Vildagliptin (1) – Galvus, Jalra, Xiliarx®, Jalra®

• 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 in which patients were investigated who were treatment-naïve for diabetes mellitus or who had received monotherapy with an oral antidiabetic agent (e.g. glimepiride 2 mg to 4 mg per day or metformin 500 mg to 1000 mg daily 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) Monotherapy, in patients who are not adequately controlled by diet and exercise alone and for whom metformin is not suitable due to contraindications or intolerance

• For patients who are not adequately managed by diet and exercise alone and for whom metformin is unsuitable due to contraindications or intolerance, the additional benefit is not proven.
• In its summary assessment of the described shortcomings in the data submitted for this patient group, the G-BA concludes that, for vildagliptin as monotherapy – where diet and exercise alone are insufficient and metformin is unsuitable due to contraindications or intolerance – no additional benefit has been established compared with the appropriate comparator therapy – sulphonylureas (glibenclamide or glimepiride).

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

• For patients whose blood glucose is inadequately controlled despite monotherapy with the maximum tolerated doses of metformin, the additional benefit is not proven.
• Overall, where blood glucose is inadequately controlled despite monotherapy with the maximum tolerated doses of metformin, there is no additional benefit for vildagliptin in combination with metformin compared with the appropriate comparator therapy (glibenclamide or glimepiride in combination with metformin).
• Mortality and morbidity
  • Findings on all-cause mortality and on cardiovascular or cerebrovascular events could only be derived from the data on adverse events (AEs).
  • Consequently, there are no meaningful data available for the endpoint categories of mortality and morbidity – in particular for the cardiovascular and cerebrovascular complications that typically determine the prognosis in type 2 diabetes mellitus – to assess the additional benefit.
• 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 (34 (2.2%) vs. 266 (17.5%); RR = 0.13, 95% CI [0.09; 0.18], p < 0.001).
  • Overall, it is not possible to make a valid assessment of the results regarding symptomatic and severe hypoglycaemia on the basis of these data.
  • An additional benefit of vildagliptin in combination with metformin in terms of preventing side effects (serious/severe/non-severe confirmed hypoglycaemia, overall rate of (serious) adverse events) cannot therefore be concluded overall.
• Overall assessment
  • Overall, 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 the lack of long-term data on cardiovascularvascular endpoints and safety, no conclusion can be drawn regarding the additional benefit of vildagliptin in combination with 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)).

c) Dual combination of vildagliptin with a sulphonylurea in patients whose blood glucose has been discontinued despite monotherapy with the maximum tolerated doses of a sulphonylurea and for whom metformin is unsuitable due to contraindications or intolerance

• For patients whose blood glucose is inadequately controlled despite monotherapy with the maximum tolerated doses of a sulphonylurea and for whom metformin is unsuitable due to contraindications or intolerance, the additional benefit is not proven.
• No study has been submitted to assess the additional benefit of a treatment consisting of vildagliptin in combination with a sulphonylurea, where blood glucose is inadequately controlled despite monotherapy with the maximum tolerated doses of a sulphonylurea and metformin is unsuitable due to contraindications or intolerance, compared with the appropriate comparator therapy (human insulin plus a sulphonylurea (glibenclamide or glimepiride) or human insulin alone).

d) Triple combination of vildagliptin with a sulphonylurea and metformin, where diet and exercise, in addition to dual therapy with these medicinal products, do not lead to adequate glycaemic control

• 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.
• No study has been submitted to assess the additional benefit of a treatment consisting of vildagliptin in combination with a sulphonylurea and metformin, where diet and exercise, in addition to dual therapy with these INN active ingredients, do not result in adequate blood glucose control, against the appropriate comparator therapy (human insulin + metformin or human insulin alone).

e) Combination of vildagliptin with insulin (with or without metformin), where diet and exercise, in addition to a stable dose of insulin, 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 in combination with insulin and metformin or with insulin alone, where 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 can be established for vildagliptin compared with the appropriate comparator therapy (metformin + human insulin or human insulin alone).

Courtesy translation only, please refer to the German original.