Implementation Strategies

Initial drug therapy continues to be metformin monotherapy, due to its low cost, proven safety record, weight neutrality, and positive benefits on cardiovascular outcomes.2 New evidence suggests that metformin may be safe in patients with mild-moderate but stable chronic kidney disease (CKD), perhaps with dose adjustments to account for reduced renal clearance.11,12,13 But if metformin is being avoided due to renal insufficiency, it would be unwise to use sulfonylureas, which carry the risk of hypoglycemia. In these cases, DPP-4 inhibitors are preferable, although they do require dosage adjustment (with the exception of linagliptin).2,14

Advancing to dual and triple combination therapy: In keeping with the original statement,1 initial combination with metformin plus a second agent may allow patients to achieve HbA1c targets more rapidly than sequential therapy, and may be appropriate in individuals whose baseline HbA1c levels are well above target (>9% [>75mmol/mol]).2 However, since there is no “proven overall advantage to achieving a glycemic target more quickly by a matter of weeks or even months…as long as close patient follow-up can be ensured, prompt sequential therapy is a reasonable alternative.”2 The authors note that SGLT2 inhibitors are “reasonable options” as second- or third-line agents, but their efficacy may be “less than additive” when used in combination with DPP-4 inhibitors.2,15 The authors add that there are no data available on the combination of SGLT2 inhibitors and the GLP-1 receptor agonists.