What is the relationship between diuretic use and the risk of incident gout in hypertensive adults, particularly those with impaired renal function?

Diuretic Use and Risk of Incident Gout in Hypertensive Adults: Analysis of the ARIC Cohort Study

Diuretic use significantly increases the risk of incident gout in hypertensive patients, with thiazide and loop diuretics associated with a 1.44-fold and 2.31-fold higher risk respectively, an effect that is mediated through elevated serum urate levels.

Study Design and Population

The "Diuretic Use, Increased Serum Urate and the Risk of Incident Gout" study used data from the Atherosclerosis Risk in Communities (ARIC) cohort, a prospective population-based study following participants from four US communities over a 9-year period with four clinical visits 1. Key elements of the study design included:

• Population: 5,789 adults with hypertension who were free of gout at baseline
• Exposure assessment: Time-varying diuretic use recorded by trained interviewers
• Outcome measurement: Self-reported incident gout
• Follow-up period: 9 years with multiple assessment points
• Statistical approach: Time-dependent Cox proportional hazards models to estimate hazard ratios

Key Findings on Diuretic Use and Gout Risk

Diuretic Prevalence and Risk

• 37% of hypertensive participants were treated with diuretics 1
• Use of any diuretic was associated with a 48% increased risk of incident gout (HR 1.48,95% CI 1.11-1.98) 1
• Thiazide diuretics increased gout risk by 44% (HR 1.44,95% CI 1.00-2.10) 1
• Loop diuretics carried the highest risk, more than doubling gout incidence (HR 2.31,95% CI 1.36-3.91) 1
• Combined use of loop and thiazide diuretics showed the highest risk (OR 4.65,95% CI 3.51-6.16) in population studies 2

Mechanism of Risk

• The association between diuretic use and gout was mediated by changes in serum urate levels 1
• Longitudinal serum urate levels increased by 0.72 mg/dl (95% CI 0.57-0.87) in those who began diuretic treatment compared to those who did not 1
• After adjusting for serum urate levels, the association between diuretic use and gout became null, confirming the mediating role of hyperuricemia 1

Risk Factors and Dose Relationships

Dose-Response Relationship

• Significant increased risk of gout was observed with thiazide doses ≥25 mg/day (hydrochlorothiazide equivalents) 3
• Lower doses did not show a statistically significant increase in risk 3

Other Antihypertensive Medications

• Non-diuretic antihypertensive medications were associated with a 36% decreased risk of gout (adjusted HR 0.64,95% CI 0.49-0.86) compared to untreated hypertension 1
• Calcium channel blockers and losartan slightly attenuated the risk of gout in patients taking diuretics 2

Implications for Clinical Practice

Monitoring and Prevention

• Patients on thiazide diuretics should be monitored for hyperuricemia, as these medications can precipitate acute gout 4, 5
• Regular monitoring of serum uric acid levels is necessary for early detection of hyperuricemia in patients on diuretics 4
• The FDA label for hydrochlorothiazide specifically warns that hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics 5

Alternative Antihypertensive Strategies

• For hypertensive patients with gout or hyperuricemia, consider alternative antihypertensive medications 6
• Losartan has mild uricosuric properties and may be beneficial for hypertensive patients with gout 6, 7
• When diuretics cannot be avoided, consider prophylactic measures against gout attacks 6

Management Recommendations for Patients with Hypertension and Gout

1. Stop diuretic therapy if possible for patients who develop gout 6
2. Consider losartan for hypertension management in patients with gout due to its uricosuric effects 6, 7
3. Use lowest effective dose of thiazide diuretics when they cannot be avoided, as doses below 25 mg/day have lower risk 3
4. Monitor serum urate levels regularly in patients on diuretic therapy 4
5. Consider prophylactic therapy for gout in high-risk patients who require diuretics 4

Conclusion on Renal Function Impact

The ARIC cohort study demonstrates that diuretic use in hypertensive adults significantly increases the risk of incident gout through elevated serum urate levels. This risk is particularly pronounced in patients with impaired renal function, as diuretics reduce renal clearance of uric acid. The findings highlight the importance of careful medication selection and monitoring in hypertensive patients, especially those with additional risk factors for gout.