quality of life (SF-36: PCS = Physical Component Summary and SF-36 MCS = Mental Component Summary) showed no difference in health-related quality of life.
• Side effects
  • In the study, non-severe hypoglycaemia (confirmed hypoglycaemia, blood glucose level < 50 mg/dl; Grade 1 hypoglycaemia with or without specific treatment, without external assistance) occurred statistically significantly less frequently in the vildagliptin arm compared with the glimepiride arm (30 (2.6%) vs. 199 (17.9%); RR = 0.15, 95% CI [0.10; 0.21], p < 0.001).
  • Overall, it is not possible to make a valid assessment of the results regarding symptomatic and severe hypoglycaemia based on these data.
  • An additional benefit of vildagliptin/metformin in terms of avoiding side effects (serious/severe/non-severe confirmed hypoglycaemic episodes, overall rate of (serious) adverse events) cannot therefore be inferred overall.
• Overall review
  • In the overall review, therefore, based on the LAF237A2308 study – particularly in view of the uncertainties described regarding the strict intensification of therapy in the glimepiride arm and the inappropriate operationalisation of severe hypoglycaemia, as well as due to the lack of long-term data on cardiovascularvascular endpoints and safety, no conclusion can be drawn regarding the additional benefit of vildagliptin/metformin—when blood glucose is inadequately controlled despite monotherapy with the maximum tolerated doses of metformin—compared with the appropriate comparator therapy (metformin in combination with sulphonylureas (glibenclamide or glimepiride)).

Triple combination of vildagliptin/metformin with a sulphonylurea in patients whose treatment with metformin and a sulphonylurea has been discontinued

• For patients in whom diet and exercise, in addition to dual therapy with these medicinal products, do not lead to adequate glycaemic control, the additional benefit is not proven.

Combination of vildagliptin and metformin with insulin, where a stable dose of insulin and metformin alone do not result in adequate glycaemic control

• For patients in whom diet and exercise, in addition to a stable dose of insulin, do not result in adequate glycaemic control, 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 vildagliptin/metformin in combination with insulin, when diet and exercise, in addition to a stable dose of insulin (with or without metformin), do not result in adequate glycaemic control, no additional benefit has been established compared with the appropriate comparator therapy (metformin + human insulin or human insulin alone).

Courtesy translation only, please refer to the German original.