Abstract Background and Aims To explore body composition and metabolic profile changes in type 2 diabetes mellitus and chronic kidney disease (T2DM-CKD) using Semaglutide added to sodium-glucose transporter 2 inhibitors (SGLT-2Is). Method The study was performed on patients with T2DM-CKD in West China Hospital of Sichuan University. The outcomes were changes in body composition and metabolic profile after 6 months among patients administrated Semaglutide based on SGLT-2Is (Semaglutide plus SGLT-2Is group) and the comparison with patients only administrated SGLT-2Is (SGLT-2Is group). Results 12 individuals with T2DM-CKD and BMI ≥28 kg/m2 were included in two groups, respectively. After 6 months, total fat mass was reduced by 0.9 kg (IQR −3.73, 0.4) vs. 0.7 kg (IQR −1.9, −0.37) with Semaglutide plus SGLT-2Is group and SGLT-2Is group (P = 0.908). Skeletal muscle mass was reduced by 0.97 kg (SD 0.86) vs. 0.5 kg (SD 0.93), respectively (P = 0.215). ACR (229.55 mg/g (IQR −389.7, −119.92) vs. 0.5 mg/g (IQR −104.6, 84.9), P = 0.032), HbA1c (−0.35% (IQR −0.85, 0) vs. 0.3% (IQR 0.15, 1.1), P = 0.024) and total cholesterol (−0.51 mmol/L (SD 1.1) vs. 0.75 mmol/L (SD 0.93), P = 0.015) significantly declined in Semaglutide plus SGLT-2Is group compared to SGLT-2Is group. Conclusion Semaglutide plus SGLT-2Is did not exacerbate muscle loss compared with SGLT-2Is alone in obese patients with T2DM-CKD, and improved glucolipid metabolism and albuminuria.