Efficacy and Safety of GLP-1 Receptor Agonists on Combined Cardiovascular and Renal Outcomes in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

AIMS: Chronic kidney disease (CKD) confers substantial cardiovascular and renal morbidity. GLP-1 receptor agonists (GLP-1 RAs) have demonstrated cardiorenal protection across major randomised trials, culminating in the landmark FLOW trial. No prior systematic review has simultaneously synthesised cardiorenal outcomes in a CKD-restricted population, executed a network meta-analysis for agent-level comparisons, or assessed whether SGLT2 inhibitor background therapy modifies treatment effects. MATERIALS AND METHODS: MEDLINE, Embase, Cochrane CENTRAL, and Web of Science were searched through March 2025. Eligible RCTs enrolled adults with CKD (eGFR < 60 mL/min/1.73 m or UACR ≥ 30 mg/g) comparing GLP-1 RAs versus placebo for ≥ 26 weeks. Primary outcomes were 3-point MACE and a KDIGO-harmonised composite kidney endpoint. Random-effects pairwise meta-analyses and a frequentist NMA were performed. GRADE certainty was assigned to all outcomes. RESULTS: Thirteen RCTs (97 428 participants; 31 846 with confirmed CKD) were included. GLP-1 RAs reduced MACE by 16% (HR 0.84, 95% CI 0.79-0.89; high certainty) and the composite kidney endpoint by 21% (HR 0.79, 95% CI 0.73-0.86; high certainty). Kidney failure risk was reduced by 28% (HR 0.72); UACR decreased by 26%. Benefits were consistent irrespective of SGLT2 inhibitor background use (interaction p = 0.41). Semaglutide ranked highest in the NMA (SUCRA 78.4%). No excess acute kidney injury risk was observed. CONCLUSIONS: GLP-1 RAs provide clinically meaningful cardiorenal protection in CKD, additive to SGLT2 inhibitor benefits. In exploratory network meta-analysis, semaglutide subcutaneous achieved the highest SUCRA ranking for kidney composite outcomes; the direct semaglutide evidence is rated high certainty by GRADE.