OBJECTIVE This study evaluated whether an oral combination of a sodium-glucose cotransporter 2 inhibitor and a dipeptidyl peptidase 4 inhibitor achieved glycemic control similar to basal insulin in patients with type 2 diabetes, poorly controlled with metformin, without increasing hypoglycemia or body weight. RESEARCH DESIGN AND METHODS In a multinational, open-label, randomized, phase 3 trial (ClinicalTrials.gov reg. no. NCT02551874), adults with type 2 diabetes inadequately controlled on metformin, with or without sulfonylurea, were randomized (1:1) to receive dapagliflozin (DAPA) plus saxagliptin (SAXA) or titrated insulin glargine (INS). The primary end point was change in glycated hemoglobin A_1c (HbA_1c) from baseline to week 24. DAPA + SAXA treatment was tested for noninferiority versus INS. RESULTS The efficacy data set included 643 patients (mean 6 SD HbA_1c, 9.1 6 1.0% [75 6 11 mmol/mol]). At week 24, DAPA + SAXA treatment versus INS resulted in noninferior reductions in HbA_1c (adjusted mean 6 SE change, 21.7 6 0.1% vs. 21.5 6 0.1% [18.3 6 0.7 mmol/mol vs. 16.8 6 0.7 mmol/mol]; P = 0.118), significantly different body weight change (between-group difference, 23.64 kg [95% CI 24.20 to 23.09]; P < 0.001), fewer patients with confirmed hypoglycemia (21.3% vs. 38.4%, P < 0.001), more patients achieving HbA_1c <7.0% (53 mmol/mol) without hypoglycemia (20.9% vs. 13.1%, P = 0.008), and a similar proportion of patients achieving HbA_1c <7.0% (33.2% vs. 33.5%, P = 0.924). Mean reductions in 24-h glucose measurements from baseline to week 2 were greater with DAPA + SAXA than with INS (P < 0.0001). No patients in the DAPA + SAXA group and three patients (0.9%) in the INS group experienced severe hypoglycemia. CONCLUSIONS Adding DAPA + SAXA to insulin-naive patients with poorly controlled type 2 diabetes achieved similar glycemic control, a lower risk of hypoglycemia, and a clinically relevant body weight difference compared with basal INS.