OBJECTIVE This study compared the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone in patients with type 2 diabetes poorly controlled with metformin.

RESEARCH DESIGN AND METHODS This was a double-blind trial in adults with HbA_1c ≥8.0% and ≤12.0% (64–108 mmol/mol), randomized to saxagliptin (SAXA) (5 mg/day) plus dapagliflozin (DAPA) (10 mg/day; n = 179), or SAXA (5 mg/day) and placebo (n = 176), or DAPA (10 mg/day) and placebo (n = 179) on background metformin extended release (MET) ≥1,500 mg/day. Primary objective compared changes from baseline in HbA_1c with SAXA+DAPA+MET versus SAXA+MET and DAPA+MET.

RESULTS Patients had a mean baseline HbA_1c of 8.9% (74 mmol/mol), diabetes duration of 7.6 years, and a BMI of 32 kg/m². At week 24, the adjusted mean change from the baseline HbA_1c was –1.5% (–16.1 mmol/mol) with SAXA+DAPA+MET versus –0.9% (–9.6 mmol/mol) with SAXA+MET (difference −0.59% [–6.4 mmol/mol], P < 0.0001) and –1.2% (–13.1 mmol/mol) with DAPA+MET (difference −0.27% [3.0 mmol/mol], P < 0.02). The proportion of patients achieving HbA_1c <7% (53 mmol/mol) was 41% with SAXA+DAPA+MET versus 18% with SAXA+MET and 22% with DAPA+MET. Urinary and genital infections occurred in ≤1% of patients receiving SAXA+DAPA+MET. Hypoglycemia was infrequent, with no episodes of major hypoglycemia.

CONCLUSIONS In this first report of adding a well-tolerated combination of saxagliptin plus dapagliflozin to background metformin therapy in patients poorly controlled with metformin, greater improvements in glycemic control were obtained with triple therapy by the dual addition of saxagliptin and dapagliflozin than dual therapy with the addition of saxagliptin or dapagliflozin alone.