What are the latest treatment options for hyperuricemia?

Latest Treatment for Hyperuricemia

Xanthine oxidase inhibitor (XOI) therapy with allopurinol or febuxostat is the first-line pharmacologic approach for treating hyperuricemia, with the goal of lowering serum urate to <6 mg/dL at minimum, and often <5 mg/dL in severe cases. 1

First-Line Pharmacologic Therapy

Xanthine Oxidase Inhibitors (XOIs)

Allopurinol remains the preferred initial XOI due to extensive clinical experience and cost-effectiveness, though neither allopurinol nor febuxostat is preferentially recommended over the other based on efficacy alone 1.

Allopurinol Dosing Strategy

• Start at ≤100 mg/day (or 50 mg/day in stage 4 or worse CKD) to reduce early gout flares and minimize hypersensitivity risk 1
• Gradually titrate upward every 2-5 weeks to achieve target serum urate levels 1
• Doses can exceed 300 mg daily, even with renal impairment, provided there is adequate patient education and monitoring for toxicity (pruritus, rash, elevated hepatic transaminases) 1
• Monitor serum urate every 2-5 weeks during titration, then every 6 months once target is achieved 1

Critical Safety Consideration for Allopurinol

Prior to initiating allopurinol, consider HLA-B*5801 screening in high-risk populations: Koreans with stage 3 or worse CKD, and all Han Chinese and Thai patients regardless of renal function, to prevent severe allopurinol hypersensitivity reactions 1

Febuxostat as Alternative

• Febuxostat can be substituted for allopurinol in cases of drug intolerance, adverse events, or failure to achieve target after appropriate dose titration 1
• No dose adjustment required in mild-to-moderate renal impairment (CrCl 30-89 mL/min) 2, 3
• Febuxostat 80 mg/day achieves superior serum urate reduction compared to conventional allopurinol 300 mg/day (67% vs 42% achieving <6 mg/dL) 2, 3

Treatment Targets

Target serum urate <6 mg/dL for all gout patients to durably improve signs and symptoms 1

For severe gout with tophi, chronic arthropathy, or frequent attacks, target <5 mg/dL to hasten crystal dissolution 1

Uricosuric Therapy

When to Use Uricosurics

Probenecid is the first choice among uricosurics for monotherapy, but is NOT recommended as first-line in patients with creatinine clearance <50 mL/min 1

Contraindications to uricosuric monotherapy include: 1

• History of urolithiasis
• Elevated urinary uric acid indicating uric acid overproduction
• Creatinine clearance <50 mL/min

Adjunctive Uricosuric Agents

Agents with uricosuric effects (fenofibrate, losartan) can be therapeutically useful as components of a comprehensive urate-lowering strategy 1

Combination Therapy for Refractory Cases

When serum urate target is not met by appropriate XOI dosing alone, combination therapy is appropriate: 1

1. First, attempt upward dose titration of the XOI to maximum appropriate dose 1
2. Add a uricosuric agent (probenecid, fenofibrate, or losartan) to the XOI 1
3. Consider switching between allopurinol and febuxostat if intolerance or adverse events occur 1

Important: Febuxostat and allopurinol should NEVER be used in combination with each other, as both are XOIs working through the same mechanism 1, 4

Advanced Therapy for Severe Refractory Gout

Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral urate-lowering therapy 1

Key considerations for pegloticase: 1

• NOT recommended as first-line therapy
• All oral urate-lowering agents must be discontinued during pegloticase therapy to avoid masking loss of efficacy and increased infusion reaction risk
• Achieves 42% response rate (serum urate <6 mg/dL) versus 0% with placebo 1
• Allergic reactions occur in approximately 25% of patients 1

Core Non-Pharmacologic Measures

Patient education on diet, lifestyle, treatment objectives, and management of comorbidities are recommended core therapeutic measures 1

Dietary and lifestyle modifications alone provide only 10-18% reduction in serum urate, which is insufficient for most patients with sustained hyperuricemia substantially above 7 mg/dL 1

Common Pitfalls to Avoid

• Do NOT start allopurinol at 300 mg in any patient—always start low (≤100 mg/day) and titrate gradually 1
• Do NOT avoid dose escalation above 300 mg allopurinol in renal impairment—doses can be increased with appropriate monitoring 1, 5
• Do NOT use probenecid as first-line in patients with CrCl <50 mL/min 1
• Do NOT combine febuxostat with allopurinol—they work through identical mechanisms 1, 4
• Pharmacologic urate-lowering therapy CAN be started during an acute gout attack, provided effective anti-inflammatory management has been instituted 1

Special Populations

Renal Impairment

Allopurinol remains first-line even in moderate-to-severe CKD, with dose adjustment: 5, 6

• CrCl 10-20 mL/min: 200 mg daily maximum
• CrCl <10 mL/min: 100 mg daily maximum
• CrCl <3 mL/min: may need to lengthen dosing interval

Febuxostat requires no dose adjustment in mild-to-moderate renal impairment but lacks safety data in stage 4 or worse CKD 1, 5

Monitoring During Therapy

Measure urinary uric acid before initiating uricosuric therapy and continue monitoring during treatment 1

Consider urine alkalinization (with potassium citrate) and increased fluid intake as risk management for urolithiasis during uricosuric therapy 1