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Purpose The aim of this study was to determine the levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) after treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitor or dipeptidyl peptidase-4 (DPP4) inhibitor in patients with type-2 diabetes inadequately controlled by insulin, and to determine whether variation in ANP levels can explain favorable cardiovascular outcome. Methods We enrolled 56 patients, aged 18–80 years, with type-2 diabetes inadequately controlled by insulin: i.e., HbA1c level 7.5–10.5% despite at least 8 weeks’ injectable insulin at a stable mean dose of 20–150 IU daily, with or without no more than two oral antidiabetic agents. Findings The 56 patients were randomized between 3 treatment groups: SGLT2 inhibitor (n = 18), DPP4 inhibitor (n = 19) and placebo (n = 19). Patients who received SGLT2 inhibitor or DPP4 inhibitor treatment all showed significantly lower HbA1c levels, fasting blood glucose (FBG) levels and systolic blood pressure at 24 weeks than controls. SGLT2 inhibitor treatment decreased ANP levels, BNP levels, systolic blood pressure and weight compared with placebo. Compared to those receiving DPP4 inhibitor, patients receiving SGLT2 inhibitor showed lower HbA1c levels (7.01 vs. 7.58%; P = 0.03), ANP levels (28.41 vs. 43.03 pg/mL; P = 0.00) and weight (66.14 vs. 71.76 kg; P = 0.04) at 24 weeks after adjusting for baseline values. The SGLT2 inhibitor group showed higher sodium concentrations than the placebo and DPP4 inhibitor groups (145.89 vs. 143.89 and 144.79 mmol/L, respectively; P = 0.00 and P = 0.04) at 24 weeks. ANP and BNP levels did not significantly correlate with HbA1c and blood glucose levels. Implications These results indicated that SGLT2 inhibitors may be superior to DPP4 inhibitors in reducing risk of cardiovascular disease in diabetic patients. The major study limitation was the small number of patients per group, which should be enlarged in further research.