SummaryObjectiveOur review analyses the studies that have specifically compared the association iDPP4/metformin with glimepiride/metformin, both in second line pharmacotherapy of type 2 diabetes mellitus (DM2).MethodsSystematic literature review with a meta‐analysis of clinical trials comparing glimepiride with any iDPP4, both used together with metformin as a second line treatment of DM2. The effectiveness variables used were as follows: %HbA1c variation, fasting plasma glucose variation, patients achieving the therapeutic objective of HbA1c <7%, treatment dropouts due to lack of effectiveness and rescue treatments needed. The safety variables included were as follows: weight variation at the end of treatment; presentation of any type of adverse event; presentation of serious adverse events; patients who experienced any type of hypoglycaemia; patients who experienced severe hypoglycaemia; treatments suspended due to adverse effects; and deaths for any reason.ResultsFour studies met the inclusion criteria. The group treated with glimepiride showed better results in all effectiveness variables. Regarding safety variables, the main differences observed were in the greater number of cases with hypoglycaemia in the group treated with glimepiride, and the serious adverse events or treatment discontinuations due to these which occurred in slightly over 2% more cases in this group compared to the iDPP4 group. The remaining adverse events, including mortality, did not show any differences between both groups. The variation in the weight difference between groups (2.1 kg) is not considered clinically relevant.ConclusionsA greater effectiveness is seen in the glimepiride/metformin association, which should not be diminished by slight differences in adverse effects, with absence of severe hypoglycaemia in over 98% of patients under treatment. The association of glimepiride/metformin, both due to cost as well as effectiveness and safety, may be the preferential treatment for most DM2 patients, and it offers a potential advantage in refractory hyperglycemic populations, tolerant to treatment.