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PRIORITY PRESS - 12th Annual European Congress of Rheumatology (EULAR)

London, UK / May 25-28, 2011

Until recently, treatment of gout involved either enhancement of renal uric acid excretion with a uricosuric, such as probenecid, or inhibition of urate production with the purine-based analogue allopurinol, a xanthine oxidase inhibitor. However, many patients treated with allopurinol are not able to achieve target serum urate levels because they cannot tolerate doses >300 mg or because of the need to reduce the dose in patients with renal insufficiency. Approval of febuxostat, a non-purine selective inhibitor of xanthine oxidase, was based on data from 3 phase III clinical trials in which 80 mg q.d. was shown to be superior to allopurinol (300 mg q.d.) in lowering serum urate levels to <6 mg/dL (<~360 mmol/L).

Diabetic Gout

Diabetes mellitus is one of the disorders commonly associated with gout, but few data have been available about the efficacy and safety of urate-lowering therapy in diabetic gout patients. The results of a study presented at EULAR by Dr. Michael A. Becker, Professor Emeritus of Medicine, Rheumatology Section, University of Chicago Pritzker School of Medicine, Illinois, showed that this patient group achieved serum urate <6 mg/dL (<~360 mmol/L) more often with febuxostat 80 mg than with commonly prescribed doses of allopurinol. The study used data from 312 patients with gout and diabetes identified from the 2269 patients with gout and hyperuricemia (serum urate =8.0 mg/dL [=~480 mmol/L]) enrolled in the CONFIRMS (Confirmation of Febuxostat in Reducing and Maintaining Serum Urate) trial (Becker et al. Arthritis Res Ther 2010;12:R63).

Compared with the nondiabetic patients in CONFIRMS, the diabetic patients were more likely to be older (mean age 58 years) and obese (mean BMI 36). Mean serum urate (9.6 mg/dL [~576 mmol/L]) and the proportion of patients with tophi present at baseline (18%) were similar to the nondiabetic cohort. The mean duration of gout was higher in the diabetic cohort (13 years vs.11 years). Comorbidities in diabetic patients were very prevalent and mostly occurred at significantly higher rates than in the nondiabetic patients: cardiovascular disease (86% vs. 53%), including hypertension (83% vs. 48%), coronary artery disease (22% vs. 6%), arrhythmias (18% vs. 9%) and myocardial infarction (10% vs. 3%), impaired renal function (estimated creatinine clearance [eCLcr] <90 mL/min) (79% vs. 63%), and hyperlipidemia (65% vs. 38%).

Randomized treatments were febuxostat 40 mg or 80 mg q.d. or allopurinol 300/200 mg q.d. (in patients with eCLcr =60/30-59 mL/min) given for 6 months. Either colchicine 0.6 mg q.d. or naproxen 250 mg b.i.d. (with lansoprazole 15 mg q.d.) was given as prophylaxis throughout the study. Patients tolerated therapy with both agents. “It is reassuring that there was no untoward response in these patients, despite their high rates of comorbidities,” Dr. Becker stated.

The overall urate-lowering rates (final visit serum urate <6.0 mg/dL [<~360 mmol/L]) were comparable with the 40 mg and allopurinol groups, although allopurinol was less effective in diabetic patients; and the 80 mg dose was significantly more effective to both (P<0.001) (Figure 1). Similar urate-lowering efficacy was observed in patients with mild and moderate renal impairment, with the 80 mg dose being significantly more effective in those with moderate renal impairment (P<0.05).

“At these doses of allopurinol, febuxostat has a more profound urate-lowering effect,” Dr. Becker told delegates. “One could argue that an increase in the allopurinol dose, which most physicians are reluctant to do, would give as good a response in terms of urate lowering as lower doses of febuxostat, but clinical practice with the use of allopurinol has evolved over 40 years and it is hard to believe that there is going to be much of a change in the use of allopurinol. At 80 mg, there is clear superiority in urate lowering over 300 mg of allopurinol. It is also superior in the sense that there is no recommendation for dose reduction with chronic renal disease, which is a common problem in diabetic patients as well as in the entire range of gout patients,” Dr. Becker added.

Figure 1.

Efficacy Data

The greater efficacy of febuxostat in decreasing serum urate and lowering the rate of acute gouty flares or attacks in patients with hyperuricemia was demonstrated in a meta-analysis carried out by researchers from the Philippine General Hospital, Manila. In a EULAR abstract accepted for publication, investigators reported that in the FAME (Febuxostat Versus Allopurinol for Hyperuricemia and Gout: A Meta-Analysis) study, data were analyzed from 3 randomized controlled trials of febuxostat vs. allopurinol in patients with hyperuricemia and gout (including CONFIRMS). Overall results showed that febuxostat was superior to allopurinol in achieving the primary outcome, serum urate <6.0 mg/dL (<~360 mmol/L) (RR 0.60). The 80 mg dose was associated with a slight increase in the number of gouty flares during the first 8 weeks of treatment compared with allopurinol (RR 1.21), but this difference was not maintained past 8 weeks of treatment. The incidence of adverse effects was slightly lower with the 80 mg dose (RR 0.94). The researchers noted that prophylaxis with colchicine should be given at the start of therapy due to a slightly increased occurrence of gouty flares during the first 2 months of therapy.

Switching Therapy

In gout patients intolerant of, or refractory to allopurinol as treatment for hyperuricemia, switching to febuxostat allows most to reach target serum urate levels, according to researchers from Paris Diderot University and Lariboisière Hospital, Paris, France. In a published abstract presented at EULAR, they described their ongoing prospective, single-centre, open-label study in which febuxostat is initiated at 80 mg q.d. or 80 mg every other day and the dose is progressively increased until either the serum urate target or the maximum approved dose in France (120 mg/day) is reached (in Canada, 80 mg is the approved dose). To date, 15 patients (14 men, 1 woman; mean age, 62 years; mean disease duration, 20 years; mean serum urate level, 8.2 mg/dL [~492 mmol/L]) have been entered into the study. Eleven were intolerant to allopurinol and 4 failed allopurinol given at a mean dose of 550 mg/day. Twelve patients have reached target serum urate levels over a mean follow-up of 4.5 months. Four received 80 mg febuxostat every other day, 7 patients 80 mg/day and 1 patient 120 mg/day. The most common side effects have been acute attacks of gout (7 patients), weight gain (3 patients), elevation of liver enzymes =3 × ULN (3 patients) and pruritus (3 patients). No cutaneous or severe side effect has been recorded.

Comorbidities Increase

While the comorbidity burden of gout and hyperuricemia is known to be substantial and has increased over the past decade, no contemporary data are available.

In the US, Boston University School of Medicine, Massachusetts, researchers have analyzed data from 5707 participants (2797 men and 2910 women) aged =20 years in the NHANES (National Health And Nutrition Examination Survey) 2007-2008 to determine the current prevalence of major comorbidities according to both gout status and hyperuricemia. In a EULAR 2011 published abstract, they reported that among adults with both gout and hyperuricemia, 78% had hypertension, 9% renal impairment, 20% nephrolithiasis, 27% diabetes, 12% myocardial infarction, 12% heart failure, 12% stroke and 56% obesity (BMI =30). These prevalences were substantially higher than those among individuals without gout or hyperuricemia. The latter was also associated with a higher prevalence of comorbidities among individuals without gout.