J-shaped associations of serum urate with all-cause and cause-specific mortality in diabetes: mediation by kidney...

Aimed to investigate the associations of serum urate with all-cause and cause-specific mortality in diabetes and to assess whether estimated glomerular filtration rate (eGFR) mediates these associations.

We analyzed 18,809 UK Biobank participants with diabetes, free of CVD or cancer at baseline, followed for a median of 13.5 (12.8-14.4) years. Cox and Fine-Gray models estimated mortality risks, restricted cubic splines assessed nonlinear associations, and Aalen additive hazards models evaluated mediation.

During follow-up, 2984 deaths occurred (739 CVD, 1065 cancer). Compared with the lowest urate quartile (< 4.6 mg/dL), participants in the highest quartile (> 6.3 mg/dL) had significantly higher risks of all-cause mortality (HR = 1.329, 95% CI 1.190-1.485), CVD mortality (HR = 1.391, 95% CI 1.115-1.736), cancer mortality (HR = 1.258, 95% CI 1.042-1.518), and other-cause mortality (HR = 1.245, 95% CI 1.042-1.487). A J-shaped association was observed, with all-cause mortality rising above 5.4 mg/dL of urate. Sex-stratified analyses revealed higher inflection points in males than females (7.2 mg/dL vs. 5.7 mg/dL). Mediation analysis indicated that eGFR explained 36.4% of the association between urate and all-cause mortality, with an indirect effect of 10 (95% CI 4.5-15.2) events per 1,000 person-years.

Elevated serum urate, even within the normal range, was independently associated with all-cause and cause-specific mortality in diabetes, partly mediated by reduced eGFR. These findings support considering subclinical hyperuricemia in risk stratification, especially among individuals with early-stage diabetes and preserved metabolic and renal function.