Gout is a rheumatic diseasethat results from the deposition of monosodium urate crystals in the joints or soft tissues. Hyperuricemia results from the accumulation of uric acid at the end of purine metabolism, whether from increased synthesis or decreased elimination. In February 2009, the US Food and Drug Administration (FDA) approved febuxostat (Uloric, Takeda Pharmaceuticals USA, Inc.), a xanthine oxidase inhibitor of uric acid production, for the treatment of hyperuricemia in patients with gout.
Renal impairment is a risk factor for gout. Since data regarding the safety and efficacy of febuxostat in patients with moderate to severe renal failure have been limited, Kenneth Saag, MD, and colleagues designed a pilot study to evaluate the impact of febuxostat on renal function in hyperuricemic gout patients. Dr Saag is a member of the Rheumatology Advisor editorial board.
Ninety-six patients who met the American Rheumatism Association diagnostic criteria for gout were enrolled in this multicenter, randomized, double-blind, placebo-controlled study. Clinical criteria for inclusion were: serum uric acid >7.0 mg/dL, blood pressure <160/95 mm Hg, serum creatinine ≥1.5 mg/dL, and estimated glomerular filtration rate (eGFR) ≥15 to ≤50 mL/min (severe impairment, ≥15 to <30 mL/min; moderate impairment, ≥30 to ≤50 mL/min).
The primary end point measured was a change in serum creatinine from baseline to end of month 12. Secondary end points included a change in estimated glomerular filtration rate (eGFR) and serum uric acid within the same time frame.
At the beginning of the study, any current urate-lowering therapies were discontinued, and subjects were randomly assigned 1:1:1 to febuxostat 30 mg twice daily, febuxostat 40 or 80 mg once daily, or placebo for up to 12 months. Randomization was accomplished by stratifying subjects according to the use of angiotensin receptor blocker or angiotensin-converting enzyme inhibitor.
The dosage for subjects receiving febuxostat 40 mg once daily was titrated up to 80 mg once daily at the month-1 follow-up visit if the serum uric acid level was ≥6.0 mg/dL at the 14-day follow-up visit. All subjects received gout flare prophylaxis (colchicine 0.6 mg every other day through 6 months; prednisone at doses of ≤10 mg per day if colchicine was not tolerated). The study did not include a treatment protocol for responding to a rise in serum creatinine; this decision was left to the clinical judgment of the clinicians.
Clinic evaluations occurred after treatment stratification, at days 1 and 14, and months 1, 3, 6, 9, and 12. Serum uric acid, serum creatinine, and eGFR were measured at each clinical assessment, along with adverse events and concomitant medication use.
At 12 months after treatment stratification, there were no observed significant differences in change from baseline in serum creatinine in the febuxostat treatment group as compared to placebo. At that point in time, there were also no significant differences in change from baseline in eGFR for any treatment groups.
The proportion of subjects at month 12 with serum uric acid level < 6.0 mg/dL was significantly greater in both febuxostat groups compared to placebo (P<.001).
Summary and Clinical Applicability
Impaired renal function is common in gout patients and has been a factor contributing to the suboptimal management of the condition. In this study, febuxostat was shown to be safe and efficacious in the treatment of patients with gout and moderate to severe renal impairment. Patients receiving febuxostat had significantly lower serum uric acid levels compared to placebo, with no significant decline in renal function as measured by eGFR. This study had a small sample size that did not allow for stratification according to renal function, and as such bias may have been introduced. Further clinical studies looking at the sustained effects of febuxostat over a longer period will support the long-term efficacy of febuxostat in patients with gout and impaired renal function.
Saag KG, Whelton A, Becker MA, et al. Impact of febuxostat on renal function in gout subjects with moderate-to-severe renal impairment. Arthritis Rheumatol. 2016; Feb 19. doi: 10.1002/art.39654. [Epub ahead of print]