Differences in the efficacy and safety of various drugs in different racial groups have been well documented and can be attributed to differing rates of comorbid conditions, concomitant medication use, and underlying genetic variations in the enzymes involved in drug metabolism [27
]. For example, dosing adjustments for warfarin are recommended in African American patients due to decreased metabolism of the drug, which can lead to increased risk for bleeding. Clinical and genetic components that may affect warfarin metabolism in African Americans include age, weight, cerebrovascular disease, and the presence of certain variants of the hepatic isoenzyme cytochrome P450 (CYP) 2C9, the primary metabolizer of warfarin [28
]. Febuxostat is extensively metabolized in the liver by conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes, including UGT1A1, UGT1A3, UGT1A9, and UGT2B7, and, to a much lesser extent, oxidation via CYP1A2, 2C8, 2C9, and non-P450 enzymes [20
]. Different gene variants for UGT1A1, UGT1A9, and CYP2C9 have been identified in African Americans vs Caucasians [29
]. However, based on our results in this limited number of African American subjects, these genetic variants do not appear to affect the metabolism of febuxostat in such a way that would interfere with its efficacy.
The higher rates of gout noted in the African American population [5
] have been attributed to high rates of comorbid conditions associated with increased risk for gout [10
], such as diabetes, hypertension, obesity, and renal disease [8
]. Along with clinical differences that may contribute to increased risk for developing gout, identification of underlying genetic differences in the various enzymes and transporters involved in purine metabolism and urate renal excretion could shed further light on why African Americans are affected with gout at higher rates. For example, a number of renal urate transporters and their genes have been identified. Variants of these genes influence sUA. While some of these genetic variants strongly influence sUA in both Caucasians and African Americans, others are more specifically associated with one race or the other [32
There is a growing body of evidence that both hyperuricemia and gout increase the risk for the development and/or progression of renal dysfunction, cardiovascular disease, hypertension, metabolic syndrome, and diabetes [35
], and all-cause and cardiovascular-related mortality [41
]. In addition, the evidence suggests a disparity between African Americans and Caucasians. In the Atherosclerosis Risk in Communities Study, a prospective epidemiological cohort study, increasing sUA as a continuous variable--after adjusting for age, baseline blood pressure, BMI, renal function, diabetes, and smoking--was shown to significantly increase the risk for the development of hypertension in African Americans, but not for Caucasians, regardless of concomitant medication use [43
]. In another such study, each unit increase in sUA was associated with a higher risk for cardiovascular mortality in African American men and women compared to their Caucasian counterparts [44
Proper management of the underlying hyperuricemia of gout is necessary for the proven reduction in the clinical manifestations of the disease, including gout flares and tophi [14
]. Although not approved for such use, treatment with allopurinol or febuxostat has also been shown to ameliorate renal damage induced by hyperuricemia in rats [48
], and to stabilize or even improve renal function in humans [50
]. A recent study in humans has also demonstrated the cardiovascular-protective impact of lowering sUA levels [35
]. Therefore, proper management of African American gout patients goes beyond the acute treatment of flares, tophi, or kidney stones and incorporates effective reduction and maintenance of sUA to target levels of < 6.0 mg/dL.
While the clinical benefits of reducing sUA long-term likely extend beyond relief from gout, providing optimum management to African American gout patients may be challenging. Data from the National Ambulatory Medical Care Survey reveal that of 3.9 million outpatient visits with a gout diagnosis that occurred in the US during 2002, only 10% were made by African Americans vs 82% by Caucasians [7
]. Caucasians with a gout visit were more likely to have private insurance (46%) compared to African Americans (11%; p < 0.001) and, importantly, African Americans were less likely than Caucasians to receive ULT with allopurinol (odds ratio [OR] 0.18; 95% CI, 0.04-0.78; p
= 0.02) [7
]. In addition, African American patients with gout are more likely to be non-adherent with ULT than Caucasian patients (OR 1.86; 95% CI, 1.52-2.27) [54
]. Interestingly, we observed in this analysis that the African American subjects were 3-times more likely to be lost to follow up than the Caucasian subjects (9.6% vs 3.0%, respectively) and less adherent with therapy (72.4% vs 82.1%, respectively).
There are no published studies specifically examining racial disparities in the diagnosis and management of gout. Therefore possible explanations for low rates of gout diagnosis despite higher risk, lower use of ULT, and lower compliance with therapy among African Americans compared to Caucasians can only be inferred from other chronic diseases. In a 2002 report on ethnic disparities in arthritis and musculoskeletal diseases [55
], Jordan et al. attributed some disparities to ethnic differences in access to care, care-seeking behavior, and utilization of care. According the 2010 National Healthcare Disparities Report [56
], healthcare quality and access continue to be suboptimal for minority and low-income groups. Perceived provider discrimination, which is higher among minorities, can lead to delay in seeking health care [57
]. There are noted racial differences in treatment preferences for rheumatoid arthritis; African American patients attach greater importance to the risks of toxicity and less importance to the likelihood of benefit than their Caucasian counterparts [58
]. Similarly, among patients with at least moderately severe osteoarthritis, African Americans were significantly less likely than Caucasians to perceive the benefit of total joint arthroplasty and more likely to recognize barriers to the procedure [60
]. Based on just the above small sampling of the literature, it is likely that the underlying reasons for racial disparities in gout are multifactorial and require investigation.
ULT with febuxostat 80 mg was significantly better than either febuxostat 40 mg or allopurinol 200/300 mg in the African American cohort of hyperuricemic gout subjects with high rates of comorbidities. This was also observed in the Caucasian cohort and reflects the overall results of the CONFIRMS trial [23
]. Similarly, among both African Americans and Caucasians with mild or moderate renal impairment, febuxostat 80 mg was significantly better at achieving sUA < 6.0 mg/dL compared to either febuxostat 40 mg or allopurinol 200/300 mg.
When the efficacy of each treatment group was compared between African American and Caucasian subjects, the only significant difference observed was in the febuxostat 40 mg treatment group, with lower efficacy observed in African American subjects in the overall cohort (34.9% vs 46.8%; p
= 0.046). One plausible explanation for this observed difference may be the noted difference in compliance with treatment. Within the febuxostat 40 mg group, Caucasian subjects had a considerably higher compliance rate (82.4%) than their African American counterparts (66.3%). This difference was greater than those observed in the other 2 treatment groups. In addition, a large numerical difference was observed in subjects with mild renal impairment (37.8% vs 54.9%) but this did not reach statistical significance (p
= 0.055). The lack of significant difference is likely due to the small number of African American subjects. In addition, no significant differences were observed between African American and Caucasian subjects with mild or with moderate renal impairment in the efficacy of febuxostat 80 mg or allopurinol 200/300 mg. In each treatment group the percentages of African American and Caucasian subjects that required treatment for gout flares were comparable. Flare rates during initial ULT correlate with the extent of sUA decrease [61
], therefore similar rates reflect comparable efficacy between the two groups. Along with comparable efficacy, ULT with either dose of febuxostat or allopurinol 200/300 mg was well-tolerated by both African Americans and Caucasian subjects.
Limitations of this subanalysis include its post-hoc nature and the low number of African Americans enrolled in the CONFIRMS trial compared to Caucasians. Despite the fact that they develop gout at higher rates than Caucasians [5
], in the CONFIRMS trial, along with other ULT RCTs, African Americans comprised ≤ 10% of the study population [21
]. Underrepresentation of African Americans in the febuxostat clinical trials is not unique to the enrollment patterns observed for the majority of Phase 3 clinical intervention trials conducted in the US and reflects the continued hurdles faced by trial investigators in recruiting minority populations [62
]. However, the data reported here represents the first report of ULT efficacy and safety in African American gout patients. Additional studies incorporating greater numbers of minorities are needed to confirm our results.