Does diuretic use increase the risk of incident gout in hypertensive adults?

Analysis of "Diuretic Use, Increased Serum Urate and the Risk of Incident Gout in a Population-based Study of Hypertensive Adults: the Atherosclerosis Risk in the Communities Cohort"

Study Overview and Design

Thiazide and loop diuretics significantly increase the risk of incident gout in hypertensive adults through elevation of serum urate levels, with diuretic use associated with a 48% increased risk compared to non-use. 1

This prospective population-based cohort study from the Atherosclerosis Risk in Communities (ARIC) study examined the relationship between diuretic use and gout development in hypertensive adults. The study included 5,789 participants with hypertension who were followed over a 9-year period across four visits.

Key Study Elements:

• Population: Adults with hypertension (defined as taking antihypertensive medication or having BP ≥140/90 mmHg)
• Exposure: Time-varying diuretic use (recorded by trained interviewers)
• Outcome: Self-reported incident gout
• Follow-up: 9-year period with 4 clinical visits
• Analysis: Time-dependent Cox proportional hazards model with adjustment for confounders

Key Findings

Diuretic Use and Gout Risk

• Any diuretic use: HR 1.48 (95% CI 1.11-1.98)
• Thiazide diuretics: HR 1.44 (95% CI 1.00-2.10)
• Loop diuretics: HR 2.31 (95% CI 1.36-3.91)

Serum Urate Changes

• Participants who began diuretic treatment experienced a 0.72 mg/dl (95% CI 0.57-0.87) greater increase in serum urate levels compared to those who did not use diuretics (p<0.001)
• After adjusting for serum urate levels, the association between diuretic use and gout became null, indicating complete mediation through urate elevation

Other Antihypertensive Medications

• Non-diuretic antihypertensive medications were associated with decreased gout risk (adjusted HR 0.64,95% CI 0.49-0.86) compared to untreated hypertension

Supporting Evidence from Other Studies

This finding is consistent with other research showing diuretics increase gout risk:

• A meta-analysis of cohort studies found diuretic use was associated with 2.39 times the risk of developing gout compared to no diuretic use (95% CI 1.57-3.65) 2
• A large UK-based case-control study found adjusted ORs for current use of loop diuretics (2.64), thiazide diuretics (1.70), and thiazide-like diuretics (2.30) compared to past use 3
• Combined use of loop and thiazide diuretics showed the highest risk (adjusted OR 4.65) 3

Pathophysiological Mechanism

The increased risk of gout with diuretic use is mediated through:

1. Reduced renal uric acid excretion: Diuretics compete with uric acid for tubular secretion
2. Volume depletion effects: Leads to increased uric acid reabsorption
3. Dose-dependent risk: Higher doses associated with greater risk

Genetic Considerations

A gene-by-diuretic interaction study from the same ARIC cohort found:

• Participants genetically predisposed to hyperuricemia were particularly susceptible to developing gout when taking thiazide or loop diuretics (OR 2.13,95% CI 1.23-3.67)
• Those without genetic predisposition showed no significant increased risk (OR 0.40,95% CI 0.14-1.15) 4

Clinical Implications and Management Recommendations

For Hypertensive Patients with or at Risk for Gout:

1. Consider stopping diuretic therapy if possible 5

   • EULAR guidelines strongly recommend discontinuing diuretic therapy when feasible (Strength of recommendation: 88,95% CI 82-94)

2. Alternative antihypertensive options:

   • Losartan: Has uricosuric properties that may lower both blood pressure and serum urate 5
   • Calcium channel blockers: May slightly attenuate the risk of gout in patients taking diuretics 3

3. For patients with hyperlipidemia:

   • Fenofibrate: Shows uricosuric effects with 20% reduction in serum urate levels 5

4. Monitoring recommendations:

   • Regular monitoring of serum uric acid levels to detect hyperuricemia early 6
   • Consider prophylactic therapy in high-risk patients 6

5. Management of acute gout attacks:

   • First-line options include colchicine (low-dose preferred), NSAIDs, or corticosteroids 5, 6

Limitations and Considerations

1. Self-reported gout diagnosis: The ARIC study relied on self-reported gout rather than clinical diagnosis
2. Confounding factors: Some studies suggest cardiovascular indications for diuretics may confound the association 7
3. Genetic variability: Individual genetic predisposition significantly modifies the risk 4

Conclusion

The ARIC study provides strong evidence that diuretic use significantly increases the risk of incident gout in hypertensive adults through elevation of serum urate levels. When managing hypertension in patients with or at risk for gout, clinicians should consider alternative antihypertensive medications when possible, or implement appropriate monitoring and prophylactic measures when diuretics cannot be avoided.