2021 Expert Consensus: Diagnosis and Treatment of Patients with Hyperuricemia and High Cardiovascular Risk (Updated Version)

1. Background and Significance

2. Diagnosis and Risk Stratification

2.1 Diagnosis of HUA

• Laboratory Testing: Fasting SUA measurement (abstain from high-purine food, alcohol, and strenuous exercise for 3 days before testing); repeated measurements on non-consecutive days to confirm persistent HUA.
• Classification of HUA Severity:
  • Mild: SUA 420–480 μmol/L (7–8 mg/dL) (men), 360–420 μmol/L (6–7 mg/dL) (women);
  • Moderate: SUA 480–540 μmol/L (8–9 mg/dL);
  • Severe: SUA >540 μmol/L (9 mg/dL).
• Etiological Classification:
  • Excretory type (90% of cases): 24-hour urinary uric acid excretion <800 mg (normal purine diet) or fractional excretion of uric acid <7%;
  • Overproduction type: 24-hour urinary uric acid excretion >800 mg (normal purine diet) or fractional excretion of uric acid >10%;
  • Mixed type: Combined features of the above two types.

2.2 Risk Stratification for HUA Patients with High CV Risk

1. Established CV disease (CAD, ischemic stroke, peripheral arterial disease, HF, AF);
2. CKD stage ≥3;
3. Type 2 diabetes mellitus (T2DM) with target organ damage (e.g., diabetic nephropathy, retinopathy);
4. Hypertension combined with ≥2 other risk factors (dyslipidemia, smoking, obesity, family history of premature CV disease).

3. Treatment Principles and Goals

3.1 General Principles

• Integrated Management: Combine lifestyle intervention, urate-lowering therapy (ULT), and control of CV risk factors (hypertension, dyslipidemia, hyperglycemia);
• Individualized Treatment: Determine ULT initiation and target SUA based on risk stratification, presence of complications, and patient tolerance;
• Long-term Monitoring: Regular follow-up of SUA, renal function, and CV events to adjust treatment plans timely.

3.2 Treatment Goals

4. Lifestyle Intervention

1. Dietary Adjustment:
   • Restrict high-purine foods (animal offal, seafood, thick broth);
   • Limit red meat intake (<500 g/week);
   • Increase low-purine foods (vegetables, fruits, whole grains, low-fat dairy products);
   • Avoid high-fructose beverages and added sugars (fructose promotes urate production and exacerbates insulin resistance).
2. Alcohol Restriction:
   • Strictly prohibit beer (high purine content); limit spirits and red wine (men ≤2 drinks/day, women ≤1 drink/day; 1 drink = 150 mL wine or 50 mL spirits).
3. Weight Management:
   • Achieve and maintain BMI 18.5–23.9 kg/m²; reduce waist circumference to <90 cm (men) or <85 cm (women) through moderate exercise (e.g., brisk walking, cycling, swimming, 150 minutes/week of moderate-intensity exercise).
4. Hydration:
   • Drink 2000–3000 mL of water daily (prefer plain water or alkaline water) to promote urate excretion; avoid dehydration (e.g., during fever, diarrhea).
5. Avoid Urate-elevating Drugs:
   • Minimize use of thiazide diuretics (replace with loop diuretics if necessary), low-dose aspirin (adjust dose if possible), cyclosporine, and tacrolimus.

5. Urate-Lowering Therapy (ULT)

5.1 Indications for ULT Initiation in High CV Risk Patients

1. Severe HUA (SUA >540 μmol/L);
2. Mild/moderate HUA with:
   • A history of gout attack or tophus;
   • CKD stage ≥3 or persistent proteinuria;
   • T2DM with nephropathy or retinopathy;
   • A history of MACE or symptomatic HF/AF;
   • Failure to achieve SUA target after 3–6 months of lifestyle intervention.

5.2 Classification and Selection of ULT Drugs

5.2.1 Uricosuric Agents (First-line for Excretory HUA)

• Probenecid:
  • Dose: Start at 250 mg bid, titrate up to 500 mg bid (maximum 2000 mg/day);
  • Contraindications: CKD stage ≥4, a history of uric acid nephrolithiasis, concurrent use of aspirin (high dose);
  • Monitoring: Renal function, urinary uric acid excretion, and risk of nephrolithiasis (maintain high fluid intake).
• Benzbromarone:
  • Dose: 50 mg qd, may increase to 100 mg qd if needed;
  • Advantages: Effective in patients with mild-to-moderate CKD (eGFR ≥30 mL/min/1.73m²);
  • Precautions: Monitor liver function (ALT/AST) at baseline and 1–3 months after initiation (risk of hepatotoxicity).

5.2.2 Xanthine Oxidase Inhibitors (XOI, First-line for Overproduction or Mixed HUA)

• Allopurinol:
  • Dose: Start at 100 mg qd (50 mg qd for CKD stage ≥3), titrate by 100 mg every 2–4 weeks (maximum 600 mg/day); adjust dose based on renal function (eGFR 30–59 mL/min: 200 mg/day; eGFR <30 mL/min: 100 mg/day);
  • Precautions: Screen for HLA-B*5801 allele before initiation in high-risk populations (Han Chinese, Thai, Korean) to reduce risk of severe cutaneous adverse reactions (SCARs); monitor skin rash and liver/kidney function.
• Febuxostat:
  • Dose: Start at 40 mg qd, increase to 80 mg qd if SUA not 达标；
  • Advantages: Minimal renal excretion, suitable for patients with CKD; lower risk of SCARs compared to allopurinol;
  • Precautions: Monitor cardiovascular events (atrial fibrillation, myocardial infarction) in patients with a history of CAD/HF (balance efficacy and CV safety).

5.2.3 Uricase Enzyme Preparations (Reserved for Severe HUA/Gout)

• Pegloticase:
  • Indication: Refractory gout (SUA >540 μmol/L despite maximum-dose XOI, or tophaceous gout);
  • Dose: 8 mg intravenously every 2 weeks;
  • Contraindications: G6PD deficiency (risk of hemolysis), severe heart failure;
  • Precautions: Risk of infusion reactions and immunogenicity (antibody formation may reduce efficacy).

5.3 Combination ULT

• Indicated for: Severe HUA, failure to reach target with monotherapy, or mixed-type HUA;
• Regimens: XOI + uricosuric agent (e.g., allopurinol + probenecid); avoid combining two uricosuric agents (increased nephrolithiasis risk);
• Monitoring: More frequent SUA and renal function checks to adjust doses and prevent adverse events.

5.4 Prophylaxis for Gout Flares During ULT Initiation

• In patients with a history of gout, initiate anti-inflammatory prophylaxis (colchicine 0.5 mg qd/bid, or low-dose NSAIDs, or prednisone 10–15 mg/day) 1–2 weeks before ULT and continue for 3–6 months;
• Adjust prophylaxis based on patient tolerance (e.g., avoid NSAIDs in CKD/HF; reduce colchicine dose in renal impairment).

6. Management of CV Risk Factors and Comorbidities

6.1 Hypertension

• Preferred antihypertensives: Losartan (ARB, mild uricosuric effect) or amlodipine (CCB, no effect on SUA);
• Avoid thiazide diuretics (replace with loop diuretics if volume overload is present); if necessary, combine with ULT to counteract urate elevation.

6.2 Dyslipidemia

• Statins are first-line (atorvastatin, rosuvastatin) – monitor liver and muscle function;
• For severe hypertriglyceridemia (TG >5.6 mmol/L), use fenofibrate (mild uricosuric effect) to reduce pancreatitis risk.

6.3 T2DM

• Preferred agents: SGLT2 inhibitors (empagliflozin, dapagliflozin) – reduce SUA levels and protect renal/cardiac function; GLP-1 receptor agonists (semaglutide) – improve insulin resistance and aid weight loss;
• Avoid sulfonylureas (may increase SUA by reducing urate excretion).

6.4 CKD

• Adjust ULT doses based on eGFR (see Section 5.2);
• Control blood pressure <130/80 mmHg (prefer ARB/ACEI) to reduce proteinuria;
• Avoid nephrotoxic drugs (aminoglycosides, NSAIDs) and maintain adequate hydration to prevent uric acid nephrolithiasis.

6.5 Heart Failure/Atrial Fibrillation

• In HUA patients with HF, prioritize SGLT2 inhibitors and ARNI (sacubitril/valsartan) for cardiorenal protection;
• For AF, choose anticoagulants (NOACs preferred over warfarin, which may interact with ULT) and rate/rhythm control while optimizing SUA levels.

7. Follow-up and Monitoring

7.1 Follow-up Schedule

• Initiation phase (0–3 months): SUA, renal function (creatinine, eGFR, urinalysis), liver function (ALT/AST) every 4–8 weeks; adjust ULT dose based on SUA;
• Maintenance phase (>3 months): SUA every 3–6 months; renal/liver function every 6–12 months; annual assessment of CV events (ECG, echocardiogram if indicated);
• High-risk patients (severe HUA, CKD ≥3, history of MACE): More frequent monitoring (SUA/renal function every 2–3 months).

7.2 Key Monitoring Indicators

• Primary: SUA (target achievement), gout flare frequency, tophus resolution;
• Secondary: Renal function (eGFR, proteinuria), liver function, blood pressure, lipid profile, blood glucose, and CV event recurrence (MI, stroke, HF hospitalization).

7.3 Management of Treatment Failure

• Definition: SUA remains above target after 6 months of optimal ULT (maximum tolerated dose) and lifestyle intervention;
• Approach:
  1. Reassess adherence to lifestyle modification and medication;
  2. Switch or combine ULT (e.g., allopurinol → febuxostat, or XOI + uricosuric agent);
  3. For refractory cases, refer to a rheumatologist/cardiologist for consideration of pegloticase or further evaluation of underlying causes (e.g., rare genetic disorders).

8. Special Populations

8.1 Elderly Patients (≥65 years)

• Start ULT at low doses (e.g., allopurinol 50 mg qd) and titrate slowly;
• Prioritize safety (monitor for hypotension, falls, and drug-drug interactions);
• Individualize SUA targets (avoid over-treatment in frail patients with multiple comorbidities).

8.2 Pregnancy/Lactation

• Lifestyle intervention is first-line (avoid ULT if possible);
• For severe HUA with gout flares, use colchicine (low dose) cautiously; avoid XOI/uricase (teratogenic risk);
• Resume ULT after delivery/cessation of breastfeeding.

8.3 Post-cardiac Surgery Patients

• Monitor SUA closely (cardiopulmonary bypass may cause transient HUA);
• Initiate ULT for persistent SUA >540 μmol/L or gout flares (avoid high-dose probenecid in patients with impaired renal perfusion).

9. Conclusion