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Allopurinol is the most commonly used drug in the prevention of gout owing to its efficacy and good tolerability. However, some patients still experience hyperuricaemia or gout, or both, despite allopurinol treatment. Fenofibrate is an established treatment for many common lipid disorders and is unique amongst the fibric acid derivatives because of its ability to lower serum urate by increasing renal uric acid clearance.1 This urate lowering property has been demonstrated in healthy volunteers1 and in diabetic and non-diabetic patients with hyperlipidaemia.2-4
To date, no studies have specifically evaluated the urate lowering effect of fenofibrate in patients with hyperuricaemia receiving established treatment with allopurinol. We report three cases in which micronised fenofibrate, a single dose formulation of the drug, was initiated in patients with established gout and hyperuricaemia, with and without coexisting hyperlipidaemia. Two of these patients were already receiving established allopurinol treatment.
A 74 year old Chinese man had recurrent attacks of gout affecting the metatarsophalangeal joints every two to three months for the preceding three years. He had treated hypertension and polygenic hypercholesterolaemia and had been taking allopurinol 300 mg daily for three months, which produced a serum urate range between 0.40 and 0.44 mmol/l. The 24 hour renal uric acid clearance was 6.4 ml/min (reference range 6–11). Treatment was started with micronised fenofibrate 200 mg daily, and three weeks later his urate had fallen by 35% to 0.26 mmol/l, with the 24 hour uric acid clearance rising to 11.5 ml/min (table 1). Alkaline phosphatase activity fell from 77 to 44 U/l, confirming compliance with the fibrate treatment. A temporary withdrawal of fenofibrate treatment for three weeks resulted in an increase in urate to 0.39 mmol/l. Fenofibrate was restarted and he continues to take it in combination with allopurinol. No acute attacks of gout have occurred since fenofibrate was started.
A 49 year old white man had recurrent episodes of gout affecting the metatarsophalangeal and knee joints despite having had allopurinol increased from 300 to 600 mg daily six months previously. These episodes occurred every two to three months and usually responded to a short course of indometacin. He was clinically obese but did not drink alcohol and was complying with a low purine diet. His serum urate was 0.58 mmol/l, and when determined three weeks later it measured 0.61 mmol/l with a corresponding 24 hour uric acid clearance of 8.0 ml/min. Micronised fenofibrate 200 mg daily was added to the allopurinol treatment and three weeks later the serum urate had been reduced by 39% to 0.37 mmol/l, with an associated doubling in uric acid clearance (table 1). Additionally, serum lipids were reduced, together with a reduction in alkaline phosphatase activity. Fenofibrate was temporarily discontinued and the serum urate returned to a higher level. It has been restarted and no further attacks of gout have occurred in 12 months of follow up.
A 43 year old white man was referred with recurrent episodes of acute gout affecting the ankle and toe interphalangeal joints every four to six weeks. There was no other medical history of note, but there was a family history of gout. During his most recent attack of gout, the serum urate was 0.35 mmol/l. When repeated after one month the urate was 0.48 mmol/l with a total cholesterol of 8.2 mmol/l and triglycerides 2.4 mmol/l. Treatment with micronised fenofibrate was started, and three weeks later his urate was 0.34 mmol/l (a 29% reduction). Both cholesterol and triglyceride concentrations were also reduced to 7.3 mmol/l and 1.5 mmol/l respectively, and the uric acid clearance rose from 5.8 to 11.2 ml/min. Alkaline phosphatase activity fell from 82 to 72 U/l. He continues to receive micronised fenofibrate 200 mg daily, and further attacks of acute gout have not recurred over a six month follow up period.
We have reported three cases of hyperuricaemia in association with recurrent episodes of gout, in which micronised fenofibrate was effective in further lowering serum urate and in reducing the frequency of gouty attacks. Importantly, two of these patients were already being treated with allopurinol. The urate effect has been previously shown in patients with hyperlipidaemia treated with fenofibrate,2-4 but this report demonstrates its efficacy specifically in patients with hyperuricaemia and gout. The reductions in urate shown in these three patients treated with fenofibrate were of similar magnitude to those seen in patients given the drug who had hyperlipidaemia with or without type 2 diabetes and who were not receiving allopurinol treatment.2-4 The doubling in uric acid clearance, which was reversed in two of the patients when fenofibrate was withdrawn, indicates a drug-specific renal effect. The particularly large reduction in serum urate in the second patient was perhaps a little surprising, but we are certain that this was largely a fenofibrate effect because a rise in uric acid clearance was seen, together with reductions in alkaline phosphatase activity and serum lipids. Furthermore, he denied any significant lifestyle changes during this period.
Importantly, none of these patients has had any adverse effect, in particular a flare of gout, while taking fenofibrate. Only the second patient wished to take a prophylactic drug against this. Each was advised to increase their fluid intake at the time, though uric acid urolithiasis has not been reported previously with fenofibrate. There has been no evidence of an adverse interaction between allopurinol and fenofibrate in the first two patients, who both continue to take this combination. Although unlikely, potential adverse reactions and interactions should be borne in mind when fenofibrate is prescribed for patients with hyperuricaemia, and measures taken to prevent them considered.
Serum urate is often raised in hyperlipidaemic patients, particularly those with hypertriglyceridaemia.5 ,6 The mechanism for the relationship is not clearly defined, though the association may arise through common environmental and genetic risk factors shared by hyperuricaemia and hypertriglyceridaemia, such as obesity and excessive alcohol consumption, or through a primary metabolic defect.5 In contrast, hypertriglyceridaemia has been reported to occur in up to 60% of patients with gout.7 ,8
Hyperlipidaemia is common in the UK population and is a major risk factor for cardiovascular disease. The relationship between ischaemic heart disease and serum urate is controversial. It has recently been shown that hyperuricaemia may be an independent risk factor for ischaemic heart disease,9 though other studies have not supported this observation.10 A reduction in both hyperlipidaemia and serum urate might therefore be desirable in order to reduce cardiovascular risk. Fenofibrate may offer a useful dual effect in this respect, so potentially reducing the need for multiple drug treatments. This specific role for the drug is an important area in need of further study.
We have confirmed in our three cases that fenofibrate effectively lowers serum urate by a uricosuric effect. Expected reductions in lipids were also seen, suggesting a specific clinical role of this drug in the treatment of the common metabolic abnormality of coexisting hyperuricaemia and hyperlipidaemia. Further, it may be considered in combination with allopurinol in patients with hyperuricaemia who still experience gout despite a lowering in their serum urate. We would encourage further studies to be performed to evaluate the role of fenofibrate alone or in combination with allopurinol in the treatment of gout and hyperuricaemia. Gout remains a common problem in the community—fenofibrate appears to be a long awaited agent with great potential for use in this condition.
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