Sitagliptin (3) – Januvia, Xelevia®, Xelevia®

• Clinical trials
  • Study P024 was a randomised, actively controlled, double-blind trial lasting 104 weeks, in which the combination of sitagliptin plus metformin was compared with the combination of glipizide plus metformin.

b) Adult patients with type 2 diabetes mellitus in whom diet and exercise, together with treatment with another blood-glucose-lowering medicinal product (other than insulin; in this case, metformin), do not adequately control blood glucose levels

• Hint for a minor additional benefit
• Overall, there is a hint of a minor additional benefit for sitagliptin in combination with metformin compared with the appropriate comparator therapy (glibenclamide or glimepiride in combination with metformin).
• The certainty of the evidence (probability of additional benefit) is classified as ‘hint’.
• mortality
  • In the HARMONY 3 and P803 studies, there was no statistically significant difference in overall mortality between the treatment groups.
  • In the P024 study, there was 1 death (0.2%) in the sitagliptin plus metformin group (588 patients) and 7 deaths (1.2%) in the glipizide plus metformin (584 patients), which represents a statistically significant result (RR: 0.14 [0.02; 1.15], p = 0.033).
  • An additional benefit of sitagliptin in combination with metformin compared with sulphonylurea in combination with metformin is not proven for overall survival.
• morbidity
  • Cardiac and cerebrovascular morbidity
  • The results regarding cardiac and cerebrovascular events were not statistically significant in any of the studies.
  • Diabetic retinopathy and changes in visual acuity:
  • In the HARMONY 3 study, no statistically significant differences were observed in the endpoint of retinopathy between the sitagliptin arm and the comparator arm.
  • Health status (EQ-5D VAS)
  • Data on the EQ-5D (VAS) were collected only in the P803 study. However, no statistically significant difference was observed between the treatment groups.
• quality of life
  • No data on quality of life were collected, not even in the long-term TECOS study.
• Side effects
  • Symptomatic hypoglycaemia
  • In the HARMONY 3 study, not a single episode of symptomatic hypoglycaemia ≤ 50 mg/dl occurred in the sitagliptin plus metformin group (302 patients). By comparison, 23 symptomatic hypoglycaemic episodes occurred in the glimepiride plus metformin group (307 patients).
  • In the P803 study, 3 symptomatic hypoglycaemic episodes ≤ 50 mg/dl occurred in patients receiving sitagliptin plus metformin (516 patients) and 33 symptomatic hypoglycaemic episodes occurred in patients receiving glimepiride plus metformin (518 patients).
  • In study P024, 5 symptomatic hypoglycaemic episodes ≤ 50 mg/dl occurred in patients receiving sitagliptin plus metformin (588 patients) and 48 symptomatic hypoglycaemic episodes occurred in patients receiving glipizide plus metformin (584 patients).
  • For all three studies – HARMONY 3, P803 and P024 – statistically significant results were observed in favour of sitagliptin compared with the control group in terms of preventing symptomatic hypoglycaemia with a blood glucose threshold of ≤ 50 mg/dl.
  • Severe hypoglycaemia
  • In the P024 study, severe hypoglycaemia occurred in 1 out of 588 patients on sitagliptin plus metformin, and in 9 out of 584 patients on glipizide plus metformin, representing a statistically significant result (Peto OR [95% CI]: 0.20 [0.06; 0.69]; p-value: 0.011).
  • The statistically significant finding regarding severe hypoglycaemia was observed only in this single study and could not be confirmed in studies P803 and HARMONY 3. Consequently, no overall conclusion can be drawn regarding the effect of sitagliptin on severe hypoglycaemia.
  • Further AEs
  • No statistically significant differences were observed in the side effects (AEs), SAEs or discontinuations due to AEs across the three studies.
• Overall assessment
  • When considering the results on mortality, morbidity and side effects in the HARMONY 3, P803 and P024, whilst also taking the TECOS study into account, there remains an overall advantage in terms of minor harm in the sitagliptin arm compared with the comparator arm.
  • This result represents a moderate improvement in the treatment-related benefit of sitagliptin compared with the appropriate comparator therapy, achieved through the significant avoidance of a side effect.
  • Conclusion
  • Overall, there is a hint of a minor additional benefit for sitagliptin in combination with metformin compared with the appropriate comparator therapy (glibenclamide or glimepiride in combination with metformin).

Courtesy translation only, please refer to the German original.