Which diuretics are less likely to precipitate a gout attack or worsen gout?

Comment by InpharmD Researcher

Although robust studies are lacking, available data suggests potassium-sparing diuretics are not associated with an increased risk of incident gout. Increased risk of gout is more strongly associated with use of loop-diuretics, followed by thiazides, with evidence suggesting increased risk with increased dosage and duration of use. Still, overall increased risk of gout due to thiazide diuretics was considered to be small.

Background

Guidelines from the American College of Rheumatology Guideline address switching thiazide diuretics in patients with gout due to their known effect to increase serum urate concentrations. While no preferred diuretic therapy is mentioned for patients with gout, patients on hydrochlorothiazide should be switched to another antihypertensive therapy if clinically feasible. [1]

A retrospective study compared the impact of diuretic therapy and the response rate of urate-lowering drugs. Patients could have received thiazides or loop agents yet more were on loop diuretics (55.5% versus 44.6%). Over half of patients in the allopurinol group were receiving hydrochlorothiazide and those in the febuxostat group predominantly received furosemide. In either group, the difference in serum urate levels between those receiving diuretics and no diuretics was not significantly different. [2]

Another retrospective cohort study evaluated the risk for initiation of treatment specific for hyperuricemia or gout among patients aged 65 or older taking thiazide diuretics (N= 9,249) who were recently initiated on antihypertensive medication from November 1981 to February 1989. Thiazide diuretic therapy and thiazide diuretic therapy in combination with any non-thiazide agent(s) led to an increased risk for initiation of anti-gout therapy (relative risk [RR] 1.99, 95% confidence interval [CI] 1.21 to 3.26 and RR 2.29, 95% CI 1.55 to 3.27, respectively). The risk of initiating anti-gout therapy was significantly increased for thiazide dosage levels of ≥ 25 mg/day (RR 2.16, 95% CI 1.36 to 3.42 for doses 25 to 49 mg/day and RR 2.1, 95% CI 1.39 to 3.17 for doses ≥ 50 mg/day). However, the risk for initiation of anti-gout therapy was not significantly increased for a thiazide dosage of <25 mg/day (RR 1.51, 95% CI 0.61 to 3.76). [3]

According to a review on the management of hyperuricemia and gout in patients with heart failure, thiazide-type diuretics have been found to increase urate and creatinine levels. However, the increase is less significant in patients with higher baseline urate levels compared to those with lower levels. The risk of gout in thiazide-treated patients was considered to be very small, as only 15 gout episodes were documented among 3,693 participants over a five-year period in the Hypertension Detection and Follow-up Program. Nevertheless, the initiation of diuretic therapy may rarely lead to the rapid development of gout tophi in susceptible individuals. While urate retention is a common occurrence with all diuretic agents, there are slight differences between different classes. Gout is more strongly associated with the use of loop diuretics compared to thiazides. Acute gout attacks are more likely to be related to loop diuretics, whereas spironolactone may cause less pronounced urate retention compared to thiazide diuretics. In patients taking thiazides without any other diuretic, an increased incidence of gout attacks has been associated with obesity and high alcohol intake. [4], [5]

References:

[1] FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management Of Gout. Arthritis Care Res. 2020;72(6):744-760. doi:10.1002/acr.24180
[2] Ranieri L, Contero C, Peral ML, Calabuig I, Zapater P, Andres M. Impact of diuretics on the urate lowering therapy in patients with gout: analysis of an inception cohort. Arthritis Res Ther. 2018;20(1):53. Published 2018 Mar 22. doi:10.1186/s13075-018-1559-2
[3] Gurwitz JH, Kalish SC, Bohn RL, et al. Thiazide diuretics and the initiation of anti-gout therapy. J Clin Epidemiol. 1997;50(8):953-959. doi:10.1016/s0895-4356(97)00101-7
[4] Spieker LE, Ruschitzka FT, Lüscher TF, Noll G. The management of hyperuricemia and gout in patients with heart failure. Eur J Heart Fail. 2002;4(4):403-410. doi:10.1016/s1388-9842(02)00086-7
[5] Handler J. Managing hypertensive patients with gout who take thiazide. J Clin Hypertens (Greenwich). 2010;12(9):731-735. doi:10.1111/j.1751-7176.2010.00346.x
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Which diuretics are less likely to precipitate a gout attack or worsen gout?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

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

Design

Prospective, population-based cohort study

N= 5,789

Objective

To quantify the role of diuretic use on gout development in an adult population with hypertension

Study Groups

Any diuretic use (n= 2,169)

Thiazide use (n= 1,212)

Loop diuretic use (n= 339)

Nondiuretic antihypertensive use (n=2,252)

Inclusion Criteria

Participants aged 45 to 64 who answered the gout query, were free of gout at baseline, and had hypertension (medication to treat hypertension or a blood pressure ≥ 140/90 mmHg)

Exclusion Criteria

Participants who did not report their gout status at visit 4, prevalent gout at cohort entry (defined as the self-report of gout onset prior to the baseline visit)

Methods

The Atherosclerosis Risk in the Communities study (ARIC) consisted of four visits. Over a follow-up period of nine years, eligible patients with diuretic exposure were assessed for incident gout, which was defined as self-reported onset after the baseline assessment. The cohort involved an initial baseline visit and three subsequent follow-up visits (referred to as visit 2, visit 3, and visit 4), which were conducted at three-year intervals. Among the participants, hydrochlorothiazide was the most commonly reported diuretic.

Duration

Follow-up: 9 years; visit 1 between 1987 and 1989, and 3 follow-up visits (visits 2,3,4) administered 3 years apart

Outcome Measures

Gout incident, serum urate concentrations

Baseline Characteristics

  

No diuretic use

(n=3,620)

Diuretic use

(n=2,169)

    

Age, years

 54.5  55.0*    

Male

 48% 33%†    
African American

26%

 39%†    

Estimated glomerular filtration rate, mL/min

<60

60–90

>90

 

2%

49.3%

48.7% 

 

4.4%†

48.5%

47.0%

    

Mean serum urate, mg/dL

6.0

6.6†

    

9-year cumulative incident gout

2.9%

5.5%†

    

*p-value <0.05 comparing diuretic use with no diuretic use.

†p-value <0.001 comparing diuretic use with no diuretic use

Baseline study population characteristics were similar for those participants with any diuretic use, as well as for thiazide and loop diuretic use compared to no diuretic use (data not shown in the paper).

Results

Endpoint

Any diuretic use (n=2,169)

Thiazide use (n=1,212)

Loop diuretic use (n=339)

Nondiuretic antihypertensive use (n=2,252)

Gout incidencet, HR (95% CI)

Unadjusted

Adjusted for confounders‡

 

1.72 (1.32, 2.25)†

1.48 (1.11, 1.98)*

 

1.54 (1.08, 2.21)*

1.44 (1.00, 2.10)

 

3.65 (2.26, 5.90)†

2.31 (1.36, 3.91)*

 

0.44 (0.30, 0.64)† 

0.64 (0.49, 0.86)*

Change in serum urate, mg/dL

Adjusted difference in change (95% CI)

0.13 ± 0.98 

Reference

0.85 ± 1.35

0.59 (0.43, 0.74)*

0.78 ± 1.29

0.55 (0.35, 0.75)*

1.09 ± 1.68

0.73 (0.32, 1.14)*

Abbreviations= HR, hazard ratio; CI, confidence interval

*p-value <0.05 compared with no diuretic use.

†p-value <0.001 compared with no diuretic use.

‡ Confounders: Sex, race, BMI, categorical eGFR, and time-varying blood pressure. Age was the time-scale. The analysis of loop diuretics included congestive heart failure as a confounder.

Adverse Events

See result

Study Author Conclusions

Thiazide and loop diuretics were associated with increased gout risk, an association mediated by a change in serum urate.

InpharmD Researcher Critique

 Reliance on self-reported gout may introduce selection bias. Additionally, the study was unable to examine the association between gout risk and specific diuretic characteristics, such as dose or brand. 



References:

McAdams DeMarco MA, Maynard JW, Baer AN, et al. Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension: the Atherosclerosis Risk in Communities cohort study. Arthritis Rheum. 2012;64(1):121-129. doi:10.1002/art.33315

 

Use of diuretics and risk of incident gout: a population-based case-control study [published correction appears in Arthritis Rheumatol

Design

Retrospective population-based case-control analysis

N= 91,530

Objective

To investigate the association between use of loop diuretics, thiazide, or thiazide-like diuretics, and potassium sparing agents and the risk of developing incident gout

Study Groups

Incident cases of gout (n= 91,530)

Matched controls (n= 91,530)

Inclusion Criteria

Age ≥ 18 years, received a first-time diagnosis of gout (date of first gout diagnosis was noted as index date)

Exclusion Criteria

Patients with < 3 years of recorded history in database prior to index date; documented cancer diagnosis (with exception of nonmelanoma skin cancer); human immunodeficiency virus infection (HIV) prior to index date; diagnosis of hemochromatosis, osteoarthritis, septic arthritis, or rheumatoid arthritis within 180 days preceding index date or 90 days following index date

Methods

Patient data were compiled via General Practice Research Database in the United Kingdom, a large primary care database. All case patients with gout diagnosis were matched to control patients without any evidence of gout; case and control patients were matched for calendar time (same index date), age, sex, general practice, and number of years active in the General Practice Research Database prior to index date. Identical exclusion criteria were applied for control patients. Current diuretic use was determined based on exposure, as evidenced by prescription date documented in patient records. Short-term duration of use was defined as 1-9 prescriptions filled from index date, intermediate duration as 10-19 prescriptions, and long-term duration as ≥ 20 prescriptions. 

Duration

 Included patients were diagnosed with gout between 1990 to 2010

Outcome Measures

 Risk of gout in association with different types of diuretics 

Baseline Characteristics

  

Incident cases of gout (n= 91,530)

Matched controls (n= 91,530)

  

Age, years

18-29

30-39

40-49

50-59

60-69

70-79

> 79

 

1.9%

7.9%

14.8%

19%

21.4%

21.4%

13.7% 

 

1.9%

7.9%

14.8%

18.9%

21.4%

21.4%

13.7% 

  

Female

25.9% 25.9%  

Body mass index, kg/m2

12.0-18.4

18.5-24.9

25.0-29.9

30.0-60.0

Unknown

 

0.5%

17.4%

33.9%

25.5%

22.8%

 

1.1%

27.4%

29.0%

12.7%

29.8% 

  

Results

Type of diuretic used

Adjusted odds ratio for incidence of gout (95% CI)

p-Value

Loop

Never used

Current use < 180 days

Overall

1-9 prescriptions

10-19 prescriptions

≥ 20 prescriptions

 

0.75 (0.71-0.80)

 

2.64 (2.47-2.83)

1.95 (1.77-2.15)

2.36 (2.12-2.62)

3.16 (2.93-3.42)

 

< 0.001

 

< 0.001

< 0.001

< 0.001

< 0.001 

Thiazide

Never used

Current use < 180 days

Overall

1-9 prescriptions

10-19 prescriptions

≥ 20 prescriptions

 

0.85 (0.81-0.88)

 

1.70 (1.62-1.79)

1.51 (1.39-1.64)

1.64 (1.51-1.79)

1.81 (1.71-1.92) 

 

< 0.001

 

< 0.001

< 0.001

< 0.001

< 0.001

Thiazide-like

Never used

Current use < 180 days

Overall

1-9 prescriptions

10-19 prescriptions

≥ 20 prescriptions

 

0.95 (0.85-1.07)

 

2.30 (1.95-2.70)

2.08 (2.61-2.70)

2.36 (1.79-3.12)

2.44 (2.01-2.97) 

 

0.425

 

< 0.001

< 0.001

< 0.001

< 0.001 

Potassium-sparing

Never used

Current use < 180 days

Overall

1-9 prescriptions

10-19 prescriptions

≥ 20 prescriptions

 

0.62 (0.55-0.69)

 

1.06 (0.91-1.23)

1.14 (0.92-1.40)

1.21 (0.94-1.57)

0.96 (0.80-1.15) 

 

< 0.001

 

0.470

0.230

0.141

0.623

Combined use of loop diuretics and thiazide diuretics was associated with the highest relative risk estimates of gout (adjusted odds ratio 4.65, 95% CI 3.51-6.16). 

Current use of calcium channel blockers or losartan slightly attenuated risk of gout in patients using diuretics. 

Obesity/over-weight, alcohol consumption, and comorbidities such as hypertension, chronic kidney disease, and congestive heart failure were associated with increased risk of incident gout. 

Use of ACE inhibitors and beta-blockers was associated with slightly increased risk of incident gout, while use of losartan and calcium channel blockers was associated with slightly decreased risks. 

Adverse Events

 N/A

Study Author Conclusions

Use of loop diuretics, thiazide diuretics, and thiazide-like diuretics was associated with an increased risk of incident gout, although use of potassium-sparing agents was not. 

InpharmD Researcher Critique

 Effects of confounding variables, although adjusted for, cannot be fully excluded from this analysis. Accuracy of conclusions is dependent on accuracy of documentation and proper classification of gout cases. 



References:

Bruderer S, Bodmer M, Jick SS, Meier CR. Use of diuretics and risk of incident gout: a population-based case-control study [published correction appears in Arthritis Rheumatol. 2014 Feb;66(2):427]. Arthritis Rheumatol. 2014;66(1):185-196. doi:10.1002/art.38203