In this large general practice cohort representative of the UK population, we found that use of calcium channel blockers and losartan was associated with a moderately lower risk of incident gout among patients with hypertension. These associations were independent of use of other evaluated antihypertensive drugs and other risk factors for gout such as age, body mass index, smoking, alcohol use, and presence of ischaemic heart disease, hyperlipidaemia, hypertension, and renal failure. These inverse associations were stronger with both a longer duration and a higher dose of use. In contrast, we found that use of diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers was associated with an increased risk of incident gout among patients with hypertension. The magnitude of relative risk was strong with diuretic use and more moderate with the other antihypertensive drugs. These associations were also independent of use of other antihypertensives and other risk factors for gout and tended to become stronger with a longer duration of use and a higher dose. The absolute risk difference was the largest with diuretic use (about six cases per 1000 person years) and more moderate with the other agents (one or two cases per 1000 person years). The current study provides the first large scale evidence for the independent differential effect of antihypertensive drugs for and against the risk for gout.
The inverse association between use of calcium channel blockers and risk of incident gout possibly stems from its action on renal function. An increase in uric acid excretion has been observed with calcium channel blockers.11 12 13
Calcium channel blockers could increase the glomerular filtration rate and consequently the clearance rates of uric acid and creatinine. For example, amlodipine has been found to increase the output of fluid from the proximal tubules, as shown by the significant decrease observed in the fractional proximal reabsorption of sodium and the corresponding increase in the reabsorption of sodium in the distal tubule11
Furthermore, nifedipine, which possesses renal vasodilatory effects,23
has been found to reduce serum uric acid levels compared with a placebo in the A Coronary Disease Trial Investigating Outcome with Nifedipine GITS (ACTION) trial (n=7665).10
Our data indicate that these amlodipine and nifedipine effects on serum uric acid levels can be translated into 21% and 13% decreased risks of gout, respectively, and a similar protective association can be expected from diltiazem as well.
Losartan reduces serum uric acid levels by 20-25% by producing a uricosuric effect in healthy volunteers, patients with hypertension, and transplant recipients.12 13 15 16 24 25 26
The uricosuric effect of losartan has been described to be similar to that observed with classic uricosuric agents such as probenecid.12 13
However, this uricosuric mechanism does not seem to be related to angiotensin II antagonism, as other angiotensin II antagonists do not share the property. For example, other angiotensin II antagonists, including valsartan 80 mg once daily,27 28 29 30
candesartan 8-16 mg daily,31
and eprosartan 600 mg34 35 36
do not increase uricosuria and thus do not decrease serum uric acid levels.8
Similarly, angiotensin converting enzyme inhibitors have not been associated with lower serum uric levels.16
Several experiments, including a Xenopus oocyte model of urate transport injected with URAT1-encoding RNA,37
have indicated that losartan can directly inhibit URAT1 from the apical side of tubular cells through cis-inhibition as with other uricosuric compounds such as probenecid and benzbromarone.3 37 38
These data suggest that URAT1 could be the key action site of losartan, as with other uricosuric agents.
We found that other antihypertensive drugs were associated with an increased risk of incident gout. Diuretics increase the net reabsorption of uric acid in the proximal tubule of the nephron and thereby reduce urinary excretion and increase the risk of hyperuricaemia7 8
The increase in serum uric acid concentration and the risk of gout caused by diuretics may be noted within a few days of the start of treatment.39 40
Although not as impressive as the hyperuricaemic property of diuretics, β blockers, including propranolol, atenolol, metoprolol, timolol, and alprenolol, also have been shown to increase serum uric acid levels.8 9
For example, atenolol 50-100 mg daily for 12 weeks increased uric acid levels by 0.5 mg/dL41
and the addition of propranolol was associated with a 0.3 mg/dL increase of serum uric acid levels.42
The mechanism of these urate raising effects of β blockers remains unknown as the data on the effects of β blockers on renal urate excretion have been unclear. For example, whereas single doses of atenolol, propranolol, and tertatolol did not modify the renal clearance of uric acid or the 24 hour urinary excretion of uric acid in healthy people,42
propranolol was found to reduce the mean renal clearance of uric acid in patients with hypertension.43
Clinical and public health implications
Our findings may have practical implications in the management of hypertension, particularly among those who are at a higher risk of developing gout. Our data suggest that calcium channel blockers or losartan would be preferred to other antihypertensive drugs if prevention of gout is relevant and other determining factors are comparable. Furthermore, from a public health perspective, using these urate lowering antihypertensive drugs could help reduce the high comorbidity burden of gout and hypertension.1
As our findings are based on the reference point of no use of each corresponding antihypertensive drug, the difference in risk of gout between urate lowering agents (for example, losartan) compared with urate raising agents (for example, thiazide) would be even greater, which could in turn lead to noteworthy differences in risk-benefit ratios, particularly in populations at high risk for gout.
Strengths and limitations of the study
This study was carried out using a large UK general practice population; therefore, findings are likely to be applicable to the general population. As antihypertensive drugs are used for other clinical conditions, the overall consistency of the results stratified by hypertension helped to sort out potential drug effects from those of the underlying conditions. Because the definition of gout was based on doctors’ diagnoses, a certain level of misclassification of use is inevitable. A diagnosis of gout could often have been recorded based on the suggestive clinical presentation of gout without documentation of monosodium urate crystals. However, any non-differential misclassification of these diagnoses would have biased the study results toward the null and would not explain the strong associations and dose-response relations observed in this study. Furthermore, when we used doctors’ diagnoses of gout combined with anti-gout drug use (which showed a validity of 90%21 22
) as our case definition, our results remained almost identical. Despite the large size of the study cohort, the number of participants in certain subgroups (for example, use of angiotensin II receptor blockers in the group without hypertension or various combination therapy options) was relatively small, which limited our ability to obtain robust estimates. Replicating these results in the context of a larger prospective cohort would be valuable. Such a larger study context would also be useful for quantifying the effects of switching antihypertensive drugs.
Our findings suggest that calcium channel blockers and losartan may be protective against the risk of gout among people with hypertension. These data are compatible with previous findings that suggested these drugs have urate lowering properties. In contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout. These data may have practical implications for choosing the appropriate antihypertensive drugs in patients with hypertension, a common comorbidity of gout.
What is already known on this topic
- Hypertension is a common comorbidity of gout, affecting up to 74% of patients with gout
- Unlike other antihypertensives, calcium channel blockers and losartan may reduce the risk of gout by lowering urate acid levels
- No study has, however, investigated this potential link
What this study adds
- Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension
- By contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout