How to manage hyperuricemia in patients on anti-hypertensive medication?

Management of Hyperuricemia in Patients on Antihypertensive Medications

First-line management involves switching to uric acid-neutral or uric acid-lowering antihypertensive agents (losartan, ACE inhibitors, ARBs, or calcium channel blockers) while avoiding diuretics, beta-blockers, and alpha-1 blockers that elevate uric acid levels. 1

Antihypertensive Medication Selection

Agents That Worsen Hyperuricemia (Avoid or Discontinue)

• Diuretics, beta-blockers, and alpha-1 blockers significantly increase serum uric acid levels by reducing glomerular filtration rate and should be avoided in hyperuricemic patients 1
• Multiple regression analysis confirms that both diuretics and beta-blockers independently contribute to hyperuricemia in treated hypertensive patients 1
• Loop diuretics are particularly problematic in heart failure patients, where they commonly cause hyperuricemia and increase gout risk 2

Preferred Antihypertensive Agents

• Losartan is the preferred antihypertensive agent for patients with gout or hyperuricemia due to its unique uric acid-lowering properties through uricosuric effects 3, 2
• Calcium channel blockers, ACE inhibitors, and other angiotensin receptor blockers (besides losartan) do not increase serum uric acid levels and are safe alternatives 1
• Fenofibrate (for concurrent hyperlipidemia) also has uricosuric effects and can be therapeutically useful as part of a comprehensive urate-lowering strategy 2, 4

When to Initiate Urate-Lowering Therapy

Do NOT Treat Asymptomatic Hyperuricemia

• Urate-lowering therapy is NOT recommended for asymptomatic hyperuricemia (serum urate >6.8 mg/dL without gout symptoms), even in hypertensive patients 5, 6, 7
• The number needed to treat is 24 patients for 3 years to prevent a single gout flare, and only 20% of patients with serum urate >9 mg/dL develop gout within 5 years 5, 6
• Treatment risks outweigh benefits for asymptomatic hyperuricemia, including in patients with comorbid cardiovascular disease or chronic kidney disease 6

Indications for Urate-Lowering Therapy

Strongly recommended for patients with: 5

• One or more subcutaneous tophi
• Radiographic damage attributable to gout
• Frequent gout flares (≥2 per year)

Conditionally recommended for patients with: 5

• First gout flare AND chronic kidney disease stage ≥3
• First gout flare AND serum urate >9 mg/dL
• First gout flare AND history of urolithiasis
• Infrequent flares (<2/year) after experiencing >1 flare

Urate-Lowering Therapy Protocol

First-Line Agent: Allopurinol

• Allopurinol is the preferred first-line urate-lowering agent for all patients, including those with moderate-to-severe chronic kidney disease 5, 7
• Start at low dose: ≤100 mg/day (50 mg/day in CKD stage ≥4) to minimize acute gout flares during initiation 2, 7
• Titrate upward by 100 mg every 2-5 weeks (or every 2-4 weeks per European guidelines) until target serum urate is achieved 2, 7
• Maximum dose is 800 mg/day, which can be exceeded in renal impairment with adequate monitoring for drug toxicity (pruritus, rash, elevated transaminases) 2, 7
• In CKD patients with creatinine clearance 10-20 mL/min, use 200 mg/day; with clearance <10 mL/min, do not exceed 100 mg/day 7

Target Serum Urate Levels

• Target serum urate <6 mg/dL for maintenance therapy in most patients 5, 2
• Target <5 mg/dL (300 μmol/L) for severe gout with tophi, chronic arthropathy, or frequent attacks to hasten crystal dissolution 2
• Avoid long-term serum urate <3 mg/dL 2

Flare Prophylaxis During ULT Initiation

• Provide colchicine 0.5-1 mg/day for the first 6 months of urate-lowering therapy to prevent acute flares 2, 5
• Use reduced colchicine dose in renal impairment and avoid with strong P-glycoprotein/CYP3A4 inhibitors 2
• If colchicine is contraindicated, use low-dose NSAIDs (with caution in hypertensive patients) or low-dose glucocorticoids 2, 5
• Continue anti-inflammatory prophylaxis until serum urate is normalized and patient has been free from acute attacks for several months 7

Alternative and Combination Strategies

Second-Line Options

• Febuxostat can be substituted for allopurinol in cases of drug intolerance, adverse events, or failure to achieve target after maximal dose titration 2
• Febuxostat and allopurinol should NOT be used in combination with each other 2

Combination Therapy for Refractory Cases

• Add a uricosuric agent (probenecid, fenofibrate, or losartan) to a xanthine oxidase inhibitor if target serum urate is not achieved with monotherapy 2
• Probenecid is first-choice uricosuric but not recommended as first-line monotherapy if creatinine clearance <50 mL/min 2
• History of urolithiasis contraindicates first-line uricosuric monotherapy 2

Severe Refractory Disease

• Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to or intolerance of conventional urate-lowering therapy at appropriate doses 2

Common Pitfalls and Caveats

Critical Medication Review

• Eliminate non-essential medications that increase uric acid (diuretics, beta-blockers) when managing other comorbidities allows for alternative agents 2, 1
• Gender differences exist: beta-blockers and alpha-1 blockers show differential effects on serum uric acid between men and women 1

Acute Gout Management

• Continue urate-lowering therapy during acute gout flares; do not discontinue 5
• In acute gout, use a short course of colchicine for pain and inflammation; NSAIDs should be avoided if possible in symptomatic hypertensive patients 2
• Prophylactic therapy with allopurinol is recommended to prevent recurrence in heart failure patients prone to hyperuricemia from loop diuretics 2

Monitoring Requirements

• Monitor serum uric acid levels regularly to guide dose titration and ensure target achievement 5, 7
• Assess serum uric acid before initiating bempedoic acid (if used for cholesterol management) and monitor for symptoms of hyperuricemia, initiating urate-lowering drugs as appropriate 2
• Measure urinary uric acid before and during uricosuric therapy; consider urine alkalinization with potassium citrate if using uricosurics 2

Lifestyle Modifications

• Implement dietary changes including reduction of animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium intake 7
• Increase oral fluid intake (minimum 2 liters daily urinary output) and dietary fiber 7
• Low purine diet can be effective as first-line therapy for hyperuricemia control, particularly considering cost-benefit relationships 8