Step-wise addition of antihyperglycemic agents (AHA) after the initiation of metformin monotherapy has been the traditional approach for the treatment of type 2 diabetes mellitus (T2DM) world-wide. Emerging evidence increasingly suggests that metformin-based combination therapy, especially with the newer AHA that lowers HbA1c glucose-dependently and do not potentiate hypoglycemia, could be a potentially better option for durable glycemic control with good tolerability compared to diabetes monotherapy. In this review, we descriptively analyzed the evidence available from the systematic reviews and meta-analyses of randomized head-to-head trials that reported the efficacy and safety outcomes of diabetes monotherapy, metformin-based combination therapies, and monotherapy versus metformin-based combination therapies.