Effects of Oral Semaglutide on Kidney Outcomes in People with Type 2 Diabetes: A Nationwide, Multicentre, Retrospective, Observational Study (Renal_ENDO2S-RWD substudy)

Abstract Background Subcutaneous semaglutide has shown kidney-protective effects in people with type 2 diabetes (PWT2D), but data on oral semaglutide remain limited. This multicenter real-world study evaluates the clinical effectiveness of oral semaglutide on kidney outcomes in PWT2D. Methods We included PW2TD aged ≥18 years who initiated oral semaglutide in routine practice between 2021 and 2022 in the Spanish National Health System, with at least one report of clinical follow-up (FU) data at 3 months. Co-primary endpoints were changes in urinary albumin to creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) slope at 6-12 months. We also assessed baseline predictors of response, drug persistence, and safety by CKD severity. Results Data were available for 819 PWT2D (median age 63 years, eGFR 88.1mL/min/1.73m2, UACR 12 mg/g, 45.8% female), median FU was 8.96 months. Oral semaglutide reduced UACR by 30.3% and 40.0% in the overall cohort, by 40.2% and 50.7% in those with a UACR ≥ 30 mg/g, and by 40.6% and 49.9% in those with a UACR ≥ 300 mg/g at 6 and 12-months FU, respectively. PWT2D with a low age-adjusted risk of liver fibrosis by the FIB-4 index had increased odds of achieving a >30% reduction in UACR (aOR 5.50 [95%CI 1.6-18.7]) regardless of baseline background. Metabolic and weight loss effectiveness, safety and persistence of oral semaglutide were consistent across CKD severities. Conclusions In a real-world setting, oral semaglutide treatment for up to 52 weeks resulted in clinically meaningful reductions in albuminuria without changes in eGFR slope in PWT2D. Effectiveness, safety and tolerability were not influenced by CKD severity.