Sitagliptin (2) – Januvia, Xelevia®, Xelevia®

• Clinical trials
  • The TECOS trial was a randomised, placebo-controlled, double-blind, multicentre study.
  • A total of 14,671 patients were randomised in a 1:1 ratio to the treatment arms sitagliptin 100 mg/day and placebo, each of which was administered in addition to the patients’ existing antidiabetic therapy.
  • The P803 study was a randomised, actively controlled, double-blind trial lasting 30 weeks.
  • The study compared sitagliptin plus metformin with glimepiride plus metformin in patients who had not achieved adequate blood glucose control (HbA1c level ≥ 6.5% and ≤ 9.0%) during prior metformin treatment (at least 1,500 mg/day). sitagliptin plus metformin was compared with glimepiride plus metformin.
  • This was a randomised, active- and placebo-controlled, double-blind, four-arm registration trial comprising a 4-week run-in phase, a 156-week treatment phase and an 8-week follow-up period (the HARMONY 3 trial).
  • The study included adult patients with type 2 diabetes mellitus who, despite stable prior treatment with 1500 mg/day of metformin for at least 8 weeks, had not achieved adequate blood glucose control (HbA1c level ≥ 7 % and ≤ 10 %).
  • 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.

a) For monotherapy in patients in whom diet and exercise alone do not sufficiently lower blood glucose levels and for whom metformin is not suitable due to contraindications or intolerance

• An additional benefit is not proven.
• Patients receiving sitagliptin as monotherapy were not included in the TECOS study; consequently, this study cannot be used to assess additional benefit, and only the studies submitted in the dossier for this purpose can be taken into account, all of which were already available for the initial assessment.
• Consequently, there are no data available for sitagliptin monotherapy that go beyond those of the initial decision and could answer the questions regarding the limitation.
• Overall, there are no new, usable data available for sitagliptin monotherapy in patients in whom diet and exercise alone do not sufficiently lower blood glucose levels and for whom metformin is not suitable due to contraindications or intolerance.

b) In combination with metformin, where diet and exercise plus metformin monotherapy do not sufficiently lower blood glucose levels

• Hint of a minor additional benefit.
• Overall, for the dual combination of sitagliptin and metformin – where diet and exercise plus metformin monotherapy do not sufficiently lower blood glucose levels – there is a hint of a minor additional benefit compared with the appropriate comparator therapy (glibenclamide or glimepiride in combination with metformin) or compared with treatment with glipizide in combination with metformin, as the results regarding symptomatic, confirmed hypoglycaemic episodes indicate a moderate improvement in treatment-related benefit.
• mortality
  • In the P803 and HARMONY 3 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 group (584 patients), which represents a statistically significant result (RR: 0.14 [0.02; 1.15], p = 0.033), with only male patients affected.
  • An additional benefit of sitagliptin in combination with metformin compared with sulphonylurea in combination with metformin is not proven for overall survival.
• morbidity
  • The results regarding cardiac and cerebrovascular events were not statistically significant in any of the studies.
  • For the endpoint of retinopathy (RR: 1.30 [1.06; 1.59]; 0.012), a statistically significant disadvantage was observed for sitagliptin, whilst for the endpoint of hospitalisation due to hyperglycaemia (RR: 0.74 [0.55; 1.00]; 0.049), a statistically significant advantage was observed.
  • The three head-to-head comparative trials were not designed to assess patient-relevant endpoints relating to diabetic complications; consequently, the available data on morbidity allow only very limited conclusions to be drawn regarding the comparison of sitagliptin plus metformin with sulphonylurea plus metformin.
  • In the overall assessment of the long-term results of the TECOS study, the significant findings regarding retinopathy and hospitalisation due to hyperglycaemia cannot be conclusively evaluated due to a lack of operationalisation; whilst for other patient-relevant morbidity endpoints, particularly cardiovascular ones, neither advantages nor disadvantages are apparent.
• Morbidity – 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
  • The results regarding confirmed symptomatic hypoglycaemia are statistically significant in all three head-to-head comparative studies.
  • In study P803, there were (516 patients) and 33 symptomatic hypoglycaemic episodes occurred in the glimepiride plus metformin group (518 patients) (Peto OR [95% CI]: 0.18 [0.09; 0.35]; p-value: < 0.001).
  • In study P024, there were 5 symptomatic hypoglycaemic episodes ≤ 50 mg/dl in the sitagliptin plus metformin group (588 patients) and 48 symptomatic hypoglycaemic episodes in the glipizide plus metformin (584 patients) (Peto OR [95% CI]: 0.18 [0.10; 0.32]; p-value: < 0.001).
  • For HARMONY 3, the results for the endpoints relating to symptomatic, confirmed hypoglycaemic episodes are taken into account; the definition of these episodes includes both the presence of symptoms and confirmation by blood glucose measurement (≤ 54 mg/dl or ≤ 70 mg/dl) (Peto OR [95% CI]: 0.14 [0.07; 0.27]; p-value: < 0.001).
  • This indicates that, for the endpoint of symptomatic hypoglycaemia, sitagliptin in combination with metformin results in a minor risk of harm compared with the appropriate comparator therapy (sulphonylurea in combination with metformin).
• Side effects – severe hypoglycaemia
  • In study P024, severe hypoglycaemia occurred in 1 out of 588 patients on sitagliptin plus metformin, and in 9 out of 584 patients on glipizide plus metformin, which represents a statistically significant result (Peto OR [95% CI]: 0.20 [0.06; 0.69]; p-value: 0.011).
  • The statistically significant result regarding severe hypoglycaemia was observed only in this single study and could not be confirmed in studies P803 and HARMONY 3.
• Overall assessment
  • When considering the results on mortality, morbidity and side effects, the dual combination of sitagliptin and metformin—where diet and exercise plus metformin monotherapy do not sufficiently lower blood glucose levels— an advantage in terms of minor harm compared with the appropriate comparator therapy (glibenclamide or glimepiride in combination with metformin) or compared with therapy using glipizide in combination with metformin, with regard to confirmed, symptomatic hypoglycaemic episodes as reported in studies P803 and P024, which represents a moderate improvement in treatment-related benefit through a significant reduction in side effects.
  • As already explained, the TECOS study, due to its duration, size and endpoint assessment, provides new insights for the benefit assessment when considered in its entirety and is therefore taken into account as supplementary evidence.
  • Overall, the TECOS study does not reveal any robust differences with regard to patient-relevant endpoints and, in particular, cardiovascular endpoints when compared with the results from the other studies presented.

c) In combination with a sulphonylurea, if diet and exercise plus sulphonylurea monotherapy at the highest tolerated dose do not sufficiently lower blood glucose levels and if metformin is not suitable due to contraindications or intolerance

• The additional benefit is not proven.
• Patients receiving sitagliptin in combination with a sulphonylurea were studied in the TECOS trial.
• However, no study was submitted that would be suitable for assessing the additional benefit of a treatment consisting of sitagliptin in combination with a sulphonylurea compared with the appropriate comparator therapy (human insulin + a sulphonylurea (glibenclamide or glimepiride) or human insulin alone).

d) In combination with a sulphonylurea and metformin, if diet and exercise plus dual therapy with these medicinal products do not sufficiently lower blood glucose levels

• An additional benefit is not proven.
• Patients receiving sitagliptin in combination with a sulphonylurea and metformin were studied in the TECOS trial.
• However, no study was presented to assess the additional benefit of a treatment consisting of sitagliptin in combination with a sulphonylurea and metformin compared with the appropriate comparator therapy (human insulin + a sulphonylurea (glibenclamide or glimepiride) or human insulin alone).

e) In combination with insulin (with or without metformin), when diet and exercise, together with a stable dose of insulin, do not sufficiently lower blood glucose levels

• The additional benefit is not proven.
• In view of these methodological shortcomings, the G-BA concludes that no relevant data are available for this patient population.
• The additional benefit of sitagliptin with insulin (with or without metformin), where diet and exercise as well as a stable insulin dose do not sufficiently lower blood glucose levels, 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.