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Introduction: Type 2 diabetes (T2D) represents a remarkable disease burden in Japan, and the cost-effectiveness of pharmacotherapy is an important consideration. In this study, we compared the long-term effects of the type of initial medication, as well as the initial frequency of clinic visits, on the occurrence of T2D-related complications. Additionally, we compared the medical costs associated with each treatment pattern. Methods: We analyzed electronic health record data collected from multiple primary care clinics in Japan. Patients were selected based on being primarily prescribed either biguanides (BG) or DPP-4 inhibitors (DPP-4i) during a 3-month baseline period, both of which are commonly used as first-choice medications in Japan. We then followed the onset of T2D-related complications and conducted survival analyses. Additionally, we calculated the accumulated medical costs up to the onset of an event or loss to follow-up, and summarized the annual costs per patient for each treatment pattern. Results: A total of 416 Japanese patients with T2D who initiated treatment between January 2015 and September 2021 were included. The median follow-up period was 2.69 years. The survival analysis showed that the use of DPP-4is and frequent visits from the beginning of treatment did not offer a benefit in suppressing the onset of complications later on. On the other hand, it was found that the annual medical costs for the group using DPP-4i with frequent visits were about 1.9 times higher than for the group using BGs with less frequent visits. Conclusions: The results suggest that for Japanese patients with T2D, the use of BGs along with relatively long follow-up intervals in the beginning of treatment can remarkably reduce medical costs while providing a level of complication suppression equivalent to that of the use of DPP-4is or frequent visits. [ABSTRACT FROM AUTHOR]

Background: Metformin is recommended as a first-line drug in the guidelines of the treatment for type 2 diabetes mellitus. However, high-quality evidence from clinical trials directly comparing the degree of hypoglycemic effect of combination therapy of metformin and a hypoglycemic agent with a different mechanism of action with that of monotherapy of a hypoglycemic drug is lacking. We aimed to examine whether combination therapy of hypoglycemic agents with metformin showed antagonism, addition, or synergism compared to monotherapy with hypoglycemic agents other than metformin regarding hemoglobin A1c levels. Methods: This retrospective cohort study used a medical information database in Japan. Non-insulin anti-hyperglycemic agents with different mechanisms of action were classified into eight drug classes. A monotherapy cohort and a combination therapy added to the metformin cohort were defined. The change in hemoglobin A1c levels was evaluated to compare the treatment effect between the cohorts. Results: A total of 13,359 patients with type 2 diabetes mellitus in the monotherapy cohort and 1,064 in the metformin combination therapy cohort were identified. A comparison of the change from baseline HbA1c level by drug class between the two cohorts showed a similar trend. Among those treated with dipeptidyl peptidase-4 inhibitor and sodium-glucose co-transporter-2 inhibitor, no clinically significant difference was observed between the two cohorts (0.00% and -0.07% for unadjusted, 0.15% and -0.03% for propensity score matching-adjusted, and 0.09% and -0.01% for inverse probability treatment weighting-adjusted analysis). Conclusions: According to the results of this study, the effect of dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor added to metformin seems to be additive with respect to the reduction in hemoglobin A1c. [ABSTRACT FROM AUTHOR]

Study Objective: The effects of the sodium‐dependent glucose transporter‐2 inhibitor ipragliflozin were compared with metformin in a previous study, which revealed that ipragliflozin reduced visceral fat content by 12%; however, the underlying mechanism was unclear. Therefore, this sub‐analysis aimed to compare metabolomic changes associated with ipragliflozin and metformin that may contribute to their biological effects. Design: A sub‐analysis of a randomized controlled study. Setting: Chiba University Hospital and ten hospitals in Japan. Patients: Fifteen patients with type 2 diabetes in the ipragliflozin group and 15 patients with type 2 diabetes in the metformin group with matching characteristics, such as age, sex, baseline A1C, baseline visceral fat area, smoking status, and concomitant medication. Interventions: Ipragliflozin 50 mg or metformin 1000 mg daily. Measurements: The clinical data were reanalyzed, and metabolomic analysis of serum samples collected before and 24 weeks after drug administration was performed using capillary electrophoresis time‐of‐flight mass spectrometry. Main Results: The reduction in the mean visceral fat area after 24 weeks of treatment was significantly larger (p = 0.002) in the ipragliflozin group (−19.8%) than in the metformin group (−2.5%), as were the subcutaneous fat area and body weight. The A1C and blood glucose levels decreased in both groups. Glutamic pyruvic oxaloacetic transaminase, γ‐glutamyl transferase, uric acid, and triglyceride levels decreased in the ipragliflozin group. Low‐density lipoprotein cholesterol levels decreased in the metformin group. After ipragliflozin administration, N2‐phenylacetylglutamine, inosine, guanosine, and 1‐methyladenosine levels increased, whereas galactosamine, glucosamine, 11‐aminoundecanoic acid, morpholine, and choline levels decreased. After metformin administration, metformin, hypotaurine, methionine, methyl‐2‐oxovaleric acid, 3‐nitrotyrosine, and cyclohexylamine levels increased, whereas citrulline, octanoic acid, indole‐3‐acetaldehyde, and hexanoic acid levels decreased. Conclusions: Metabolites that may affect visceral fat reduction were detected in the ipragliflozin group. Studies are required to further elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

We aimed to compare the effects of cardiovascular disease risk in Japanese patients with type 2 diabetes on sodium–glucose cotransporter 2 inhibitors (SGLT2Is) or metformin. This retrospective, real‐world cohort study was carried out using a claims database and propensity score matching; 58,402 eligible patients (29,201 per group) were included. The outcomes included nonfatal myocardial infarction, angina pectoris, nonfatal stroke, hospitalization for heart failure and composite end‐points. The hazard ratio (HR) for the composite end‐point was 0.79, which was lower for SGLT2Is than for metformin. For male patients (HR 0.76), patients aged <65 years (HR 0.94), patients aged ≥75 years (HR 0.78) and patients with body mass index ≥25 kg/m2 (HR 0.76), the HRs for the composite end‐point were significantly lower in the SGLT2I group than in the metformin group. SGLT2Is might be superior to metformin in reducing the composite risk of cardiovascular disease in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims/Introduction: We aimed to clarify the real‐world risk of lower‐limb amputation and identify factors related to increased risk in Japanese patients with type 2 diabetes using sodium–glucose cotransporter 2 inhibitors (SGLT2is). Materials and Methods: We carried out a retrospective observational cohort study utilizing the Japanese Medical Data Vision, a diagnosis procedure combination database. We identified 107,296 patients with type 2 diabetes who were initiated on SGLT2is or metformin (control; n = 53,648 per group) using 1:1 propensity score matching from April 2014 to October 2019. The hazard ratio (HR) for the risk of lower‐limb amputation was analyzed using a Cox proportional hazards model adjusted for patients' baseline characteristics and use of concomitant medical agents. Results: Of the 107,296 patients, 66 (0.06%); that is, 41 (0.08%) in the SGLT2is group and 25 (0.05%) in the metformin group, underwent amputation, with no significant difference in the proportions between the groups. There was no significant difference in the risk of amputation between the SGLT2is and metformin groups (HR 1.34, 95% confidence interval [CI] 0.80–2.24). However, female sex (HR 2.78, 95% CI 1.12–6.94) and use of strong statins (HR 2.68; 95% CI 1.18–8.20) were significantly associated with a higher risk of amputation in the SGLT2is group than in the metformin group. Conclusions: SGLT2is might not be related to an increased risk of lower‐limb amputation in patients with type 2 diabetes in real‐world clinical practice. The possible increased risk of SGLT2is‐associated amputation in female patients with type 2 diabetes and patients with type 2 diabetes requiring strong statins is notable. [ABSTRACT FROM AUTHOR]

Background: Metformin had been recommended as the first-line treatment for type 2 diabetes since 2006 because of its low cost, high efficacy, and potential to reduce cardiovascular events, and thus death. However, dipeptidyl peptidase-4 (DPP-4) inhibitors are the most commonly prescribed first-line agents for patients with type 2 diabetes in Japan. Therefore, it is necessary to clarify the effect of DPP-4 inhibitors on preventing cardiovascular events, taking into consideration the actual prescription of antidiabetic drugs in Japan. Methods: This study examined the effect of DPP-4 inhibitors on preventing cardiovascular events. The Japanese Adverse Drug Event Report (JADER) database, a spontaneous reporting system in Japan, and the Japanese Medical Data Center (JMDC) Claims Database, a Japanese health insurance claims and medical checkup database, were used for the analysis. Metformin was used as the DPP-4 inhibitor comparator. Major cardiovascular events were set as the primary endpoint. Results: In the analysis using the JADER database, a signal of major cardiovascular events was detected with DPP-4 inhibitors (IC: 0.22, 95% confidence interval: 0.03–0.40) but not with metformin. In the analysis using the JMDC Claims Database, the hazard ratio of major cardiovascular events for DPP-4 inhibitors versus metformin was 1.01 (95% CI: 0.84–1.20). Conclusions: A comprehensive analysis using two different databases in Japan, the JADER and the JMDC Claims Database, showed that DPP-4 inhibitors, which are widely used in Japan, have a non-inferior risk of cardiovascular events compared to metformin, which is used as the first-line drug in the United States and Europe. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is an incurable disease, demanding new therapeutic approaches. Our preclinical studies proved that the antidiabetic drug metformin could induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation, suggesting the potential of metformin for treating glioblastoma. Taking into consideration that the anti-cancer effects of metformin are known to be dose-dependent, we conducted a dose-escalation phase I study to evaluate the safety and determine the recommended phase II dose of metformin in combination with maintenance temozolomide in patients with newly diagnosed glioblastoma. We show that the 2250 mg/day metformin appeared to be well tolerated with acceptable toxicity. Therefore, we proceed to a phase II study with 2250 mg/day metformin to evaluate its clinical benefits. Cancer stem/initiating cells are resistant to existing radiotherapy or chemotherapy; thus, our strategy targeting glioma-initiating cells using metformin is a novel therapeutic strategy which could possibly improve the outcome of glioblastoma. Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF. [ABSTRACT FROM AUTHOR]

Background: This study was aimed to compare the efficacy of two combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin with different dosages, alogliptin/metformin (AM) and vildagliptin/metformin (VM), on glycemic control in patients with type 2 diabetes (T2D). Methods: This was a prospective, multicenter, open-label, randomized, parallel group, comparative trial. After a run-in period of treatment with metformin alone, a total of 59 Japanese outpatients with T2D, aged 20-79 years with glycated hemoglobin (HbA1c) levels of 6.5%-10% were randomly assigned to 12-week AM treatment, alogliptin 25 mg/metformin 500 mg combination tablet orally once a day, or VM treatment, vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day. The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12 between the two groups. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12. The incidence of adverse events during the study was also evaluated. Results: In all, 52 participants were analyzed. Significant decreases in HbA1c and FPG levels from baseline to week 12 were observed in both treatment groups. However, there were no significant differences between the AM and VM groups in the change in HbA1c level (-0.3% and -0.4%, P = 0.309) or the FPG level (-9.0 and -15.0 mg/dL, P = 0.789). The isCGM revealed that both treatments achieved the recommended glycemic target range. No adverse events, such as severe hypoglycemia, were observed in either group. Conclusions: We concluded that there were no significant differences in the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in patients with T2D.

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]

Filgotinib, a preferential Janus Kinase‐1 inhibitor, is approved in Europe and Japan for treatment of rheumatoid arthritis and is being developed for treatment of other chronic inflammatory diseases. Three drug‐drug interactions studies were conducted in healthy subjects to evaluate the effect of P‐glycoprotein (P‐gp) modulation (study 1: P‐gp inhibition by itraconazole and study 2: P‐gp induction by rifampin) on filgotinib pharmacokinetics and the potential of filgotinib to impact exposure of metformin, an organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2K substrate (study 3). Co‐administration of filgotinib with itraconazole increased filgotinib exposure (maximum concentration [Cmax] by 64% and area under the curve to infinity [AUCinf] by 45%) but had no effect on the exposure of GS‐829845, filgotinib's primary metabolite. Rifampin moderately reduced exposures of filgotinib and GS‐829845 (Cmax by 26% and AUCinf by 27% for filgotinib; Cmax by 19% and AUCinf by 38% for GS‐829845). The data confirmed that filgotinib is a P‐gp substrate. However, the magnitude of change in filgotinib/GS‐829845 exposure by P‐gp modulators is not deemed to be clinically relevant based on filgotinib exposure‐response analyses in subjects with rheumatoid arthritis. Filgotinib did not alter metformin exposures, indicating that filgotinib and GS‐829845 do not inhibit OCT2 and MATE1/2K at the clinical doses. Filgotinib was generally well‐tolerated when administered alone or with the co‐administered drugs in the studies. Results from these studies were the basis to enable the use of P‐gp modulators and substrates of OCT2, MATE1, and MATE2K with filgotinib without the need for dose modifications in the current approved rheumatoid arthritis population. [ABSTRACT FROM AUTHOR]

Background: Similar to metformin, dipeptidyl peptidase-4 inhibitors (DPP-4 Is), glucagon-like peptidase 1 receptor agonists (GLP-1 RAs), and sodium glucose co-transporter-2 inhibitors (SGLT-2 Is) may improve control of asthma owing to their multiple potential mechanisms, including differential improvements in glycemic control, direct anti-inflammatory effects, and systemic changes in metabolism., Objective: To investigate whether these novel antihyperglycemic drugs were associated with fewer asthma exacerbations compared with metformin in patients with asthma comorbid with type 2 diabetes., Methods: Using a Japanese national administrative database, we constructed 3 active comparators-new user cohorts of 137,173 patients with a history of asthma starting the novel antihyperglycemic drugs and metformin between 2014 and 2022. Patient characteristics were balanced using overlap propensity score weighting. The primary outcome was the first exacerbation requiring systemic corticosteroids, and the secondary outcomes included the number of exacerbations requiring systemic corticosteroids., Results: DPP-4 Is and GLP-1 RAs were associated with a higher incidence of exacerbations requiring systemic corticosteroids compared with metformin (DPP-4 Is: 18.2 vs 17.4 per 100 person-years, hazard ratio: 1.09, 95% confidence interval [CI]: 1.05-1.14; GLP-1 RAs: 24.9 vs 19.0 per 100 person-years, hazard ratio: 1.14, 95% CI: 1.01-1.28). In contrast, the incidence of exacerbations requiring systemic corticosteroids was similar between the SGLT-2 Is and metformin groups (17.3 vs 18.1 per 100 person-years, hazard ratio: 1.00, 95% CI: 0.97-1.03). While DPP-4 Is and GLP-1 RAs were associated with more exacerbations requiring systemic corticosteroids, SGLT-2 Is were associated with slightly fewer exacerbations requiring systemic corticosteroids (53.7 vs 56.6 per 100 person-years, rate ratio: 0.95, 95% CI: 0.91-0.99)., Conclusions: While DPP-4 Is and GLP-1 RAs were associated with poorer control of asthma compared with metformin, SGLT-2 Is offered asthma control comparable to that of metformin., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Low-quality medicines and falsified medicines represent long-standing problems in developing countries. In Southeast Asia, the circulation of low-quality diabetes drugs (metformin) has been confirmed. It is possible that low-quality metformin has entered Japan via personal import through the Internet. This study evaluated the pharmaceutical quality and authenticity of metformin tablets obtained via the Internet in Japan. Methods: In total, 33 samples of 500-mg metformin tablets and 7 samples of extended-release/sustained-release tablets (500, 750, and 1,000 mg) were purchased via personal import in January 2017. Confirmation of a prescription was never requested purchase. The obtained samples were subjected to visual observations and authenticity investigations. Additionally, quantitative analysis, content uniformity and dissolution tests were performed using HPLC–PDA. Results: Our authenticity investigations revealed that seven samples were genuine products, whereas the authenticity of the remaining 33 samples was unclear. Referring to United States Pharmacopeia 2014 for validation, four samples failed quality testing, five samples failed content uniformity testing, and two samples failed dissolution testing. Conclusions: Our findings illustrate that metformin tablets of poor-quantity and unregistered/unlicensed doses are available online and that it is important to increase consumer awareness about the presence of these medicines on the Internet to prevent the purchase of substandard medicines. [ABSTRACT FROM AUTHOR]

Aim: To examine healthcare resource utilization in type 2 diabetes (T2D) patients after initiation of sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) versus dipeptidyl peptidase‐4 inhibitors (DPP‐4is) or other glucose‐lowering drugs (oGLDs). Materials and Methods: A cost‐utilization analysis was performed using a nationwide hospital‐based administrative claims database (Medical Data Vision) during 2014‐2018 in Japan, where universal healthcare coverage is maintained under a single‐payer system. Data on T2D patients initiated on either SGLT‐2is or oGLDs during the study period (228 514 patients) were extracted and subjected to a 1:1 propensity score‐matching analysis (7626 patient pairs for DPP‐4is and 28 484 for oGLDs). Direct healthcare resource utilizations and inpatient and outpatient costs were compared. Results: After matching, baseline characteristics were well balanced, including healthcare costs within 3 and 12 months before the index date (standardized difference <5% for all variables), with a mean age of 61.6‐64.1 years. While diabetes medication costs were higher in patients initiated with SGLT‐2is than in those initiated with DPP‐4is or oGLDs, further breakdown of individual cost components showed that SGLT‐2is were associated with a lower hospitalization frequency and a shorter total hospital stay (by 213.0 or 204.6 days/100 patient‐years compared with DPP‐4is or oGLDs, respectively; P <.001). Accordingly, overall mean cumulative cost per patient at the 2.5‐year postindex date was lower in patients with SGLT‐2is than in those with DPP‐4is or oGLDs by $2545 (1384.6‐3759.7) and $2330 (1793.1‐2882.9), respectively (P <.001). Conclusions: Our results show the benefits in healthcare resource utilization associated with SGLT‐2i use in Japanese T2D patients. [ABSTRACT FROM AUTHOR]

Introduction: Patients with type 2 diabetes (T2D) in Japan are prescribed a lower dose of metformin that their counterparts in Western countries due to concerns for the risk of lactic acidosis incidence. Here we report our study on the association between high-dose metformin administration and the incidence of lactic acidosis in Japanese patients with T2D. Methods: A Japanese claims database (April 2008–November 2018) was analyzed. Factors associated with the incidence of lactic acidosis were first identified from the database records by conducting a case–control study, and these were then used as confounding factors in subsequent analyses. The association between high-dose metformin administration (≥ 1000 mg/day) and the incidence of lactic acidosis was compared with that between low-dose metformin (< 1000 mg/day) or no metformin administration and lactic acidosis incidence by using the following approaches: a logistic regression analysis hypothesizing that metformin-associated lactic acidosis is short term; a time-dependent proportional hazard model hypothesizing that the influence of metformin is cumulative; and a case–control study in which lactic acidosis incidence was the case and metformin administration within 3 months prior to the incidence of lactic acidosis (or corresponding date for the control) was the exposure. Results: Prescriptions for biguanide and vitamin B complex and volume depletion were identified as factors associated with the incidence of lactic acidosis. The incidence rate was higher in patients prescribed metformin than in those not receiving metformin; however, it was not higher in those prescribed high-dose metformin compared to those prescribed low-dose metformin. The estimated regression coefficient for high-dose metformin administration was 0.816 (p < 0.001); this was not higher than those for low-dose metformin (1.047), vitamin B complex (2.725) and volume depletion (3.301). The time-dependent proportional hazard analysis did not indicate any effect of metformin prescription. Conclusion: The results suggest an association between metformin administration and the incidence of lactic acidosis, but an increase in the incidence rate of lactic acidosis was not observed in those patients receiving high-dose metformin compared to those receiving low-dose metformin. [ABSTRACT FROM AUTHOR]

Introduction: Metformin has dose-dependent hypoglycemic effects on patients with type 2 diabetes (T2D). In Japan, metformin has been prescribed at lower doses than in Western countries. We analyzed the effect of increasing the metformin dose on glycemic control and compared it to a combination therapy with dipeptidyl peptidase-4 inhibitors (DPP-4i) and a replacement therapy with DPP-4i. Methods: This is a cohort study using a Japanese claims database. Patients with T2D who had been initially treated with low-dose metformin (≥ 500 mg/day and < 1000 mg/day) and then given a prescription change by increasing metformin to a higher dose (≥ 1000 mg/day) (increased-dose), adding DPP-4i (drug-added), or switching to DPP-4i (drug-switched) were included in this study. The primary outcome was the change in HbA1c levels at 12 months from the baseline period. Results: Among 2,726,437 patients with T2D, 494 were included. Of these patients, 226, 240, and 28 patients were classified as increased-dose, drug-added, and drug-switched groups, respectively. The HbA1c levels at 12 months from the index significantly decreased compared to that during the baseline period. The change was the highest in the drug-added group (− 1.06%), followed by the increased-dose (− 0.91%) and the drug-switched groups (− 0.37%). Among the subset of patients who did not receive any antidiabetic drugs other than metformin or DPP-4i, the highest change in HbA1c levels was observed in the increased-dose group (− 0.84%), followed by the drug-added (− 0.67%) and the drug-switched (− 0.42%) groups. The order of decrease from baseline remained the same for all the study groups after the propensity score weighting adjustment. Conclusion: The effect on glycemic control when increasing the metformin dose was studied in patients who had been receiving low-dose metformin. Increasing metformin dosage shows effectiveness and could be one of the next treatment options in patients who were prescribed low-dose metformin as the first-line treatment. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Metformin therapy has been associated with vitamin B12 (VB12) deficiency, but information regarding this adverse effect in Asian populations is limited. We have now examined the relationship between metformin use and VB12 status in individuals with type 2 diabetes mellitus in Japan. Materials and Methods: This cross‐sectional study was carried out with type 2 diabetes mellitus patients treated (Met group, n = 122) or not treated (control group, n = 63) with metformin. The primary end‐point was the difference in the serum concentration of homocysteine, a marker of VB12 activity, between the two groups. The serum concentrations of VB12, blood hemoglobin level and mean corpuscular volume were also compared between the groups. Subset analysis was carried out with individuals aged ≥70 years. The potential correlation between the daily dose or duration of metformin treatment and the other measured parameters was also examined. Results: The level of homocysteine, as well as the VB12 level, hemoglobin concentration and mean corpuscular volume, did not differ significantly between the control and treated with metformin groups. The level of homocysteine was positively and that of VB12 negatively correlated with the daily dose of metformin. Among elderly individuals, the hemoglobin level was significantly lower in the treated with metformin group than in the control group, although the mean corpuscular volume was similar in the two groups. Conclusions: The risk of VB12 deficiency during metformin treatment appears to be low in Japanese type 2 diabetes mellitus patients. However, high doses of metformin might result in a moderate decrease in the circulating VB12 level, as well as in anemia in elderly individuals. [ABSTRACT FROM AUTHOR]

Background: Metformin is the most widely used oral antihyperglycemic agent for patients with type 2 diabetes mellitus (T2DM). Despite the possible benefits of metformin on diabetes mellitus (DM) and heart failure (HF), acute or unstable HF remains a precaution for its use. Objective: The aim of the present prospective randomized controlled trial was to assess whether metformin treatment has beneficial effects on patients with T2DM with hypertension without overt HF. Methods: A total of 164 patients (92 males, 72 females; median age 66 years) were included in this study. Patients with T2DM with a history of hypertension were randomized 1:1 to treatment for 1 year with either metformin (metformin-treated group) or other hypoglycemic agents (control group). The primary endpoints were changes in brain natriuretic peptide (BNP) levels, left ventricular (LV) mass index, and indicators of LV diastolic function. We also evaluated changes in both clinical findings and blood laboratory examination data. Results: We observed no significant changes between baseline and 1-year post-treatment in LV mass index, BNP levels, or E/e′ (early diastolic transmitral flow velocity/early diastolic mitral annular velocity; an indicator of LV diastolic function) in either the metformin-treated (n = 83) or the control (n = 81) groups. The metformin-treated group had a significant reduction of body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C), but the control group did not. We determined that renal function, including serum creatinine and estimated glomerular filtration rate, deteriorated significantly in the control group but not in the metformin-treated group. Conclusion: LV mass and diastolic function were not affected after 1 year of metformin treatment in patients with T2DM. However, we observed benefits in terms of reductions in both BMI and LDL-C levels and preservation of renal function. Trial Registration: UMIN000006504. Registered 7 October 2011. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a serious metabolic disorder affecting millions of people worldwide. Phenformin and metformin are biguanide antidiabetic agents that are conveniently synthesized in a single‐step chemical reaction. Phenformin was once used to lower blood glucose levels, but later withdrawn from the market in several countries because it was frequently associated with lactic acidosis. Metformin is still a widely prescribed medication for the treatment of type 2 diabetes despite the introduction of several newer antidiabetic agents. Metformin is administered orally and has desirable pharmacokinetics. Incidence of metformin‐induced lactic acidosis is serious but very rare. Imeglimin, a novel molecule being investigated by Poxel and Sumitomo Dainippon Pharma in Japan, is currently in clinical trials for the treatment of type 2 diabetes. Unlike metformin, imeglimin is a cyclic molecule containing a triazine ring. However, like metformin, imeglimin is also a basic small molecule. Imeglimin is synthesized from metformin as a precursor via a single step chemical reaction. Recent mechanism of action studies suggests that imeglimin improves mitochondria function, when given in combination with metformin it helps achieve better glycemic control in patients with type 2 diabetes. We herein describe and compare the current status, synthesis, physicochemical properties, pharmacokinetic parameters, mechanism of action, and preclinical/clinical studies of metformin and imeglimin. [ABSTRACT FROM AUTHOR]

Aims and Objectives: Dipeptidyl peptidase‐4 inhibitor (DPP4i) is widely used for the treatment of type 2 diabetes (T2DM) in several countries such as Japan, whereas biguanide (BG; mostly metformin) is recommended as a first‐line antidiabetic medication in many countries according to evidence mainly from Western countries. Although previous studies reported that DPP4i may be more efficacious for East Asians, direct comparisons of effectiveness and cost between DPP4i and BG have never been conducted in East Asia. Methods: We extracted claims and medical check‐up data (observation period from January 2010 to March 2016) of adult patients under 70 years old with T2DM who received DPP4i or BG as first‐line antidiabetic drugs. Changes in HbA1c and BMI before and 2 years after the first prescription and annual cost of antidiabetic medication during the second year were compared between the DPP4i and BG groups. Results: We extracted 1034 patients who received DPP4i and 365 patients who received BG as the first antidiabetic medication (male sex, 83.0% and 84.9%; HbA1c (mean [SD]), 7.7 [1.4]% and 7.9 [1.4]%; BMI, 26.6 [4.5] kg/m2 and 28.1 [4.3] kg/m2). After propensity score matching, changes in HbA1c and BMI were not significantly different between the groups (HbA1c, −0.67% vs −0.80% [P =.28]; BMI, −0.3 kg/m2 vs −0.4 kg/m2 [P =.42]). Annual cost of antidiabetic drugs was significantly higher in the DPP4i group (US $458.7 vs 273.3 [P <.001]). Many patients continued each medication at the follow‐up visit (78.3% of the DPP4i group and 73.7% of the BG groups). Conclusions: The first antidiabetic prescription for the patient was mostly continued thereafter. BG may be recommendable as the first‐line medication for patients with T2DM, especially for middle‐aged, male population with greater BMI. It is worth addressing the discrepancy between practice in Japan and that recommended in international guidelines. [ABSTRACT FROM AUTHOR]

A prospective, multicentre, open‐label, blinded‐endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium‐dependent glucose transporter‐2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%‐10%, and body mass index (BMI) ≥ 22 kg/m2. Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000‐1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (−12.06% vs. −3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)‐resistance, and increased HDL‐cholesterol levels. Metformin significantly reduced HbA1c and LDL‐cholesterol levels and increased HOMA‐beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase‐4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Introduction: The Japanese guidelines for type 2 diabetes mellitus (T2DM) emphasize individualization of treatment based on patient need and encourage physicians to select an appropriate oral antidiabetes drug (OAD). However, limited evidence is available on the factors influencing the selection by physicians (diabetes specialists and nonspecialists) of the first-line OAD to treat drug-naive patients with T2DM. A survey was designed to explore the treatment factors and patient characteristics that influence physicians when they choose an initial OAD to prescribe to a drug-naive patient with T2DM in a real-world setting in Japan.Methods: The 25-min web-based online survey consisted of simple and focused multiple-choice questions, and was circulated to physicians across eight selected regions in Japan. The primary endpoints were the proportions of physicians who considered particular treatment factors and patient characteristics when selecting the appropriate treatment for drug-naive T2DM patients.Results: A total of 491 physicians participated in the survey. Dipeptidyl peptidase-4 inhibitors (DPP-4is) were the most-preferred first-line OADs, followed by metformin, of both specialists (69% vs. 60%) and nonspecialists (73% vs. 47%). The most influential factors when a DPP-4i was selected were found to be glycated hemoglobin (HbA1c), postprandial glucose (PPG)-lowering effect, and a low risk of hypoglycemia, which were considered by > 80% of physicians, whereas the key factors when metformin was selected were improvement in insulin resistance, low cost, low risk of hypoglycemia, and PPG- and HbA1c-lowering effects, which were considered by > 85% of physicians. Regression analysis revealed that the dominant reason for choosing DPP-4is over metformin was their ease of use in patients with renal impairment, whereas the dominant reasons for choosing metformin over DPP-4is were improvement in insulin resistance and low cost. The key patient characteristics driving the choice of DPP-4is or metformin as the first-line OAD by physicians were similar to those that influenced the treatment intensification decision (DPP-4is: PPG and renal function; metformin: age, BMI, insulin resistance, and renal function).Conclusion: In Japan, DPP-4is are the preferred first-line OADs, followed by metformin. The key treatment factors and patient characteristics considered when selecting DPP-4is or metformin are similar for both specialists and nonspecialists. These results may prompt further discussion of the differences in T2DM treatment between Japan and other counties.Funding: Novartis. [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 prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence.Methods: This trial was a multicentre, double-blind, placebo-controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254.Findings: Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 [38·0%; 95% CI 26·7-49·3] of 71 patients, placebo group 35 [56·5%; 95% CI 44·1-68·8] of 62; p=0·034, risk ratio [RR] 0·67 [95% CI 0·47-0·97]; adenomas: metformin group 22 [30·6%; 95% CI 19·9-41·2] of 71 patients, placebo group 32 [51·6%; 95% CI 39·2-64·1] of 62; p=0·016, RR 0·60 [95% CI 0·39-0·92]). The median number of polyps was zero (IQR 0-1) in the metformin group and one (0-1) in the placebo group (p=0·041). The median number of adenomas was zero (0-1) in the metformin group and zero (0-1) in the placebo group (p=0·037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial.Interpretation: The administration of low-dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions.Funding: Ministry of Health, Labour and Welfare, Japan. [ABSTRACT FROM AUTHOR]

Metformin monotherapy as first-line treatment for patients with type 2 diabetes (T2D) has been shown to effectively improve blood glucose levels and motivation to undergo treatment and prevent complications. However, no studies have reported its effect when combined with other drugs or compared the effect based on administration time. This study aimed to investigate the effect of metformin administration in Japanese patients with T2D, examine how the introduction line impacts the effect of metformin, and examine the characteristics of patients demonstrating improved blood glucose levels. Data on characteristics of patients who were newly prescribed metformin with no shifting of hypoglycemic agents in the subsequent 24-week observation period, and their age [mean, 56.8 years], body mass index [mean, 27.5 kg/m 2 ], glycated hemoglobin [HbA1c] [mean, 8.1%], and duration of diabetes [mean, 3.0 years] were obtained from the medical records of 201 patients. The changes in HbA1c by introduction line after 24 weeks were -1.59%, -0.91%, -0.89%, and -0.65% in the first, second, third, and fourth induction lines, respectively; earlier introduction more significantly improved blood glucose. The factors significantly associated with HbA1c changes were early introduction, high baseline HbA1c, high estimated glomerular filtration rate, decreased insulin secretion, short estimated duration of diabetes, and increased metformin dose. Furthermore, factors contributing to the largest HbA1c improvement by metformin were high baseline HbA1c and early administration. Metformin is expected to lower blood glucose levels in Japanese patients with T2D, even in those with decreased insulin secretion, due to its early introduction as a first-line drug.

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]

Introduction: To present longitudinal data from the Real-world Observational Study on Patient Outcomes in Diabetes (RESPOND) in Japan., Research Design and Methods: In this multicenter, prospective, observational cohort study, patients with type 2 diabetes mellitus (T2DM) newly initiated on monotherapy were followed up for 2 years. Primary outcomes included changes in treatment pattern over time, target hemoglobin A1c (HbA1c) attainment and treatment satisfaction per Oral Hypoglycaemic Agent Questionnaire (OHA-Q)., Results: Among 1474 enrolled patients (male, 62.1%; mean age, 59.7 years; HbA1c, 8.08%), the oral antidiabetic drug (OAD) monotherapy prescription rate decreased to 47.2% and that of 2 and ≥3 OADs increased to 14.8% and 5.4% at 24 months, respectively. Switch/add-on OAD was associated with higher HbA1c and body mass index (BMI), baseline OAD being non-dipeptidyl peptidase-4 inhibitor (DPP-4i)/non-sodium glucose cotransporter-2 inhibitor (SGLT2i), diabetes complications, no comorbidities and consulting a diabetes specialist. The mean (SD) HbA1c (%) was 6.73 (0.85) at 24 months. Higher HbA1c, diabetes complications, cardiovascular disease, being employed, no hypertension and younger treating physician were associated with ≥2 OAD classes prescription or target HbA1c non-attainment at 24 months. OHA-Q subscale scores were significantly higher in patients achieving (vs not achieving) target HbA1c and in those continuing monotherapy (vs combination therapy). Baseline age (<65 years), sex (female), HbA1c, alcohol use, use of non-‍DPP-4i OADs or non-T2DM drugs, diabetes complications and cardiovascular disease had a significant negative impact, while EuroQol five-dimensional five-level and Summary of Diabetes Self-Care Activities-specific diet scores, BMI and unemployment had a significant positive impact on OHA-Q scores at 24 months., Conclusions: Primary outcomes show real-world treatment patterns and glycemic control over 2 years in patients with T2DM newly initiated on OAD monotherapy in Japan. Key factors associated with durability of initial monotherapy, target achievement or treatment satisfaction included baseline HbA1c, comorbidity and initial OAD choice., Competing Interests: Competing interests: AT, KT, JE and ST are employees of MSD K.K., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or hold stock options in the company. HO has received personal fees from MSD during the conduct of the study. HW has received grants and personal fees from MSD during the conduct of the study. His relevant financial activities outside the submitted work are grants and personal fees from Astellas, Daiichi Sankyo, Eli Lilly, Mitsubishi Tanabe, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, Ono, Sanofi, Sanwa Kagaku, Sumitomo Dainippon and Takeda; grants from Johnson & Johnson, Teijin, Yakult, Kissei, Kowa, Kyowa Hakko Kirin, Pfizer and Taisho Toyama and personal fees from Fujifilm, Terumo and AstraZeneca. IS has received personal fees from MSD during the conduct of the study. His relevant financial activities outside the submitted work are grants and personal fees from Kowa, Novo Nordisk and Takeda; grants from Kobayashi, Daiichi Sankyo, Kyowa Kirin, Mitsubishi Tanabe, Mochida, Rohto, Sanofi, Sumitomo Dainippon and Teijin; and personal fees from Ono, Taisho and Eli Lilly. TK has received honoraria (e.g., lecture fees) from MSD K.K., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., Teijin Pharma Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Sumitomo Dainippon Pharma Co., Ltd., Sanofi K.K., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Novartis Pharma K.K., Daiichi Sankyo Co., Ltd., FUJIFILM Toyama Chemical Co., Ltd., Kowa Co., Ltd. and Kyowa Kirin Co., Ltd.; received research grants from Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., MSD K.K., Daiichi Sankyo Co., Ltd., Novo Nordisk Pharma Ltd., Sanofi K.K., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation and Sumitomo Dainippon Pharma Co., Ltd.; received consulting fees from Abbott Japan LLC, Medtronic Japan Co., Ltd. and Novo Nordisk Pharma Ltd. and endowed departments by commercial entities (Asahi Mutual Life Insurance Company)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of this study was to identify alternative compounds to the tumor suppressor miR-375 using the connectivity map (CMAP) and to validate the antitumor effects of the identified drugs in esophageal squamous cell carcinoma (ESCC). Methods: Gene profiling of miR-375-treated TE2 and T.Tn cells was applied in order to search the CMAP database. Among the compounds identified using the CMAP, we focused on 8 drugs [(-)-epigallocatechin-3-gallate, metformin, rosiglitazone among others], excluding 2 drugs among the top 10 compounds. We evaluated whether these compounds possess tumor-suppressive functions in ESCC. Results: A cytotoxicity assay showed that the sensitivity of TE2 and T.Tn cells treated with the 8 compounds was evaluated based on IC50 values of 42.9 µM to 3.8 mM. A cell cycle analysis revealed that the percentage of TE2 and T.Tn cells incubated with 6 compounds in the G0/G1 phase or the G2/M phase increased by approximately 40-80%. A TUNEL assay showed that the percentages of apoptotic cells treated with almost all compounds were significantly increased (p < 0.05) compared with the control cells. Conclusion: The CMAP database is a useful tool for identifying compounds affecting the same molecular pathways, particularly products that are difficult to apply via practical approaches, such as microRNAs. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims/Introduction We investigated the efficacy and safety of repaglinide as an add-on therapy for Japanese patients with type 2 diabetes mellitus receiving metformin monotherapy (at a dose of 1,500 mg/day, mainly) in addition to diet and exercise. Materials and methods In the 16-week multicenter, placebo-controlled, randomized, double-blind, parallel-group trial (the phase III study), patients with type 2 diabetes mellitus with metformin monotherapy were randomly assigned to the repaglinide or placebo group. Thereafter, a 36-week, multicenter, uncontrolled, dose-titration method study was extended to a total duration of 52 weeks (the long-term study). The primary end-point of each study was a change in glycated hemoglobin (HbA1c) from baseline. Results After 16 weeks, mean reductions in HbA1c were significantly greater for the repaglinide group than for the placebo group (-0.98 ± 0.72% vs 0.13 ± 0.63%, P < 0.001). In the long-term study, the mean change in HbA1c was −0.76 ± 0.83%. The rate of adverse events was 60.6 and 50.0% in the repaglinide and placebo groups, respectively, in the phase III study, and 78.3% in the long-term study. Hypoglycemia was reported in 11.7, 0 and 13.3% of patients in the repaglinide group, placebo group and long-term study, respectively. Conclusions Combination therapy with repaglinide and metformin resulted in an approximately 1% reduction in HbA1c at week 16 and in a significant long-term improvement in HbA1c at the end of the study. No safety problems were noted during the concomitant use of repaglinide and metformin. These studies were registered with Japic CTI (nos. Japic CTI-101202 and Japic CTI-101203). [ABSTRACT FROM AUTHOR]

Aims To evaluate the efficacy and safety of alogliptin added to metformin versus metformin monotherapy in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on metformin (500 or 750 mg/day) + diet/exercise. Methods In a randomized, double-blind trial, 288 patients with type 2 diabetes mellitus T2DM received either 12.5 or 25 mg alogliptin once daily + metformin or placebo + metformin for 12 weeks. Thereafter, 276 patients continued on one of the two alogliptin dosages + metformin in an open-label extension for 40 weeks. The primary efficacy endpoint in the randomized, double-blind phase was the change in HbA1c from baseline (week 0) to the end of treatment (week 12). The primary endpoint during the long-term extension phase was adverse events. Results After 12 weeks both dosages of alogliptin + metformin produced significantly greater changes from baseline in HbA1c than placebo (metformin monotherapy: with changes in LS means − 0.55 and − 0.64% vs. 0.22%, respectively; p < 0.0001). Incidences of adverse effects were comparable between groups, with no increases in hypoglycaemia. Over 52 weeks, there were no safety or tolerability concerns with alogliptin when added to metformin. Conclusions Alogliptin 12.5 and 25 mg once daily was safe and effective when added to metformin (500 or 750 mg/day) in Japanese patients with inadequately controlled type 2 diabetes on metformin alone. [ABSTRACT FROM AUTHOR]

Aim: Metformin plays an important role in the inhibition of cancer cell growth and prolongs remission durations. It reverses progestin-resistance in endometrial cancer cells by downregulating glyoxalase I (GloI) expression. This study aimed to investigate the effect of metformin on endometrial cancer cell chemotherapeutic sensitivity and explore the underlying molecular mechanisms. Material and Methods: MTT assay was performed to determine the rate of cell death after cisplatin and paclitaxel with or without metformin. Western blot was carried out to analyze GloI expression. SiRNA-targeting of GloI was used to knockdown GloI expression before further treatment with chemotherapeutic agents to examine the effect of GloI downregulation on chemotherapy-induced cell killing. In addition, plasmid transfection was used to overexpress GloI and determine whether high GloI levels blocked metformin-enhanced cell sensitivity to chemotherapy. PCR was used to analyze the efficiency of RNA interference and plasmid transfection. Results: The addition of metformin enhanced the sensitivity of endometrial cells to cisplatin and paclitaxel, which was associated with reduced levels of GloI expression. Moreover, low-dose chemotherapeutic drugs alone could not significantly reduce GloI expression, whereas the addition of metformin potently downregulated GloI protein levels. Cisplatin and paclitaxel markedly inhibited the proliferative ability of GloI-depleted endometrial cancer cells. However, the overexpression of GloI abolished the effect of metformin-enhanced cell sensitivity to chemotherapeutic drugs. Conclusion: Metformin enhances the rate of cell-killing induced by chemotherapeutic agents by repressing GloI expression. [ABSTRACT FROM AUTHOR]

Combination therapy with a dipeptidyl peptidase (DPP)-4 inhibitor and metformin or sulfonylurea results in substantial and additive glucose-lowering effects in patients with type 2 diabetes mellitus (T2DM). However, it is not known whether triple combination therapy with a DPP-4 inhibitor, metformin, and sulfonylurea has greater additive effects or synergic effects. In the present report, we investigated the effect of addition of sitagliptin, the first-in-class DPP-4 inhibitor, to ongoing metformin and sulfonylurea therapy in three female Japanese patients with T2DM who refused insulin therapy. Combined treatment with all three drugs resulted in marked improvements in HbA1c. In the first patient, HbA1c levels decreased from 11.1% to 6.1% after the addition of sitagliptin to metformin 1000 mg, glibenclamide, and miglitol, even though the dose of glibenclamide was decreased. HbA1c levels decreased similarly in the second patient, who was being treated with metformin and glibenclamide, from 7.9% to 6.0% after addition of sitagliptin and an increase in metformin to 2250 mg; this patient ceased glibenclamide because of hypoglycemia and instead was started on lowdose glimepiride. In the third patient, HbA1c levels decreased from 8.6% to 7.1% after addition of glimepiride to ongoing sitagliptin and metformin therapy. All three patients had refused insulin therapy, despite the fact that ongoing combination therapy had failed to achieve satisfactory glycemic control. Based on these results, it is likely that the addition of sitagliptin to metformin and at least a small dose of sulfonylurea may be effective in reducing HbA1c levels without weight gain. This triple combination therapy may prove useful in at least some patients who need initiation of insulin therapy [ABSTRACT FROM AUTHOR]

The maximum dosage of metformin allowed for clinical use in Japan is much less than half that in Western countries, making it difficult to apply the results of clinical trials in Western countries to Japanese patients. In particular, the efficacy and safety of metformin in elderly patients are largely unknown. Among 1508 patients who were newly prescribed metformin at our hospital from 2000-2006, patients with sufficient clinical data were retrospectively studied for the safety ( n = 1132) and efficacy ( n = 568) of the drug. Of 568 patients in whom the efficacy of metformin was analyzed, 180 patients (31.7%) were elderly, aged 65 years or over. Metformin was effective for the treatment of type 2 diabetes in Japanese patients, with significant improvement in HbA level at all time-points after 1 month, with the largest decrease by approximately 0.9% in patients treated with 750 mg/day and approximately 0.7% in those treated with 500 mg/day, at 4 months. Metformin improved glycemic control in elderly patients as well as non-elderly patients. The efficacy was independent of age, sex, degree of obesity and concomitant use of other drugs. No significant difference was observed in elevated lactic acid levels between elderly and non-elderly patients. No case of lactic acidosis was observed. These results suggest that the efficacy of metformin in Japanese elderly patients with type 2 diabetes is not different from that in non-elderly patients, and that its safety might be linked to specific and well-documented contraindications rather than age itself. [ABSTRACT FROM AUTHOR]

Aim: Recent studies suggest that insulin resistance is associated with increased intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) contents. While metformin improves insulin resistance mainly in liver, its effects on IHL and IMCL have not been clarified yet. The aim of this study was to investigate the effects of low-dose metformin (750 mg/day) on peripheral insulin sensitivity, IHL and IMCL. Methods: Before and 3 months after low-dose metformin therapy, eight overweight/obese Japanese subjects [body mass index (BMI) >25 kg/m2] were studied with blood sampling, measurement of IHL and IMCL by 1H magnetic resonance spectroscopy and glucose infusion rate (GIR) during euglycaemic–hyperinsulinaemic clamp as an index of peripheral insulin sensitivity. Results: A 3-month low-dose metformin therapy did not alter body weight, total body fat, fat distribution or physical activity level but increased GIR by 31% (from 6.24 ± 0.86 to 7.82 ± 0.82 mg/kg/min, p < 0.01). Although metformin treatment did not alter IMCL (from 4.1 ± 1.0 to 4.2 ± 0.9, not significant), it decreased IHL by 21% (from 15.9 ± 2.8 to 11.8 ± 2.2%, p < 0.05). Conclusions: A 3-month low-dose metformin treatment improved peripheral insulin sensitivity and reduced IHL, without significantly changing BMI, adiposity or IMCL. [ABSTRACT FROM AUTHOR]

Abstract: Background: Insulin resistance is a critical aspect of the pathophysiology of type 2 diabetes mellitus and is also associated with other risk factors for cardiovascular disease (eg, dyslipidemia and hypertension). Accordingly, insulin resistance is a possible target for lowering plasma glucose concentration and preventing diabetic macroangiopathy. Biguanides, such as metformin, and thiazolidinediones (TZDs), such as pioglitazone, improve insulin resistance. Objectives: The aims of this study were to assess the effects of replacing a biguanide with a TZD on glycemic control in patients with poorly controlled type 2 diabetes mellitus, and also to identify the factors affecting interpatient variation in the effects of treatment change. Methods: This was a 12-week, open-label, prospective study in which previously prescribed metformin (500 or 750 mg/d) was replaced with pioglitazone (15 or 30 mg/d) in patients with poorly controlled type 2 diabetes mellitus. Patients with a glycosylated hemoglobin (HbA1c) concentration >7% despite treatment with diet, exercise, and hypoglycemic agents other than TZDs were eligible for the study. Patients who never received TZDs were also eligible for inclusion. Vital signs, metabolic parameters, and arterial stiffness were assessed at baseline and after 12 weeks of treatment with pioglitazone. The primary end point was change in HbA1c concentration after replacing metformin with pioglitazone. Tolerability was assessed by medical history, physical examination, and laboratory tests (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase). Results: Twenty-one Japanese patients (15 women, 6 men; mean [SD] age, 61.8 [8.4] years; body mass index, 25.5 [3.0] kg/m2) were included in the study. HbA1c concentration was not significantly changed from baseline after 12 weeks of pioglitazone treatment (8.0% [0.7%] vs 8.2% [0.7%]). Fasting plasma glucose (FPG) concentration also was not significantly changed after the replacement of treatment (156 [27] vs 144 [30] mg/dL). In addition, the resistin concentration did not change significantly from baseline after 12 weeks of pioglitazone treatment (6.6 [3.8] vs 6.4 [3.6] ng/mL). In contrast, significant improvement from baseline was observed in triglyceride (TG) concentrations (157 [109] vs 117 [68] mg/dL; P = 0.003), high-density lipoprotein cholesterol (HDL-C) (55 [12] vs 61 [16] mg/dL; P = 0.016), remnant-like particle cholesterol (6.6 [6.0] vs 5.3 [3.5] mg/dL; P = 0.048), and serum adiponectin (8.8 [4.3] vs 23.3 [11.7] μg/mL; P < 0.001). Pulse wave velocity was also significantly improved (1730 [361] vs 1622 [339] m/sec; P = 0.009). Changes in HbA1c were significantly correlated with serum fasting insulin concentration at baseline in the patients not receiving insulin preparations (r = -0.635, P = 0.013). The percentage change in serum adiponectin concentration was correlated with the percentage changes in HbA1c and FPG concentrations (HbA1c, r = -0.518, P = 0.019; FPG, r = -0.594, P = 0.006). Body weight was significantly increased after treatment (62.6 [11.9] vs 65.5 [12.2] kg; P < 0.001). Mild edema was reported in 5 patients. One patient discontinued treatment due to an increase in serum creatine kinase activity to ~6.6 times the upper limit of normal. Conclusions: Replacement of metformin with pioglitazone did not produce significant differences in HbA1c and FPG concentrations from baseline after 12 weeks of treatment in these patients with poorly controlled type 2 diabetes mellitus. However, the replacement was effective in a subset of patients whose serum insulin concentrations were high or whose serum adiponectin concentrations were sensitive to TZDs. In addition, the replacement was associated with significant improvements in TG, HDL-C, serum adiponectin concentration, pulse wave velocity, and body weight increase from baseline. [Copyright &y& Elsevier]

The article discusses the post-war claims filed in the Japanese Court for compensation for damages against the unlawful act committed during the Second World War in Japan. It highlights the classification of cases caused by Japan in violation of International humanitarian law which includes the cases brought by the comfort women system victims who were exploited and treated as sexual slaves, cases relating to forced labor and forced transportation of Chinese or Korean, and cases brought by civilians who suffered from inhuman treatment. It briefly examines the negative attitudes concerning the denied compensation claims in terms of International law and Japanese courts. It notes on the several judgments in which the significant departure from earlier jurisprudence in Japan is represented.

Objectives: Due to the increase of type 2 diabetes (T2D), the number of patients in treatment with multiple anti-diabetic agents is increased. According to the recent recommendation of treatment guidelines, sodium-glucose cotransporter 2 (SGLT2) inhibitors would be used as additional treatment to the currently administered anti-diabetic drugs for poorly controlled T2D patients. Here, we assessed the efficacy of SGLT2 inhibitors added to the current treatment with metformin, dipeptidyl peptidase-4 (DPP4) inhibitors, or both in Japanese T2D patients., Results: Japanese T2D subjects with poor glucose control, who were treated with metformin (n = 10), DPP4 inhibitors (n = 11), or both (n = 28) and who were in need of additional treatment, were recruited. HbA1c levels before and 6 months after addition of SGLT2 inhibitor treatment were used to compare the effectiveness. The HbA1c levels after addition of SGLT2 inhibitors significantly decreased in all groups. The change in HbA1c levels (delta HbA1c) showed no significant difference between the three groups. The present data indicated that addition of SGLT2 inhibitors to metformin and/or DPP4 inhibitors is equally effective in the treatment of Japanese T2D patients., (© 2022. The Author(s).)

Introduction: Although metformin is recommended as a first-line treatment for patients with type 2 diabetes (T2D) in Western countries, no specific treatment is recommended in Japan, and various agents are used. Metformin has long been used at low doses in Japan, and information regarding its effect at the maximum maintenance dose is lacking. Here, we compared the efficacy and safety of metformin at 1500 mg/day with those of the other oral anti-diabetic drugs (OADs) approved in Japan., Methods: Randomized controlled trials comparing a change in hemoglobin A1c (HbA1c) from baseline at 12 weeks or later (ΔHbA1c) among OADs (including placebo) as a first-line treatment in adult patients with T2D were selected by systematic review with comprehensive searching of CENTRAL, MEDLINE, Ichushi Web, and EMBASE and manual searching of clinical trial registries. The ΔHbA1c and incidence of hypoglycemia were compared among OAD treatments using Bayesian network meta-analysis (NMA). The relative risk (RR) of the incidence of hypoglycemia was determined relative to that of placebo., Results: Forty-six randomized controlled trials were identified in the systematic review, and 37 studies, comprising 38 different types of treatments, including placebos, were selected for the NMA of ΔHbA1c. Compared with metformin 1500 mg/day, 20 OAD treatments were significantly less effective in reducing HbA1c from baseline (differences from metformin 1500 mg/day: 0.40-0.96%). Two treatments (glimepiride 2 mg/day and pioglitazone 45 mg/day) showed greater mean reductions in HbA1c from baseline than metformin 1500 mg/day (- 0.38% and - 0.03%), although these differences were not significant. Regarding the incidence of hypoglycemia, only pioglitazone 30 mg/day among 31 treatments showed a lower RR (< - 0.01), whereas 23 treatments showed a significantly higher RR (1.02-66.71) than metformin 1500 mg/day., Conclusion: The NMA suggested a preferable efficacy and safety profile of metformin 1500 mg/day compared with the other OADs approved in Japan., (© 2021. The Author(s).)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of a deterioration in heart failure (HF) and mortality in patients with a broad range of cardiovascular risks. Recent guidelines recommend considering the use of SGLT2 inhibitors in patients with type 2 diabetes (T2D) and HF, irrespective of their glycemic control status and background use of other glucose-lowering agents including metformin. However, only a small number of studies have investigated whether the effects of SGLT2 inhibitor in these patients differ by the concomitant use of other glucose-lowering agents., Methods: This was a post-hoc analysis of the CANDLE trial (UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. The primary aim of the analysis was to assess the effect of 24 weeks of treatment with canagliflozin, relative to glimepiride, on N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in patients with T2D and clinically stable chronic HF. In the present analysis, the effect of canagliflozin on NT-proBNP concentration was assessed in the patients according to their baseline use of other glucose-lowering agents., Results: Almost all patients in the CANDLE trial presented as clinically stable (New York Heart Association class I to II), with about 70% of participants having HF with a preserved ejection fraction phenotype (defined as a left ventricular ejection fraction ≥ 50%) at baseline. Of the 233 patients randomized to either canagliflozin (100 mg daily) or glimepiride (starting dose 0.5 mg daily), 85 (36.5%) had not been taking any glucose-lowering agents at baseline (naïve). Of the 148 patients who had been taking at least one glucose-lowering agent at baseline (non-naïve), 44 (29.7%) and 127 (85.8%) had received metformin or a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, respectively. The group ratio (canagliflozin vs. glimepiride) of proportional changes in the geometric means of NT-proBNP concentration was 0.95 (95% confidence interval [CI] 0.76 to 1.18, p = 0.618) for the naïve subgroup, 0.92 (95% CI 0.79 to1.07, p = 0.288) for the non-naïve subgroup, 0.90 (95% CI 0.68 to 1.20, p = 0.473) for the metformin-user subgroup, and 0.91 (95% CI 0.77 to 1.08, p = 0.271) for the DPP-4 inhibitor-user subgroup. No heterogeneity in the effect of canagliflozin, relative to glimepiride, on NT-proBNP concentration was observed in the non-naïve subgroups compared to that in the naïve subgroup., Conclusion: The impact of canagliflozin treatment on NT-proBNP concentration appears to be independent of the background use of diabetes therapy in the patient population examined. Trial registration University Medical Information Network Clinical Trial Registry, number 000017669. Registered on May 25, 2015., (© 2021. The Author(s).)

Background: The most recent treatment guidelines for type 2 diabetes (T2D) recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors should be considered preferentially in patients with T2D with either a high cardiovascular risk or with cardiovascular disease (CVD), regardless of their diabetes status and prior use of conventional metformin therapy. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy however remains unclear., Methods: The study was a post hoc analysis of the EMBLEM trial (UMIN000024502). All participants (n = 105; women 31.4%; mean age 64.8 years) had both T2D and CVD and were randomized to either 24 weeks of empagliflozin 10 mg daily or placebo. Analysis of the data assessed the effect of empagliflozin on changes from baseline to 24 weeks in glycemic and non-glycemic clinical parameters, according to the baseline use of metformin., Results: Overall, 53 (50.5%) patients received baseline metformin. In the 52 patients treated with empagliflozin (48.1% with baseline metformin), the decrease in systolic blood pressure from baseline levels was greater in patients receiving metformin, compared to that observed in metformin-naïve patients (group difference - 8.5 [95% confidence interval (CI) - 17.7 to 0.6 mmHg], p = 0.066). Reduction in body mass index (BMI) was significantly greater in patients receiving baseline metformin, relative to nonusers (- 0.54 [95% CI - 1.07 to - 0.01] kg/m 2 , p = 0.047). The group ratio (baseline metformin users vs. nonusers) of proportional changes in the geometric mean of high-sensitivity Troponin-I (hs-TnI) was 0.74 (95% CI 0.59 to 0.92, p = 0.009). No obvious differences were observed in glycemic parameters (fasting plasma glucose, glycohemoglobin, and glycoalbumin) between the baseline metformin users and nonusers., Conclusion: Our findings suggest 24 weeks of empagliflozin treatment was associated with an improvement in glycemic control, irrespective of the baseline use of metformin therapy. The effects of empagliflozin on reductions in BMI and hs-TnI were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502., (© 2021. The Author(s).)

Aims: To assess efficacy and safety of fixed-ratio (1:1) combination insulin glargine and lixisenatide (iGlarLixi) compared to insulin glargine U100 (iGlar), with metformin, in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on basal insulin and oral antidiabetic drugs (OADs)., Materials and Methods: This 26-week, randomized, open-label study compared iGlarLixi to iGlar, both with metformin in adult Japanese patients with T2DM and hemoglobin (Hb) A1c ≥7.5% to ≤9.5%, treated with basal insulin and 1 or 2 OADs. Five hundred and twelve patients were randomized after a 12-week run-in, when iGlar was introduced and/or further titrated and OADs other than metformin were stopped. The primary endpoint was change in HbA1c from baseline to week 26., Results: iGlarLixi (n = 255) demonstrated significantly greater reductions in HbA1c (-1.27%) than iGlar (n = 257, -0.53%) (LS mean difference: -0.74%, P < .0001) at week 26, confirming the superiority of iGlarLixi. Significantly, more iGlarLixi patients reached target HbA1c <7% at week 26 (51.8% vs 16.0% for iGlar). iGlarLixi patients lost weight in contrast to iGlar patients (-0.51 kg vs +0.55 kg). Documented symptomatic hypoglycemia (plasma glucose ≤ 3.9 mmol/L) was observed in 18.8% of iGlarLixi patients vs 16.7% of iGlar patients. iGlarLixi patients had more gastrointestinal-related adverse events than iGlar patients (33.3% vs 8.6%), primarily nausea (16.9% vs 0.8%). However, the treatment was generally well-tolerated., Conclusions: A once-daily injection of iGlarLixi with metformin is an effective, well-tolerated, and simple therapeutic intervention providing significant improvement in glycemic control in Japanese patients with T2DM inadequately controlled on basal insulin and up to two OADs. Clinical Trial Number: NCT02752412., (© 2020 John Wiley & Sons Ltd.)

Aims/introduction: Metformin therapy has been associated with vitamin B 12 (VB12) deficiency, but information regarding this adverse effect in Asian populations is limited. We have now examined the relationship between metformin use and VB12 status in individuals with type 2 diabetes mellitus in Japan., Materials and Methods: This cross-sectional study was carried out with type 2 diabetes mellitus patients treated (Met group, n = 122) or not treated (control group, n = 63) with metformin. The primary end-point was the difference in the serum concentration of homocysteine, a marker of VB12 activity, between the two groups. The serum concentrations of VB12, blood hemoglobin level and mean corpuscular volume were also compared between the groups. Subset analysis was carried out with individuals aged ≥70 years. The potential correlation between the daily dose or duration of metformin treatment and the other measured parameters was also examined., Results: The level of homocysteine, as well as the VB12 level, hemoglobin concentration and mean corpuscular volume, did not differ significantly between the control and treated with metformin groups. The level of homocysteine was positively and that of VB12 negatively correlated with the daily dose of metformin. Among elderly individuals, the hemoglobin level was significantly lower in the treated with metformin group than in the control group, although the mean corpuscular volume was similar in the two groups., Conclusions: The risk of VB12 deficiency during metformin treatment appears to be low in Japanese type 2 diabetes mellitus patients. However, high doses of metformin might result in a moderate decrease in the circulating VB12 level, as well as in anemia in elderly individuals., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: The effects of type 2 diabetes mellitus (T2DM) medications on secondary prevention after acute coronary syndrome (ACS) remain unclear. We evaluated recurrent cardiovascular disease (CVD) after primary diagnosis of ACS in T2DM patients., Methods: This retrospective cohort study included 569 patients with newly diagnosed ACS from 2007 to 2012. The endpoint was recurrent CVD up to a five-year maximum follow-up until 2016. Kaplan-Meier analysis and Cox proportional hazard regressions were performed to examine the association between T2DM diagnosis, different antidiabetic drugs, and recurrent CVD., Results: Among 569 patients, 198 had T2DM. The mean follow-up was 1540 (interquartile range, 864-2157) days. Patients with diabetes showed higher risk of recurrent cardiovascular event compared with those without (P = 0.004). Patients with diabetes treated with metformin (65 patients) showed longer event-free survival, compared with those on other antidiabetic medications (P = 0.005). Multivariable analysis confirmed a reduced risk of recurrent CVD associated with metformin (hazard ratio, 0.33; 95% confidence interval, 0.12-0.91), while lower hemoglobin A1c levels on admission were not associated with better CVD outcomes., Conclusions: T2DM increases risk of recurrent CVD after first ACS episode regardless of glycemic control on admission, while use of metformin may reduce recurrence., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Guidelines for Type 2 diabetes mellitus (T2DM) management in Japan provide physicians the discretion to select treatment options based on patient pathophysiology of the disease. There exists a wide variation of preference for initial antidiabetes drugs (AD). The current database analysis aimed to understand the real world treatment patterns in drug-naive patients with T2DM in Japan. Methods: We analyzed data of patients (≥ 18 years) diagnosed with T2DM between October 2012 and September 2016 from the Medical Data Vision, a Diagnosis Procedure Combination database. The primary objective was to determine the proportion of T2DM patients receiving each type of treatment as first-line therapy among the drug-naive cohort. Results: Of the 436,546 drug-naive patients, 224,761 received their first-line T2DM treatment in the outpatient setting. The mean age of the patient population was 65.6 years at index date. Dipeptidyl peptidase-4 (DPP-4) inhibitor was the most prescribed (56.8%) outpatient AD monotherapy, followed by metformin (15.4%). DPP-4 inhibitors were prescribed over metformin in patients with renal disease (odds ratio [OR]: 4.20; p < 0.0001), coronary heart disease and stroke (OR: 2.22; p < 0.0001). Male (OR: 1.03; p = 0.0026), presence of diabetic complications [retinopathy (OR: 1.33; p < 0.0001), neuropathy (OR: 1.05; p = 0.0037), nephropathy (OR: 1.08; p < 0.0001)] and a high baseline HbA1c (OR: 1.45; p < 0.0001) received treatment intensification during 180 days. Conclusion: DPP-4 inhibitors were the most prevalent first-line T2DM treatment followed by metformin in Japan. The findings from this retrospective analysis also support the previously published web survey results and can help understand the real world utilization of T2DM treatment. Trial registration Retrospectively registered [ABSTRACT FROM AUTHOR]

In Japan, the choice of anti-diabetic medication is officially recommended according to the patient's glycemic condition and disease phenotype, unlike most other regions where metformin is recommended as the first-line medication. There has been an increase in the number of available glucose-lowering agents, making it necessary to select these agents based on ever-improving evidence obtained from clinical trials. For the dipeptidyl peptidase-4 inhibitor class of drugs, nine drugs are currently available on the market in Japan. Although previous cardiovascular outcome trials (CVOTs) demonstrated non-inferiority for both major adverse cardiovascular events (MACEs) and safety for some drugs of the class, the design and results of the CARMELINA trial seemed to be slightly different from earlier trials in that it showed the drugs were safe and partially effective even in patients with renal impairment. Thus, recent CVOTs on newer glucose-lowering agents have mainly focused on the major impacts of individual classes and drugs on clinical outcomes behind their glucose-lowering action. The diverse features of the classes and individual drugs may have also highlighted not only the class-effects, but also the drug-effects of glucose-lowering agents. This will lead to clinical-based evidence and assist with optimum selection of the class and/or drug for tailored medication in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]