Aims: To evaluate the effects of separate and combined use of the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin and the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide on measures of kidney function. Methods: In this prespecified secondary analysis of the DECREASE trial, we enrolled 66 obese patients with type 2 diabetes in a 16-week randomized double-blind placebo-controlled clinical trial to investigate the effects of dapagliflozin and exenatide twice daily, alone or in combination, versus placebo on 24-hour urinary albumin:creatinine ratio (UACR), creatinine and cystatin C-estimated glomerular filtration rate (GFR) and kidney injury molecule-1:creatinine ratio (KIM-1:Cr). Results: At week 16, the mean UACR change from baseline was −39.6% (95% confidence interval [CI] −58.6, −11.9; P = 0.001) in the combined exenatide-dapagliflozin group, −18.1% (95% CI −43.1, 18.0; P = 0.278) in the dapagliflozin group, −15.6% (95% CI −41.4, 21.6; P = 0.357) in the exenatide group and − 11.0% (95% CI −39.8, 31.5; P = 0.552) in the placebo group. Compared to placebo, UACR difference at week 16 in the exenatide-dapagliflozin group was −32.2% (95% CI −60.7, 16.9; P = 0.159). Effects were similar in 37 participants who were using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at baseline. Compared to placebo, in the exenatide-dapagliflozin group, an acute dip in estimated GFR was observed with creatinine-estimated GFR (−4.0 mL/min/1.73 m 2 [95% CI −9.3, 1.2]; P = 0.129) and cystatin C-estimated GFR (−10.4 mL/min/1.73 m 2 [95% CI −14.9, −5.8]; P < 0.001). The mean KIM-1:Cr difference in the combined treatment arm versus placebo was −43.8% (95% CI −73.5, 18.9; P = 0.129). Conclusion: This prespecified secondary analysis suggests that combined therapy with exenatide and dapagliflozin may have synergistic effects on markers of kidney function compared to either therapy alone or placebo in obese patients with type 2 diabetes.