Unreported outcomes

There were no relevant studies covering the majority of pre-defined outcomes. This applied particularly to the following outcomes: mortality, late complications, inpatient treatments, hyperosmolar and ketoacidotic comas, symptoms caused by chronic hyperglycaemia, health-related quality of life and patient satisfaction.

Most of the studies had included data on deaths and late complications within the framework of evaluating adverse events. However, due to the comparatively small number of patients and the short duration of the included studies, there were relatively few events. Due to insufficient data, the benefit (or harm) of glinides with regard to late complications and mortality is thus unclear.

Reported outcomes

Information was only available on hypoglycaemia in relation to glucose control, serious adverse events and other adverse events such as a change in body weight or body mass index (BMI), at least for some of the therapy comparisons. However, even for these outcomes, the reporting of results was mostly insufficient. This also applied to some extent to studies, where the clinical study report (CSR) had been provided by the study sponsor concerned.

Hypoglycaemia in relation to long-term glucose control

In all comparisons of treatment options, the data on the conjoint assessment of long-term glucose lowering and hypoglycaemia were insufficient.

With regard to severe and serious hypoglycaemia in conjunction with glucose lowering, the data did not provide proof of a difference in harm potential for the 2 glinides compared to their corresponding treatment options. However, the data were insufficient, as events were rare or non-existent in the studies.

With regard to non-severe, confirmed cases of hypoglycaemia in conjunction with glucose lowering, the evaluation of repaglinide compared with sulfonylureas remained unclear overall due to insufficient data. There was no proof of variation in the occurrence of non-severe confirmed cases of hypoglycaemia for the other treatment options investigated. However, apart from the comparison of repaglinide with metformin, there was only one study available for these evaluations.

Harm potential (serious adverse events and study discontinuations due to adverse events)

None of the relevant studies included the aim of investigating the long-term safety of glinides. Data on serious adverse events and study discontinuations due to adverse events were extracted from the identified studies for a general evaluation of the harm potential. Due to the size and duration of the studies, the results are only of limited value.

With reference to the occurrence of such events, the analysis of results on serious adverse events did not show any statistically significant differences between repaglinide or nateglinide and the therapy alternatives investigated.

With reference to study discontinuations due to adverse events, there was a statistically significant difference between the intervention and comparator groups in the placebo-controlled repaglinide study (065) and in the study comparing nateglinide with sulfonylureas (both in combination with metformin; Study 2308). In Study 065, there were statistically significantly fewer study discontinuations due to adverse events in the repaglinide group (low dose) than in the placebo group. However, according to information in the CSR, the discontinuations that occurred in the placebo group can be interpreted specifically as therapy failure. In Study 2308 on nateglinide, significantly more patients from the gliclazide/metformin group discontinued the trial due to adverse events than from the nateglinide/metformin group. However, in view of the comparable number of patients with serious adverse events in both treatment groups, it cannot be deduced that there is less harm potential from nateglinide compared to sulfonylureas.

Overall, the results on serious adverse events and study discontinuations due to adverse events did not provide any indication of greater or lesser harm either for repaglinide or for nateglinide compared to one of the therapy options investigated.

Body weight and BMI

In both the placebo-controlled studies for repaglinide and nateglinide, there was a greater weight increase from taking the glinide than the placebo. This difference was statistically significant for nateglinide in a dose of 180 mg/day. The relevance of the effect of 1 kg is unclear. No test for statistical significance was performed in the repaglinide study.

In the 2 studies comparing repaglinide with metformin, only minimal weight changes occurred in the repaglinide group, while the patients receiving metformin lost on average 2 kg. The difference in weight was statistically significant in one of the studies; the other study contained no information on significance. Overall, there was an indication of greater weight loss from taking metformin. However, the relevance of the effect of 2 kg is unclear.

In the comparisons of both repaglinide (monotherapy) and nateglinide (combination therapy with metformin) with sulfonylureas, there was no statistically significant difference in any of the studies with regard to weight changes between the treatment groups. However, for nateglinide, this assessment was only based on one study.