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Antihypertensive therapy and incident gout

Choi HK, Soriano LC, Zhang Y, Rodriguez LA. Antihypertensive drugs and risk of incident gout among patients with : population based case–control study. BMJ 344, d8190 (2012). A nested case–control study aimed at determining the independent associations of antihypertensive drugs with the risk of incident gout among individuals with hypertension. Calcium channel blockers and were associated with lower risk of incident gout among individuals with hypertension. By contrast, , b-blockers, angiotensin-converting enzyme inhibitors and nonlosartan angiotensin II receptor blockers were associated with an increased risk of gout. In addition, both duration of treatment and dose influenced the magnitude of the response to both calcium channel blockers and losartan.

KEYWORDS: b-blockers n calcium channel blockers n diuretics n gouty Raquel Cuchacovich n hypertension n n losartan & Luis R Espinoza* LSU Health Sciences Center, Gout is an acquired autoinflammatory disor- directly addressed the relationship between Department of Medicine, Section, 1542 Tulane der characterized by severe various antihypertensive agents and the risk of Avenue, New Orleans, LA 70112-2822, and deposition of monosodium urate crystals gout [9,10]. USA *Author for correspondence: in the . Hypertension (HTN), , In the January 2012 issue of the BMJ, [email protected] chronic renal failure, , , Choi et al. [11] studied the association of mul- hypercholesterolemia, and tiple use and risk of new- are common comorbid- onset gout in a large population of hyperten- associated conditions [1–5]. sive patients in the UK. From January 2000 Normotensive individuals with baseline to December 2007, 24,768 people with newly hyperuricemia (HU) have an 80% excess risk for diagnosed gout and 50,000 matched in age, developing HTN compared with those who do sex and calendar year controls from the health not have HU. Approximately 25–40% of adult improvement database (UK general practice patients with untreated HTN might develop database) were followed for an average of HU (>6.0 mg/dl). Multiple population-based 5.2 years. The study population was followed human studies have established a strong asso- up until one of the following end points was ciation between increasing levels of serum urate met: detection of gout, 90th birthday, death or and subsequent development of HTN by deter- end of study period. Gout cases were diagnosed mining whether lowering serum urate improves by the general practitioner (first diagnosis or HTN [6,7]. Feig et al. showed that in children the first antigout treatment, whichever came with newly diagnosed HTN, serum was first). The impact of the antihypertensive drugs highly correlated with both systolic and diastolic was evaluated by class: diuretics, b-blockers, blood pressure. Elevated uric acid level (>5.5 mg calcium channel blockers, angiotensin-convert- per deciliter [330 µmol/l]) was observed in ing enzyme inhibitors, nonlosartan angioten- nearly 90% of adolescents with essential HTN, sin II receptor blockers and losartan. Losartan whereas uric acid levels were significantly lower was analyzed by itself owing to its well-known in controls and teenagers with either white-coat effect. These medications were clas- or secondary HTN [8]. sified as current use (prescription lasted until On the other hand, many drugs can to index date or ended in the 30 days before that HU and gout , such as low-dose date), recent use (prescription ended between , cyclosporine, , b-blockers 31 and 365 days before the index date) and past and diuretics among others. In addition, cer- use (ended more than 365 days earlier). In addi- tain angiotensin II receptors antagonists, such tion, personal data, risk factors such as as losartan, have also been shown to increase use, smoking, BMI, and , such as renal uric acid clearance and therefore lower ischemic heart disease, HTN, hyperlipidemia, uric acid levels. However, to date no study has renal failure and , were included.

10.2217/IJR.12.27 © 2012 Future Medicine Ltd Int. J. Clin. Rheumatol. (2012) 7(3), 1–xxx ISSN 1758-4272 1 Priority Paper Evaluation Cuchacovich & Espinoza Antihypertensive therapy & incident gout Priority Paper Evaluation

A total of 24,768 incidental gout cases were incident gout among HTN patients, being the found, which were associated with an increased highest for diuretics (six per 1000 person-years) number of visits to the general practitioner, as compared with the other agents (one to two alcohol use, adiposity, ischemic heart disease, per 1000 person-years). hyperlipidemia and renal failure. Almost 52% A recent study by McAdams DeMarco of the gout patients had the diagnosis of HTN et al. has corroborated some of the previously before the diagnosis of gout; after adjust- described findings [12]. The objective of their ing for age, sex, calendar year and visits to a study was to quantify the role of use general practitioner, the relative risk of gout in gout development in an adult population among those with HTN was 1.99 compared with HTN. Participants, who were free of with those without HTN. After adjusting for gout at baseline, included in The ARIC study, several covariates (gender, age, BMI, visits to a prospective population-based cohort from the general practitioner, alcohol consumption, four US communities were included in the pertinent drugs, associated comorbidities) the ana­lysis. Trained interviewers recorded use of multivariate relative risk of incident gout asso- antihypertensive drugs, and incident gout was ciated with antihypertensive drugs use was 0.87 defined as self-reported onset of gout after base- for calcium channel blockers, 0.81 for losartan, line. There were 5789 participants with HTN; 2.36 for diuretics, 1.48 for b-blockers, 1.24 for 37% were treated with a diuretic. Use of any angiotensin-converting enzyme inhibitors and diuretic (hazard ratio [HR]: 1.48 [95% CI: 1.29 for nonlosartan angiotensin II receptor 1.11–1.98]), a diuretic (HR: 1.44 blockers. The multivariate relative risk for [95% CI: 1.00–2.10]) or a (HR: antihypertensive duration treatment for cal- 2.31 [95% CI: 1.36–3.91]) was associated with cium channel blockers in the HTN group was incident gout compared with no diuretic, no 1.02 (<1 year), 0.88 (1–1.9 years), 0.75 (2 or thiazide diuretic or no loop diuretic, respec- more years), and for losartan was 0.98, 0.87 tively. After adjusting for serum urate level, and 0.71, respectively (p < 0.05) for trend of the association between diuretic use and gout treatment duration, except for b-blockers and was null. Use of antihypertensive medica- nonlosartan angiotensin II receptor blockers. tion other than diuretic agents was associated In addition, these associations tended to be with decreased gout risk (adjusted HR: 0.64 stronger with higher rather than medium or [95% CI: 0.49–0.86]) compared with untreated low doses, except for angiotensin-converting HTN. The longitudinal change in serum urate enzyme inhibitors. The inverse association levels was 0.72 mg/dl (95% CI: 0.57–0.87) tended to be stronger with high-dose losar- higher in those who began treatment with a tan than with medium- or low-dose use. By diuretic than in those who did not (p < 0.001). contrast, current use of diuretics, b-blockers, The authors concluded that thiazide and loop angiotensin-converting enzyme inhibitors and diuretics were associated with increased gout non-losartan angiotensin II receptor blockers in risk, an association mediated by a change in the hypertensive population were all associated serum urate levels. with increased risk of developing gout. In the Notwithstanding the differences between combination therapy including diuretics, the studies, both reached a similar conclusion in multivariate relative risk for incidence of gout regard to use of diuretics and gout, their use compared with no use of antihypertensive med- is associated with increased gout risk. There ication were larger with angiotensin-converting are important clinical implications from the enzyme inhibitors and with b-blockers than reported findings, and as suggested by Choi with calcium channel blockers. In this study et al. calcium channel blockers or losartan calcium channel blockers and losartan use was should be the drugs of choice in the hyperten- associated with a moderately lower risk of new- sive population at higher risk of developing gout onset gout among hypertensive patients; these and its comorbidities. In addition, these drugs associations were independent of the classic risk should also be highly considered in people with factors for gout. This is the first time that an HU and at risk of developing HTN, chronic inverse association between longer treatment renal disease, Type 2 diabetes mellitus and duration and a higher dose were found to be those with increased cardiovascular risk [13]. protective against gout. Diuretics, b-blockers, Another issue that deserves further study angiotensin-converting enzyme inhibitors and and discussion is whether diuretic agents non-losartan angiotensin II receptor block- should be used in patients with gouty arthritis. ers were associated with an increased risk of Hueskes et al. recently reviewed the literature

2 Int. J. Clin. Rheumatol. (2012) 7(3) future science group Priority Paper Evaluation Cuchacovich & Espinoza Antihypertensive therapy & incident gout Priority Paper Evaluation

investigating the relationship between use of et al. clearly established a link between the use diuretics and the risk of gouty arthritis. Three of certain antihypertensive agents and risk of cohort studies and four case–control studies incident gout in patients with HTN [12]. The found higher risks of gouty arthritis in users findings may have important clinical and public compared with nonusers of diuretics. They health implications for choosing the appropriate showed that there was a trend towards a higher antihypertensive therapy in patients with HTN. risk for acute gouty arthritis attacks in patients on loop and thiazide diuretics, but the magni- Future perspective tude and independence was not consistent. The Data presented clearly establishes a link between authors concluded that, based on their findings, the use of certain antihypertensive drugs and an discontinuing these useful drugs in patients increased risk of gout. In addition, the protec- who develop gouty arthritis is not supported tive role of calcium channel blockers and losar- by the results of their review [14]. tan against the risk of developing gout among Losartan also deserves further attention. An individuals with HTN is also clearly confirmed. angiotensin II receptor antagonist with urico- A number of questions remain to be clarified, suric properties, and its principal metabolite including whether results obtained could be E-3174 inhibit the urate anion exchanger extrapolated to other ethnic groups, other clini- URAT1 and diminish urate reabsorption in cal disorders in which antihypertensive drugs the brush border of the proximal tubules, and are used and also the elucidation of the effects of as a result the urate excretion fraction increases switching antihypertensive drugs. Other future by 13–30%. This effect is not associated with studies may be directed at defining the role of an increase in incidence of uric acid stones and combination therapy, such as losartan and cal- is also not observed with other drugs in this cium channel blockers, in reducing the overall class [15,16]. In addition, in the LIFE study, burden of comorbidities associated with gout Hoieggen et al. clearly demonstrated that uric and HTN. acid is an independent cardiovascular risk fac- tor [17]. As shown by Choi et al. combination Financial & competing interests disclosure therapy, duration of therapy and dose admin- The authors have no relevant affiliations or financial istered are all associated with a lower risk of involvement with any organization or entity with a finan- incident gout among people with HTN [11]. cial interest in or financial conflict with the subject matter With this in mind, other agents, such as statins or materials discussed in the manuscript. This includes and alone or in combination, with employment, consultancies, honoraria, stock ownership or known urate-lowering capacity should also be options, expert testimony, grants or patents received or pend- investigated [18–20]. ing, or royalties. In summary, the findings of Choi et al. and No writing assistance was utilized in the production of corroborated by those of McAdams DeMarco this manuscript.

Executive summary Findings from the study ƒƒ Losartan and calcium channel blockers may protect against the risk of gout in patients with hypertension. ƒƒ Both losartan and calcium channel blockers have urate-lowering effects. ƒƒ Diuretics, b-blockers, angiotensin-converting enzyme inhibitors and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout. Impact on the use of antihypertensive drugs in patients with gout ƒƒ Use of losartan and calcium channel blockers alone or in combination may be associated with a decrease in the burden of comorbidities associated with gout and hypertension. Conclusion ƒƒ The use of certain antihypertensive drugs may be associated with a decreased risk of developing gout. ƒƒ Use of combination therapy, including losartan, statins and calcium channel blockers, may also reduce serum urate level and confer a protective effect against the risk of gout and associated comorbidities. Future perspective ƒƒ The effects of switching antihypertensive drugs in patients with gout needs further investigation. ƒƒ The urate-lowering effect of losartan, calcium channel blockers and others need to be investigated in normal people with hyperuricemia and other clinical disorders.

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