Antihypertensives in people with gout or asymptomatic hyperuricaemia

In the linked case-control study (doi:10.1136/bmj.d8190), Choi and colleagues assess the association between antihypertensive drugs and the development of incident gout, stratified by the presence of hypertension.1

The link between uric acid and arterial hypertension was first noted in the 1960s, when prospective studies reported that 26% of untreated hypertensive patients with normal renal function had raised serum uric acid concentrations. This figure rose to 58% for those receiving antihypertensive drugs, and it was particularly high in those taking diuretics (70%).2 Since then, raised uric acid concentrations in people with normotensive, borderline, and established hypertension have been shown to be associated with decreased renal blood flow, without affecting glomerular filtration rate, and with increased renal and peripheral resistances. This suggests that unexplained hyperuricaemia in patients with essential hypertension probably reflects early renal vascular involvement, specifically, nephrosclerosis.3 On the other hand, hypertension is one of the most common comorbidities of gout and hypertension is independently associated with incident gout.4

Interest in the role of uric acid in cardiorenal disease has recently been reignited. Epidemiological studies consistently find that uric acid concentrations predict the development of chronic kidney disease,5 and a recent meta-analysis reported that uric acid predicts the development of hypertension,6 diabetes,7 and stroke.8 The association between coronary artery disease and uric acid remains controversial.

Choi and colleagues conducted a case-control study nested within a UK general practice database by identifying all incident cases of gout (n=24 768) and randomly sampling 50 000 controls who were 20-79 years old between 2000 and 2007.1 They found that the use of calcium channel blockers and losartan in patients with hypertension was associated with a significantly reduced risk of incident gout (relative risk 0.87, 95% confidence interval 0.82 to 0.93; 0.81, 0.70 to 0.94, respectively); this is compatible with their effect of reducing urate concentrations through increased uricosuria. In contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin receptor blockers were associated with a significantly increased risk of gout. Interestingly, similar results were found in people with normal blood pressure.

The authors suggest that urate lowering antihypertensive drugs could help to reduce the high comorbidity burden of gout and hypertension in patients at high risk of developing gout.4 This potential effect is supported by the LIFE (Losartan Intervention For Endpoint reduction in hypertension) trial, which found that a losartan based regimen reduced cardiovascular morbidity and mortality more effectively than an atenolol based one.9 Subsequent analysis of the trial showed that the greater reduction in serum uric acid concentrations obtained with losartan than with atenolol explained 29% of the treatment effect on the primary composite end point of fatal and non-fatal myocardial infarction and stroke.10 Similarly, the decrease in uric acid seen with losartan in the RENAAL study correlated with the extent of the long term reduction in risk of renal damage compared with placebo, which partly explains the renoprotective effects of losartan.11 Furthermore, a recent study found that allopurinol may have a protective renal and cardiovascular effect in people with hyperuricaemia.12 Further studies are needed on the protective effects of allopurinol and on the effects of a reduction in uric acid on cardiovascular and renal damage.

In summary, hypertension and hyperuricaemia commonly coexist. Antihypertensive drugs can increase or decrease the development of incident gout in patients with hypertension, with losartan and calcium channel blockers having the greatest lowering effect on blood pressure because of their uricosuric properties. As well as reducing incident gout, a decrease in the concentration of serum uric acid could also improve the cardiovascular and renal prognosis of patients with hypertension.