Optimising gout treatment: insights from a nurse-led cohort study.

OBJECTIVES: Currently, gout management, particularly urate-lowering therapy (ULT), is often suboptimal. Nurses successfully manage various diseases including gout. As gout prevalence is rising, and rheumatologists and general practitioners face shortages, a new approach is imperative. This real-life prospective cohort study evaluated the effectiveness of nurse-led care employing a treat-to-target strategy for gout management over a 2-year period. METHODS: All consecutively confirmed gout patients were included. The nurse-led clinic provided a structured treatment plan with consultations, patient leaflets, telephone contacts and laboratory monitoring. After a year of nurse-led care, patients transitioned to continued care in general practice. Follow-up data were complete through registries. The primary outcome was achieving target p-urate levels (<0.36 mmol/L) at 2 years after diagnosis. Secondary outcomes included treatment continuation and achievement of target p-urate levels in specific subgroups. The results were compared with patients diagnosed in the same clinic but followed up in 'usual care'. RESULTS: In the nurse-led group (n=114), 83% achieved target p-urate levels and ULT was continued by 98%. This trend persisted across various patient subgroups. Only 44% of patients in usual care achieved target p-urate and with insufficient doses of allopurinol . Nurse-led care involved an average of two visits and three telephone contacts over 336 days. The 2-year mortality rate was 15%. CONCLUSIONS: Nurse-led gout care, employing a targeted approach, was associated with a very high uptake of and adherence to ULT. The encouraging results were not achieved in usual care although a direct comparison might be influenced by selection bias.

The development and evaluation of dose-prediction tools for allopurinol therapy (Easy-Allo tools).

AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.

Estimation of adherence to urate-lowering therapy in people living with gout using Australia's Pharmaceutical Benefits Scheme and patient-reported dosing.

AIMS: The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day). METHODS: Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement. RESULTS: Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%). CONCLUSIONS: Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range.

Consensus Statement Regarding the Efficacy and Safety of Long-Term Low-Dose Colchicine in Gout and Cardiovascular Disease.

Over the last decade, evidence has demonstrated that long-term, low-dose colchicine (0.5 mg daily) is effective for preventing gout flare and cardiovascular (CV) events in a wide range of patients. Given the potentially expanding use of colchicine in CV disease, we here review and update the biologic effects and safety of colchicine based on recent data gathered from bench and pharmacodynamic studies, clinical reports, controlled clinical trials, and meta-analyses, integrated with important studies over the last 50 years, to offer a consensus perspective by experts from multiple specialties familiar with colchicine's long-term use. We conclude that the clinical benefits of colchicine in gout and CV disease achieved at low dose do not sustain serum levels above the upper limit of safety when used in patients without advanced renal or liver disease or when used concomitantly with most medications. Further, data accrued over the last 50 years strongly suggest that the biologic effects of long-term colchicine do not increase the risk of cancer, sepsis, cytopenia, or myotoxicity.

Colchicine in Patients With Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome.

BACKGROUND: Colchicine reduces risk of cardiovascular events in patients post-myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of onset of treatment following an acute coronary syndrome (ACS). OBJECTIVES: This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status. METHODS: The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed. RESULTS: In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59). CONCLUSIONS: The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease [LoDoCo2] ACTRN12614000093684).

Acute oral colchicine caused gastric mucosal injury and disturbance of associated microbiota in mice.

Colchicine (COL), an ancient and well-known drug, has been used in clinical practice for centuries. On the other hand, COL has also attracted extensive concerns for its potent toxic effects, especially gastrointestinal adverse reactions (nausea, vomiting, and diarrhea) before clinical symptoms relief. In this study, we used a rodent model to study the effects of COL on gastric mucosa and associated microbiota. The mice were exposed to various concentrations of COL (0.1, 0.5, and 2.5 mg kg-1 body weight per day) for 7 days, and the results showed that COL treatment caused severe gastric mucosal damage, accompanied by a significant decrease in gastric mucosal proinflammatory cytokines (IL-1ß, IL-6, and TNF-α). The 16S rRNA gene sequencing revealed that COL significantly perturbed the gastric microbiota composition and reduced the gastric microbiota diversity in mice. Also, we identified bacterial biomarkers associated with diarrhea, including phylum Firmicutes, class Bacilli, order Lactobacillales, family Lactobacillaceae, genu Lactobacillus, and genu Blautia, suggesting that COL-triggered adverse reactions are closely related to gastric microbial perturbations. Our findings open new paths for understanding the mechanism of COL-related adverse gastrointestinal reactions, broadening the scientific view on the interaction between drugs and host gastrointestinal microbiota.

Inflammation and Stroke Risk: A New Target for Prevention.

New therapeutic approaches are required for secondary prevention of residual vascular risk after stroke. Diverse sources of evidence support a causal role for inflammation in the pathogenesis of stroke. Randomized controlled trials of anti-inflammatory agents have reported benefit for secondary prevention in patients with coronary disease. We review the data from observational studies supporting a role for inflammation in pathogenesis of stroke, overview randomized controlled trials of anti-inflammatory therapy in cardiac disease and discuss the potential implications for stroke prevention therapy.

Formulation, characterization, optimization, and in-vivo performance of febuxostat self-nano-emulsifying system loaded sublingual films.

Febuxostat (FXS) is a potent antigout drug with poor water solubility and relative high first-pass effect leading to moderate oral bioavailability (<49%). This study aimed to increase FXS solubility and bioavailability by optimizing sublingual fast-dissolving films (SFs) containing a selected FXS self-nano-emulsifying system (s-SNES) previously prepared by our team. The s-SNES was loaded into SFs by solvent casting technique. A full factorial design (32) was applied to study the effects of polymer and plasticizer types on mechanical characteristics and the dissolution profile of FXS from the SFs. Numerical optimization was performed to select the SF having highest desirability according to predetermined characteristics. The optimized SF (O-SF) contained 1 g of s-SNES, polyvinylpyrrolidone K30 (6%w/v), polyethylene glycol 300 (20%w/w of polymer wt.), and Avicel PH101 (0.5%w/v). O-SF showed good permeation of FXS through sheep sublingual tissue. Storage of O-SF for three months showed no significant change in the FXS dissolution profile. In-vivo performance of O-SF in rabbits was compared to that of oral marketed tablets (Staturic® 80 mg). A cross-over design was applied and pharmacokinetic parameters were calculated after ensuring absence of sequence effect. Statistical analysis revealed better performance for O-SF with significantly higher Cmax, AUC0-24, AUC0-∞, apparent t1/2 together with lower tmax, and apparent kel than marketed tablets. Relative bioavailability of O-SF compared to the marketed tablet was found to be 240.6%. This confirms the achievement of the study aims of improving dissolution rate and bioavailability of FXS using a patient-wise convenient formula.

Nephroprotective effects of febuxostat and/or mirtazapine against gentamicin-induced nephrotoxicity through modulation of ERK 1/2, NF-κB and MCP1.

OBJECTIVES: This study was conducted to evaluate the potential nephroprotective effects of febuxostat, mirtazapine, and their combination against gentamicin-induced nephrotoxicity. METHODS: Induction of nephrotoxicity was achieved via gentamicin injection (100 mg/kg, I.P., for 7 days). Two different doses of mirtazapine (15-30 mg/kg), febuxostat (5-10 mg/kg), and their combination were administered daily for 14 days prior to gentamicin injection and then concomitantly with gentamicin for additional 7 days. Nephrotoxicity was evaluated histopathologically and biochemically. Renal caspase-3, extracellular signal-regulated protein kinase 1/2 (ERK1/2), nuclear factor-kappa-ß (NF-κß), and monocyte chemoattractant protein (MCP-1) were assayed. RESULTS: Febuxostat and mirtazapine significantly (p < 0.05) alleviated biochemical and histopathological alterations that were induced by gentamicin and, for the first time, significantly decreased the renal levels of ERK1/2 and MCP-1. Conclusion: Febuxostat and mirtazapine were found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity. EXPERT OPINION: The utility of nonpurine xanthine oxidase inhibitor, such as febuxostat and mirtazapine are offering a new potential opportunity for the future nephroprotective effects therapy: Febuxostat and mirtazapine are found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity.

Comparative efficacy of low-dose versus regular-dose colchicine to prevent flares in gout patients initiated on urate-lowering therapies.

OBJECTIVE: The objective of this study was to compare the prophylactic effect of regular-dose (RD, 1.2 mg/day) vs low-dose (LD, 0.6 mg/day) colchicine on gout flare when initiating urate-lowering therapy. METHODS: In this retrospective cohort study, we included gout patients who were initiated on either allopurinol or febuxostat, in combination with colchicine therapy and followed them up for 3 months. We analysed the rates of gout flare and adverse events according to the dose of colchicine. We performed the inverse probability of treatment weighting (IPTW) and weighted logistic regression analysis to assess the treatment effect. Analysis of gout flares and adverse events was performed on an intention-to-treat (ITT) and per-protocol (PP) basis. RESULTS: Of the total of 419 patients with gout, 177 patients (42.2%) received LD colchicine, whereas 242 patients (57.8%) received RD colchicine. Lower BMI and estimated glomerular filtration rate, and higher incidence of cardiovascular disease were seen in the LD group than in the RD group. In IPTW-adjusted analysis, events of gout flare were not significantly different between the LD and RD groups [ITT: 14.3% vs 11.3%; odds ratio (OR): 1.309, 95% CI: 0.668, 2.566, P = 0.432; PP: 15.3% vs 10.0%; OR: 1.623, 95% CI: 0.765, 3.443, P = 0.207]. However, LD colchicine was associated with a lower rate of adverse events than RD colchicine [ITT: 8.2% vs 17.9%; OR: 0.410, 95% CI: 0.217, 0.777; P < 0.05; PP: 8.4% vs 17.2%; OR: 0.442, 95% CI: 0.223, 0.878; P < 0.05]. CONCLUSION: Our data suggest that LD colchicine can adequately prevent gout flare with fewer adverse events compared with RD colchicine.

Reducing Immunogenicity of Pegloticase With Concomitant Use of Mycophenolate Mofetil in Patients With Refractory Gout: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Pegloticase is used for the treatment of severe gout, but its use is limited by immunogenicity. This study was undertaken to evaluate whether mycophenolate mofetil (MMF) prolongs the efficacy of pegloticase. METHODS: Participants were randomized 3:1 to receive 1,000 mg MMF twice daily or placebo for 14 weeks, starting 2 weeks before receiving pegloticase and continuing while receiving intravenous pegloticase 8 mg biweekly for 12 weeks. Participants then received pegloticase alone from week 12 to week 24. The primary end points were the proportion of patients who sustained a serum urate level of ≤6 mg/dl at 12 weeks and the rate of adverse events (AEs). Secondary end points included 24-week durability of serum urate level ≤6 mg/dl. Fisher's exact test and Wilcoxon's 2-sample test were used for analyses, along with Kaplan-Meier estimates and log rank tests. RESULTS: A total of 32 participants received ≥1 dose of pegloticase. Participants were predominantly men (88%), with a mean age of 55.2 years, mean gout duration of 13.4 years, and mean baseline serum urate level of 9.2 mg/dl. At 12 weeks, a serum urate level of ≤6 mg/dl was achieved in 19 (86%) of 22 participants in the MMF arm compared to 4 (40%) of 10 in the placebo arm (P = 0.01). At week 24, the serum urate level was ≤6 mg/dl in 68% of MMF-treated patients versus 30% of placebo-treated patients (P = 0.06), and rates of AEs were similar between groups, with more infusion reactions occurring in the placebo arm (30% versus 0%). CONCLUSION: Our findings indicate that MMF therapy with pegloticase is well tolerated and shows a clinically meaningful improvement in targeted serum urate level of ≤6 mg/dl at 12 and 24 weeks. This study suggests an innovative approach to pegloticase therapy in gout.

Therapeutic potential of the FPR2/ALX agonist AT-01-KG in the resolution of articular inflammation.

The resolution of inflammation is a dynamic process, characterized by the biosynthesis of pro-resolving mediators, including the lipid Lipoxin A4 (LXA4). LXA4 acts on the N-formyl peptide receptor 2 (FPR2/ALX) to mediate anti-inflammatory and pro-resolving effects. In order to exploit the therapeutic potential of endogenous LXA4 in the context of inflammation we have recently developed synthetic LXA4 mimetics (sLXms) including a dimethyl-imidazole-containing FPR2/ALX agonist designated AT-01-KG. Here, we have investigated the effect of treatment with AT-01-KG in established models of articular inflammation. In a model of gout, mice were injected with MSU crystals and treated with AT-01-KG at the peak of inflammatory response. The treatment decreased the number of neutrophils in the knee exudate, an effect which was accompanied by low levels of myeloperoxidase, CXCL1 and IL-1ß in periarticular tissue. AT-01-KG treatment led to reduced tissue damage and hypernociception. The effects of AT-01-KG on neutrophil accumulation were not observed in MSU treated FPR2/3-/-mice. Importantly, AT-01-KG induced resolution of articular inflammation by increasing neutrophil apoptosis and subsequent efficient efferocytosis. In a model of antigen-induced arthritis, AT-01-KG treatment also attenuated inflammatory responses. These data suggest that AT-01-KG may be a potential new therapy for neutrophilic inflammation of the joints.

Hyperuricemia Inhibition Protects SD Rats Against Fructose-Induced Obesity Hypertension Via Modulation of Inflammation and Renin-Angiotensin System in Adipose Tissue.

OBJECTIVE: The present study was aimed to reveal the relationship between uric acid and fructose-induced obesity hypertension and its mechanisms. METHODS: A rat model with obesity hypertension was induced by a high-fructose diet. In the experiment I, the rats were fed with fructose for 8 wks along with allopurinol or benzbromarone at the beginning. In the experiment II, the rats were fed with fructose for 8 wks firstly. And then, these rats were treated with allopurinol or benzbromarone for additional 6 wks. RESULTS: Fructose-fed rats showed hyperuricemia, abdominal obesity hypertension and an activation in adipose renin-angiotensin system (RAS). Also, fructose-fed rats had higher levels of proinflammatory cytokines and more macrophages infiltrating in adipose tissue. In the experiment I, allopurinol and benzbromarone significantly reduced serum uric acid at 8 wk. Adipose RAS overactivation, adipose inflammatory responses and the development of obesity hypertension were all effectively prevented by hyperuricemia inhibition. In the experiment II, 6-wk treatment with allopurinol and benzbromarone significantly decreased serum uric acid, downregulated adipose RAS, abolished adipose inflammation and improved obesity hypertension. CONCLUSION: In conclusion, urate-lowering therapy protects rats against fructose-induced obesity hypertension. The mechanisms appear to be via downregulated adipose RAS and reduced inflammation in adipose tissue.

Dapagliflozin Added to Verinurad Plus Febuxostat Further Reduces Serum Uric Acid in Hyperuricemia: The QUARTZ Study.

CONTEXT: Combining a sodium-glucose cotransporter 2 inhibitor with a xanthine oxidase inhibitor (XOI) and a urate transporter 1 (URAT1) inhibitor may enhance serum uric acid (sUA) lowering. However, concerns exist regarding high urinary UA (uUA) excretion rates and subsequent crystallization in renal tubules. OBJECTIVE: To assess whether dapagliflozin added to verinurad, a selective URAT1 inhibitor, and febuxostat, an XOI, increases uUA excretion. DESIGN: Randomized, placebo-controlled, 2-way crossover study (NCT03316131). PATIENTS: Adults with asymptomatic hyperuricemia. INTERVENTIONS: Subjects (N = 36) were randomized to oral once-daily 9 mg verinurad plus 80 mg febuxostat plus 10 mg dapagliflozin for 7 days and 7 days of oral once-daily 9 mg verinurad plus 80 mg febuxostat plus placebo with an intervening 7- to 21-day washout period. MAIN OUTCOME MEASURE: Difference in peak uUA excretion between groups from baseline to day 7. Secondary outcomes included changes in sUA levels and 24-h uUA excretion. RESULTS: Both regimens lowered mean peak uUA excretion (least squares mean changes from baseline: -12.9 mg/h [95% confidence interval (CI): -21.0 to -4.7], dapagliflozin; -13.2 mg/h [95% CI -21.3 to -5.0], placebo). sUA concentrations were lower with dapagliflozin (mean treatment difference -62.3 µmol/L [95% CI -82.8 to -41.8]). Dapagliflozin did not impact verinurad pharmacokinetics, its main metabolites, or febuxostat or fasting plasma glucose levels vs verinurad plus febuxostat. There were no clinically relevant changes in safety parameters. CONCLUSIONS: Dapagliflozin further reduced sUA without influencing uUA excretion, suggesting that its combination with verinurad and febuxostat at the doses tested does not adversely affect kidney function. CLINICAL TRIAL REGISTRATION NUMBER: NCT03316131.

Assessment of rasburicase utilization for tumor lysis syndrome management in pediatric and adult patients in the inpatient and outpatient settings.

INTRODUCTION: At Wake Forest Baptist Health, an adult tumor lysis syndrome pocket card was created in order to optimize management of tumor lysis syndrome and outline specific recommendations for the use of rasburicase. Due to the increased use of rasburicase at our institution and its cost, the purpose of this study was to evaluate the utilization of rasburicase for the management of tumor lysis syndrome in pediatric and adult patients in the inpatient and outpatient settings. METHODS: This was an observational, single-center, non-randomized, retrospective chart review conducted between September 2018 and August 2019. The primary objective was to evaluate the utilization of rasburicase and appropriateness for the management of tumor lysis syndrome in pediatric and adult patients based on the Wake Forest Baptist Health tumor lysis syndrome pocket card. The secondary objectives were to assess response to prophylactic and treatment doses of rasburicase and to quantify drug cost versus expense of rasburicase utilization. RESULTS: Overall, 64 patients (57 adults and 7 pediatric patients) were included in the study. Rasburicase use for tumor lysis syndrome indication adhered to the pocket card 64% of the time. Appropriate fluids and/or allopurinol were initiated in only 34% of patients. For monitoring, 80% of patients had all necessary tumor lysis syndrome laboratory values collected after rasburicase administration. All 11 patients (17%) who received rasburicase in the outpatient setting did not have follow-up labs collected. Of the patients who had tumor lysis syndrome laboratory values collected post rasburicase, 39% were appropriately timed to accurately assess efficacy of rasburicase with the median time of laboratory monitoring after rasburicase being 6.5 h. Response was observed with rasburicase 3 mg (92%), 6 mg (100%), and weight-based dosing (100%). The wholesale acquisition cost per patient was $5203 (1101-10,406). The potential cost savings of using the 3 mg dose versus the 6 mg dose for the patients who did not meet tumor lysis syndrome treatment recommendations based on the Wake Forest Baptist Health pocket card was estimated to be $36,419.46. CONCLUSION: There are several opportunities for improvement in tumor lysis syndrome management and rasburicase utilization at our institution. This study will lead to the implementation of formal restrictions for rasburicase use and selection of rasburicase dose. Updating the rasburicase order panel to include appropriate prophylaxis and require input of uric acid level, populating pertinent tumor lysis syndrome laboratory values on the order verification screen for pharmacists to appropriately assess if rasburicase meets the institution restriction criteria, and providing education to providers on the appropriate ordering and timing of labs.

Real-world treatment of gout and asymptomatic hyperuricemia: A cross-sectional study of Japanese health insurance claims data.

OBJECTIVES: To assess gout and asymptomatic hyperuricemia in Japan and review treatment conditions. METHODS: This retrospective cross-sectional study analyzed the prevalence of hyperuricemia and gout, and characteristics and treatment of patients with those conditions, using Japanese health insurance claims and medical check-up data collected from April 2016 through March 2017. RESULTS: Among 2,531,383 persons registered in the database, 1.1% (men 1.9%, women <0.1%) were diagnosed with gout and 2.6% (4.1%, 0.4%) with asymptomatic hyperuricemia. Medical check-ups showed 13.4% (19.6%, 1.0%) of patients with hyperuricemia (serum uric acid [sUA] > 7.0 mg/dL). Urate-lowering therapy (ULT) was prescribed for 80.7% of patients identified with gout and 72.4% identified with asymptomatic hyperuricemia. ULT adherence was satisfactory, but most patients were treated with low-dose ULT. Less than half of patients receiving ULT achieved the sUA target (≤6.0 mg/dL). In gout patients, the incidence of gout flare was 47.8% (0.74 flares/person-year). CONCLUSIONS: Although hyperuricemia prevalence is similar in Japan and worldwide, gout is comparatively rare in Japan. Gout and asymptomatic hyperuricemia are often treated with low-dose ULT, and many patients fail to reach target sUA, suggesting that gout management is suboptimal in Japan. Patients would benefit from stricter focus on a treat-to-target approach for gout management.

Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial.

RATIONALE & OBJECTIVE: Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). STUDY DESIGN: Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. SETTING & PARTICIPANTS: Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. INTERVENTION: Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks. OUTCOMES: The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. RESULTS: 60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks: -38.6% (90% CI, -60.9% to-3.6%), -39.4% (90% CI, -61.8% to-3.8%), and-49.3% (90% CI, -68.2% to-19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated. LIMITATIONS: Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. CONCLUSIONS: Verinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. FUNDING: This study was supported by AstraZeneca. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03118739.

Clinical Effects of Xanthine Oxidase Inhibitors in Hyperuricemic Patients.

This review aims to critically present the available clinical evidence supporting the treatment of chronic hyperuricemia with xanthine oxidase inhibitors. For this reason, the studies published on uric acid (UA)-lowering drugs in the English language from 2000 to August 2019 have been carefully reviewed. The terms "serum uric acid," "xanthine oxidase," "allopurinol," "febuxostat," and "topiroxostat" were incorporated into an electronic search strategy, alone and in combinations, in both MEDLINE (National Library of Medicine, Bethesda, MD) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). Even if new urate-lowering drugs seem of particular efficacy for acute treatment of refractory hyperuricemia, their use is supported by relatively small clinical evidence. On the contrary, large long-term clinical trials have demonstrated that xanthine oxidase inhibitors (XOIs, namely, allopurinol and febuxostat) are effective, safe, and relatively well-tolerated in most of the patients. They have mainly been tested in the elderly, in patients affected by chronic diseases such as heart failure and cancer, and in patients taking a large number of drugs, confirming their safety profile. Recent data also show that they could exert some positive effects on vascular health, renal function, and glucose metabolism. Their cost is also low. In conclusion, XOIs remain the first choice of UA-lowering drug for chronic treatment.