Vildagliptin (2) – Galvus, Jalra, Xiliarx®, Jalra®

• Clinical trials
  • To demonstrate the additional benefit of vildagliptin in combination with a sulphonylurea compared with the appropriate comparator therapy (human insulin in combination with a sulphonylurea (glibenclamide or glimepiride), or, where applicable, treatment with human insulin alone), the pharmaceutical company submitted the randomised, open-label study LAF237ADE08 (BENEFIT), in which the combination of vildagliptin with the sulphonylurea glimepiride was investigated in comparison with human insulin (NPH insulin) in combination with glimepiride.

a) Patients with type 2 diabetes mellitus whose blood glucose is inadequately controlled despite monotherapy with the maximum tolerated doses of a sulphonylurea and for whom metformin is unsuitable due to contraindications or intolerance

• An additional benefit is not proven compared with the appropriate comparator therapy (human insulin in combination with a sulphonylurea (glibenclamide or glimepiride), or, where appropriate, therapy with human insulin alone).
• mortality
  • Findings on overall mortality could only be derived from the data on (serious) adverse events ((S)AE).
  • The mortality results cannot be conclusively assessed in light of the endpoint being designed as a safety endpoint (and thus not adjudicated by an independent endpoint committee), the low number of events (no events in the vildagliptin arm (N=82), 1 event in the comparator arm (N=79)) and, in particular, the relatively short follow-up period (24 weeks).
  • Long-term data on overall survival, cardiovascular safety and the general safety profile are not available for vildagliptin (in combination with a sulphonylurea).
• morbidity
  • The study did not include any endpoints for microvascular and macrovascular complications.
  • Furthermore, in terms of patient numbers and study duration, the study was not designed to provide proof of an advantage of vildagliptin in combination with glimepiride over NPH insulin in combination with [...], with regard to these patient-relevant endpoints.
  • There are therefore no meaningful data available for the endpoint categories of mortality and morbidity – in particular for the cardiovascular and cerebrovascular complications that are crucial in type 2 diabetes mellitus – to assess the additional benefit of vildagliptin in combination with a sulphonylurea (glimepiride).
  • A reduction in body weight (mean difference = -0.47, 95% CI [-1.68; -0.73], p = 0.437) was observed in the study. However, the significance or impact of this observed weight loss over the long term, particularly with regard to cardiovascular safety, remains unclear.
• Health-related quality of life
  • No usable data on health-related quality of life were available.
  • It is therefore not possible to infer any additional benefit or less benefit of vildagliptin in combination with a sulphonylurea (glimepiride) from the data presented, when compared with the appropriate comparator therapy.
• Side effects
  • The hypoglycaemic events described by the pharmaceutical manufacturer in the dossier, which are based solely on a description of symptoms by the patient without a confirmed low blood glucose reading or on measured asymptomatic plasma glucose levels < 71 mg/dl, are not sufficiently valid.
  • Overall, a valid assessment of the results regarding symptomatic, confirmed hypoglycaemia and severe hypoglycaemia is not possible on the basis of these data.
  • No statistically significant differences were observed with regard to the overall rates of adverse events, serious adverse events or discontinuations due to adverse events.
  • Long-term data on overall survival, cardiovascular safety and the general safety profile are not available for vildagliptin (in combination with a sulphonylurea). These are urgently required due to the chronic nature of type 2 diabetes mellitus and the resulting long-term treatment of patients.
  • It is therefore not possible to conclude that vildagliptin, in combination with a sulphonylurea, offers any additional benefit in terms of preventing side effects (confirmed hypoglycaemia – serious, severe or non-severe – overall rate of (serious) adverse events) cannot therefore be concluded overall.
• Overall assessment
  • In its overall assessment, the G-BA therefore concludes, on the basis of the LAF237ADE08 study, in particular due to the uncertainties described regarding the strict intensification of therapy with NPH insulin in the comparator arm, the lack of long-term data on cardiovascular endpoints and safety, and the fact that, notwithstanding this, there is no statistically significant difference between the vildagliptin and comparator arms for any of the patient-relevant endpoints, concludes that there is no additional benefit from vildagliptin in combination with a sulphonylurea in patients whose blood glucose is inadequately controlled despite monotherapy with the maximum tolerated doses of a sulphonylurea and for whom metformin is unsuitable due to contraindications or intolerance, compared with the appropriate comparator therapy (human insulin in combination with sulphonylureas (glibenclamide or glimepiride); or, where appropriate, treatment with human insulin alone).

Courtesy translation only, please refer to the German original.