Interactions Between Hyperuricaemia, Gout and Its Common Comorbidities
Hyperuricaemia is common in patients with hypertension. Twenty-five per cent of patients with untreated hypertension, 50% of patients on diuretics and >75% of patients with malignant hypertension have hyperuricaemia. Conversely, among patients with gout, ~40% have hypertension.[2,3] Hyperuricaemia may have a pathogenic role in hypertension, and many medications used in the management of hypertension have effects on serum urate (SU) (Table 1). Loop and thiazide diuretics increase SU, whereas the angiotensin II receptor antagonist losartan and the calcium channel blocker amlodipine reduce SU.[7,8] A nested case–control study of 24 768 people with newly diagnosed gout and 50 000 control subjects examined the risk of incident gout in patients with hypertension. The relative risk of incident gout was 0.87 (95% CI 0.82, 0.93) for calcium channel blockers, 0.81 (95% CI 0.70, 0.94) for losartan, 2.36 (95% CI 2.21, 2.52) for diuretics, 1.48 (95% CI 1.4, 1.57) for β-blockers, 1.24 (95% CI 1.17, 1.32) for ACE inhibitors and 1.29 (95% CI 1.16, 1.43) for non-losartan angiotensin II receptor blockers. Surprisingly, a recent meta-analysis reported that there was a trend toward a higher risk for acute gout in patients on loop and thiazide diuretics, but the magnitude and independence of the association was not consistent. The authors concluded that stopping these drugs in patients who develop gout was not supported. Although there may be no specific literature on the effects of stopping diuretics in those patients who develop gout, their presence may make urate lowering more difficult.
Treatment with the xanthine oxidase (XO) inhibitor allopurinol may contribute to a reduction in blood pressure. In a study of 48 hyperuricaemic patients, treatment with allopurinol 300 mg/day for 3 months resulted in a significant reduction in blood pressure. In another study of 30 adolescents (aged 11–17 years) with essential hypertension, allopurinol 200 mg b.i.d. for 4 weeks resulted in a significant reduction in blood pressure. Similar studies have not been undertaken in patients with gout. Although there are no similar human studies with febuxostat (a newer XO inhibitor), in the clinical studies of febuxostat, changes in blood pressure were not reported. However, a study in rats reported that febuxostat partly reduced blood pressure in rats with oxonic acid-induced hypertension, with no effect on blood pressure in normal rats.
Gout is associated with an increased risk of CVD and death, particularly in those with a high cardiovascular risk.[22–24] Hyperuricaemia is an independent risk factor for CVD. Associations between hyperuricaemia/gout and stroke and peripheral vascular disease have also been reported. Conversely, many of the drugs used to treat CVD can have an impact on SU ( Table 1 ) and contribute to hyperuricaemia and the development of gout.
A number of studies have examined the effects of XO inhibition on cardiovascular outcomes. In a large retrospective, nested case–controlled study of 25 090 patients with congestive heart failure (CHF), a history of gout and a recent acute episode of gout (≤60 days) were associated with an increased risk of re-admission for CHF or death [relative risk (RR) 2.06; 95% CI 1.39, 3.06; P < 0.001]. In the subgroup of patients with gout, allopurinol use was associated with a significant reduction in CHF re-admissions or death (RR 0.69; 95% CI 0.60, 0.79) and reduced all-cause mortality (RR 0.74; 95% CI 0.61, 0.90). In a placebo-controlled trial, the addition of oxypurinol or placebo to standard CHF therapy in 405 patients reported a trend toward improved outcomes in the subgroup of patients with baseline SU ≥ 9.5 mg/dl. Allopurinol, through its ability to reduce myocardial oxygen demand, also appears to be beneficial in patients with ischaemic heart disease.[30,31] These data give weight to the need for urate-lowering therapy (ULT) in patients with gout who are at high risk of CVD. Whether the current target SU of < 0.36 mmol/l is appropriate for preventing cardiovascular events is unknown.
There are well-recognized relationships between renal function, SU and gout. Renal impairment is associated with hyperuricaemia, which also contributes to renal impairment. Renal under-excretion of urate is a common cause of hyperuricaemia, and is the dominant mechanism of hyperuricaemia in the majority of patients with gout. Patients with gout are also much more likely to have renal impairment than those with OA.
There are a number of inter-related variables that can influence both SU and creatinine, including hypertension, diuretic use, body mass index and increasing age (for a review see). However, creatinine has been shown to correlate with SU independent of these variables and is one of the most important determinants of SU.[35–42] Creatinine clearance (CrCL), which adjusts for some of the variability in creatinine due to age, weight and gender, is a better indicator of renal function and correlates inversely with SU.[43–46]
Hyperuricaemia (SU > 0.40 mmol/l) is an independent risk factor for renal impairment in healthy normotensive individuals, is a predictor of renal progression in IgA nephropathy and is associated with early glomerular filtration rate (GFR) loss in patients with type 1 diabetes. Hyperuricaemia has also been associated with an increased incidence of end-stage renal disease and has been shown to be an independent predictor of end-stage renal disease in women. Unlike the situation with chronic kidney disease, acute gout is rarely a complication of acute renal failure.
Effect of Urate Lowering on Renal Function In patients with chronic kidney disease, allopurinol has been shown to slow the progression of renal disease.[51,52] In patients with gout, effective ULT improves renal function. At least part of this effect may be due to reduced NSAID use when gout is adequately controlled. Specific studies on the effects of febuxostat on renal function have not been undertaken. However, a post-hoc analysis of the FOCUS study demonstrated that urate lowering with febuxostat was associated with an improvement in renal function.
There is a complex relationship between blood glucose and SU, as well as between diabetes and gout. Using data from the Third US National Health and Nutrition Examination Survey, SU increased with increasing haemoglobulin A1c (HbA1c) up to 6–6.9% and then decreased with a further increase in HbA1c. The authors suggested that people with pre-diabetes (moderately increased HbA1c) may be at increased risk of hyperuricaemia and gout, whereas those with established diabetes or significantly increased HbA1c may be at lower risk. A subsequent case–controlled nested study from a UK general practice database reported that the RR of incident gout in patients with diabetes was 0.67 (95% CI 0.63, 0.71) compared with patients without diabetes. This inverse relationship was stronger for patients with type 1 diabetes than those with type 2 diabetes and stronger in men compared with women. This lower risk of future gout in patients with diabetes likely relates to the uricosuric effect of glycosuria and the impaired inflammatory responses observed in diabetes.
Despite the aforementioned observations, men with gout and high cardiovascular risk are at risk of developing type 2 diabetes independent of other known risk factors compared with men without gout (RR for incident type 2 diabetes 1.34 (95% CI 1.09, 1.64). Whether optimal management of gout with ULT reduces the risk of future diabetes is unknown.
Rheumatology. 2013;52(1):34-44. © 2013 Oxford University Press