Sitagliptin (1) – Januvia, Xelevia®, Xelevia®

• Clinical trials
  • Study P063 was a randomised, active-controlled, double-blind study conducted over a period of 54 weeks, which exclusively included patients with moderate or severe renal impairment. Sitagliptin monotherapy was compared with glipizide monotherapy.
  • Study P803 was a randomised, active-controlled, double-blind trial lasting 30 weeks. In the study, 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 prior 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 trial lasting 104 weeks, in which the combination of sitagliptin plus metformin was compared with the combination of glipizide plus metformin.
  • Study P251 was a randomised, actively controlled, double-blind trial with a study duration of 30 weeks, which enrolled elderly patients aged between 65 and 85 with type 2 diabetes mellitus to compare sitagliptin with glimepiride.
  • The Hong 2012 study was an exploratory, randomised, open-label trial which investigated the addition of sitagliptin compared with an increase in the insulin dose on top of existing insulin therapy.

a) 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

• 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, there is a hint of a minor additional benefit.
• The certainty of the evidence is classified as ‘hint’.
• mortality
  • In the G-BA’s view, demonstrating additional benefit with regard to the endpoint of mortality—particularly in the case of long-term therapies used for chronic conditions such as diabetes mellitus—requires a particularly high degree of validity in the results. The G-BA therefore considers that, particularly due to methodological shortcomings, the results on mortality presented here cannot be regarded as sufficiently valid to be taken into account in the assessment of additional benefit. Additional benefit with regard to mortality is thus considered not to have been proven.
• morbidity
  • The results regarding cardiac and cerebrovascular events in study P063 were not statistically significant.
  • The study was not prospectively 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 a comparison of sitagliptin and glipizide.
  • The primary endpoint selected in study P063, HbA1c (change in HbA1c level compared with the baseline value at the start of the study after week 54), represents a surrogate parameter in the treatment of diabetes mellitus.
  • Study P063 shows no significant difference in HbA1c levels between the treatment groups.
  • No valid data are available for study P063 regarding changes in body weight.
• Health-related quality of life
  • No data on quality of life were collected in study P063.
• Side effects
  • In the relevant patient population of study P063, 4 confirmed symptomatic hypoglycaemic episodes occurred in the sitagliptin group (149 patients) and 13 symptomatic hypoglycaemic episodes in the glipizide group (154 patients). The result is statistically significant (risk ratio [95% CI]: 0.32 [0.11; 0.95]; p-value: 0.03).
  • Based on the reduction in confirmed symptomatic hypoglycaemic episodes, the G-BA concludes that, overall, there is a significant reduction in non-serious side effects compared with treatment with glipizide. With regard to side effects, the G-BA therefore concludes that sitagliptin offers a minor additional benefit compared with treatment with glipizide.
  • For the other side effect endpoints investigated in the study, no statistically significant differences were observed for the relevant study subpopulation.
• Overall assessment
  • On balance, based on the data on confirmed symptomatic hypoglycaemia, monotherapy with sitagliptin in patients for whom diet and exercise alone do not sufficiently lower blood glucose and for whom metformin is not suitable due to contraindications or intolerance, there is a hint of a minor additional benefit compared with treatment with glipizide.

b) Dual combination of sitagliptin and metformin, where diet and exercise plus metformin monotherapy do not sufficiently lower blood glucose

• 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.
• The certainty of the evidence (probability of additional benefit) is classified as ‘hint’.
• mortality
  • In study P803, there was no statistically significant difference in overall mortality between the treatment groups.
  • In study P024, there was 1 death (0.2%) in the sitagliptin plus metformin group (588 patients) and 8 deaths (1.4%) in the glipizide plus metformin group (584 patients), which represents a statistically significant result (Peto OR: 0.21 [0.06; 0.77], p = 0.021).
  • In the G-BA’s view, in order to demonstrate additional benefit with regard to the endpoint of mortality – particularly in the case of long-term therapies used for chronic conditions such as diabetes mellitus – the results must meet a particularly high standard of validity.
  • However, the data on mortality presented here do not meet this high standard of validity, as the mortality results can only be derived from a post-hoc analysis of the data on adverse events. The study was not designed to demonstrate a difference in overall mortality.
  • It cannot therefore be ruled out that the finding is a chance result.
  • In light of the uncertainties mentioned above and the fact that these findings were not confirmed in study P803, the findings regarding mortality are to be regarded as insufficiently valid and are therefore not taken into account in the assessment of the additional benefit.
• morbidity
  • The results regarding cardiac and cerebrovascular events were not statistically significant in either study.
  • Studies P803 and P024 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 a comparison of sitagliptin plus metformin and glimepiride plus metformin.
  • The primary endpoint selected in studies P803 and P024, HbA1c (change in HbA1c level compared with baseline at the start of the study after week 30), represents a surrogate parameter in the treatment of diabetes mellitus.
  • In both studies, there was no significant difference in HbA1c levels between the treatment groups.
  • No valid data on changes in body weight are available for either study.
• Health-related quality of life
  • In study P803, data on quality of life were collected using the EQ-5D (VAS). However, no statistically significant difference was observed between the treatment groups.
  • In study P024, no data on quality of life were collected.
• Side effects
  • In study P803, 3 symptomatic hypoglycaemic episodes occurred in the sitagliptin plus metformin group (516 patients) and 33 symptomatic hypoglycaemic episodes in the glimepiride plus metformin group (518 patients) (Peto odds ratio [95% CI]: 0.18 [0.09; 0.35]; p-value: < 0.001).
  • In study P024, 5 symptomatic hypoglycaemic episodes occurred in the sitagliptin plus metformin group (588 patients) and 48 symptomatic hypoglycaemic episodes in the glipizide plus metformin (584 patients) (Peto odds ratio [95% CI]: 0.18 [0.10; 0.32]; p-value: < 0.001).
  • Given the largely consistent trends in HbA1c levels across both treatment groups, the present findings on symptomatic, confirmed hypoglycaemic episodes should be regarded as a significant reduction in side effects and, consequently, as a moderate improvement in treatment-related benefit.
  • In study P024, severe hypoglycaemia occurred in 1 out of 588 patients receiving sitagliptin plus metformin, and in 9 out of 584 patients receiving glipizide plus metformin, which represents a statistically significant result (Peto odds ratio [95% CI]: 0.20 [0.06; 0.69]; p-value: 0.011).
  • In study P803, there were 10 therapy discontinuations due to adverse events in the sitagliptin plus metformin group (516 patients) and 2 therapy discontinuations due to adverse events in the glimepiride plus metformin group (518 patients). This result is statistically significant (RR [95% CI]: 3.86 [1.24; 12.05]; p-value = 0.02) to the detriment of sitagliptin in combination with metformin.
  • No statistically significant differences were observed for the other side effect endpoints investigated in the study.
• Overall assessment
  • In the overall analysis, 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 therapy with glipizide in combination with metformin, as the results on symptomatic, confirmed hypoglycaemic episodes indicate a moderate improvement in treatment-related benefit.

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

• For the dual combination of sitagliptin and a sulphonylurea, where diet and exercise plus monotherapy with a sulphonylurea at the highest tolerated dose do not sufficiently lower blood glucose levels and where metformin is not suitable due to contraindications or intolerance, The additional benefit is not proven.
• No study has been submitted to assess 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) Triple combination of sitagliptin with a sulphonylurea and metformin, where diet and exercise plus dual therapy with these medicinal products do not sufficiently lower blood glucose

• For the triple combination of sitagliptin with a sulphonylurea and metformin, where diet and exercise plus dual therapy with these medicinal products do not sufficiently lower blood glucose levels, the additional benefit is not proven.
• No study has been submitted to assess the additional benefit of a treatment consisting of sitagliptin in combination with a sulphonylurea and metformin, where diet and exercise, in addition to dual therapy with these INN active ingredients, do not lead to adequate blood glucose control, compared with the appropriate comparator therapy (human insulin + metformin or human insulin alone).

e) Combination of sitagliptin with insulin (with or without metformin), where diet and exercise, together with a stable dose of insulin, do not sufficiently lower blood glucose

• For the combination of sitagliptin with insulin (with or without metformin), where diet and exercise, together with a stable dose of insulin, do not sufficiently lower blood glucose levels, the additional benefit is not proven.
• However, the G-BA considers the data presented from the Hong 2012 study to be unsuitable for demonstrating additional benefit for the following reasons. Sitagliptin has marketing authorisation in combination with insulin and metformin, but not in combination with insulin and other oral antidiabetics. In the Hong 2012 study, patients in both treatment arms therefore received concomitant treatment with oral antidiabetic agents (α-glucosidase inhibitors, sulphonylureas, glinides and glitazones) that did not comply with the marketing authorisation. Data on a patient population treated in accordance with the marketing authorisation (no concomitant oral treatment or concomitant treatment with metformin only) were not provided by the pharmaceutical manufacturer.

Courtesy translation only, please refer to the German original.