Sitagliptin / Metformin (2) – Janumet, Velmetia®, Velmetia®

• Clinical trials
  • Study P803 was a randomised, actively controlled, double-blind study lasting 30 weeks.
  • In the trial, sitagliptin plus metformin was compared with glimepiride plus metformin in patients who had not achieved adequate blood glucose control (HbA1c level ≥ 6.5% and ≤ 9.0%) during previous treatment with metformin (at least 1500 mg/day). sitagliptin plus metformin was compared with glimepiride plus metformin.
  • Study P024 was a randomised, actively controlled, double-blind study lasting 104 weeks, in which the combination of sitagliptin plus metformin was compared with the combination of glipizide plus metformin.
  • To demonstrate the additional benefit of the combination of sitagliptin/metformin with insulin (with and without metformin), the pharmaceutical manufacturer submitted study P260.
  • This was a multicentre, randomised, double-blind, placebo-controlled trial lasting 24 weeks, which investigated adult patients with type 2 diabetes mellitus who, despite existing treatment with insulin (with or without metformin or a sulphonylurea) were unable to achieve adequate blood glucose control.

a) The dual combination of sitagliptin and metformin, in addition to diet and exercise, to improve blood glucose control in patients in whom monotherapy with metformin at the highest tolerated dose does not sufficiently lower blood glucose

• Overall, the G-BA concludes that, for the sitagliptin/metformin dual combination—where diet and exercise plus metformin monotherapy do not sufficiently lower blood glucose levels—an additional benefit is not proven compared with the appropriate comparator therapy.
• mortality
  • In study P803, there was no statistically significant difference in overall mortality between the treatment groups.
  • In study P024, there were 0 deaths occurred, and 7 deaths (1.6 per cent) under glipizide plus metformin (427 patients), which represents a statistically significant result (RR: 0.13 [0.03; 0.59]), with only male patients affected.
  • However, the mortality data presented here do not possess this high degree of validity, as the mortality results can only be derived from a post-hoc analysis of the data on adverse events.
  • It cannot therefore be ruled out that the finding is a chance result.
• morbidity
  • No data on morbidity endpoints were presented for the target population.
  • The results regarding cardiac and cerebrovascular events were not statistically significant in either study.
  • There are therefore no meaningful data available for the morbidity endpoint category – in particular for the cardiovascular and cerebrovascular complications that are typically decisive for the prognosis in type 2 diabetes mellitus – to assess the additional benefit.
• Morbidity – Health status (EQ-5D VAS)
  • Data on the EQ-5D (VAS) were collected only in study P803. However, no statistically significant difference was observed between the treatment groups.
  • There are therefore no meaningful data available for the endpoint category of morbidity to assess the additional benefit.
• quality of life
  • No data on quality of life were collected.
• Side effects
  • The results regarding symptomatic, confirmed hypoglycaemia are statistically significant in both studies (Study P803 and Study P024).
  • In Study P803, 3 symptomatic hypoglycaemic episodes occurred in the relevant target population receiving sitagliptin plus metformin (324 patients) and 22 symptomatic hypoglycaemic episodes occurred in the group receiving glimepiride plus metformin (333 patients) (Peto OR [95% CI]: 0.21 [0.10; 0.47]; p-value: < 0.001).
  • In study P024, there were 5 symptomatic hypoglycaemic episodes in the sitagliptin plus metformin group (429 patients) and 34 symptomatic hypoglycaemic episodes in the glipizide plus metformin group (427 patients) up to week 104 (Peto OR [95% CI]: 0.21 [0.11; 0.40]; p-value: < 0.001).
  • Severe hypoglycaemic episodes up to week 104 occurred in study P024 in 1 out of 429 patients on sitagliptin plus metformin and in 6 out of 427 patients on glipizide plus metformin, which represents a statistically significant result (odds ratio [95% CI]: 0.24 [0.05; 1.04]; p-value: 0.011).
  • No statistically significant differences were observed for the other side effect endpoints investigated in the study.
• Conclusion
  • Taking the results of studies P024 and P803 as a whole, the minor reduction in the number of confirmed, non-severe hypoglycaemic episodes under sitagliptin/metformin indicates a moderate improvement compared with the appropriate comparator therapy.
  • However, based on current evidence, it appears questionable in both studies whether intensification of therapy was even indicated for some patients in both treatment groups, as the HbA1cinclusion criteria of ≥ 6.5 % fell within the target range of 6.5 % to 7.5 % recommended by the guidelines.
  • As the pharmaceutical manufacturer did not submit, after the deadline had expired, any adequate analyses for the benefit assessment of sitagliptin/metformin that went beyond the data from the initial decision, the outstanding questions regarding the sitagliptin/metformin combinationmetformin remain unanswered.

b) Triple combination of sitagliptin/metformin with a sulphonylurea, in addition to diet and exercise, for patients in whom a combination of the highest tolerated dose of metformin and a sulphonylurea is insufficient to lower blood glucose

• For patients being treated with a triple combination consisting of sitagliptin/metformin plus a sulphonylurea, in whom a combination of the highest tolerated dose of metformin and a sulphonylurea is insufficient to lower blood glucose, The additional benefit is not proven.
• No study has been submitted to assess the additional benefit of a treatment consisting of sitagliptin/metformin in combination with a sulphonylurea, in addition to diet and exercise, in patients for whom a combination of the highest tolerated dose of metformin and a sulphonylurea is insufficient, compared with the appropriate comparator therapy (human insulin + metformin or human insulin alone) for assessing the added benefit of a treatment consisting of sitagliptin/

c) Triple combination of sitagliptin/metformin with insulin as an adjunct to diet and exercise in patients in whom a stable dose of insulin and metformin alone do not sufficiently lower blood glucose

• For patients being treated with a triple combination of sitagliptin/metformin plus insulin, in whom a stable dose of insulin and metformin alone do not sufficiently lower blood glucose levels, the additional benefit is not proven.
• In view of these methodological shortcomings, the study cannot be used to establish any additional benefit.
• Conclusion
  • Taken together, the G-BA concludes that for the combination of sitagliptin and metformin with insulin as an adjunct to diet and exercise in patients in whom a stable dose of insulin and metformin alone do not sufficiently lower blood glucose levels, the additional benefit compared with the appropriate comparator therapy (metformin + human insulin or human insulin alone) is not proven.

Courtesy translation only, please refer to the German original.