Exploratory Mediation-Informed Analysis and Dose–Response Analysis of Uric Acid Reduction and Kidney Outcomes in SGLT2 Inhibitor Therapy Compared to Allopurinol

Background: Hyperuricemia has long been linked to the progression of chronic kidney disease (CKD), although the role of serum uric acid (sUA) reduction in kidney preservation remains uncertain. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower sUA levels and exert renoprotective effects, but it is unclear whether these findings are mechanistically related. Methods: Adult patients with type 2 diabetes mellitus and hyperuricemia were included from a retrospective cohort. Patients treated with empagliflozin (n = 70) or dapagliflozin (n = 78) were pooled into a single group and compared with an allopurinol-treated group (n = 66). Exploratory mediation-informed analysis models assessed associations between treatment, changes in sUA (ΔsUA), and changes in estimated glomerular filtration rate (ΔeGFR) at 12 and 36 months. Dose–response and nonlinear associations between ΔsUA and ΔeGFR were additionally examined. Results: At 12 months, SGLT2 inhibitor treatment was associated with greater ΔsUA compared with allopurinol (B = 22.62, p = 0.040); its direct association with ΔeGFR remained significant after adjustment for ΔsUA (B = −6.14, p < 0.001). At 36 months, the association of treatment with ΔsUA was no longer significant, whereas association with ΔeGFR persisted (B = −11.8, p < 0.001). No dose–response or nonlinear relationship was identified between ΔsUA and ΔeGFR, while treatment remained an independent predictor of ΔeGFR at both time points. Conclusions: Reductions in sUA do not appear to mediate the renoprotective effects of SGLT2 inhibitors. The preservation of kidney function associated with SGLT2 inhibitor therapy is likely driven by mechanisms independent of sUA lowering.