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

Abstract

Background: 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. Methods: 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. Results: 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 (p < 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), p < 0.001. In patients with baseline eGFR < 60 mL/min/1.73 m², the slope improved from -3.77 to -1.01 (p < 0.0001), while patients on concurrent SGLT2i therapy saw slope changes from -2.96 to -0.37 (p < 0.0001). Patients with albuminuria 30-1000 mg/g also improved from -2.96 to -0.04 (p < 0.0001); however, those > 1000 mg/g did not show a significant change (p = 0.184). Semaglutide also reduced BMI (p = 0.04), HbA1c (p = 0.002), triglycerides (p = 0.001), CRP (p = 0.003), and GGT values (p = 0.004). Conclusions: 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.

Keywords: SGLT2 inhibitors; chronic kidney disease; diabetes; eGFR slope; estimated glomerular filtration rate; semaglutide.

Figure 1

Estimated glomerular filtration rate (eGFR) values of all patients before (A) and after (B) starting semaglutide treatment. Trend line with 95% confidence interval is shown.

Figure 2

Estimated glomerular filtration rate (eGFR) values before (A) and after (B) treatment with semaglutide in patients with eGFR < 60 L/min/1.73 m². Trend line with 95% confidence interval is shown.

Figure 3

Mean values of estimated glomerular filtration rate (eGFR) slopes before and after treatment with semaglutide in patients who were already using SGLT2i (A) and in those who were not (B). ** p = 0.01, *** p < 0.0001.

Figure 4

Impact of semaglutide on the estimated glomerular filtration rate (eGFR) slope in patients with urinary albumin-to creatinine ratio (UACR) = 30–1000 mg/g (A) and patients with UACR > 1000 mg/g (B). Mean values are shown. *** p < 0.0001; ns, not significant.

Figure 5

Synergistic nephroprotective mechanism of GLP-1 RA and SGLT2i. Red lines denote inhibition. RAAS, Renin–Angiotensin–Aldosterone system; AGEs, advanced glycation end products; ROS, reactive oxygen species; REN, renin; AGII, angiotensin II; TFG-B1, transforming growth factor B1; TNF, tumor necrosis factor; NK-kB, nuclear factor kappa B; eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease.