Aims The efficacy and safety of sodium-glucose linked transporters (SGLT2s) plus metformin and a sulfonylurea (MET + SU) for the treatment of type 2 diabetes mellitus (T2DM) in patients who fail to achieve glycemic control with MET + SU, relative to other triple therapies licensed in the EU, were estimated. Methods A systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) involving anti-diabetes treatments added to MET + SU were conducted.

Results: Of 2236 abstracts identified through a systematic literature review, 30 RCTs published between 2003 and 2013 were included. RCTs ranged from 12 to 52 weeks in duration, included 28 to 1274 patients, were of parallel design, and most were open-label. Comparators included placebo (reference treatment), SGLT2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), meglitinides, glucagon-like peptide 1 (GLP-1) analogues, and basal, bolus, and biphasic insulin, all added on to MET + SU, as well as basal and biphasic insulin added to MET and monotherapy. The mean change (%) in HbA1c levels compared to placebo was -0.86 for SGLT2 inhibitors, -0.68 for DPP-4 inhibitors, -0.93 for TZDs, and -1.07 for GLP-1 analogues, respectively. Only SGLT2 inhibitors and GLP-1 analogues led to a weight loss (-1.71 kg and -1.14 kg, respectively) and decrease in systolic blood pressure (SBP; -3.73 mmHg and -2.90 mmHg, respectively), while all other treatments showed either an increase or no changes in weight or SBP. Conclusion SGLT2 inhibitors are at least as effective as other classes of antidiabetic agents at controlling HbA1c levels, while providing the additional benefits of weight loss and reducing SBP. Additionally, since the risk of hypoglycemia is similar or reduced with SGLT2 inhibitors, patients do not have to trade off efficacy for tolerability. Similar findings were observed for GLP-1 analogues.