Linagliptin (2) – Trajenta®

a) Monotherapy

• For patients in whom diet and exercise alone are insufficient to control blood glucose levels, and for whom metformin is unsuitable due to intolerance or contraindicated due to renal impairment, and who are treated with linagliptin monotherapy, the additional benefit is deemed not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of linagliptin monotherapy compared with the appropriate comparator therapy.

b) Dual combination therapy: linagliptin + metformin

• For patients treated with dual combination therapy consisting of linagliptin plus metformin, in whom diet and exercise as well as metformin monotherapy are insufficient to control blood glucose levels, the additional benefit is not proven.
• Overall, therefore, there is no additional benefit of linagliptin in combination therapy with metformin compared with the appropriate comparator therapy (glimepiride in combination with metformin).
• mortality
  • With regard to overall mortality, no statistically significant differences were observed between the linagliptin arm and the glimepiride arm.
• Morbidity – Non-fatal strokes
  • Although there were statistically significantly fewer non-fatal strokes in the linagliptin group (11 in the glimepiride arm versus 3 in the linagliptin arm, RR=0.27 [0.08;0.97].
  • However, given that this endpoint was designed as a safety endpoint, the low event rate, the relatively short study duration and the lack of follow-up for participants who withdrew from the study to assess cardiovascular complications, its clinical relevance cannot be conclusively assessed.
• Side effects – hypoglycaemia
  • In the study, both severe and non-severe hypoglycaemia occurred statistically significantly less frequently in the linagliptin arm compared with the glimepiride arm.
  • Severe hypoglycaemia should generally be regarded as a serious side effect.
  • However, it should be noted that the occurrence of hypoglycaemia correlates with the extent of the reduction in blood glucose levels.
  • It can be assumed that the different treatment strategies for glimepiride and linagliptin in the initial phase of the study led to a greater reduction in blood glucose levels in the glimepiride arm and thus to an increased risk of hypoglycaemia.
  • This assumption is supported by the temporal pattern of hypoglycaemia occurrence, as documented by the IQWiG for more severe cases of hypoglycaemia across the entire study population.
  • Episodes of more severe hypoglycaemia occurred particularly during the first 16 weeks of the study and were more frequent with glimepiride.
• Morbidity – HbA1c levels
  • The primary endpoint selected in the study – HbA1c in the treatment of diabetes mellitus – represents a surrogate parameter.
  • The difference in HbA1c levels between the treatment groups was statistically significant.
  • Measuring a blood glucose level at a fixed point in time (in this case after 2 years) is considered less relevant to patients than assessing the reduction in blood glucose levels over the entire 2-year period.
  • Over this period, glimepiride reduces the HbA1c level significantly more than linagliptin.
• Health-related quality of life
  • The data presented on quality of life showed no difference in terms of health-related quality of life.
• Overall assessment
  • In the overall assessment, therefore, there is no additional benefit of linagliptin in combination therapy with metformin compared with the appropriate comparator therapy (glimepiride in combination with metformin).

c) Triple combination therapy: linagliptin + sulphonylurea + metformin

• For patients treated with triple combination therapy comprising linagliptin, metformin and a sulphonylurea, in whom diet and exercise, as well as dual therapy with metformin and a sulphonylurea, are insufficient to control blood glucose levels, the additional benefit is deemed not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of triple combination therapy with linagliptin, metformin and a sulphonylurea compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.