Abstract / Summary
Abstract Background Patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) are at high risk for kidney failure and death. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) improve cardiovascular and renal outcomes; yet, their real-world use in patients with diabetic CKD is incompletely characterized and they remain underutilized. Methods This nationwide, real-world cohort study conducted in Israel evaluated patients with T2D and a urinary albumin-to-creatinine ratio of more than 30 mg/g, using data from January 1, 2019 to December 31, 2024. Patients were stratified according to baseline estimated glomerular filtration rate (eGFR) < 30 or ≥ 30 ml/min/1.73 m 2 and categorized according to treatment status (SGLT2i alone, GLP-1RA alone, combined therapy, or neither therapy). The primary composite outcome was death from any cause or end-stage kidney disease (ESKD). Results A total of 240,734 patients with T2D and CKD were included. Of these, 132,693 patients (55.1%) were not treated with either a GLP-1RA or a SGLT2i. In contrast, 30,803 patients (12.8%) received both agents, 44,007 (18.3%) received a GLP-1RA alone, and 33,231 (13.8%) received an SGLT2i alone. Among patients with an eGFR of ≥ 30 ml/min/1.73 m 2 , the adjusted hazard ratios for the primary outcome, as compared with no treatment, were 0.37 (95% confidence interval [CI] 0.36–0.38) with SGLT2i alone, 0.51 (95% CI 0.49–0.53) with GLP-1RA alone, and 0.32 (95% CI 0.31–0.33) with combined therapy. In multivariable models, heart failure emerged as the strongest predictor of the composite outcome regardless of baseline kidney function (eGFR ≥ 30 or < 30 ml/min/1.73 m 2 ). Beyond the effects of the study treatments, treatment with aspirin, ACE inhibitors or ARBs was independently associated with a lower risk of the composite outcome. Conclusions In this nationwide, real-world cohort of more than 240,000 patients with T2D and CKD, combined SGLT2i and GLP-1RA therapy was associated with up to a 68% reduction in the risk of death or ESKD compared with no treatment. Importantly, these benefits were also observed in patients with advanced CKD, a population often underrepresented in clinical trials. Additionally, over half of eligible high-risk patients did not receive either therapy, highlighting a substantial implementation gap between clinical guidelines and routine practice.