Canagliflozin (1) – Invokana®

• Clinical trials
  • This three-arm, double-blind, multicentre, randomised clinical trial investigated the efficacy and safety of canagliflozin in combination with metformin compared with a combination of metformin and glimepiride over a period of 104 weeks.
  • The DIA3006 study was a four-arm, double-blind, randomised clinical trial with a total duration of 52 weeks.

a) As monotherapy, when diet and exercise alone do not adequately control blood glucose levels and the use of metformin is considered unsuitable due to intolerance or contraindications

• For monotherapy with canagliflozin, where diet and exercise alone do not adequately control blood glucose and the use of metformin is considered unsuitable due to intolerance or contraindications, the additional benefit is not proven.
• No study has been submitted that would have been suitable for assessing the additional benefit of canagliflozin monotherapy, in the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride).

b) In combination with another blood glucose-lowering medicinal product (other than insulin), where this medicinal product does not adequately control blood glucose in conjunction with diet and exercise <BR>(combination with metformin)

• For the combination of canagliflozin with metformin, where metformin, in combination with diet and exercise, does not adequately control blood glucose, the additional benefit is not proven.
• Having assessed the methodological shortcomings described in the data submitted for this patient group from the DIA3009 study, as well as the failure to take into account the specified appropriate comparator therapy in the DIA3006 study, the G-BA concludes that no additional benefit has been established for canagliflozin in combination with metformin compared with the appropriate comparator therapy of a sulphonylurea (glibenclamide or glimepiride) combined with metformin.
• To demonstrate the additional benefit of canagliflozin in combination with metformin compared with the appropriate comparator therapy of metformin in combination with a sulphonylurea (glibenclamide), the pharmaceutical manufacturer submitted study DIA3009.
• In addition, the pharmaceutical manufacturer submitted the DIA3006 study, which compares canagliflozin and sitagliptin, each in combination with metformin.
• Conclusion
  • The validity of the DIA3009 study is compromised, amongst other things, by the inability to increase the dose of canagliflozin, by the strict glimepiride titration regimen, and by the low target value (fasting plasma glucose: 110 mg/dL; treatment target guideline: 100–125 mg/dL) and by the low threshold for documented hypoglycaemia (< 70 mg/dL), to such an extent that no valid conclusions regarding additional benefit can be drawn.

c) In combination with another blood glucose-lowering medicinal product (other than insulin), if this medicinal product does not adequately control blood glucose in conjunction with diet and exercise <BR>(combination with a sulphonylurea)

• For the combination of canagliflozin with a sulphonylurea, where the latter does not adequately control blood glucose in conjunction with diet and exercise, the additional benefit is not proven.
• No study has been submitted that would have been suitable for assessing the additional benefit of treatment with canagliflozin in combination with a sulphonylurea, in the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (metformin + sulphonylurea).

d) In combination with at least two other blood glucose-lowering medicinal products, where these do not adequately control blood glucose levels in addition to diet and exercise

• The additional benefit of combining canagliflozin with at least two other blood glucose-lowering medicinal products, where these do not adequately control blood glucose levels in addition to diet and exercise, is not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of treatment with canagliflozin in combination with at least two other blood glucose-lowering medicinal products, within the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (metformin + human insulin).

e) In combination with insulin (with or without an oral antidiabetic agent)

• For the combination of canagliflozin with insulin (with or without an oral antidiabetic agent), the additional benefit is not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of treatment with canagliflozin in combination with insulin (with or without an oral antidiabetic agent) compared with the appropriate comparator therapy (metformin + human insulin).

Courtesy translation only, please refer to the German original.