Why do thiazides (diuretics) exacerbate gout?

Thiazide Diuretics and Gout: Understanding the Controversy

Thiazide diuretics significantly increase the risk of gout through reduced renal uric acid excretion, with an odds ratio of 1.70-1.72 compared to non-users, and should be discontinued if possible in patients with a history of gout. 1

Mechanism of Thiazide-Induced Hyperuricemia

Thiazide diuretics contribute to gout development through several mechanisms:

• Reduced renal uric acid excretion: Thiazides compete with uric acid for excretion at the proximal tubule
• Volume depletion effects: Leads to increased uric acid reabsorption
• Dose-dependent risk: Higher doses (≥25 mg/day of hydrochlorothiazide or equivalent) have greater impact on uric acid levels 1, 2

This leads to hyperuricemia, which can precipitate gout attacks in susceptible individuals when uric acid crystals form and deposit in joints, triggering an inflammatory response.

Evidence for Increased Gout Risk

The controversy around thiazides and gout isn't about whether they increase risk (they clearly do), but rather about:

1. Magnitude of risk: Population-based case-control studies show thiazide diuretics increase gout risk with adjusted odds ratios of:

   • 1.70 (95% CI 1.62-1.79) for thiazide diuretics 3
   • 2.30 (95% CI 1.95-2.70) for thiazide-like diuretics 3

2. Dose relationship: Doses ≥25 mg/day of hydrochlorothiazide significantly increase gout risk, while lower doses may have minimal impact 2

3. Combined therapy risks: Using loop diuretics with thiazides creates the highest risk (adjusted OR 4.65 [95% CI 3.51-6.16]) 3

Management Recommendations for Hypertension in Gout Patients

1. Discontinue thiazides when possible: The European League Against Rheumatism (EULAR) and other guidelines strongly recommend stopping diuretic therapy when clinically feasible 4, 1

2. Consider alternative antihypertensives:

   • Losartan (has uricosuric properties)
   • Calcium channel blockers (no adverse effect on uric acid)
   • ACE inhibitors (except in renovascular disease) 4, 1, 5

3. If thiazides must be continued:

   • Use lowest effective dose possible
   • Consider prophylactic urate-lowering therapy
   • Monitor serum uric acid levels regularly 1

4. Avoid thiazides in high-risk patients: Guidelines explicitly list gout as a compelling contraindication for thiazide use 4

Clinical Implications

The controversy exists because:

1. Therapeutic dilemma: Thiazides are effective, inexpensive first-line antihypertensives, but their use conflicts with gout management

2. Risk-benefit assessment: For most hypertensive patients without gout history, the cardiovascular benefits of thiazides outweigh the small risk of developing gout

3. Individualized approach: The DCRM 2.0 guidelines (2024) state that thiazide diuretics should be used with caution in persons with a history of acute gout unless they are on uric acid-lowering therapy 4

4. Monitoring requirements: Patients on thiazides should be monitored for hyperuricemia, hyponatremia, and hypokalemia 4

Special Considerations

• Elderly patients: Higher risk for thiazide-induced gout due to age-related decline in renal function 4, 1
• Metabolic impact: Thiazides have also been associated with increases in insulin resistance and higher risk of progression to type 2 diabetes 4
• Alternative diuretics: Potassium-sparing diuretics do not significantly increase gout risk (adjusted OR 1.06 [95% CI 0.91-1.23]) 3

The controversy around thiazides and gout ultimately centers on balancing their proven cardiovascular benefits against their well-established risk of precipitating gout, particularly in susceptible individuals.