Hypoglycaemia when adding sulphonylurea to metformin: a systematic review and network meta-analysis

AimsThe risk of hypoglycaemia may differ among sulphonylureas (SUs), but evidence from head-to-head comparisons is sparse. Performing a network meta-analysis to use indirect evidence from randomized controlled trials (RCTs), we compared the relative risk of hypoglycaemia with newer generation SUs when added to metformin. MethodsA systematic review identified RCTs lasting 12-52 weeks and evaluating SUs added to inadequate metformin monotherapy (1000mg/day) in type 2 diabetes. Adding RCTs investigating the active comparators from the identified SU trials, we established a coherent network. Hypoglycaemia of any severity was the primary end point. ResultsThirteen trials of SUs and 14 of oral non-SU antihyperglycaemic agents (16260 patients) were included. All reported hypoglycaemia only as adverse events. Producing comparable reductions in HbA(1C) of -0.66 to -0.84% (-7 to -9mmol/mol), the risk of hypoglycaemia was lowest with gliclazide compared to glipizide (OR 0.22, CrI: 0.05 to 0.96), glimepiride (OR 0.40, CrI: 0.13 to 1.27), and glibenclamide (OR 0.21, CrI: 0.03 to 1.48). A major limitation is varying definitions of hypoglycaemia across studies. ConclusionsWhen added to metformin, gliclazide was associated with the lowest risk of hypoglycaemia between the newer generation SUs. Clinicians should consider the risk of hypoglycaemia agent-specific when selecting an SU agent.