Long-Term Effect of Semaglutide on the Glomerular Filtration Rate Slope in High-Risk Patients with Diabetic Nephropathy: Analysis in Real-World Clinical Practice

<b>Background:</b> Semaglutide, a GLP-1 receptor agonist, has shown promising nephroprotective effects in clinical trials, though real-world data on its long-term impact on renal function in high-risk diabetic nephropathy patients remain scarce. <b>Methods:</b> We conducted a multicenter, retrospective observational study involving 156 patients with type 2 diabetes and chronic kidney disease (CKD) treated with subcutaneous semaglutide between 2019 and 2023. Inclusion required an eGFR > 15 mL/min/1.73 m² or albuminuria > 30 mg/g and at least two years of follow-up. The primary outcome was the change in eGFR slope after semaglutide initiation. Subgroup analyses were performed based on baseline eGFR, albuminuria, and SGLT2i co-treatment. <b>Results:</b> In the whole study population, the median eGFR slope significantly improved from -3.29 (IQR 7.54) to -0.79 (IQR 6.01) mL/min/1.73 m²/year post-treatment (<i>p</i> < 0.001). Multiple linear regression showed a hazard ratio for the effect of semaglutide on the eGFR slope of 4.06 (2.43-5.68), <i>p</i> < 0.001. In patients with baseline eGFR < 60 mL/min/1.73 m², the slope improved from -3.77 to -1.01 (<i>p</i> < 0.0001), while patients on concurrent SGLT2i therapy saw slope changes from -2.96 to -0.37 (<i>p</i> < 0.0001). Patients with albuminuria 30-1000 mg/g also improved from -2.96 to -0.04 (<i>p</i> < 0.0001); however, those > 1000 mg/g did not show a significant change (<i>p</i> = 0.184). Semaglutide also reduced BMI (<i>p</i> = 0.04), HbA1c (<i>p</i> = 0.002), triglycerides (<i>p</i> = 0.001), CRP (<i>p</i> = 0.003), and GGT values (<i>p</i> = 0.004). <b>Conclusions:</b> In real-world practice, semaglutide significantly attenuated renal function decline in high-risk diabetic patients, particularly those with advanced CKD or concurrent SGLT2i therapy. These findings support its nephroprotective role beyond glycemic control.