Reduced Serum Uric Acid Levels Research Articles

Empagliflozin and uric acid metabolism in diabetes: A post hoc analysis of the EMPA-REG OUTCOME trial.

AimTo evaluate the effect of empagliflozin on uric acid (UA) levels, antigout medication and gout episodes in the EMPA‐REG OUTCOME trial (NCT01131676).Materials and methodsA total of 7020 patients with type 2 diabetes (T2D) were randomized to either empagliflozin (10 or 25 mg) or placebo. The effects of empagliflozin versus placebo on UA concentration were assessed using mixed linear models. A composite outcome of new prescription of antigout medication or gout episode was studied with Cox proportional hazards models.ResultsEmpagliflozin reduced serum UA levels versus placebo: week 52 adjusted mean treatment difference = −0.37 (95% confidence interval [CI] −0.42, −0.31) mg/dL; this was more pronounced in patients with baseline UA ≥ 7.0 mg/dL versus <7.0 mg/dL: week 52 adjusted mean treatment difference = −0.56 (95% CI −0.68, −0.43) and −0.30 (95% CI −0.37, −0.24) mg/dL, respectively. Among 6607 patients not taking antigout medications at baseline, 5.2% had a gout episode or initiated antigout treatment versus 3.6% in the placebo and empagliflozin groups, respectively: hazard ratio 0.67 (95% CI 0.53, 0.85; P = 0.001). Both components of the composite outcome contributed to the reduction with empagliflozin in the composite. Risk reduction was similar with both empagliflozin doses.ConclusionsEmpagliflozin reduced UA levels and the composite of gout episodes or prescription of antigout medication. These clinically important findings expand the utility of empagliflozin as a potential antigout treatment in patients with T2D, beyond its well‐established cardio‐renal benefits.

Eggshell Membrane Ameliorates Hyperuricemia by Increasing Urate Excretion in Potassium Oxonate-Injected Rats.

Hyperuricemia is the primary cause of gouty arthritis and other metabolic disorders. Eggshell membrane (EM) is an effective and safe supplement for curing pain and stiffness connected with osteoarthritis. However, the effect of EM on hyperuricemia is unclear. This study determines the effects of EM on potassium oxonate-injected hyperuricemia. Uric acid, creatinine, blood urea nitrogen concentrations in the serum, and xanthine oxidase activity in the liver are measured. Protein levels of renal urate transporter 1 (URAT1), organic anion transporters 1 (OAT1), glucose transporter 9 (GLUT9), and ATP-binding cassette transporter G2 (ABCG2) in the kidney are determined with renal histopathology. The results demonstrate that EM reduces serum uric acid levels and increases urine uric acid levels in hyperuricemic rats. Moreover, EM downregulates renal URAT1 protein expression, upregulates OAT1 and ABCG2, but does not change GLUT9 expression. Additionally, EM does not change xanthine oxidase activity in the liver or the serum. EM also decreases uric acid uptake into oocytes expressing hURAT1. Finally, EM markedly reduces renal inflammation and serum interleukin-1β levels. These findings suggest that EM exhibits antihyperuricemic effects by promoting renal urate excretion and regulating renal urate transporters. Therefore, EM may be useful in the prevention and treatment of gout and hyperuricemia.

Pharmacologic inhibiting STAT3 delays the progression of kidney fibrosis in hyperuricemia-induced chronic kidney disease

AimsKidney fibrosis is a histological hallmark of chronic kidney disease (CKD), where hyperuricemia is a key independent risk factor. Considerable evidence indicated that STAT3 is one of the crucial signaling pathways in the progression of kidney fibrosis. Here, we investigated that pharmacological blockade of STAT3 delayed the progression of renal fibrosis in hyperuricemia-induced CKD. Main methodsIn the study, we used the mixture of adenine and potassium oxonate to perform kidney injury and fibrosis in hyperuricemic mice, accompanied by STAT3 activation in tubular and interstitial cells. Key findingsTreatment with STAT3 inhibitor S3I-201 improved renal dysfunction, reduced serum uric acid level, and delayed the progression of kidney fibrosis. Furthermore, S3I-201 could suppress fibrotic signaling pathway of TGF-β/Smads, JAK/STAT and NF-κB, as well as inhibit the expression of multiple profibrogenic cytokines/chemokines in the kidneys of hyperuricemic mice. SignificanceThese data suggested that STAT3 inhibition was a potent anti-fibrotic strategy in hyperuricemia-related CKD.

Inulin-type prebiotics reduce serum uric acid levels via gut microbiota modulation: a randomized, controlled crossover trial in peritoneal dialysis patients.

Increased levels of uric acid (UA), which is mainly excreted through the kidneys, are independently associated with higher mortality in end-stage renal disease (ESRD) patients. The uricolysis of gut microbiota plays an important role in extrarenal excretion of UA. This study aimed to examine the effect of inulin-type prebiotics (a type of fermentable dietary fiber) on intestinal microbiota modulation and serum UA levels in ESRD patients. Continuous ambulatory peritoneal dialysis (CAPD) patients were recruited to a randomized, double-blind, placebo-controlled crossover trial of 12-week inulin-type prebiotics. Participants were visited before and after treatment with prebiotics or placebo. Serum UA levels, dietary purine intake, serum xanthine oxidase (XO) activity, daily "renal excretion" of UA, and fecal UA degradation capability were measured at each visit. Fecal metagenomic analysis was conducted to assess microbial composition and function. Sixteen participants (mean age = 37 y; 10 men and 6 women) completed the trial, and 64 specimens were analyzed. The average concentration of serum UA decreased by approximately 10% in the prebiotic intervention group in comparison to the placebo group (p = 0.047) without an increase in daily "renal excretion" of UA via urine and dialysate. There were no significant changes in purine intake or activity of XO. Notably, enhanced fecal UA degradation was observed after prebiotic intervention (p = 0.041), and the ratio of Firmicutes/Bacteroidetes, which was positively associated with fecal UA degradation, increased in the prebiotic period (p = 0.032). Furthermore, prebiotics enriched purine-degrading species in the gut microbiota, including unclassified_o_Clostridiales, Clostridium sp. CAG:7, Clostridium sp. FS41, Clostridium citroniae, Anaerostipes caccae, and Clostridium botulinum. Inulin-type prebiotics is a promising therapeutic candidate to reduce serum UA levels in renal failure patients, and this urate-lowering effect could possibly be attributed to intestinal microbial degradation of UA. This study was registered at the Chinese Clinical Trials Registry ( http://www.chictr.org.cn/ ), registration ID: ChiCTR-INR-17013739, registration date: 6th Dec 2017.

High MW polyethylene glycol prolongs circulation of pegloticase in mice with anti-PEG antibodies

Pegloticase is an enzyme used to reduce serum uric acid levels in patients with chronic, treatment-refractory gout. Clinically, about 40% of patients develop high titers of anti-PEG antibodies (APA) after initial treatment, which in turn quickly eliminate subsequent doses of pegloticase from the systemic circulation and render the treatment ineffective. We previously found that pre-infusion with high MW free PEG (40 kDa) can serve as a decoy to saturate circulating APA, preventing binding to a subsequently administered dose of PEG-liposomes and restoring their prolonged circulation in mice, without any detectible toxicity. Here, we investigated the use of 40 kDa free PEG to restore the circulation of radio-labeled pegloticase in mice using longitudinal Positron Emission Tomography (PET) imaging over 4 days. Mice injected with pegloticase developed appreciable APA titers by Day 9, which further increased through Day 14. Compared to naïve mice, mice with pegloticase-induced APA rapidly cleared 89Zr-labeled pegloticase, with ~75% lower pegloticase concentrations in the circulation at four hours after treatment. The 96-h AUC in APA+ mice was less than 30% of the AUC in naïve mice. In contrast, pre-infusion of free PEG into PEG-sensitized mice restored the AUC of pegloticase to ~80% of that seen in naïve mice, resulting in a similar biodistribution to pegloticase in naïve mice over time. These results suggest that pre-infusion of free PEG may be a promising strategy to enable the safe and efficacious use of pegloticase and other PEGylated drugs in patients that have previously failed therapy due to induced APA.

Network pharmacology and molecular docking analysis on molecular targets: Mechanisms of baicalin and baicalein against hyperuricemic nephropathy

Oxidative stress and inflammation in kidney are the main causes for hyperuricemic nephropathy (HN). Baicalin and baicalein, two flavonoids, have anti-inflammatory and anti-oxidative effects and they are interconvertible in the body. In this study, both baicalin and baicalein were administered by intragastric administration (i.g.) or intraperitoneal injection (i.p.) at the dose of 50 mg kg−1, once a day for 15 consecutive days to HN mice, a model established by i.g. of yeast extract combined with i.p. of potassium oxonate. In HN mice, baicalin and baicalein reduced serum uric acid (SUA) levels and protected kidneys by anti-inflammatory and anti-oxidative effects. Mechanistically, the effect of baicalin and baicalein on reducing SUA levels might due to their inhibitory effect on xanthine oxidase (XO) activity in vivo and in vitro. Furthermore, the mechanisms of baicalin and baicalein against HN were analyzed with network pharmacology and molecular docking technology. The network pharmacology indicated that the protective effects of baicalin and baicalein against HN were mainly related to their down-regulating effects on TLRs, NF-κB, MAPK, PI3K/AKT and NOD-like receptor signaling pathways. Molecular docking indicated high binding affinity of baicalin/baicalein to targets such as AKT1 and MAPK1. In summary, baicalin and baicalein are promising drug candidates for the treatment of HN by inhibiting XO activity, reducing inflammation and cell apoptosis through down-regulating TLRs/NLRP3/NF-κB, MAPK, PI3K/AKT/NF-κB pathways.

Synthesis and biological evaluation of 2-(4-alkoxy-3-cyano)phenylpyrimidine derivatives with 4-amino or 4-hydroxy as a pharmacophore element binding with xanthine oxidase active site

Xanthine oxidase is the rate-limiting enzyme critical for the synthesis of uric acid, and therefore xanthine oxidase inhibitors are considered as one of the promising therapies for hyperuricemia and gout. In our previous study, series of 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids and 2-(4-alkoxy-3-cyano)phenyl-6-imino-1,6-dihydropyrimidine-5-carboxylic acids were synthesized that presented excellent in vitro xanthine oxidase inhibitory potency. Interestingly, molecular docking studies revealed that the interaction behavior of these compounds with xanthine oxidase was changed after the conversion from a hydroxy group to amine group. To further investigate the structure–activity relationships of these pyrimidine-containing xanthine oxidase inhibitors and explore the contribution of amino or hydroxy group on xanthine oxidase inhibitory potency, several 2-phenylpyrimidine derivatives with amino or hydroxy functional group were designed and synthesized. Thereafter, the structure–activity research and molecular modeling study proved that hydroxy and amino groups could be used as pharmacophore elements for the design of 2-phenylpyrimidines xanthine oxidase inhibitors. Particularly, the optimized compound, 2-(3-cyano-4-isopentoxy)phenylpyrimidine-4-ol, emerged the strongest xanthine oxidase inhibitor potency, with an IC50 value of 0.046 µM, which was approximately 120-fold more potent than that of allopurinol (IC50 = 5.462 µM). Additionally, Lineweaver-Burk plot analysis revealed that the optimized compound acted as a mixed-type inhibitor. Furthermore, the in vivo hypouricemic effect of the optimized compound was investigated in a hyperuricemia rat model induced by potassium oxonate, and the results showed that the optimized compound could effectively reduce serum uric acid levels at an oral dose of 30 mg/kg.

Comparative effects of topiroxostat and febuxostat on arterial properties in hypertensive patients with hyperuricemia.

Elevated serum uric acid is a cardiovascular risk factor in patients with hypertension, even when blood pressure (BP) is well controlled. Xanthine oxidoreductase inhibitors (XORi) reduce serum uric acid levels and have several other potential effects. This multicenter, randomized, open‐label study compared the effects of two XORi, topiroxostat and febuxostat, on arterial stiffness, uric acid levels, and BP in hypertensive patients with hyperuricemia. Patients received topiroxostat 40–160 mg/day or febuxostat 10–60 mg/day, titrated to maintain serum uric acid <6 mg/dl, for 24 weeks. The primary endpoint was change in the cardio‐ankle vascular index (CAVI) from baseline to 24 weeks. There were no significant changes in CAVI from baseline to 24 weeks (from 9.13 to 9.16 [feboxustat] and 8.98 to 9.01 [topiroxostat]). Compared with baseline, there were significant reductions in serum uric acid (–2.9 and –2.5 mg/dl; both p < 0.001) and morning home systolic BP (–3.6 and –5.1 mm Hg; both p < 0.01) after 24 weeks' treatment with febuxostat and topiroxostat. BP decreased to the greatest extent in the subgroup of patients with uncontrolled blood pressure at baseline. Topiroxostat, but not febuxostat, significantly decreased plasma xanthine oxidoreductase activity versus baseline. The urinary albumin‐creatinine ratio (UACR) decreased significantly from baseline to 24 weeks with topiroxostat (–20.8%; p = 0.021), but not febuxostat (–8.8%; p = 0.362). In conclusion, neither topiroxostat nor febuxostat had any significant effects on arterial stiffness over 24 weeks' treatment.

Impact of fenofibrate therapy on serum uric acid concentrations: a review and meta-analysis.

Fenofibrate is a marketed fibric acid derivative for lipid-lowering in patients with lipid disorders. Numerous studies have proven fenofibrate had a certain effect on serum uric acid, here we conducted this study to quantitatively assess the effect of fenofibrate intervention in modulating serum uric acid concentration and the influence on serum creatinine. The PubMed, Embase and Cochrane were systematically searched for randomized controlled trials update to January, 2020. Primary endpoints focused on serum uric acid concentration and serum creatinine concentration. The pooled effects were calculated as weighted mean difference (WMD) by a random-effects model. Finally, 9 studies representing 487 patients were included in the meta-analysis. The meta-analysis demonstrated that fenofibrate significantly reduced serum uric acid levels (WMD -1.32 mg/dL, 95%CI -1.61 to -1.03, p < 0.001) and an elevated level in serum creatinine (WMD 0.09 mg/dL, 95%CI 0.02 to 0.15, p < 0.001) following fenofibrate therapy compared with placebo. The present study provided strong evidence that fenofibrate intervention exerted a significant reduction on serum uric acid and a mild increase on serum creatinine. Meta-analysis suggested that there were no significant association between the serum uric acid lowering effect with either dose or treatment duration. Overall, our meta-analysis ascertained that fenofibrate have potential therapeutic effects in patients with lipid metabolic abnormalities but with mid nephrotoxicity. There is strong evidence to provide future direction of practical application and clinical researches of fenofibrate.

How much does fat mass change affect serum uric acid levels among apparently clinically healthy Korean men?

Objective:The aim of this study was to examine the impact of fat mass alteration on serum uric acid (SUA) levels in apparently clinically healthy men.Methods:We evaluated 27,387 men who consecutively underwent health check ups between 2015 and 2017. We assessed the likelihood of achieving a SUA level of <0.41 mmol/L and compared the SUA levels according to fat mass changes.Results:Compared with those without fat mass change (the reference group), the odds ratios (95% confidence interval) of achieving a SUA level of <0.41 mmol/L for fat mass decreases of ⩾2.5, 1.5–2.5, and 0.5–1.5 kg were 1.63 (1.45–1.82), 1.19 (1.06–1.34), and 1.07 (0.97–1.18), respectively, while those for a fat mass increase of ⩾2.5, 1.5–2.5, and 0.5–1.5 kg were 0.71 (0.64–0.78), 0.87 (0.79–0.97), and 0.95 (0.86–1.04), respectively. The corresponding beta-coefficients of SUA levels (mmol/L) were –0.26 [–0.29–(–0.23)], –0.12 [–0.16–(–0.09)], and –0.09 [–0.12–(–0.06)] for fat mass decreases of ⩾2.5, 1.5–2.5, and 0.5–1.5 kg, respectively. Every 1-kg fat mass reduction was associated with 9% increased odds of achieving the target SUA level. The multivariate SUA level difference per 1-kg fat mass gain was 2.97 µmol/L. Similar levels of association persisted among the prespecified subgroups.Conclusion:We quantitatively demonstrated that fat mass reduction contributes to a clinically relevant decrease in SUA levels and a significant increase in the likelihood of achieving target SUA levels. Our findings may help to provide clear clinical guidance on fat mass alteration to reduce SUA levels in patients with hyperuricemia.

November 2020 at a glance: focus on comorbidities and medical treatment.

The role of glycaemic control in patients with heart failure (HF) and concomitant diabetes is controversial. Insulin treatment is associated with poorer outcomes in these patients.1, 2 McAlister et al.3 investigated the relationship between glycaemic control, i.e. glycated haemoglobin (HbA1c), and cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus and atherosclerosis from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Results showed a U-shaped association between baseline HbA1c and CV outcome, with the lowest risk when HbA1c was around 7%.3 Iron deficiency impairs cardiac contractility through decreased mitochondrial function.4 Hirsch et al.5 assessed iron concentrations in non-ischaemic HF with reduced ejection fraction (HFrEF), using endomyocardial biopsies. Lower iron concentrations were associated with a greater severity of HF. Hyperkalaemia is frequent in HFrEF patients, above all when on renin–angiotensin–aldosterone system inhibitors.6, 7 An administrative database analysis showed the association of hyperkalaemia with mortality and CV events in HF patients on renin–angiotensin–aldosterone system inhibitors.8 In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, both hypokalaemia and hyperkalaemia were associated with a higher risk of CV death, compared with potassium levels between 4.1 and 4.9 mmol/L (hazard ratio 2.40 and 1.42, respectively). No interaction between serum potassium and sacubitril/valsartan efficacy vs. enalapril was found.9 Frailty is a major independent determinant of outcomes in HF.10 A new Frailty Score has recently been developed.11 The FRAGILE-HF study was a prospective multicentre study investigating the prevalence, overlap, and prognostic implications of physical and social frailties and cognitive dysfunction in patients hospitalized with HF. Patients with a greater number of frailty domains had higher mortality and HF rehospitalization.12 The prevalence of frailty is increased in HF with preserved ejection fraction (HFpEF) patients and is associated with worse outcome.13 Similarly, frailty was highly prevalent in HFrEF patients and was associated with poor quality of life and outcomes in a retrospective analysis of PARADIGM-HF and ATMOSPHERE.14 Biomarkers, namely natriuretic peptides, play a major role in the management of HF.15 Aimo et al.16 analysed the prognostic value and the influence of age on circulating levels of biomarkers in 5301 patients with chronic HF. N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predicted outcomes. sST2 was less influenced by age than the other two biomarkers. In the Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial, serum uric acid (SUA) was an independent predictor of poor outcome in HFpEF. Sacubitril/valsartan reduced SUA levels and the need for SUA-related drugs.17 Sex-based differences in biomarkers, health status, and reverse cardiac remodelling in HFrEF patients treated with sacubitril/valsartan in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodelling During Entresto Therapy for HF (PROVE-HF) were analysed by Ibrahim et al.18 Sex is a major determinant of clinical characteristics and outcomes in patients with HFrEF and HFpEF.19-21 In the study by Ibrahim et al.18, women treated with sacubitril/valsartan had more rapid reduction in NT-proBNP plasma levels and reverse cardiac remodelling and a larger improvement in quality of life. McEwan et al.22 showed the cost-effectiveness of dapagliflozin for the treatment of HFrEF with significant life-year and quality-adjusted life-year gains for the patients treated. The Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in HF (GALACTIC-HF) trial assessed the safety and efficacy of the cardiac myosin activator omecamtiv mecarbil in HFrEF patients. The baseline characteristics of enrolled patients are presented in this issue. The trial enrolled well-treated and high-risk inpatients and outpatients, representative of recent HF registries and trials.23

Lifeceramics-treated water reduces serum uric acid levels and improves hemorheological activity in hyperuricemic rats.

Lifeceramics (LC) is made of zeolite and oyster shell and is hypothesized to act as an anti-oxidative agent. In the present study, the effects of LC-treated water (LC water) on the concentration of serum uric acid (SUA) and the hemorheological parameters in male rats with hyperuricemia (HUA) was assessed. To prepare LC water, distilled water was mixed with LC particles. HUA was induced in rats by daily potassium oxonate (PO) injection (250 mg/kg). The PO-injected rats were separated into three different groups and were administered distilled water (PO rats), allopurinol [a xanthine oxidase (XOD) inhibitor] solution [PO + allopurinol (AP) rats] or LC water (PO+LC rats) by gavage. Control rats were intraperitoneally injected with sodium carboxymethyl cellulose solution and administered untreated distilled water by gavage. After injection and gavage for 5 weeks, the SUA concentration, hemorheology index and antioxidant index were measured. The SUA concentration and blood deformation index of the PO rats were significantly higher and lower, respectively, compared with the control rats. However, in the PO+LC rats, the SUA concentration and blood deformation index decreased and increased, respectively, to a level similar to that of the control as well as that in the PO+AP rats. Furthermore, the PO-induced increase in XOD activity was suppressed by combined treatment with LC water, resulting in a decrease in malondialdehyde concentration. These results suggest that LC water can reduce the SUA concentration, increase serum antioxidant activity and improve hemorheological activity in hyperuricemic rats.

Comparison of uric acid reduction and renal outcomes of febuxostat vs allopurinol in patients with chronic kidney disease

Whether the clinical trial treatment effect of urate-lowering therapy (ULT) in patient with chronic kidney disease (CKD) is generalizable to real-word settings is unclear. This study aimed to compare febuxostat with allopurinol for uric acid reduction and renal protection in patients with CKD. Adult CKD patients newly treated with ULT were identified using electronic health records from 2010 to 2015 from a large healthcare delivery system in Taiwan. Patients with renal replacement therapy or undergoing ULT for <3 months were excluded. Propensity score–matched cohort study design was conducted to compare outcomes between patients initiated with febuxostat or allopurinol therapy. Cox regression analyses were employed to compare the adjusted hazards ratio (aHR) of incident event of estimated glomerular filtration rate (eGFR) ≥ 30% decrease, and the difference in longitudinal changes in serum uric acid (SUA) and eGFR between groups was analyzed using linear mixed model. Overall, 1050 CKD patients who initiated febuxostat (n = 525) or allopurinol (n = 525) treatment were observed for 2.5 years. Compared with allopurinol, febuxostat use was associated with higher rate of patients maintaining SUA target <6 mg/dL in >80% of follow-up time with a reduction in mean SUA change. There were no significant differences in the mean eGFR changes over time between the febuxostat and allopurinol groups or in the risk of eGFR decline ≥30% of baseline. Febuxostat was associated with greater reduction in SUA level than allopurinol in patients with CKD. However, febuxostat and allopurinol showed no difference in renal function changes during study follow-up. These findings require further investigation with long-term follow up in CKD patients with hyperuricemia.

The clinical efficacy of urate-lowering therapy in acute gout: a meta-analysis of randomized controlled trials.

Gout is a common chronic disease with a high recurrence rate. To date, the debate continues about the best time for using urate lowering therapy (ULT) during an acute gout attack. This updated meta-analysis is designed to assess the clinical efficacy of ULT in the management of acute exacerbations of gout. Through the results, we hope to determine whether uric acid lowering agents should be used to manage acute exacerbations of gout. A comprehensive search of six databases without language restrictions includes PubMed, Cochrane Library, Web of Science, EMBASE, CNKI, and WanFang data. The literature used was published before October 2019. Six randomized controlled trials (RCTs) with 557 patients met the inclusion criteria. Standardized mean difference (SMD), weighted mean difference (WMD), risk ratio (RR), and 95% confidence interval (CI) were used for estimating the clinical efficacy of ULT in acute gout. Data results showed no statistical difference in the pain visual analogue score (VAS) by day 3 (weighted mean difference (WMD), 0.06; 95% CI, - 0.13 to 0.25; I2 0%; P = 0.55), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) between the group using uric acid lowering agents and the group that was not using such agents. Moreover, the patients using ULT agents had lower serum uric acid level (standardized mean difference (SMD), - 0.73; 95% CI, -0.92 to -0.54; I2 23%; P < 0.00001) and showed better adherence to medication (risk ratio (RR), 1.40; 95% CI, 1.18 to 1.65; I2 0%; P < 0.0001) as compared with the patients not that were not using such agents. However, there was no substantial difference in the recurrence rate of acute gout attacks (RR, 0.84; 95% CI, 0.59 to 1.19; I2 0%; P = 0.33).The evidence for this is, however, very moderate. Our finding shows that it is beneficial in many aspects to use uric-acid-lowering drugs at the initial stage of an acute gout attack. However, larger sample size studies are still needed to prove our results. Registration number: PROSPERO (CRD42020153924). Key Points • This is a first meta-analysis about the clinical efficacy of urate-lowering therapy (ULT) in acute gout without language restrictions. • ULT in acute gout may not aggravate the pain (WMD, 0.06; 95% CI, - 0.13 to 0.25). • ULT at the initial stage of an acute gout attack can reduce serum uric acid level (SMD, -0.73; 95% CI, - 0.92 to - 0.54) and improve medication compliance in patients (RR, 1.40; 95% CI, 1.18 to 1.65). • ULT in acute gout is not associated with the risk of gout flares (RR, 0.84; 95% CI, 0.59 to 1.19).

Polygenic analysis of the effect of common and low-frequency genetic variants on serum uric acid levels in Korean individuals

Increased serum uric acid (SUA) levels cause gout and are associated with multiple diseases, including chronic kidney disease. Previous genome-wide association studies (GWAS) have identified more than 180 loci that contribute to SUA levels. Here, we investigated genetic determinants of SUA level in the Korean population. We conducted a GWAS for SUA in 6,881 Korean individuals, calculated polygenic risk scores (PRSs) for common variants, and validated the association of low-frequency variants and PRS with SUA levels in 3,194 individuals. We identified two low-frequency and six common independent variants associated with SUA. Despite the overall similar effect sizes of variants in Korean and European populations, the proportion of variance for SUA levels explained by the variants was greater in the Korean population. A rare, nonsense variant SLC22A12 p.W258X showed the most significant association with reduced SUA levels, and PRSs of common variants associated with SUA levels were significant in multiple Korean cohorts. Interestingly, an East Asian-specific missense variant (rs671) in ALDH2 displayed a significant association on chromosome 12 with the SUA level. Further genetic epidemiological studies on SUA are needed in ethnically diverse cohorts to investigate rare or low-frequency variants and determine the influence of genetic and environmental factors on SUA.

Induction of Autophagy by Pterostilbene Contributes to the Prevention of Renal Fibrosis via Attenuating NLRP3 Inflammasome Activation and Epithelial-Mesenchymal Transition.

Chronic kidney disease (CKD) is recognized as a global public health problem. NLRP3 inflammasome activation has been characterized to mediate diverse aspect mechanisms of CKD through regulation of proinflammatory cytokines, tubulointerstitial injury, glomerular diseases, renal inflammation, and fibrosis pathways. Autophagy is a characterized negative regulation mechanism in the regulation of the NLRP3 inflammasome, which is now recognized as the key regulator in the pathogenesis of inflammation and fibrosis in CKD. Thus, autophagy is undoubtedly an attractive target for developing new renal protective treatments of kidney disease via its potential effects in regulation of inflammasome. However, there is no clinical useful agent targeting the autophagy pathway for patients with renal diseases. Pterostilbene (PT, trans-3,5-dimethoxy-4-hydroxystilbene) is a natural analog of resveratrol that has various health benefits including autophagy inducing effects. Accordingly, we aim to investigate underlying mechanisms of preventive and therapeutic effects of PT by reducing NLRP3 inflammasome activation and fibrosis through autophagy-inducing effects. The renal protective effects of PT were evaluated by potassium oxonate (PO)-induced hyperuricemia and high adenine diet-induced CKD models. The autophagy induction mechanisms and anti-fibrosis effects of PT by down-regulation of NLRP3 inflammasome are investigated by using immortalized rat kidney proximal tubular epithelial NRK-52E cells. To determine the role of autophagy induction in the alleviating of NLRP3 inflammasome activation and epithelial-mesenchymal transition (EMT), NRK-52E with Atg5 knockdown [NRK-Atg5-(2)] cells were applied in the study. The results indicated that PT significantly reduces serum uric acid levels, liver xanthine oxidase activity, collagen accumulation, macrophage recruitment, and renal fibrosis in CKD models. At the molecular levels, pretreatment with PT downregulating TGF-β-triggered NLRP3 inflammasome activation, and subsequent EMT in NRK-52E cells. After blockage of autophagy by treatment of Atg5 shRNA, PT loss of its ability to prevent NLRP3 inflammasome activation and EMT. Taken together, we suggested the renal protective effects of PT in urate nephropathy and proved that PT induces autophagy leading to restraining TGF-β-mediated NLRP3 inflammasome activation and EMT. This study is also the first one to provide a clinical potential application of PT for a better management of CKD through its autophagy inducing effects.

OP0205 PHASE I STUDY OF D-0120, A NOVEL URAT1 INHIBITOR IN CLINICAL DEVELOPMENT FOR HYPERURICEMIA AND GOUT

Background:D-0120 is a novel oral selective uric acid transporter (URAT1) inhibitor being developed for the treatment of hyperuricemia and gout by blocking the reabsorption of uric acid (UA) within the renal proximal tubule, thereby reducing serum uric acid concentrations. As a novel URAT1 inhibitor, D-0120 is anticipated to have more potent serum UA reducing effect than the approved URAT1 inhibitor lesinurad, but with less toxicity and wider therapeutic window. The pharmacological potential of D-0120 for the treatment of hyperuricemia and gout was demonstrated in preclinical studies. The results of the in vitro hURAT1 expressed CHO cell model showed that the inhibitory activity of D-0120 is 150-fold more potent than lesinurad and slightly more potent than verinurad.Objectives:The purpose of this dose escalation study is to evaluate the safety and tolerability of D-0120 in multiple ascending doses in healthy volunteer, to characterize the pharmacokinetics (PK) of D-0120 and to assess pharmacodynamic (PD) effects and determine the drug-drug interaction (DDI) effect of febuxostat and D-0120 in healthy volunteers.Methods:This is a randomized, double blind, multiple ascending doses Phase I study of D-0120 in healthy volunteers conducted at one site. Thirty-two healthy eligible volunteers with serum uric acid level ≥ 4.5 mg/dL but within normal range at screening were enrolled and dosed with D-0120 within 4 different single agent cohorts for a period of 7 days. Each cohort had 8 subjects randomized at 3:1 ratio for D-0120:placebo. A fifth cohort of 8 healthy eligible volunteers were enrolled and dosed with 5 mg of D-0120 in combination with 40 mg of febuxostat over a period of 9 days. Evaluation of safety, PK and PD was conducted at various timepoints while the patients were in confinement. Further safety evaluation took place on Day 14. A Safety Review Committee reviewed safety, PK and PD data for each cohort of D-0120 dose level (2.5 mg, 5 mg, 10 mg, 20 mg) as well as when D-0120 5 mg was combined with 40 mg febuxostat. PK evaluation for multiple dose parameters included AUC0-τ, Cmax, Cmin, Tmax and Fl.Results:Dose escalation of D-0120 from 2.5 mg/day to 20 mg/day was completed without any dose limiting toxicities. Most AEs occurred during the study were mild to moderate in severity and did not require any treatment before resolution. There was no SAE and no dose reduction during the treatment period. The pharmacokinetic (PK) evaluation of ascending dose levels of D-0120 suggested a dose proportional increase in drug exposure and there was no significant change of PK profile between Day 1 and Day 7 of dosing. For pharmacodynamic (PD) evaluation, the serum uric acid (UA) levels before and after D-0120 dosing was evaluated on multiple days. The UA reduction effect achieved maximum at about 4-8 hours after dosing and the effect lasted for at least 24 hours. After the 7-day dosing period, the mean percentage of UA reduction from baseline showed an increasing trend as the dose level increased.More detailed safety, PK and PD data from multiple D-0120 dose cohorts and D-0120/febuxostat combination cohort will be presented at the meeting.Conclusion:The oral daily administration of a novel URAT1 inhibitor, D-0120, in healthy volunteers for 7 days was well tolerated at dose levels from 2.5 mg/day to 20 mg/day. The PK profile demonstrated a dose proportional increase. D-0120 administration for 7 days resulted in significant reduction of serum UA levels. Further evaluation of this novel agent in longer treatment period and in patients with hyperuricemia and/or gout is warranted.

Comparative effect of allopurinol and febuxostat on long-term renal outcomes in patients with hyperuricemia and chronic kidney disease: a systematic review.

Patients with chronic kidney disease (CKD) are more likely to develop hyperuricemia and gout. Allopurinol and febuxostat are the most commonly used urate-lowering therapies with established safety and efficacy in CKD patients. The objective of the systematic review is to assess the long-term renal outcomes of allopurinol compared with febuxostat in patients with hyperuricemia and CKD or kidney transplantation. PubMed MEDLINE, Embase, Web of Science, Scopus, and Cochrane CENTRAL databases were searched from inception to December 2019 using the key terms "allopurinol," "febuxostat," "xanthine oxidase inhibitors," "gout suppressants," "hyperuricemia," "gout," "chronic renal insufficiency," and "kidney transplantation." Studies with follow-up duration ≥ 12months were included. Risk of bias was assessed using the Cochrane Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool. Three retrospective observational studies with follow-up duration ranging from 1 to 5years were reviewed. Febuxostat patients had a significantly higher estimated glomerular filtration rate, reduced risk for renal disease progression, and reduced serum uric acid levels compared with allopurinol patients. All studies had a serious risk of bias. Febuxostat may be more renoprotective than allopurinol in patients with both hyperuricemia and CKD based on evidence from small long-term retrospective studies with serious risk of bias. More methodologically rigorous studies are needed to determine the clinical applicability of these results.

Clinical Predictors of the Hypoglycemic Effect of Sodium-Glucose Co-transporter-2 Inhibitors in Hyperuricemic Patients: A Retrospective Descriptive Observational Study.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors decrease glycated hemoglobin (HbA1c) and prevent the progression of cardiovascular and kidney diseases. Because uric acid and electrolytes are physiologically similar to blood glucose in renal excretion, we assessed predictors for the hypoglycemic effect of SGLT2 inhibitor treatment by focusing on serum uric acid and serum electrolytes. We performed a retrospective descriptive observational study at the Tokyo Women's Medical University, Medical Center East, from June 2015 to July 2018. Patients who received treatment with any type of SGLT2 inhibitor were selected, which included a total of 165 patients. The response to SGLT2 inhibitors defined as changes in HbA1c after SGLT2 inhibitor treatment was the main outcome measure. Multiple linear regression analysis was used to assess predictors for the hypoglycemic effect by SGLT2 inhibitors. Among the 165 patients, SGLT2 inhibitor treatment decreased HbA1c from 8.2 to 7.6% after 12 weeks (p < 0.01). Multiple linear regression analysis revealed that predictors of early response to SGLT2 inhibitors were serum uric acid values (p = 0.014) and baseline HbA1c (p < 0.001). Furthermore, late response to SGLT2 inhibitors was associated with serum uric acid value (p = 0.047) and baseline HbA1c (p < 0.001). Serum uric acid did not vary during SGLT2 inhibitor treatment; specifically, the SGLT2 inhibitors did not reduce serum uric acid levels. There was no correlation between changes in serum uric acid and HbA1c (p = 0.13). Thus, this study showed that serum uric acid value is associated with the control of diabetes mellitus during SGLT2 inhibitor treatment. Further studies are required to validate these results.

Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: A randomized, controlled trial.

BackgroundAn elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia.Methods and findingsThe study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10–60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat − control], −0.007 mm [95% confidence interval (CI) −0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, −0.016 mm [95% CI −0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI −0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI −0.5% to 3.3%] in the control group (n = 193); mean between-group difference, −0.2% [95% CI −2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI −0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, −2.62 mg/dL [95% CI −2.86 mg/dL to −2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia.ConclusionsIn Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population.Trial registrationUniversity Hospital Medical Information Network Clinical Trial Registry UMIN000012911.