OBJECTIVES:  Empagliflozin is an insulin-independent, oral glucose lowering agent. As an inhibitor of the sodium glucose co-transporter 2 (SGLT2), it causes sugar in the blood to be excreted by the kidneys and eliminated in the urine. This results in lowered blood glucose, weight loss, and blood pressure reduction. The objective was to conduct a systematic literature review (SLR) and network meta-analysis (NMA) to assess the relative efficacy and safety of empagliflozin for the treatment of adults with T2DM inadequately controlled with diet and exercise. METHODS:  Efficacy and safety endpoints have been explored using NMA at 24 (+/-6) weeks follow up, and 52 (+4) weeks follow up. Outcomes of interest included mean change from baseline in HbA1c, weight and systolic blood pressure (SBP). The outcome measures chosen were in line with the standard outcome measures that were assessed in the randomised clinical trials in T2DM. RESULTS:  The SLR identified 69 publications that were suitable for inclusion in the NMA. The majority of the analyses were performed using fixed-effect models as there were insufficient studies to estimate the between study variance with precision. Empagliflozin demonstrated a significantly greater reduction in HbA1c at 24 weeks compared with placebo. Empagliflozin also demonstrated significantly greater reductions in HbA1c compared with placebo at 52 weeks and ≥ 52 weeks. Empagliflozin 25 mg demonstrated greater reductions in HbA1c vs placebo in comparison with the DPP-4 inhibitors and dapagliflozin at 24 weeks. Similarly, empagliflozin demonstrated a greater reduction in weight vs placebo at 24 weeks. Empagliflozin also demonstrated greater reductions in weight vs placebo at 52 weeks. CONCLUSIONS: Empagliflozin demonstrated greater HbA1c, weight and SBP reduction compared to placebo and other comparators. The results of this NMA have been used during a National Institute for Health and Care Excellence Multiple Technology Appraisal.