In observational studies, high serum urate levels are associated with adverse outcomes, including mortality. However, the hypothesis that urate-lowering may improve nongout outcomes has not been confirmed by placebo-controlled clinical trials. On the contrary, 7 recent placebo-controlled trials of urate-lowering drugs with different mechanisms of action (uricosuric: lesinurad; xanthine oxidase inhibition: febuxostat; uricase: pegloticase) have observed higher mortality or trends to higher mortality in gout patients, with the largest decreases in serum urate. Because all urate-lowering mechanisms were implicated, this raises safety concerns about urate-lowering itself. Far from unexpected, the higher mortality associated with more intense urate-lowering is in line with the U-shaped association of urate with mortality in some observational studies. Urate accounts for most of the antioxidant capacity of plasma, and strategies to increase urate are undergoing clinical trials in neurological disease. Post hoc analysis of recent trials should explore whether the magnitude of urate-lowering is associated with adverse outcomes, and safety trials are needed before guidelines recommend lowering serum urate below certain thresholds.
Keywords: Allopurinol; Febuxostat; Gout; Hypouricemia; Lesinurad; Mortality; Pegloticase; Tophi; Urate; Xanthine oxidase.
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