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 hypertensive patients 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 may mediate the association of diuretic use with incident gout in hypertensive patients. 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
). 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 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 is relatively healthy and diuretic use may be a marker of worse health. In contrast, a pharmacoepidemology case-control study using records from a single Dutch primary care center reported that the association between being prescribed a diuretic and a diagnosis of gout was null after adjusting for history of hypertension and other confounders (12
). Our results may differ from this previous study because of the control selection utilized in this Dutch case-control study: matching on comorbid conditions rather than adjusting for these 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 a community-based cohort reporting 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
). However, these studies were not designed to assess gout as an outcome. A pharmacoepidemiology study using New Jersey Medicaid prescription data, found 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 for nonthiazide antihypertensive agents (21
). This study is 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 an 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 due to diuretics has been noted in case studies, clinical trials, and epidemiology studies and is most often attributed to thiazide diuretics (3
). For example, the Systolic Hypertension in the Elderly Program randomized trial of community-living adults with hypertension aged 60 years or older found 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, a rise in serum urate levels similar to our own findings (5
). Data on loop diuretics and serum urate are, however, more limited. Pooled analysis of 2 small studies found no change in serum urate after the initiation of a loop diuretic (16
). A UK study of the 25 participants using a diuretic before the onset of gout, found that 16 (64%) continued the diuretic (24
). These results were consistent with our findings in hypertensive middle-aged adults with the slight differences perhaps attributable to different practices in the management of gout in the UK.
Hyperuricemia occurs when there is an over-production or under-excretion of uric acid. Hypertension decreases renal blood flow, which may augment urate reabsorption and thus lead to urate under-excretion (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 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 on both serum urate levels and incident gout in hypertensive participants in a prospective, population-based cohort. Additionally, ARIC 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 with gout. 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 medications. 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 eGFR, which has previously been thought to explain the association of diuretic use and gout (26
). Two measures of serum urate allowed for analysis of new initiators of diuretics 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 hypertensive participants 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 of onset is both sensitive and reliable (18
). Participants had to survive until visit 4 and be healthy enough to attend the follow-up assessment to be included in this study. This may induce 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 non-participation at follow-up of the more comorbid participants, those at greater risk to develop gout, would lead to an attenuation of the true association. Additionally, the study 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
). Additionally, the cohort did not collect data on whether participants were treated for hypertension through lifestyle interventions. 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 was insufficient data – only 22 cases of 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 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, as this would be the source of the confounding. Although serum urate 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, in new initiators with hypertension, those who initiated a diuretic experienced, on average, a greater escalation in serum urate levels than those who did not initiate 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 antihypertensives because diuretics were the most commonly used class of antihypertensive. 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 can 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 diuretic use is associated with an increased risk of gout independent of hypertension and other chronic conditions.