Serum Uric Acid Hyperproduction as a Potentially Distinct Phenotype in Gout Patients on Chronic Treatment With Xanthine Oxydase Inhibitor: A Post Hoc Analysis

Objective: Febuxostat (F) and allopurinol(A) are xanthine oxidase (XO) inhibitors indicated for gout treatment. While impaired serum uric acid (sUA) excretion is a major underlying mechanism, hyperuricemia might also be determined by increased sUA production, driving cardiovascular outcomes (CVO). The aim of this analysis was to identify sUA hyperproduction phenotype with driven CVO, informing future trials and tailored therapeutic strategies. Design and method: A post-hoc analysis was performed on a large, randomized, open-label, blinded-endpoint, non-inferiority trial of F versus A in patients with gout (FAST study, EudraCT 2011-001883-23). Eligible patients were >= 60 years with >= 1 additional CV risk factors and treated with A. After a lead-in phase with A dose optimization, patients were randomized (1:1 ratio) to continue optimized A dose or start F at 80 mg/day, increasing to 120 mg/day if necessary to achieve sUA target. Median follow up was 1467 (IQR 1029–2052) days for the primary outcome (a composite of hospitalization for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death). Baseline sUA/sCr ratio was categorized into five equal-sized increasing percentiles used for descriptive statistics and multivariate Cox Regression. Results: In the overall population, Cox Regression model for the primary endpoint showed a significantly reduced risk for composite events occurrence with increasing baseline sUA/s Creatinine ratio level (Figure 1). The HRs significantly increased in the 1st and 2nd quintiles of sUA/sCr ratio (1.81, 95% CI 1.380–2.372, P< 0.001; 1.632, 95% CI 1.238–2.151, P=0.001; respectively), whereas the 3 rd and 4 th quintiles were not significantly different from the 5th quintile (reference) regardless of sUA decrease from baseline. Over the 4-years follow-up period, gout patients with a presumably sUA hyperproduction- phenotype - as suggested by a higher baseline sUA/s Creatinine ratio - had a lower risk for occurrence of major CV events with an XO inhibitor, regardless of urate-lowering effect.Conclusions: These findings suggest a distinct gout phenotype where increased XO activity is a primary CVOs driver. Further studies are needed to confirm these findings and potentially inform tailored therapeutic strategies in sUA hyperproduction phenotype.