Optimal uric acid levels by febuxostat treatment and cerebral, cardiorenovascular risks: post hoc analysis of a randomised controlled trial

Rheumatology (Oxford). 2021 Oct 4;keab739. doi: 10.1093/rheumatology/keab739. Online ahead of print.


Objectives: Hyperuricaemia is recognised as an independent risk marker for cardiovascular and renal diseases. However, uric acid is a powerful free-radical scavenger, and the optimal level of serum uric acid (SUA) determining outcomes are unknown. This study explored whether interventional treatments for excessive SUA reduction were harmful and what constituted the optimal lowering of SUA levels for the prevention of events in patients with asymptomatic hyperuricaemia.

Methods: This was a post hoc analysis of a randomised trial (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy [FREED]) in which 1070 older patients with asymptomatic hyperuricaemia were enrolled and allocated to febuxostat (n = 537) or non-febuxostat treatment group (n = 533). We assessed the relationship between the end point (withdrawal or study completion) SUA levels and clinical outcomes. Primary end point was defined as a composite of all-cause mortality, cerebral and cardiorenovascular events.

Results: In the febuxostat group, patients achieving SUA levels ≤4 mg/dl (hazard ratio: 2.01 [95% confidence interval: 1.05-3.87]), >4 to ≤ 5 mg/dl (2.12 [1.07-4.20], >6 to ≤ 7 mg/dl (2.42 [1.05-5.60]), and >7 mg/dl (4.73 [2.13-10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels >5 to ≤ 6 mg/dl (p= 0.003 [log-rank test]). This J-shaped relationship applied to patients with renal impairment (p= 0.007 [Gray's test]) and was not significant in the non-febuxostat treatment group (p= 0.212 [log-rank test]).

Conclusion: Optimal SUA levels by febuxostat treatment is 5-6 mg/dl for reducing all-cause mortality, cerebral, cardiovascular, and renal events. Excessive SUA reduction may be harmful in older hyperuricaemic populations.

Trial registration: ClinicalTrial.gov, https://clinicaltrials.gov, NCT01984749.

Keywords: FREED; Febuxostat; Hyperuricaemia; Hypouricaemia; Kidney; Serum uric acid.

Associated data

  • ClinicalTrials.gov/NCT01984749