Introduction: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of glucose-lowering agents developed for the treatment of type 2 diabetes mellitus (T2DM). These agents have a mechanism of action that is independent of pancreatic β-cell function or the degree of insulin resistance; consequently, SGLT2 inhibitors have the potential to be used not only as monotherapy but also in combination with any of the existing classes of glucose-lowering agents, including insulin. As part of the extensive clinical development programs for modern T2DM therapies, SGLT2 inhibitors have been studied in combination with the most commonly used classes of glucose-lowering medications.

Areas covered: This report summarizes the key clinical trials data for combination therapies using SGLT2 inhibitors currently approved in the United States and/or the European Union, namely, dapagliflozin, canagliflozin, and empagliflozin.

Expert opinion: When given as add-on combination therapy with other glucose-lowering agents, or as monotherapy, SGLT2 inhibitors produced modest but clinically meaningful reductions in glycated hemoglobin, body weight, and systolic blood pressure. These changes have been sustained over long-term follow-up. SGLT2 inhibitors have a generally favorable safety profile similar to that of placebo, and are well tolerated. The risk of hypoglycemia appears to depend on coadministered glucose-lowering agents: when used as monotherapy, the frequency is comparable to that of placebo, but an increased risk is associated with concomitant use of sulfonylureas or insulin. In addition, an increased risk of genitourinary infections has been reported with SGLT2 inhibitors. However, these infections are usually mild, nonrecurrent, and respond to standard treatment.