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

Journal Club Analysis: "Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension"

Diuretics significantly increase the risk of incident gout in hypertensive patients through elevation of serum urate levels, with thiazide and loop diuretics showing the strongest association. 1

Background Information Assessment

The authors provided appropriate background information by establishing:

• The relationship between diuretics and gout in hypertensive patients
• The mechanism by which diuretics may influence serum urate levels
• The gap in quantifying this relationship in a population-based cohort

However, the background could have been strengthened by including:

• More detailed information about the prevalence of gout in hypertensive populations
• Prior evidence on specific diuretic classes and their differential effects on urate levels
• Discussion of alternative antihypertensive medications that might not increase gout risk

Study Rationale and Contribution

The authors justified this study based on the need to:

• Quantify the specific role of diuretics in gout development in hypertensive patients
• Determine whether the relationship is mediated by changes in serum urate levels
• Compare different classes of diuretics (thiazide vs. loop) in their association with gout

This research adds significantly to the literature by:

• Using a large, prospective population-based cohort (ARIC study)
• Employing time-dependent analysis to account for changes in medication use
• Examining the mediating role of serum urate levels in the diuretic-gout relationship
• Comparing different antihypertensive strategies in relation to gout risk

Research Objective and Study Design

Population Studied

• Adults with hypertension (defined as taking antihypertensive medication or BP ≥140/90 mmHg)
• From the Atherosclerosis Risk in Communities (ARIC) cohort
• Free of gout at baseline
• Followed over a 9-year period with 4 visits

Risk Factors/Exposures

• Primary exposure: Diuretic use (any, thiazide, loop)
• Secondary exposure: Other antihypertensive medications
• Time-varying exposure assessment through trained interviewer recording

Outcomes Measured

• Primary outcome: Self-reported incident gout
• Secondary outcome: Changes in serum urate levels

The study addressed a clearly formulated research objective by examining the specific relationship between diuretic use and incident gout in hypertensive patients, with appropriate consideration of the mediating role of serum urate levels.

Methodological Assessment

Case Definition

• Cases were defined as participants who self-reported new onset of gout after baseline
• This definition lacks clinical validation through synovial fluid analysis, which is the gold standard for gout diagnosis 2
• Self-reported gout is subject to misclassification bias

Case Selection

• Cases were identified from participants who answered queries about gout during follow-up visits
• No specific sampling strategy was used; all eligible participants with incident gout were included
• Potential selection bias exists if participants with more severe symptoms were more likely to report gout

Sample Size and Power

• 5,789 participants with hypertension were included
• 37% were treated with a diuretic
• No formal power calculation was reported, but the sample size appears adequate given the observed effect sizes

Control Selection

• This was a cohort study, not a case-control design, so traditional controls were not selected
• The comparison groups were hypertensive participants not using diuretics or specific classes of diuretics
• Time-dependent analysis appropriately accounted for changes in exposure status

Exposure Measurement

• Diuretic use was recorded by trained interviewers
• Objective measurement through medication inventory rather than self-report
• Potential for misclassification if participants did not accurately report all medications

Reliability and Validity of Measurements

• Medication use was likely reliably recorded but dependent on participant disclosure
• Serum urate levels were measured using standard laboratory methods
• Outcome (gout) was self-reported without clinical confirmation, reducing validity

Potential Biases

• Recall bias for the outcome (self-reported gout)
• Confounding by indication (sicker patients more likely to receive diuretics)
• Potential misclassification of both exposure and outcome

Time Frame Appropriateness

• 9-year follow-up period was appropriate to observe the development of incident gout
• Time-dependent analysis accounted for changes in medication use over time

Risk Factors and Confounders

• The authors identified and adjusted for key confounders including:
  • Age, sex, race, BMI, alcohol consumption
  • Kidney function (estimated GFR)
  • Comorbidities (diabetes, cardiovascular disease)

Statistical Analysis

• Time-dependent Cox proportional hazards models were appropriate for this study design
• Mediation analysis to assess the role of serum urate levels was methodologically sound
• Alpha level was not explicitly specified but standard 95% confidence intervals were reported

Sample Sizes

• 5,789 participants with hypertension
• The number of incident gout cases was not clearly stated in the abstract but was sufficient for the analyses performed

Clinical Implications

The findings from this study align with guidelines recommending caution with diuretic use in patients at risk for gout 2. The European League Against Rheumatism (EULAR) recommends stopping diuretics if possible in patients with gout, with a strength of recommendation of 88% (95% CI, 82% to 94%) 2.

For hypertensive patients requiring treatment, the study supports considering alternative antihypertensive medications, particularly in those with elevated urate levels or history of gout. The EULAR guidelines specifically suggest losartan as an alternative due to its uricosuric effects 2.

The study's demonstration that the association between diuretics and gout is mediated by serum urate levels provides mechanistic support for the clinical recommendations and highlights the importance of monitoring urate levels in patients on diuretic therapy.