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Introduction: The combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin are used for both once-daily and twice-daily agents in Japan. If there is no difference in effectiveness between the once-daily and twice-daily DPP-4 inhibitor/metformin combination tablets, the once-daily agent is advantageous in terms of frequency of administration. The aim of this study was to compare the effectiveness of once-daily alogliptin/metformin combination tablet (alogliptin 25 mg/metformin 500 mg) and twice-daily anagliptin/metformin combination tablet low dose (LD) (anagliptin 100 mg/metformin 250 mg). Methods: Forty-eight Japanese patients with type 2 diabetes whose metformin administration of 250 mg twice daily had remained unchanged for at least 8 weeks, except when using DPP-4 inhibitors, glucagon-like peptide-1 receptor agonists, or insulin, were randomized to either the once-daily alogliptin/metformin combination tablet group or the twice-daily anagliptin/metformin combination tablet LD group. The primary endpoint was the difference in glycosylated hemoglobin (HbA1c) levels from baseline to week 12 of administration, whereas the secondary endpoints were fasting blood glucose, body mass index (BMI), and adherence. Results: Forty-four patients completed the study, and intention-to-treat analyses were performed. The adjusted mean value (standard error) for the change in HbA1c from week 0 to 12, was − 0.75 (0.109)% for the once-daily alogliptin/metformin combination tablet group and − 0.65 (0.109)% for the twice-daily anagliptin/metformin combination tablet LD group, with an intergroup difference of − 0.10% (95% confidence interval, CI − 0.407, 0.215). The upper limit of the bilateral 95% CI was 0.215%, below the 0.40% pre-defined as the non-inferiority margin. Fasting blood glucose, BMI, and adherence were not significantly different between the groups. Conclusions: The once-daily alogliptin/metformin combination tablet was non-inferior to the twice-daily anagliptin/metformin combination tablet LD in Japanese patients with type 2 diabetes. Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (registration number: UMIN000034951). [ABSTRACT FROM AUTHOR]

Objective: Hyperuricemia is a strong precursor of gout, which deteriorates patients' health and quality of life. Sustained adherence to urate-lowering therapies (ULTs) is crucial for efficacy and therapeutic cost-effectiveness. Recently, several new ULTs have been proposed. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to reassess the efficacy and safety of the current ULTs, focusing on adherence attrition-related adverse event reporting. Method: The Bayesian network meta-analysis was applied to compare ULTs. Drug efficacy and safety were measured by whether the target level of serum urate acid was achieved and whether any adverse events occurred. The results were summarized using the pooled estimates of effect sizes (odds ratios), their precisions (95% credible interval), and the ranking probabilities. Results and Conclusions: Thirty-nine RCTs were identified, accumulating 19,401 patients. Consistent with previous studies, febuxostat (≥ 40 mg/day) was superior to other monoagent ULTs. The new findings were as follows: (i) dual-agent ULTs were superior to febuxostat alone, and further surveillance on the adverse effects when lesinurad is uptitrated is needed, and (ii) terminalia bellerica 500 mg/day, a novel xanthine oxidase inhibitor (XOI) made of natural fruit extracts, and topiroxostat ≥ 80 mg/day, an XOI used mostly in Japan, could be new effective options for lowering the occurrence of adherence attrition events. Evidence from RCTs regarding second-line agents, such as probenecid and pegloticase, remains insufficient for clinical decision-making. Key Points • Dual-agent ULTs were superior to febuxostat alone, and further surveillance on the adverse-effects when lesinurad is uptitrated is needed. • Terminalia bellerica 500 mg/day, a novel xanthine oxidase inhibitor (XOI) made of natural fruit extracts, and topiroxostat 80 mg/day, an XOI used mostly in Japan, could be new effective options for lowering the occurrence of adherence attrition events. [ABSTRACT FROM AUTHOR]

Background: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by selective inhibition of the urate transporter 1. We evaluated the efficacy and safety of dotinurad versus febuxostat, a widely used drug in Japan, in hyperuricemic Japanese patients with or without gout. Methods: This was a multicenter, randomized, double-blind, active-controlled, parallel-group, forced-titration study in hyperuricemic patients. Study treatment in the dotinurad and febuxostat groups was initiated at 0.5 and 10 mg/day, followed by dose titration to 2 and 40 mg/day, respectively, over 14 weeks. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. Results: A total of 203 hyperuricemic patients with or without gout were enrolled in the study and randomized to receive dotinurad or febuxostat. The percent change in serum uric acid level from the baseline to the final visit was 41.82% in the dotinurad group and 44.00% in the febuxostat group. The mean difference was − 2.17% (two-sided 95% confidence interval − 5.26% to 0.92%). The lower limit of the interval was above the non-inferiority margin (− 10%), demonstrating the non-inferiority of dotinurad to febuxostat. The profiles of adverse events and adverse drug reactions raised no noteworthy safety concerns in either group. Conclusion: The non-inferiority of dotinurad to febuxostat in terms of serum uric acid lowering effect was confirmed. No noteworthy safety concerns arose. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: Differences in the efficacy and safety of antidiabetic drugs among different ethnic groups are well documented. Metformin is widely used in the treatment of type 2 diabetes in Western countries, but high doses of metformin have been approved only recently for clinical use in Japan. The aim of the present study was to investigate the effects of dosage and dosing frequency on the efficacy and safety of high‐dose metformin in Japanese patients. Materials and Methods: A total of 71 Japanese patients with type 2 diabetes were prospectively studied for the effects of dosage and dosing frequency on the efficacy and safety of metformin during hospitalization. Dose effects were studied in 27 patients treated with 0, 500, 1,000, 1,500 and 2,250 mg/day of metformin. The effect of dosing frequency was compared in 56 patients with 1,500 mg/day of metformin administered either two or three times per day. Results: Significant dose‐dependent improvement in daily profiles of blood glucose was observed with metformin dosages up to 1,500 mg/day, with a trend towards further improvement observed at 2,250 mg/day. The efficacy of 1,500 mg of metformin was comparable when the drug was administered either two or three times per day. The most frequently reported side‐effects were gastrointestinal symptoms, which were not affected by the dosage or dosing frequency of metformin. Conclusions: These results show that the efficacy of high‐dose metformin is dose‐dependent in Japanese patients. The efficacy and safety of metformin were similar when the drug was administered either two or three times per day. [ABSTRACT FROM AUTHOR]

Background The March 2012 regulatory action issued by the Japanese government signalled the rare but serious complication of lactic acidosis that can occur during metformin treatment, especially with the high dose formulation, h-metformin, and in those above 75 years old. Objective To assess quantitatively the impact of this regulatory action on patient management using a medical information database (MID). Setting Eight hospitals in Japan. Method Using a commercial MID, we collected data on adult outpatients treated with metformin, including h-metformin, during a 2-year study period between April 1, 2011 and March 31, 2013. The 2-year study period spanned 1 year before and after the regulatory action. The frequencies of lactate measurement in all metformin users, h-metformin users, and new users (started on metformin during the study period) were compared between the periods before and after the regulatory action, using generalized estimating equations. Trends in metformin prescription for elderly patients were analysed month-wise by regression analysis using an interrupted time series design. Main outcome measure The rate ratios (RR) of lactate testing before and after the regulatory action. Results Of 4347 metformin users, 784 patients were >75 years old. A significant increase in lactate measurement was observed after the regulatory action than before in the overall study population, with an adjusted RR of 2.14 (95 % confidence interval 1.24-3.68). No significant change was found in h-metformin users and new users because lactate measurements were being performed as frequently in these subgroups before the regulatory action. There were no meaningful changes in the proportion of elderly metformin users in the overall population. Conclusion The regulatory action led to increased lactate measurement in the overall metformin users, but did not affect metformin prescription rate in the elderly patients. Our findings probably reflect the doctors' judgement that the benefits of metformin use outweigh the risk of lactic acidosis if lactate testing is performed regularly. [ABSTRACT FROM AUTHOR]

Objective Serum uric acid (SUA) levels in humans are mainly regulated by urate transporters. Recent genome-wide association studies suggested that common variants of the human sodium-dependent phosphate cotransporter type 1 gene ( NPT1/SLC17A1) influence SUA. NPT1 has been reported to mediate urate transport, but its physiologic role in regulating SUA in humans remains unclear. Furthermore, the findings of replication studies of the relationship between NPT1 variants and gout have been inconsistent. The aims of this study were to investigate the effect of NPT1 on gout and to determine its physiologic role. Methods Five hundred forty-five male Japanese patients with gout and 1,115 male Japanese control subjects were genotyped for rs1165196 (I269T), a common missense variant in NPT1. Analyses of the association between rs1165196 and gout were then conducted, focusing especially on renal underexcretion (RUE) gout. Immunohistochemical analysis and functional analysis using Xenopus oocytes were also performed. Results Single-nucleotide polymorphism rs1165196 significantly decreased the risk of RUE gout (odds ratio 0.73, P = 0.031) but did not confer a risk for all gout ( P = 0.123). The immunohistochemical analysis revealed that human NPT1 is localized to the apical membrane of the renal proximal tubule. The functional analysis using Xenopus oocyte expression systems showed that rs1165196 increases NPT1-mediated urate export. Conclusion This study showed that NPT1 is a urate exporter located in the renal proximal tubule in humans, and that its common gain-of-function variant, rs1165196, causes RUE gout, a major subtype of gout. These findings enable us to deepen our understanding of the physiologic role of NPT1 as a renal urate exporter as well as its pathophysiologic role in gout. [ABSTRACT FROM AUTHOR]