Abstract Context Diabetic kidney disease is a major burden among diabetic patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) were shown to reduce renal outcomes in clinical trials and real-world studies. However, head-to-head comparisons with individual classes of glucose-lowering agents warranted further investigation. Objective This work aimed to investigate the associations between SGLT2is use vs dipeptidyl peptidase-4 inhibitors (DPP4is) use and 4 renal outcomes: end-stage renal disease (ESRD), albuminuria, acute renal failure (ARF), and the rate of estimated glomerular filtration rate (eGFR) change using a territory-wide electronic medical database in Hong Kong. Methods For this retrospective cohort study, the “prevalent new-user” design was adopted to account for previous exposure to study drugs. Propensity score matching was used to balance baseline characteristics. Electronic health data of type 2 diabetes patients using SGLT2is and DPP4is between 2015 and 2018 were collected. Results The matched cohort consisted of 6333 SGLT2is users and 25 332 DPP4is users, with a median follow-up of 3.8 years. Compared to DPP4is, SGLT2is use was associated with lower risks of ESRD (hazard ratio [HR]: 0.51; 95% CI, 0.42-0.62; P < .001) and ARF (HR: 0.59; 95% CI, 0.48-0.73; P < .001), and a slower decline in eGFR. The associations remained statistically significant among patients with or without rapid eGFR decline and patients who added or switched to SGLT2is from DPP4is. The association with albuminuria was inconsistent across analyses. Conclusion Compared to DPP4is, SGLT2is use was associated with reduced risks of ESRD and ARF, and a slower eGFR decline in a real-world setting. The associations remained statistically significant in patients with or without preindex rapid eGFR decline.