SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

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

Methods

The Atherosclerosis Risk in Communities study, a prospective population-based cohort from 4 US communities, consisted of 4 visits over a 9-year period. Participants were included in this analysis if they answered a query about gout, were free of gout at baseline, and had hypertension (defined as taking medication to treat hypertension or having blood pressure of ≥140/90 mm Hg). Trained interviewers recorded use of antihypertensive drugs. Incident gout was defined as self-reported onset of gout after baseline. Using a time-dependent Cox proportional hazards model, we estimated hazard ratios (HRs; with 95% confidence intervals [95% CIs]) for incident gout by time-varying diuretic use, both adjusted for confounders and tested for mediation by serum urate level.

Results

There were 5,789 participants with hypertension; 37% were treated with a diuretic. Use of any diuretic (HR 1.48 [95% CI 1.11, 1.98]), a thiazide diuretic (HR 1.44 [95% CI 1.00, 2.10]), or a loop diuretic (HR 2.31 [95% CI 1.36, 3.91]) was associated with incident gout as compared with not using any diuretic, not using a thiazide diuretic, or not using a loop diuretic, respectively. After adjusting for serum urate level, the association between diuretic use and gout was null. Use of antihypertensive medication other than diuretic agents was associated with decreased gout risk (adjusted HR 0.64 [95% CI 0.49, 0.86]) compared to untreated hypertension. The longitudinal change in serum urate levels was 0.72 mg/dl (95% CI 0.57, 0.87) higher in those who began treatment with a diuretic than in those who did not (P < 0.001).

Conclusion

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

Diuretic agents reduce morbidity and mortality related to stroke and congestive heart failure in patients with hypertension (1). This class of antihypertensive medication is recommended as initial therapy for hypertension (1, 2). Notwithstanding their favorable control of blood pressure, these medications may increase the risk of gout. Diuretics, particularly thiazide diuretics, are associated with an increase in serum urate levels (3–6), and hyperuricemia is the leading risk factor for gout (7). The association between thiazide diuretic use and gout was first noted in case series from the medical literature (8, 9). In trials and observational studies, diuretic use was associated with an increased risk of gout (3, 7, 10, 11). However, 1 observational case–control study showed that diuretic use was not associated with gout after adjusting for comorbid conditions (12). Thus, it remains uncertain whether diuretic use is independently associated with the development of gout.

While hypertension is the main indication for diuretic use, it is also an independent risk factor for gout (10). Previous observational studies have not been able to differentiate whether it is diuretic use or the underlying hypertension that causes gout, leading to confounding by indication, a common bias in observational studies of prescription drugs (13). Additionally, reports of the observational studies did not note the type of diuretic used by study participants, and there was no adjustment for time-varying blood pressure or testing of whether serum urate level was on the intermediate pathway between diuretic use and gout (10, 11). Studies of patients with hypertension that include controlling for changes in blood pressure due to antihypertensive treatment may be better suited to quantify the association of diuretic use with gout. Additionally, previous clinical trials have not been designed to study gout as an outcome but rather have focused on the change in serum urate levels (3–5, 14). Furthermore, the studies of diuretics have focused on thiazide diuretics, and few studies have assessed the association of loop diuretics with serum urate levels and the risk of gout (15, 16). To our knowledge, no population-based study has jointly evaluated the association of diuretic use with serum urate level and risk of incident gout.

We quantified the hazard of incident gout by diuretic use, and class of diuretic agent, over 9 years of followup in a longitudinal population-based cohort of middle-aged adults. To limit confounding by indication, the study was restricted to participants with hypertension and included multiple measures of diuretic use. Additionally, we tested whether serum urate level acts as an intermediate on the pathway between diuretic use and incident gout.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Setting and participants.

The Atherosclerosis Risk in Communities (ARIC) study is a prospective population- based cohort study of 15,792 individuals recruited from 4 US communities (Washington County, MD; Forsyth County, NC; Jackson, MS; and suburbs of Minneapolis, MN). The Institutional Review Boards of the participating institutions approved the ARIC study protocol, and study participants provided written informed consent. Participants ages 45–64 years were recruited to the cohort in 1987–1989. This cohort was established to study the natural history of atherosclerosis and consisted of 1 baseline visit (visit 1) between 1987 and 1989 and 3 followup visits (visits 2, 3, and 4) 3 years apart.

This analysis was limited to participants who were Caucasian or African American; few participants reported other races (n = 48). We excluded participants who did not report their gout status at visit 4 (n = 2,356) and those with prevalent gout at cohort entry (n = 310), defined as the self-report of gout onset prior to the baseline visit.

We limited our study sample to those with hypertension at 1 or more visits. At each visit, technicians used a random-zero sphygmomanometer to take 3 blood pressure measurements. An average of the second and third measurements was recorded at the first 3 visits, and an average of the first and second measurements was recorded at the fourth visit. Hypertension was defined as the self-report of medication to treat hypertension or as a measured systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg. Previous work has suggested that restriction is a better method than propensity score to control for confounding by indication when a drug is the best marker of the disease (17); antihypertensive medications are clear markers of hypertension. As such, we excluded those who were free of hypertension during followup (n = 7,289). Therefore, there were 5,789 participants with hypertension included in our study.

Exposure to diuretics.

Trained interviewers collected information on the medications that participants used in the 2 weeks prior to the visit. Participants reported whether they used a medication to treat hypertension. We considered this exposure to be time-varying and defined diuretic use as the report of a diuretic at visit 1, 2, or 3. Diuretic use had to occur prior to the onset of gout to be considered in this analysis. We did not include diuretic use at visit 4 in our analysis because we wanted to ensure that use of this medication occurred prior to gout onset (reported at visit 4). Participants who were missing data on diuretic use at visits 2 or 3 had their previous reported diuretic use information carried forward. Additionally, we considered thiazide and loop diuretics as separate classes of diuretics. In the class-specific analyses we considered thiazide and loop diuretics as monotherapy, and we did not include participants with use of >1 diuretic class, to isolate the effects. However, there were very few participants at each visit who were taking >1 diuretic (<0.5% of participants at each visit).

Incident gout as outcome.

At visit 4, participants were asked “Has a doctor ever told you that you had gout?” Participants who answered “Yes” to the gout query then reported their age at gout diagnosis. The outcome of interest was incident gout based on self-report. Incident gout was defined as the onset of gout after baseline. Our previous research suggests that self-report of a physician diagnosis of gout is a reliable (3-year reliability κ = 0.73) and a sensitive (84% sensitivity) measure of gout (18).

Other measures.

Other covariates of interest that were assessed at baseline (1989) included age (in years), sex (male or female), race (white or African American), alcohol intake (grams/week), diabetes (present or absent), and body mass index (BMI; in kg/m2). Additionally, blood pressure was measured at each visit and thus was considered to be time-varying. Serum creatinine was estimated using a modified kinetic Jaffé reaction. Glomerular filtration rate (GFR) was estimated by using the 4-variable Modification of Diet in Renal Disease study equation adjusted to the ARIC study (19) and categorized as <60 mg/dl, 60–90 mg/dl, or >90 mg/dl. Additionally, the self-report of a history of congestive heart failure (CHF; present or absent) at visit 4 was also considered as a covariate of interest. These variables were considered to be potential confounders, and the categories were chosen to reduce residual confounding.

Serum urate concentrations (in mg/dl) were measured with the uricase method at visits 1 and 2. The reliability coefficient of serum urate level measurement was 0.91, and the coefficient of variation was 7.2% in a sample of 40 individuals with repeated measurements taken at least 1 week apart (20). In the complete ARIC cohort study, the mean serum urate levels were 0.36 mg/dl higher at visit 2 due to laboratory drift compared with visit 1 after adjustment for age at the visit. Therefore, we subtracted 0.36 mg/dl from the visit 2 serum urate levels to make them comparable to visit 1 values to correct for laboratory drift.

Statistical analysis.

First, the mean ± SD as well as the prevalence of the covariates were calculated and compared by diuretic use at visit 1, 2, or 3. The mean of continuous variables in those exposed to a diuretic was compared with the mean of those who were not exposed to a diuretic, by t-test; the prevalence of categorical factors was compared using chi-square tests.

Using a time-dependent Cox proportional hazards model, the hazard ratios (HRs) and 95% confidence intervals (95% CIs) of incident gout by time-varying diuretic use were estimated with age as the time scale. The comparator group was those not using any diuretic. Diuretic use and measured blood pressure were treated as time-varying and updated at each of the ARIC study visits. Results did not change when BMI was considered as time-varying. Therefore, the BMI and the other variables were considered time-fixed at baseline. The HR of incident gout by thiazide diuretics and the HR of incident gout by loop diuretics were estimated separately. For the thiazide and loop diuretic analyses, the comparator groups were those who were not taking a thiazide or loop diuretic agent, respectively. These comparator groups include those treated with other antihypertensive medications or those with untreated hypertension. This comparator group was selected because there is thought to be an increased risk with all classes of diuretics, and there was little power for head-to-head comparisons between diuretics and other antihypertensive medications (exposed sample, n = 557). However, to allow for direct comparison of the risk of gout by any, thiazide, and loop diuretics, we estimated the HR of incident gout using as the comparator group those who were not taking any antihypertensive medication to treat their hypertension (participants with untreated hypertension).

Models were adjusted for confounders of the association of diuretic use and incident gout, including sex, race, baseline BMI, categorical estimated GFR, and time-varying blood pressure. The unadjusted cumulative incidence function was plotted using a Kaplan-Meier approach. Alcohol use and diabetes were not included in the adjusted model because they were not strong confounders in this study. The model with loop diuretics as the exposure was also adjusted for history of CHF. The Cox proportional hazards models did not violate the proportional hazards assumptions, except for the analysis with loop diuretics as the exposure of interest, which did not satisfy the assumption early in the followup period.

Additionally, we examined the association of antihypertensive medications other than diuretics with incident gout; the comparator group consisted of those who were not taking any antihypertensive medication to treat their hypertension (participants with untreated hypertension). Primarily, the other antihypertensive medications were from the angiotensin-converting enzyme (ACE) inhibitor class and included captopril, lisinopril, and enalapril, as well as the beta-blocker class, including atenolol, nadolol, propranolol, and metoprolol.

We assessed whether serum urate levels mediated the association of diuretic use and incident gout. We added visit 2 serum urate level to the adjusted Cox proportional hazards model to test for mediation. Additionally, using a t-test and linear regression, we investigated whether the change in serum urate level between visits 1 and 2 differed by the initiation of a diuretic between visits 1 and 2; the comparison group consisted of those who did not report diuretic use at either visit 1 or visit 2. Finally, we assessed the percentage of participants with incident gout who were taking a diuretic at the visit prior to gout onset, at the visit after gout onset, and at both visits. All analyses were performed using SAS software, version 9.1.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Study population characteristics.

A total of 5,789 ARIC study participants had hypertension and met the study criteria. The study population was 42% male and 31% African American. The mean ± SD age at cohort entry was 55 ± 5.7 years, and the mean ± SD BMI was 29 ± 5.5 kg/m2.

There were 2,169 participants (37%) who were exposed to a diuretic during followup; 1,212 participants were exposed to a thiazide diuretic, 339 were exposed to a loop diuretic, and only 89 switched between loop and thiazide diuretics during followup. The most common diuretic listed by participants was hydrochlorothiazide. The frequency of diuretic use remained the same over the 3 followup visits (27%, 25%, and 26%, respectively). However, there was an increase in the percentage of participants who used an antihypertensive medication over followup (42%, 47%, and 56%, respectively). Reflecting the dynamic nature of antihypertension treatment, 2,252 participants were exposed to a nondiuretic antihypertensive medication during followup, with many participants using >1 class of antihypertensive medication over followup. For example, 1,062 used an ACE inhibitor and 1,430 were exposed to a beta-blocker; 331 were exposed to both these classes over followup.

Table 1 lists the characteristics of ARIC participants by diuretic use during followup. Baseline study population characteristics were similar for participants with any diuretic use and those with no diuretic use (Table 1), as well as for participants with thiazide and loop diuretic use and those with no diuretic use (data not shown). The 9-year cumulative incidence of gout was 3.9% (2.8% in women and 5.3% in men).

Table 1. Baseline gout risk factors by diuretic use at baseline or at followup in the Atherosclerosis Risk in Communities study participants with hypertension (n = 5,789)*
Baseline risk factorNo diuretic use (n = 3,620)Diuretic use (n = 2,169)
  • *

    Except where indicated otherwise, values are the mean ± SD. BMI = body mass index; GFR = glomerular filtration rate.

  • P < 0.001 versus no diuretic use.

  • P < 0.05 versus no diuretic use.

Male, no. (%)1,727 (48)718 (33)
Age, years54.5 ± 5.755.0 ± 5.7
African American, no. (%)955 (26)836 (39)
Blood pressure, mm Hg  
 Systolic128 ± 16.1129 ± 18.2
 Diastolic77 ± 10.478 ± 10.9
BMI, kg/m227.8 ± 4.930.1 ± 6.1
Estimated GFR, no. (%)  
 <60 ml/minute70 (2.0)95 (4.4)
 60–90 ml/minute1,770 (49.3)1,042 (48.5)
 >90 ml/minute1,745 (48.7)1,010 (47.0)
Alcohol intake, gm/week44.6 ± 9532.0 ± 84
Serum urate, mg/dl6.0 ± 1.46.6 ± 1.6
Nine-year cumulative incidence of gout, no. (%)105 (2.9)120 (5.5)

Association of diuretic use and gout.

As seen in Table 1, the cumulative incidence of gout was greater among participants with diuretic use during followup than among those without diuretic use (5.5% versus 2.9%; P < 0.001 by log rank test). Figure 1 presents the Kaplan-Meier cumulative incidence function of gout by any diuretic use, suggesting a higher rate of gout among those who are exposed to a diuretic (P < 0.001 by log rank test). Table 2 lists the unadjusted and adjusted HR of incident gout by diuretic use. The unadjusted HR of incident gout was 1.72 (95% CI 1.32, 2.25) comparing diuretic use to no diuretic use. Use of any diuretic was associated with a 1.48-fold increase (95% CI 1.11, 1.98) in the hazard of incident gout after adjustment for time-varying blood pressure and confounders of the diuretic and gout association. After further adjustment for serum urate level, use of a diuretic compared to no diuretic use was no longer associated with incident gout (HR 0.96 [95% CI 0.71, 1.28]), suggesting that serum urate level may be a key intermediate on the pathway between diuretic use and incident gout. Furthermore, when diuretic use was compared to untreated hypertension, any diuretic use was associated with a 3-fold increase in the risk of gout (adjusted HR 3.35 [95% CI 2.49, 4.51]).

thumbnail image

Figure 1. Cumulative incidence of gout according to any diuretic use in the Atherosclerosis Risk in Communities (ARIC) study. The log rank P value was less than 0.001 for any diuretic use.

Download figure to PowerPoint

Table 2. Hazard ratios of incident gout by time-varying diuretic use in the Atherosclerosis Risk in Communities study participants with hypertension (n = 5,789)*
ModelAny diuretic use (n = 2,169)Thiazide diuretic use (n = 1,212)Loop diuretic use (n = 339)Nondiuretic antihypertensive use (n = 2,252)
  • *

    Values are the hazard ratio (95% confidence interval). See Table 1 for definitions.

  • The analyses of thiazide and loop diuretics are subsets of the analysis for any diuretic use. Therefore, the number of participants using a loop or thiazide diuretic does not sum to the total number of participants using any diuretic. The comparator groups for any diuretic use, thiazide diuretic use, and loop diuretic use are, respectively, no diuretic use, no thiazide diuretic use, and no loop diuretic use.

  • The comparator group includes those who were not treated for hypertension.

  • §

    P < 0.001 versus no diuretic use.

  • P < 0.05 versus no diuretic use.

  • #

    Confounders were sex, race, BMI, categorical estimated GFR, and time-varying blood pressure. Age was the time scale. The analysis of loop diuretics included congestive heart failure as a confounder.

  • **

    To test for mediation by serum urate level, we added the serum urate level at visit 2 to the model that was adjusted for confounders.

Unadjusted1.72 (1.32, 2.25)§1.54 (1.08, 2.21)3.65 (2.26, 5.90)§0.44 (0.30, 0.64)§
Sex- and race-adjusted1.72 (1.31, 2.26)§1.50 (1.05, 2.16)3.99 (2.45, 6.51)§0.46 (0.31, 0.68)
Adjusted for confounders#1.48 (1.11, 1.98)1.44 (1.00, 2.10)2.31 (1.36, 3.91)0.64 (0.49, 0.86)
Mediation by serum urate level**0.96 (0.71, 1.28)0.94 (0.64, 1.38)1.35 (0.78, 2.34)0.64 (0.48, 0.84)

Association of thiazide and loop diuretic use and gout.

Among the participants who took a thiazide diuretic, there were 63 incident gout cases, corresponding to a cumulative incidence of 5%. Among those taking a loop diuretic, there were 23 gout cases and a cumulative incidence of 7%. Table 2 presents the HR of gout by thiazide and loop diuretic use. After adjustment for confounders, thiazide diuretic use was associated with an ∼1.44-fold increase in risk (95% CI 1.00, 2.10) compared to no thiazide diuretic use. Loop diuretic use was associated with a 2.31-fold increase in risk of incident gout (95% CI 1.36, 3.91) compared to no loop diuretic use. When serum urate level was added to the adjusted model, neither thiazide diuretic use (HR 0.94 [95% CI 0.64, 1.38]) nor loop diuretic use (HR 1.35 [95% CI 0.78, 2.34]) remained associated with incident gout compared to no thiazide diuretic use or no loop diuretic use, respectively. Additionally, thiazide diuretic use and loop diuretic use were each associated with an increased risk of gout when compared to untreated hypertension (HR 2.53 [95% CI 1.75, 3.67] and HR 2.09 [95% CI 1.19, 2.83], respectively).

Association of antihypertensive medication use (other than diuretics) and gout.

Among these participants, there were 89 cases of incident gout in those exposed to a nondiuretic antihypertensive agent, corresponding to a cumulative gout incidence of 4%. Table 2 lists the unadjusted and adjusted hazard of incident gout by use of nondiuretic antihypertensive agents. After adjustment for confounders, use of nondiuretic antihypertensive agents was inversely associated with incident gout (HR 0.64 [95% CI 0.49, 0.86]) compared to untreated hypertension, and remained associated even after adjustment for serum urate level (HR 0.64 [95% CI 0.48, 0.84]).

Initiation of diuretics and change in serum urate level.

Three hundred thirty participants newly began treatment with any diuretic between visits 1 and 2, and 3,827 did not. The mean serum urate levels at these visits are listed in Table 3. The change in serum urate level was 0.72 mg/dl (95% CI 0.57, 0.87) higher in those who began taking a diuretic than in those who did not (P < 0.001). Similarly, the increase in serum urate level was greater in those who began taking thiazide (0.65 mg/dl [95% CI 0.45, 0.85]) and loop diuretics (0.96 mg/dl [95% CI 0.44, 1.48]) compared with those who did not (P < 0.001 for both). However, the initiation of a nondiuretic antihypertension medication was associated with a decrease in serum urate levels (−0.21 mg/dl [95% CI −0.32, −0.11]) compared with untreated hypertension at visit 2. Additionally, the mean change in serum urate level between visit 1 and visit 2 was similar, although slightly attenuated, after adjustment for age, sex, race, estimated GFR, previous use of nondiuretic antihypertensive agents, and BMI.

Table 3. Change in serum urate level associated with new diuretic use in the Atherosclerosis Risk in Communities study participants with hypertension (n = 4,157)*
Serum urate levelNo diuretic use (n = 3,827)New diuretic use (n = 330)New thiazide diuretic use (n = 171)New loop diuretic use (n = 43)
  • *

    Except where indicated otherwise, values are the mean ± SD. 95% CI = 95% confidence interval (see Table 1 for other definitions).

  • The analyses of thiazide and loop diuretics are subsets of the analysis for any diuretic use. Therefore, the number of participants using a loop or thiazide diuretic does not sum to the total number of participants using any diuretic.

  • Change represents visit 2 serum urate level minus visit 1 serum urate level. P value tests the hypothesis that the change in serum urate level from visit 1 to visit 2 is different from zero.

  • §

    P < 0.001 for change, difference in change, and adjusted difference in change.

  • Difference represents change in serum urate level for diuretic use minus change in serum urate level for no diuretic use. P value tests the hypothesis that the unadjusted difference in change in serum urate level for those taking a diuretic is different from that for those not taking a diuretic. Adjusted difference in change accounted for age, sex, race, estimated GFR, previous nondiuretic antihypertensive use, and BMI.

Visit 15.95 ± 1.406.23 ± 1.516.34 ± 1.646.41 ± 1.41
Visit 26.09 ± 1.497.08 ± 1.667.10 ± 1.747.87 ± 1.79
Change0.13 ± 0.980.85 ± 1.35§0.78 ± 1.29§1.09 ± 1.68§
Difference in change (95% CI)Referent0.72 (0.57, 0.87)§0.65 (0.45, 0.85)§0.96 (0.44, 1.48)§
Adjusted difference in change (95% CI)Referent0.59 (0.43, 0.74)§0.55 (0.35, 0.75)§0.73 (0.32, 1.14)§

Diuretic use before and after the onset of gout.

Overall, of 225 participants with gout, 86 (38%) were taking a diuretic at the visit prior to the onset of gout. At the visit after gout diagnosis, 105 participants (47%) were taking a diuretic. Additionally, 74 of the 86 participants (86%) who were taking a diuretic prior to the onset of gout were still taking a diuretic at the visit after their gout onset. Finally, only 3 of the participants (3%) with gout switched from a diuretic at the visit prior to gout onset to another antihypertensive medication at the visit after gout onset.

Sensitivity analyses.

The study results did not differ 1) after adjustment for alcohol intake (grams/week) and diabetes, 2) after adjustment for history of thiazide use among those using a loop diuretic, and 3) when visit 1 serum urate levels were substituted for visit 2 serum urate levels. The results did not differ by sex or race in stratified analyses, inasmuch as the sex and race interactions were not statistically significant.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

In a large prospective population-based study of middle-aged adults with hypertension, we found that both thiazide and loop diuretics were independently associated with an increased risk of incident gout. The results suggest that the initiation of a diuretic raises serum urate levels. Other antihypertensive medications were associated with a decreased risk of gout, which may reflect the protective effect of reducing blood pressure in patients with hypertension and the resulting decrease in serum urate level achieved after initiation of these medications. Additionally, findings from this large biracial cohort suggest that elevation of serum urate levels may mediate the association of diuretic use with incident gout in patients with hypertension. Finally, few participants with gout discontinued the use of a diuretic after the onset of gout.

Epidemiologic studies have suggested that a history of diuretic use is associated with gout (7, 10, 11). For example, in a community-based cohort of white adults, the history of any diuretic use was associated with a 2.4-fold increased risk of gout in women and a 3.4-fold increased risk in men after adjustment for hypertension and other gout risk factors (11). The results may be biased away from the null due to confounding by indication, because this cohort was relatively healthy and diuretic use may be a marker of worse health. In contrast, a pharmacoepidemiologic case–control study using records from a single Dutch primary care center showed that the association between being prescribed a diuretic and a diagnosis of gout was null after adjustment for history of hypertension and other confounders (12). Our results may differ from those of the Dutch case–control study because of the control selection used in that study; matching on comorbid conditions rather than adjusting for those conditions will allow for a more accurate comparison in which both the case and the control are likely to be exposed to a diuretic. By restricting our study to participants with hypertension and adjusting for time-varying blood pressure, we were better able to control for confounding by indication. However, our results were similar to those of a community-based cohort study showing that diuretic use was associated with the development of gout in men (HR 1.77 [95% CI 1.42, 2.20]) (10).

In clinical trials, gout was associated with the use of a thiazide diuretic compared with standard care or placebo (3, 4). However, those studies were not designed to assess gout as an outcome. A pharmacoepidemiologic study using New Jersey Medicaid prescription data showed a 1.99 relative risk (95% CI 1.21, 3.26) of initiating an antigout medication for patients taking thiazide agents, but no increased risk with nonthiazide antihypertensive agents (21). That study was missing the more clinically relevant outcome of incident gout and was limited to treated cases of gout defined by a prescription claim for allopurinol, colchicine, or a uricosuric agent. Thiazide and loop diuretics were also associated with recurrent attacks in patients with gout (22). In a case–control study, gout was more strongly related to the use of loop diuretics (15).

The increase of serum urate level due to diuretics has been noted in case studies, clinical trials, and epidemiologic studies and is most often attributed to thiazide diuretics (3–6, 23). For example, the Systolic Hypertension in the Elderly Program randomized trial of community-living adults with hypertension age ≥60 years showed that the 3-year increase in serum urate level was 0.90 mg/dl in those randomized to the thiazide arm compared with the placebo arm (5), a rise in serum urate levels similar to our own findings (9). However, data on loop diuretics and serum urate level are more limited. Pooled analysis of 2 small studies showed no change in serum urate levels after the initiation of a loop diuretic (16). A UK study of 25 participants using a diuretic before the onset of gout showed that 16 (64%) continued the diuretic (24). Those results were consistent with our findings in middle-aged adults with hypertension, with the slight differences perhaps attributable to different practices in the management of gout in the UK.

Hyperuricemia occurs when there is an overproduction or underexcretion of uric acid. Hypertension decreases renal blood flow, which may augment urate reabsorption and thus lead to urate underexcretion (25). Diuretics cause water loss and this leads to volume depletion. In particular, loop diuretics are often prescribed for volume control. Additionally, diuretics are thought to affect ion exchanger proteins at the proximal tubule lumen membrane in the kidney. This would increase both sodium and urate reabsorption and thus increase serum urate levels (25). These mechanisms may be associated with an increase in serum urate level and the development of gout beyond the effects of hypertension. However, blood pressure control may increase serum urate excretion and decrease the risk of gout.

To our knowledge, this is the first study to jointly quantify the association of diuretic use with both serum urate levels and incident gout in participants with hypertension in a prospective, population-based cohort. Additionally, the ARIC study is a well-characterized cohort with very high response rates. This is one of the largest biracial studies of gout, which included both men and women. Restricting our study population to those with hypertension allowed us to better control for confounding by indication than previous studies. Additionally, we used a broad definition of hypertension that included both measured blood pressure and antihypertension treatment. We were able to control for the treatment effects of antihypertensive medications by adjusting for measured blood pressure at each ARIC study visit. Additionally, we controlled for estimated GFR, which has previously been thought to explain the association of diuretic use and gout (26). Two measures of serum urate level allowed us to analyze subjects newly beginning diuretic treatment and to quantify the change in serum urate levels associated with diuretic initiation. Finally, we were able to show that the elevated risk of gout in participants with hypertension was specific to the diuretic class of antihypertensive agents and not associated with the use of other antihypertensive medications.

The main limitation of our study was that gout was self-reported by participants at visit 4. However, previous work has suggested that self-reported gout and age at onset are both sensitive and reliable (18). Participants had to survive until visit 4 and be healthy enough to attend the followup assessment to be included in this study. This might have induced selection bias if those who attended visit 4 were different from the baseline study population with respect to their health status profile (i.e., hypertension, renal function, and obesity status). However, such a bias, with nonparticipation at followup of participants with more comorbidity (those at greater risk of developing gout), would lead to an attenuation of the true association. Additionally, we collected information on diuretic use in the 2 weeks prior to the visit and not detailed information on diuretic use each month after baseline. However, antihypertension medications are often taken for years, and there is moderate persistence with this class of drugs (27). Further, data on whether participants were treated for hypertension through lifestyle interventions were not collected.

We cannot be assured that we have fully controlled for confounding by indication, although we have adjusted for the main confounders and restricted the population to those with hypertension. In particular, there may be confounding by indication due to CHF for the association of loop diuretics and gout. However, there were insufficient data—only 22 patients with gout among those with CHF, of whom only 4 were exposed to a diuretic—to examine the association of diuretic use with incident gout among those participants with CHF.

We could not rule out the possibility that serum urate level is a confounder and not a mediator of this association. However, it is unlikely that physicians would be selectively prescribing a diuretic to those with elevated serum urate levels, as this would be the source of the confounding. Although serum urate level has been found to predict the onset of hypertension (25), a randomized controlled trial would be necessary to determine the directionality of the uric acid and hypertension association. Our analysis was not designed to test whether the urate level was a consequence of changing blood pressure levels. However, among these participants with hypertension, those who began treatment with a diuretic experienced, on average, a greater escalation in serum urate levels than those who did not begin taking a diuretic. We were not able to test whether dose or a specific brand of thiazide or loop diuretic was associated with higher gout risk. We did not assess the association of other classes of antihypertensive agents because diuretics were the most commonly used class. Additionally, the first angiotensin receptor blockers (ARBs), some of which have uricosuric properties, were approved in 1995. As such, we were unable to assess the association of ARBs, such as losartan, with incident gout because we only considered diuretic exposure prior to the last ARIC study visit, which occurred prior to the introduction of these agents (28).

Finally, we are unable to rule out the possibility that the inverse association of other antihypertensive medications is due to the fact that use of an antihypertension medication is also associated with other healthy behaviors beyond what we could adjust for in this analysis. This healthy-user bias often occurs in observational studies of the protective effects of prescription medications (29).

The results from this population-based, longitudinal study support the hypothesis that diuretic use increases serum urate levels and is related to an increase in incidence of gout. Future studies should not only confirm the risk of gout associated with diuretic-induced hyperuricemia but also further elucidate the complicated relationship of hypertension, diuretics, uric acid, and gout. Although diuretic use has proven to be a safe and effective first-line treatment for hypertension, our results contribute to the evidence that its use is associated with an increased risk of gout independent of hypertension and other chronic conditions.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. McAdams DeMarco had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. McAdams DeMarco, Maynard, Coresh.

Acquisition of data. McAdams DeMarco, Coresh.

Analysis and interpretation of data. McAdams DeMarco, Maynard, Baer, Gelber, Young, Alonso, Coresh.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

The authors thank the staff and participants of the ARIC study for their important contributions.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
  • 1
    Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 298197.
  • 2
    Ong HT. The JNC 7 hypertension guidelines. JAMA 2003; 290: 1312.
  • 3
    Staessen J. The determinants and prognostic significance of serum uric acid in elderly patients of the European Working Party on High Blood Pressure in the Elderly trial. Am J Med 1991; 90: 504S.
  • 4
    Langford HG, Blaufox MD, Borhani NO, Curb JD, Molteni A, Schneider KA, et al. Is thiazide-produced uric acid elevation harmful? Analysis of data from the Hypertension Detection and Follow-up Program. Arch Intern Med 1987; 147: 6459.
  • 5
    Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, et al, for the SHEP Cooperative Research Group. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: the Systolic Hypertension in the Elderly Program. Arch Intern Med 1998; 158: 74151.
  • 6
    Berglund G, Andersson O, Widgren B. Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic: a 10-year controlled trial with bendroflumethiazide. Acta Med Scand 1986; 220: 41924.
  • 7
    Lin KC, Lin HY, Chou P. The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. J Rheumatol 2000; 27: 15015.
  • 8
    Macfarlane DG, Dieppe PA. Diuretic-induced gout in elderly women. Br J Rheumatol 1985; 24: 1557.
  • 9
    Scott JT, Higgens CS. Diuretic induced gout: a multifactorial condition. Ann Rheum Dis 1992; 51: 25961.
  • 10
    Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the Health Professionals Follow-up Study. Arch Intern Med 2005; 165: 7428.
  • 11
    Bhole V, de Vera M, Rahman MM, Krishnan E, Choi H. Epidemiology of gout in women: fifty-two–year followup of a prospective cohort. Arthritis Rheum 2010; 62: 106976.
  • 12
    Janssens HJ, van de Lisdonk EH, Janssen M, van den Hoogen HJ, Verbeek AL. Gout, not induced by diuretics? A case-control study from primary care. Ann Rheum Dis 2006; 65: 10803.
  • 13
    Salas M, Hofman A, Stricker BH. Confounding by indication: an example of variation in the use of epidemiologic terminology. Am J Epidemiol 1999; 149: 9813.
  • 14
    Fletcher AE. Adverse treatment effects in the trial of the European Working Party on High Blood Pressure in the Elderly. Am J Med 1991; 90: 424S.
  • 15
    Waller PC, Ramsay LE. Predicting acute gout in diuretic-treated hypertensive patients. J Hum Hypertens 1989; 3: 45761.
  • 16
    Musini VM, Wright JM, Bassett K, Jauca CD. Blood pressure lowering efficacy of loop diuretics for primary hypertension. Cochrane Database Syst Rev 2009:CD003825.
  • 17
    Psaty BM, Siscovick DS. Minimizing bias due to confounding by indication in comparative effectiveness research: the importance of restriction. JAMA 2010; 304: 8978.
  • 18
    McAdams MA, Maynard JW, Baer AN, Kottgen A, Clipp S, Coresh J, et al. Reliability and sensitivity of the self-report of physician-diagnosed gout in the campaign against cancer and heart disease and the atherosclerosis risk in the community cohorts. J Rheumatol 2011; 38: 13541.
  • 19
    Astor BC, Arnett DK, Brown A, Coresh J. Association of kidney function and hemoglobin with left ventricular morphology among African Americans: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis 2004; 43: 83645.
  • 20
    Eckfeldt JH, Chambless LE, Shen YL. Short-term, within-person variability in clinical chemistry test results: experience from the Atherosclerosis Risk in Communities Study. Arch Pathol Lab Med 1994; 118: 496500.
  • 21
    Gurwitz JH, Kalish SC, Bohn RL, Glynn RJ, Monane M, Mogun H, et al. Thiazide diuretics and the initiation of anti-gout therapy. J Clin Epidemiol 1997; 50: 9539.
  • 22
    Hunter DJ, York M, Chaisson CE, Woods R, Niu J, Zhang Y. Recent diuretic use and the risk of recurrent gout attacks: the online case-crossover gout study. J Rheumatol 2006; 33: 13415.
  • 23
    Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, et al. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens 2000; 18: 114954.
  • 24
    Roddy E, Zhang W, Doherty M. Concordance of the management of chronic gout in a UK primary-care population with the EULAR gout recommendations. Ann Rheum Dis 2007; 66: 13115.
  • 25
    Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003; 41: 118390.
  • 26
    Pascual E, Perdiguero M. Gout, diuretics and the kidney. Ann Rheum Dis 2006; 65: 9812.
  • 27
    Bramlage P, Hasford J. Blood pressure reduction, persistence and costs in the evaluation of antihypertensive drug treatment—a review. Cardiovasc Diabetol 2009; 8: 18.
  • 28
    McAdams MA, Governale LA, Swartz L, Hammad TA, Dal Pan GJ. Identifying patterns of adverse event reporting for four members of the angiotensin II receptor blockers class of drugs: revisiting the Weber effect. Pharmacoepidemiol Drug Saf 2008; 17: 8829.
  • 29
    Garbe E, Suissa S. Hormone replacement therapy and acute coronary outcomes: methodological issues between randomized and observational studies. Hum Reprod 2004; 19: 813.