Nephroprotective effects of GLP-1 receptor agonists in patients receiving lithium treatment: a multinational cohort study using the TriNetX network

BACKGROUND: Use of GLP-1 receptor agonists (GLP-1 RAs) is an established therapy that delays progression of chronic kidney disease in type 2 diabetes mellitus (T2DM), but their impact on lithium-associated nephrotoxicity is unclear. We evaluated whether GLP-1 RA use is associated with reduced renal risk in adults receiving long-term lithium therapy. METHODS: We conducted a retrospective, propensity score-matched cohort study using TriNetX electronic health records (>127 million patients across 109 healthcare organizations). Adults (≥18 years) with T2DM and lithium exposure within 2 years prior to index were included. The primary outcome was renal nephrotoxicity, defined as a composite of ICD-10 and CPT-coded renal disease. Incidence and time-to-event outcomes were assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: In a 24-month analysis of 452 matched patient pairs, GLP-1 RA initiation during lithium therapy was associated with a marked reduction in renal events versus lithium alone (23.5% vs 44.7%), corresponding to a risk difference of -21.2% (95% CI -36.9 to -5.5) and a risk ratio of 0.53 (95% CI 0.30-0.91; p = 0.013). Event-free survival was higher (62.5% vs 43.4%; log-rank p = 0.0115), with a hazard ratio of 0.45 (95% CI 0.23-0.85; p = 0.0089). This represents a 47% relative risk reduction and a number needed to treat (NNT) of 5 over 24 months. CONCLUSION: These findings support further mechanistic and prospective studies of GLP-1 RAs as a renoprotective strategy for patients receiving lithium treatment.