Source: Rosenstock J, et al. Diabetes Care 2015;38:376-383.

The current (2015) American Diabetes Association guidance for progression of treatment when A1c goals are not attained with metformin implies stepwise initiation of additional monotherapies. But would it make sense to consider dual add-on?

Rosenstock et al studied patients with type 2 diabetes (T2DM) whose A1c was 8.9% at baseline on monotherapy with metformin. Subjects were randomized to add a DPP4 inhibitor (saxagliptin), an SGLT2 inhibitor (Dapagliflozin), or both, and were followed for 24 weeks.

All three regimens were successful to reduce A1c from baseline, and it probably comes as no surprise that the addition of two drugs (DPP4 inhibitor and SGLT2 inhibitor) to metformin outperformed the addition of either monotherapy. The addition of an SGLT2 to metformin demonstrated substantially better A1c reductions than the addition of a DPP4 inhibitor (-0.9% vs -0.59%), but the three-drug combination was far more effective, providing a -1.5% A1c reduction.

The simultaneous addition of two drugs to metformin monotherapy is probably an uncommon step for clinicians, who are more accustomed to progressive monotherapeutic step advancements. The fact that there were no episodes of major hypoglycemia during the 6 months of the trial is reassuring that similar therapeutic steps may be safely taken in practice settings where patients continue to have an elevated A1c on metformin. Because of the very potent A1c reduction, however, it is equally important to select patients with a sufficiently elevated A1c on metformin (at least 8.9%) so that the addition of dual add-on treatment does not lead to problematic hypoglycemia.