Fenofibrate enhances urate reduction in men treated with allopurinol for hyperuricaemia and gout

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1 Rheumatology 2003;42: doi: /rheumatology/keg103, available online at Fenofibrate enhances urate reduction in men treated with allopurinol for hyperuricaemia and gout M. D. Feher, A. L. Hepburn 1,M.B.Hogarth 1,S.G.Balland S. A. Kaye 1 Objective. To assess the short-term urate-lowering effect of fenofibrate in men on long-term allopurinol therapy for hyperuricaemia and gout. Methods. Ten male patients (38 74 yr) with a history of chronic tophaceous or recurrent acute gout with hyperuricaemia and on established allopurinol at mguday for 03 months were studied in an open-crossover study of fenofibrate therapy. Allopurinol at the established dose was continued throughout the study. Clinical and biochemical assessments (serum urate and creatinine, 24-h urinary excretion of urate and creatinine, liver function tests, creatine kinase and fasting serum lipids) were undertaken at: (i) baseline, (ii) after 3 weeks of once-daily therapy with micronized fenofibrate (Lipantil Micro 1 ) at 200 mg and (iii) 3 weeks after fenofibrate was withdrawn. Results. Fenofibrate was associated with a 19% reduction in serum urate after 3 weeks of treatment (mean"s.e. 0.37"0.04 vs 0.30"0.02 mmul; P=0.004). The effect was reversed after a 3-week fenofibrate withdrawal period (0.30"0.02 vs 0.38"0.03 mmul). There was a rise in uric acid clearance with fenofibrate treatment of 36% (7.2"0.9 vs 11.4"1.6 mlumin, normal range 6 11; P=0.006) without a significant change in creatinine clearance. Both total cholesterol and serum triglycerides were also reduced. No patient developed acute gout whilst taking fenofibrate. Conclusions. Fenofibrate has a rapid and reversible urate-lowering effect in patients with hyperuricaemia and gout on established allopurinol prophylaxis. Fenofibrate may be a potential new treatment for hyperuricaemia and the prevention of gout, particularly in patients with coexisting hyperlipidaemia or those resistant to conventional therapy for hyperuricaemia. KEY WORDS: Fenofibrate, Allopurinol, Hyperuricaemia, Gout. Gout is a group of metabolic rheumatic disorders associated with hyperuricaemia and is the most common cause of an inflammatory arthropathy in middle-aged men. Hyperuricaemia is associated with an increased risk of developing gout and this increases with the degree and duration of the hyperuricaemia w1x. Dietary and pharmacological urate-lowering therapies principally aim to prevent clinical joint damage. Allopurinol, an inhibitor of xanthine oxidase, is the most frequently used drug in the treatment of hyperuricaemia and the prevention of gout. This drug is usually well tolerated and lowers serum urate in the order of 20% w2x. However, despite allopurinol-associated urate lowering, recurrent attacks may still occur. Furthermore, hypersensitivity rashes can be problematic, despite attempts at desensitization. Additional urate-lowering therapies may therefore be required. Alternative drugs for preventing gout include the uricosuric agents Lipid Clinic and 1 Department of Rheumatology, Chelsea and Westminster Hospital, London SW10 9NH, UK Submitted 7 December 2001; revised version accepted 9 August Correspondence to: M. D. Feher, Beta Cell Diabetes Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. m.feher@chelwest.nhs.uk 321 ß 2003 British Society for Rheumatology

2 322 M. D. Feher et al. sulphinpyrazone, limited by its side-effect profile, and benzbromarone and probenecid, the availabilities of which are restricted in certain European countries. Fenofibrate is a fibric acid derivative that is well established in the treatment of various forms of hyperlipidaemia w3, 4x. Recent outcome trial data have extended its role in the prevention of the progression of angiographically defined coronary heart disease w5x. Fenofibrate has a marked triglyceride, total and low-density lipoprotein (LDL) cholesterol lowering and high-density lipoprotein (HDL) raising effect and is unique amongst the fibric acid derivatives owing to its ability to lower serum urate. This effect, due to an increase in renal uric acid clearance, has been demonstrated in normal volunteers w6x and in patients with hyperlipidaemia, with w7x or without w8x coexistent type 2 diabetes mellitus. However, no studies have specifically assessed the urate-lowering effect of fenofibrate in patients with hyperuricaemia and gout. The aims of this study were therefore to assess the short-term effects of micronized fenofibrate, a oncedaily formulation of the drug, on serum urate and the incidence of acute arthritis in men with hyperuricaemia and gout who were currently receiving allopurinol therapy. Patients and methods Patients Ten male patients, mean age 57 yr (range 38 74), with a history of recurrent acute or chronic tophaceous gout were recruited from a rheumatology out-patient clinic of a teaching hospital. Demographic data for the study group are presented in Table 1. Each patient had been receiving allopurinol at a dose >300 mg daily for at least 3 months and had been free from acute gout for a minimum of 1 month. Each patient had been experiencing between one and four attacks of acute gout per year, prior to recruitment into the study. No patient had renal impairment (serum creatinine >130 mmul), abnormal baseline liver function tests or raised muscle enzymes. Of the four patients with known hyperlipidaemia, two were receiving another lipid-lowering agent prior to recruitment into the study. In both cases the respective drug was discontinued at least 3 weeks prior to commencing fenofibrate therapy. Full ethical approval was obtained from the local ethics committee. Each patient gave written consent to participate in the study. Study design The study design followed an open-crossover protocol. Clinical and biochemical assessments were performed: (i) before commencement of fenofibrate therapy, (ii) after 3 weeks of once-daily therapy with micronized fenofibrate (Lipantil Micro 1 ) at 200 mg and (iii) 3 weeks after fenofibrate was withdrawn. Serum was analysed for the following using an Olympus AU600 analyser: urate, creatinine, liver function tests (alanine aminotransferase, alkaline phosphatase and bilirubin), creatine kinase and lipid profile (total cholesterol, triglycerides and HDL cholesterol); LDL cholesterol was calculated using the Friedwald equation. Throughout the study the usual daily dose of allopurinol was continued. During the fenofibrate withdrawal phase, allopurinol was maintained at the usual daily dose. Prophylaxis against an acute flare of gout was not routinely given, as this occurrence has not previously been observed with fenofibrate w9, 10x. No dietary or other lifestyle changes were made throughout the study period. Patients were advised to maintain an adequate daily intake of fluids in view of the theoretical risk of nephrolithiasis developing during the treatment period. A 24-h collection of urine for uric acid and creatinine clearance calculations was made from each patient at the same time points as venesection. Patient self-reporting and direct questioning were used at the end of the 6-week study period to assess for any occurrence of an acutely painful joint which had developed, as well as any other new symptom whilst receiving fibrate therapy. Statistical analysis Results are expressed as mean and standard error. Statistical differences were sought using the Wilcoxon signed rank test. Based on the urate-lowering effects of fenofibrate treatment in non-gouty patients w6 8, 11x, nine subjects would be required to achieve 90% power at conventional statistical significance. Hence 10 subjects were recruited. Data were analysed using Prism software (GraphPad, San Diego, CA). TABLE 1. Clinical characteristics of study group Patient Age (yr) Weight (kg) Diagnosis Duration of gout (yr) Allopurinol dose (mguday) Relevant comorbidity CTG Angina RAG RAG Mixed hyperlipidaemia RAG Hypertension Polygenic hypercholesterolaemia RAG RAG Type 2 diabetes Mixed hyperlipidaemia RAG Sarcoidosis RAG CTG Hypertension Mixed hyperlipidaemia RAG CTG, chronic tophaceous gout; RAG, recurrent acute gout.

3 Fenofibrate in hyperuricaemia and gout 323 FIG. 1. Effect of fenofibrate therapy and withdrawal on mean (S.E.) serum urate in men with gout treated with allopurinol. FIG. 3. Effect of fenofibrate therapy and withdrawal on mean (S.E.) total cholesterol and serum triglycerides in men with gout treated with allopurinol. FIG. 2. Effect of fenofibrate therapy and withdrawal on mean (S.E.) renal uric acid clearance in men with gout treated with allopurinol. Results Serum urate and uric acid clearance All patients completed the study. Fenofibrate was associated with a 19% reduction in serum urate wmean (S.E.) baseline 0.37 ("0.04) vs 0.30 ("0.02) mmolul; P=0.004x, which was reversed on fibrate withdrawal w0.30 ("0.02) vs 0.38 ("0.03) mmolulx (Fig. 1). Fenofibrate therapy was also associated with a significant rise in uric acid clearance of 36% w7.2 ("0.9) vs 11.4 ("1.6) mlumin; reference range 6 11; P=0.006x (Fig. 2) without any significant change in creatinine clearance w111.5 ("11.9) vs ("15.1) mlumin; P=0.47x. The largest reductions in serum urate occurred in those patients with the highest levels at baseline (a 39% reduction was seen in the patient with the highest baseline urate level). Serum lipids Both total cholesterol and serum triglycerides were reduced by fenofibrate, but this was not statistically significant in either case w5.9 ("0.3) vs 5.3 ("0.3) mmul and 2.45 ("0.35) vs 1.76 ("0.22) mmolul, respectively; P=0.059 and P=0.064x (Fig. 3). No significant rise in HDL cholesterol was seen in association with fenofibrate therapy, but there was a slight reduction in LDL FIG. 4. Effect of fenofibrate therapy and withdrawal on mean (S.E.) alkaline phosphatase activity in men with gout treated with allopurinol. cholesterol w3.76 ("0.33) vs 3.28 ("0.31) mmolul; P=0.11x. No significant changes in body weight occurred between any of the treatment phases. Other biochemical parameters Alkaline phosphatase activity was reduced in each patient w68 ("4) vs 51 ("3) Uul; P=0.002x (Fig. 4). The fibrate-induced reduction in alkaline phosphatase has been used as a marker of drug compliance. One patient developed an asymptomatic, transient rise in creatine kinase activity during fenofibrate therapy w Uul (reference range 0 200)x, which rapidly returned to normal with drug cessation. No significant rise in serum creatinine was observed w108.0 ("8.5) vs ("6.6) mmolulx after treatment with fenofibrate and no rise in alanine transferase occurred. Adverse effects No patient reported any significant side-effects during therapy with fenofibrate. Importantly, no patients developed a flare of gouty arthritis when micronized fenofibrate was commenced or discontinued. Of three patients who have continued fenofibrate post-study, all have remained free of acute gout over a 6-month follow-up period.

4 324 M. D. Feher et al. Discussion This is the first study to confirm the rapid-onset and reversible urate-lowering effect of fenofibrate in men with hyperuricaemia and gout, who are already receiving allopurinol prophylaxis. The level of reduction in serum urate was similar to that observed in previous studies performed in patients with hyperlipidaemia treated with fenofibrate w6 9x. Bastow et al. w8x compared fenofibrate with bezafibrate in men with hypertriglyceridaemia in a double-blind, placebo-controlled trial over 6 weeks and observed a 20% reduction in serum urate with only the fenofibrate treatment. In another placebo-controlled study, fenofibrate was associated with a 31% reduction in serum urate when given for 12 weeks to patients with type 2 diabetes mellitus and hypercholesterolaemia w7x. In a longer term study in patients with either mixed hyperlipidaemia or hypercholesterolaemia treated with fenofibrate, a 23% reduction in serum urate at 3 months was seen, which was maintained for 2 yr w11x. Both the time scale and the magnitude of this fenofibrate uratelowering effect appear to be comparable with the reduction in urate levels observed with allopurinol, irrespective of coexisting metabolic disorders w12x. This present study has also confirmed that fenofibrate lowers serum urate by increasing renal uric acid clearance. The unique action of fenofibrate compared with other fibrates, on renal uric acid clearance, has been attributed to its unique chemical structure w6x. This mechanism of action had been observed previously in normal volunteers w6x and in patients with hyperlipidaemia w7, 8x. The new finding is the additive urate-lowering effect of fenofibrate when combined with allopurinol. This observation can be explained by the differing mechanisms of urate lowering, with an allopurinolinduced reduction in urate production and an increase in urate excretion due to fenofibrate. Fenofibrate may therefore have a useful role as an additional therapy for lowering serum urate in patients who still experience gout despite treatment with allopurinol. An important new finding in this study was the added benefit of the avoidance of acute gout when fenofibrateinduced changes in serum urate occurred. Rapid reductions in serum urate induced by allopurinol are frequently accompanied by an acute flare of gout. This may be due to rapid changes in the flux of monosodium urate in and out of the joint. Prophylaxis with low-dose colchicine or a non-steroidal anti-inflammatory drug is often necessary. In this study, however, fenofibrate did not precipitate acute gout despite rapid reductions in serum urate of a magnitude similar to that induced by xanthine oxidase inhibition. Furthermore, evidence from short- and long-term follow-up with fenofibrate in treating hyperlipidaemia suggests that this potential adverse effect is not observed clinically w3, 9, 10x. The mechanism of this effect is unclear, although it may be in part due to a potential anti-inflammatory action w14, 15x. There was no evidence of an adverse interaction between allopurinol and fenofibrate in this study, and in those patients who continued to take this combination post-study, problems have not arisen. An interesting observation in this study was that fenofibrate did not lower lipid levels to a significant degree. However, maximal lipid lowering may take several weeks to occur, with the greatest effect occurring with higher lipid levels. Lack of compliance was unlikely to be a factor since alkaline phosphatase activity fell in each patient, which is a well-described fibrate effect and has been used as a marker of compliance w4, 7, 16x. Serum urate is frequently raised in patients with hyperlipidaemia, particularly in those with hypertriglyceridaemia w17, 18x. In contrast, the majority of patients with hyperuricaemia have a hypertriglyceridaemia w18 20x. The mechanisms involved in this association are unclear it may arise through common shared environmental risk factors such as abdominal obesity and excessive alcohol consumption w16 18x. Alternatively, a primary metabolic defect may be present. The insulin resistance syndrome with impaired glucose tolerance and hyperinsulinaemia is frequently accompanied by hyperuricaemia w20, 21x. Acute gout may be one form of presentation of this syndrome. Fenofibrate may offer a useful dual role in this respect, both in the reduction of serum urate and the modification of abnormal lipid profiles. Hyperlipidaemia is both common in the UK and a major risk factor for the development of coronary artery disease. Some studies have suggested that hyperuricaemia may also be an independent risk factor for coronary artery disease w22, 23x. Others, however, have failed to show such an association w24, 25x. A reduction in both serum urate and cholesterol may therefore be useful in terms of reducing cardiovascular risk. Fenofibrate may have a useful therapeutic role in this area, thus avoiding the need for multiple drug therapies. Furthermore, fenofibrate has been shown to lower fibrinogen concentrations w11x, which may provide additional benefits with regards to cardiovascular risk factor modification. Fenofibrate may also have a role in patients with gout who do not respond or are intolerant to allopurinol. Allopurinol in conventional doses reduces serum urate to normal levels in the majority of patients. However, some patients still experience gout despite treatment with even higher doses. Limitations to its use may also be due to the development of rash, with a reported 2% occurrence and a drug-specific hypersensitivity in up to 1 in 1000 patients w26, 27x. Alternative urate-lowering therapy may therefore be necessary. Probenecid was withdrawn from the UK market in Together with the restricted availability of benzbromarone, this has added to the difficulty in treating patients who do not respond to or are intolerant to allopurinol. Fenofibrate may potentially be a useful monotherapy alternative or be used as an additional uricosuric drug in this situation, with the added benefits of cardiovascular risk reduction. Acknowledgements We wish to thank Dr R. Newson (medical statistician) and Dr J. Sedgwick (public health physician) for their

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