Febuxostat, Allopurinol Show Comparable Hepatic Safety in Patients with Gout

Neily Zakiyah, MSc, PhD

Credit: Universitas Padjadjaran

New results from a systematic review of randomized clinical trials suggest adult patients with gout exhibited comparable hepatic safety profiles following treatment with either febuxostat or allopurinol.¹

The review of 11 trials reported most hepatic safety parameters assessed in adult patients with gout did not show statistically significant differences between allopurinol and febuxostat treatment, aligning with previous analyses of liver damage risk associated with each medication.

“An accurate description of the hepatic safety profile of allopurinol and febuxostat will assist healthcare practitioners in determining appropriate liver monitoring for patients receiving these medications for the management of gout,” wrote the investigative team, led by Neily Zakiyah, MSc, PhD, department of pharmacology and clinical pharmacy, faculty of pharmacy, Universitas Padjadjaran.

Allopurinol is a xanthine oxidase inhibitor typically initiated at a starting dose of 100 mg/day, with an effect daily dose generally around 300 mg. Febuxostat is a non-purine selective inhibitor of xanthine oxidase, selectively inhibiting the enzyme to reduce serum uric acid levels.

Extensive clinical trial data have reported the strong efficacy and safety of febuxostat and allopurinol as urate-lowering therapies for patients with gout. In particular, the optimal control of serum uric acid levels can also reduce the clinical and financial burden linked to gout.²

However, despite reports on the superior clinical efficacy of febuxostat compared to allopurinol, there is a lack of systematic analysis data on the comparable hepatic safety of the medications in adult patients with gout. Zakiyah and colleagues performed a systematic review of PubMed, Cochrane Library, and Scopus until May 2023 to gather relevant data and assess hepatic safety.¹

Eligibility criteria included any published randomized controlled trials involving adult patients with gout comparing allopurinol and febuxostat reporting liver function safety results. The collected studies included assessments on liver function outcomes that outweigh the upper limits normal. Assessment of the effects in the study focused on hepatotoxicity and liver function outcomes.

To ensure the accuracy of selection, 2 reviewers independently screened articles during both initial title-and-abstract and full-text screening. A Jadad score was used to evaluate the quality of studies to determine the validity of eligible randomized controlled trials. It comprised 3 components: randomization, blinding, and extent of loss to follow-up.

A total of 619 citations were identified in the 3 databases and 512 publications were screened. After applying inclusion and exclusion criteria, investigators identified 11 studies that met the criteria and were included in the review. Of these 11 studies, 9 were double-blind randomized clinical trials.

Baseline demographics showed the study population mostly comprised male patients aged ≥18 years, mirroring the known higher prevalence of gout in males over 40 years. The patient population included in trials comparing febuxostat and allopurinol was 7810 patients, ranging from daily low doses (10/20 mg) and high doses (240 mg) of febuxostat, compared to daily allopurinol (50/100 to 600 mg).

Upon analysis, investigators observed consistent adverse events in liver function for both febuxostat and allopurinol. The majority of included studies did not show statistically significant differences in hepatic safety data between febuxostat and allopurinol. Often, adverse events resulted in study withdrawal, but most elevations in liver function parameters were mild to moderate in severity.

Investigators noted a particular study showed significant differences in abnormal liver function test results, which were the most frequent adverse event leading to subject withdrawal. Comparisons between 120 mg febuxostat (2.79%) and the allopurinol group (0.4%) showed statistical significance (P = .04). However, most adverse events were assessed as mild to moderate and reversible after discontinuation of febuxostat.

Given the small number of patients involved in clinical trials investigating febuxostat and allopurinol, Zakiyah and colleagues suggest the importance of continuous monitoring of pharmacovigilance databases and conducting future pharmacoepidemiology studies.

“Conducting future pharmacoepidemiology studies to explore the hepatic safety data of allopurinol and febuxostat is of utmost importance, given their frequent use by patients to treat this chronic disease,” investigators wrote. “Such studies would be highly beneficial for ensuring patient safety and understanding any potential risks associated with these medications.”

References

1. Dewi C, Puspita F, Puspitasari IM, Zakiyah N. Hepatic Safety of Febuxostat and Allopurinol for Gout Patients: A Systematic Review of Randomized Controlled Trial. Ther Clin Risk Manag. 2023;19:731-743. Published 2023 Sep 18. doi:10.2147/TCRM.S424598
2. Suzuki S, Yoshihisa A, Yokokawa T, et al. Comparison between febuxostat and allopurinol uric acid-lowering therapy in patients with chronic heart failure and hyperuricemia: a multicenter randomized controlled trial. J Int Med Res. 2021;49(12):030006052110627. doi:10.1177/03000605211062770