Febuxostat Use Is Linked to Reduced Risk of Kidney Events for Patients with Gout

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A new study found febuxostat is associated with a decreased risk of kidney events and a slow decline in the estimated glomerular filtration rate (eGFR) in patients with gout.¹

“Febuxostat may be an effective drug for delaying the progression of kidney function deterioration in patients with gout or hyperuricemia,” wrote investigators, led by Xiu Hong Yang, from Shanghai Pudong Hospital and Huadong Hospital at Fudan University.

Febuxostat has been stable in therapy for a long time. The US Food and Drug Administration (FDA) approved febuxostat (ULORIC) 40 mg and 80 mg for the chronic management of hyperuricemia in patients with gout back in 2009.² It was approved as a once-daily oral medication. Despite the drug being on the market for ≥ 10 years, questions remain regarding its outcomes.

It had been unknown whether febuxostat can delay the progression of kidney dysfunction and reduce kidney events.¹ Investigators aimed to assess the renoprotective effect of febuxostat in patients with hyperuricemia or gout.

The team conducted a meta-analysis of 16 randomized controlled trials (RCTs), leveraging studies from MEDLINE (PubMed: January 1, 1966, to November 1, 2023, Web of Science, EMBASE (January 1, 1966, to November 1, 2023), ClinicalTrials.gov, and the Cochrane Central Register for Randomized Controlled Trials. The primary outcomes included kidney events—either serum creatinine doubling, progression to end-stage kidney disease, or dialysis—and secondary outcomes such as the rate of change in the eGFR and changes in the urine protein or urine albumin to creatinine ratio from baseline to the end of the follow-up. In total, 7 studies examined recorded kidney events, 13 evaluated EFR, and 6 evaluated urine protein or urine albumin to creatinine ratio values.

Compared to controls, patients who received febuxostat demonstrated a reduced risk of kidney events (relative risk [RR], 0.56; 95% confidence interval [CI], 0.37 to 0.84; P = .006) and a slower decline in eGFR (WMD, 0.90; mL/min/1.73 m2, 95% CI, 0.31 to 1.48, P = .003). A pooled analysis showed febuxostat use decreased the urine albumin to creatinine ratio (standardized mean difference [SMD], - 0.21; 95% CI, - 0.41 to – 0.01; P = .042).

“Notably, the results of our meta-analysis were not consistent with those of other meta-analyses,” investigators wrote.

Prior meta-analyses evaluated urate-lowering therapy with either febuxostat or allopurinol. One meta-analysis examining 7 RCTs on febuxostat vs placebo or other drugs found febuxostat was not superior at improving eGFR over placebo. However, the meta-analysis had flaws: it did not include any trials on febuxostat use and kidney outcomes and it the assessment of renal function progression did not include hard kidney endpoints—only the change of eGFR. Another meta-analysis did not evaluate the hard kidney endpoints and only the eGFR.

“In our meta-analysis, our pooled results from the change in the eGFR was 0.9 ml/min/1.73 m2, probably being of little clinical significance for clinicians; however, it is significant from a statistical perspective,” investigators wrote. “This result is consistent with the concomitant hard kidney endpoint result.”

Questions about febuxostat’s safety remain up in the air. In February 2019, the FDA issued a boxed warning for febuxostat due to the fact the drug was associated with an increased cardiovascular disease risk.³ However, the results of this new meta-analysis demonstrate febuxostat use was not associated with increased risks of all-cause mortality, death from cardiovascular disease or cardiovascular events, and is safe for gout treatment.¹

The team wrote the study was limited by the substantial heterogeneity in the changes in eGFR, which might be due to the differences in follow-up times as a meta-regression found. Additionally, the results were limited by the low number of RCTs, and the team explained there need to be larger multicenter trials with hard kidney endpoints.

“More RCTs designed with hard kidney endpoints, other than surrogate marker-change of eGFR, is needed to further verify this results in future,” investigators wrote.

References

1. ^{Yang XH, Zhang BL, Cheng Y, Fu SK, Jin HM. Febuxostat provides renoprotection in patients with hyperuricemia or gout: a systematic review and meta-analysis of randomized controlled trials. Ann Med. 2024;56(1):2332956. doi:10.1080/07853890.2024.2332956}
2. ^{FDA Approves ULORIC® (febuxostat) for the Chronic Management of Hyperuricemia in Patients with Gout. Takeda. February 12, 2009. https://www.takeda.com/en-us/newsroom/news-releases/20102/fda-approves-uloric-febuxostat-for-the-chronic-management-of-hyperuricemia-in-patients-with-gout. Accessed May 14, 2024.}
3. ^{Febuxostat is Out for Gout Treatment. HCPLive. April 18, 2019. https://www.hcplive.com/view/febuxostat-out-gout-treatment?slide=2. Accessed May 14, 2024.}