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Aims/Introduction: Healthcare resource utilization (HCRU) and healthcare costs are important factors to consider when selecting appropriate treatment for type 2 diabetes mellitus. We compared the HCRU and healthcare costs of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with type 2 diabetes mellitus in Japan. Materials and Methods: This was a Japanese retrospective cohort study conducted using the JMDC Claims Database (January 1, 2015-December 31, 2021). Patients newly treated with an SGLT2i (31,872 patients) or a DPP4i (73,279 patients) were matched 1:1, using propensity score, after excluding patients without continuous SGLT2i or DPP4i prescriptions after the index date. HCRU and healthcare costs were compared between the treatment groups in the full cohort and subcohorts/subgroups of different baseline characteristics, including body mass index (BMI). Results: After matching, patient characteristics were well balanced (17,767 patients each). Patients receiving an SGLT2i vs those receiving a DPP4i had significantly lower numbers of hospitalizations per person per month (PPPM) and outpatient visits PPPM, and had shorter lengths of stay per hospitalization. Healthcare costs, including all-cause overall healthcare costs PPPM and all-cause hospitalization costs PPPM, were generally lower in patients receiving an SGLT2i than those receiving a DPP4i. Similar results were observed among patients with a higher BMI but not among patients with a lower BMI. Conclusions: SGLT2i were associated with lower HCRU and healthcare costs than DPP4i, suggesting economic benefits with SGLT2i vs DPP4i in type 2 diabetes mellitus management. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To evaluate the benefit of sodium–glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase‐4 inhibitors (DPP4i) in reducing cardiovascular disease (CVD) events in patients with type 2 diabetes mellitus with and without a CVD history. Materials and Methods: This retrospective cohort study used Japanese hospital administrative data from the Medical Data Vision database (January 2015 to April 2020). Patients with type 2 diabetes mellitus (n = 625,739) who were new users of an SGLT2i (n = 57,070; 9.1%) or DPP4i (n = 568,669; 90.9%) were included. Outcomes included hospitalization for heart failure (hHF), all‐cause death (ACD) and the composite of hHF or ACD. Hazard ratios (HR) were calculated using the inverse probability weighting Cox proportional hazards model to compare CVD event risks between treatment groups. Results: Compared with DPP4i, SGLT2i was associated with a significant reduction in hHF risk among patients without a CVD history (HR 0.507, 95% confidence interval 0.283–0.907), but not in the full cohort or those with a CVD history. SGLT2i was associated with a significant risk reduction of ACD (HR 0.592, 95% confidence interval 0.481–0.729) and the composite of hHF or ACD (HR 0.712, 95% confidence interval 0.613–0.826), compared with DPP4i in the full cohort; similar results were observed among patients with and without a CVD history. Conclusions: In this real‐world study, SGLT2i versus DPP4i was associated with a significant reduction in hHF, ACD and hHF or ACD events in patients with type 2 diabetes mellitus without a CVD history. [ABSTRACT FROM AUTHOR]

Aims/introduction: Healthcare resource utilization (HCRU) and healthcare costs are important factors to consider when selecting appropriate treatment for type 2 diabetes mellitus. We compared the HCRU and healthcare costs of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with type 2 diabetes mellitus in Japan., Materials and Methods: This was a Japanese retrospective cohort study conducted using the JMDC Claims Database (January 1, 2015-December 31, 2021). Patients newly treated with an SGLT2i (31,872 patients) or a DPP4i (73,279 patients) were matched 1:1, using propensity score, after excluding patients without continuous SGLT2i or DPP4i prescriptions after the index date. HCRU and healthcare costs were compared between the treatment groups in the full cohort and subcohorts/subgroups of different baseline characteristics, including body mass index (BMI)., Results: After matching, patient characteristics were well balanced (17,767 patients each). Patients receiving an SGLT2i vs those receiving a DPP4i had significantly lower numbers of hospitalizations per person per month (PPPM) and outpatient visits PPPM, and had shorter lengths of stay per hospitalization. Healthcare costs, including all-cause overall healthcare costs PPPM and all-cause hospitalization costs PPPM, were generally lower in patients receiving an SGLT2i than those receiving a DPP4i. Similar results were observed among patients with a higher BMI but not among patients with a lower BMI., Conclusions: SGLT2i were associated with lower HCRU and healthcare costs than DPP4i, suggesting economic benefits with SGLT2i vs DPP4i in type 2 diabetes mellitus management., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

In patients with type 2 diabetes mellitus (T2DM), controlling serum uric acid (SUA) and blood glucose levels is important. Moreover, sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease SUA levels by accelerating urinary uric acid excretion. We investigated the effect of baseline urinary glucose levels on the relationship between SGLT2 inhibitors and SUA levels. We conducted a retrospective observational study using the electronic medical records of patients with T2DM of Kindai University Nara Hospital (April 2013 to March 2022). We divided the patients into two groups according to their baseline urinary glucose levels: the N-UG group, which included patients with negative urinary glucose strip test results (-), and the P-UG group, which included patients with positive urinary glucose strip test results (± or more). The changes in SUA levels before and after SGLT2 inhibitor administration were investigated. For comparison, the changes in SUA levels before and after the prescription of antidiabetic agents, excluding SGLT2 inhibitors, were also investigated. Our results revealed that SGLT2 inhibitors significantly decreased the SUA levels in patients in the N-UG group but tended to decrease its levels in those in the P-UG group. Regardless of the urinary glucose status at baseline, the administration of SGLT2 inhibitors may be useful for patients with T2DM to prevent the complications of hyperuricemia.

Supplemental Digital Content is available in the text. Background: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SACRA (Sodium-Glucose Cotransporter 2 [SGLT2] Inhibitor and Angiotensin Receptor Blocker [ARB] Combination Therapy in Patients With Diabetes and Uncontrolled Nocturnal Hypertension) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy. Methods: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks' treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline and weeks 4, 8, and 12; 24-hour ambulatory BP monitoring was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. The primary efficacy end point was change from baseline in nighttime BP (ambulatory BP monitoring). Results: One hundred thirty-two nonobese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m2). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (–6.3 mm Hg; P =0.004); between-group difference in change from baseline was –4.3 mm Hg (P =0.159). Reductions in daytime, 24-hour, morning home, and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (–9.5, –7.7, –7.5, and –8.6 mm Hg, respectively; all P ≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (–1.3 kg and –0.33%; both P <0.001). At 4 weeks, N-terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (–12.1%; P =0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (–8.2% [ P =0.008] and –9.7% [ P =0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups. Conclusions: Nonseverely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of sodium-glucose cotransporter 2 inhibitors in specific groups (eg, those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03050229. [ABSTRACT FROM AUTHOR]

Background: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SGLT2 inhibitor and ARB Combination theRapy in pAtients with diabetes and uncontrolled nocturnal hypertension (SACRA) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy.Methods: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks' treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline, and weeks 4, 8 and 12; 24-hour ambulatory BP monitoring (ABPM) was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. Primary efficacy end point was change from baseline in nighttime BP (ABPM).Results: 132 non-obese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m2). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (-6.3 mmHg; p=0.004); between-group difference in change from baseline -4.3 mmHg (p=0.159). Reductions in daytime, 24-hour, morning home and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (-9.5, -7.7, -7.5 and -8.6 mmHg, respectively; all p≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (-1.3 kg and -0.33%; both p<0.001). At 4-weeks, amino terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (-12.1%; p=0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (-8.2% [p=0.008] and -9.7% [p=0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups.Conclusions: Non-severely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of SGLT2 inhibitors in specific groups (e.g. those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality.Clinical Trial Registration: URL: http://www.clinicaltrials.gov Unique identifier: NCT03050229. [ABSTRACT FROM AUTHOR]

Background: Several studies have reported the cost-effectiveness of sodium-glucose co-transporter 2 inhibitors in heart failure patients; however, their economic implications have not been sufficiently elucidated in Japan., Methods: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin plus standard of care (SoC) vs. SoC for patients with heart failure with reduced ejection fraction (HFrEF) in Japan. Model inputs, including risk of clinical events, costs, and utilities based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores were derived from EMPEROR-Reduced trial data, published literature, and a claims database., Results: The model predicted lower lifetime hospitalizations for heart failure (HHFs) and additional quality-adjusted life-years (QALYs; 0.21) for empagliflozin plus SoC vs. SoC in the overall population. Increased costs of ¥100,495/patient ($772/patient), primarily driven by higher drug costs of ¥239,558/patient ($1,840/patient), were largely offset by reduced HHF management costs of -¥166,160/patient (-$1,276/patient), yielding an incremental cost-effectiveness ratio (ICER) of ¥469,672/QALY ($3,608/QALY). Results were consistent among subgroups and sensitivity analyses. In probabilistic sensitivity analysis, 82.5 % of runs were below the Japanese ICER reference value of ¥5,000,000/QALY ($38,408/QALY)., Conclusions: Empagliflozin was demonstrated to be cost-effective for HFrEF patients in Japan based on the EMPEROR-Reduced trial data., Competing Interests: Declaration of competing interest Hiroyuki Tsutsui received remuneration for attending meetings from Kowa Company, Limited, TEIJIN PHARMA, Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Ono Pharmaceutical CO., LTD, Daiichi Sankyo Company, Novartis Pharma K.K, Bayer Yakuhin, Ltd., Otsuka Pharmaceutical, AstraZeneca K.K, received manuscript fee from Nippon Rinsho, received research funding from Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., IQVIA Services Japan K.K, medinet,inc, Medical Innovation Kyushu, Co., Ltd., Kowa Company, Daiichi Sankyo Company, Johnson & Johnson, NEC Corporation, received scholarship funds from Nippon Boehringer Ingelheim Co., Ltd., St.Mary's Hospital, TEIJIN PHARMA, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation. Hiroyuki, Sakamaki received research funding from TOWA PHARMACEUTICAL CO., LTD. Shin-ichi Momomura received remuneration for attending meeting from Nippon Boehringer Ingelheim Co., Ltd. Yasushi Sakata received remuneration for attending meeting from Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K, Ono Pharmaceutical, CO., LTD, Novartis Pharma K.K, received research funding from Nippon Boehringer Ingelheim, received scholarship funds from Ono Pharmaceutical, CO., LTD, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd. Yutaro Kotobuki and Daisuke Nitta are employees of Nippon Boehringer Ingelheim Co., Ltd., while Stephan Linden is employed by Boehringer Ingelheim International GmbH. Tatsunori Murata is an employee of CRECON Medical Assessment Inc. Tetsuaki Hirase is an employee of Eli Lilly Japan K. K. and has stock from Eli Lilly and Company. Odette Reifsnider, Pal Rakonczai, and Matthew Stargardter are employees of Evidera, a biopharmaceutical research and consulting firm. In these salaried positions, they work with a variety of companies and are explicitly precluded from accepting any payment or honoraria directly from those companies for services rendered. Evidera received payment from Nippon Boehringer Ingelheim Co., Ltd. for collaboration on this project and article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: To investigate the baseline demographic and clinical characteristics of patients with type 1 diabetes mellitus (T1DM) newly treated with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) as an add-on to insulin, or treated with insulin alone or in combination with oral anti-diabetic drugs other than an SGLT2i.Methods: Retrospective study using data from the JMDC database (December 21, 2018, to October 31, 2020). Included patients with T1DM treated with an SGLT2i (add-on to insulin) (n = 1027) or with insulin (n = 4320). Baseline demographic and clinical characteristics were summarized, and change in insulin dose and efficacy outcomes, including hemoglobin A1c (HbA1c) and body mass index (BMI), before and after the first SGLT2i or insulin prescription were evaluated.Results: The SGLT2i add-on group had higher HbA1c and BMI than the insulin group. Daily insulin doses decreased from immediately before to after the first SGLT2i prescription. HbA1c and BMI improved from baseline to after the first SGLT2i prescription.Conclusions: This large real-world study reported the baseline demographic and clinical characteristics of patients with T1DM newly treated with an SGLT2i in Japan. The findings may guide the appropriate use of SGLT2i and support large-scale database studies in T1DM research. [ABSTRACT FROM AUTHOR]

Background: Empagliflozin, a glucose-lowering drug licensed for type 2 diabetes (T2D), demonstrated tolerability and effectiveness overall in a post-marketing surveillance (PMS) study in Japan. However, the impact of body mass index (BMI) is unclear., Research Design and Methods: This was a prespecified sub-analysis of the prospective, 3-year, PMS study of empagliflozin in Japan where the primary endpoint was adverse drug reactions (ADRs). We evaluated results according to BMI., Results: We enrolled 7931 T2D patients treated with empagliflozin. Baseline mean age was 58.7 years; 63.01% were male. Baseline BMI was <20 kg/m 2 in 2.06% of patients, while 21.28%, 37.35%, and 24.97% had BMI 20-<25, 25-<30 and ≥30 kg/m 2 , respectively. ADRs occurred in 19 (11.66%), 203 (12.03%), 411 (13.88%), and 295 (14.90%) patients with BMI <20, 20-<25, 25-<30 and ≥30 kg/m 2 , respectively. Excessive/frequent urination was the most frequent ADR of special interest in all BMI subgroups except 20-<25 kg/m 2 (urinary tract infection). Mean change in glycated hemoglobin from baseline was -0.75%, with similar magnitude across BMI subgroups. Body-weight reduction seemed dependent on BMI, with almost no change in the <20 kg/m 2 subgroup., Conclusions: Empagliflozin appeared well tolerated and effective in Japanese T2D patients regardless of BMI, although the number of patients with BMI <20 kg/m 2 was small in this study.

Background: Empagliflozin, a sodium-glucose co-transporter-2 inhibitor, was licensed for treating type 2 diabetes (T2D) in Japan and elsewhere in recent years. We conducted a post-marketing surveillance study of empagliflozin in Japan., Research Design and Methods: This was a 3-year, prospective, multicenter, observational study of the safety and effectiveness of empagliflozin in T2D patients in Japanese clinical practice who had not previously received this medication. The primary endpoint was the incidence of adverse drug reactions (ADRs)., Results: Of 8145 patients enrolled from 1103 sites, 7931 received ≥1 dose of empagliflozin. Mean age was 58.7 years (10.5% aged ≥75), glycated hemoglobin (HbA1c) 8.0%, body mass index 28.1 kg/m 2 (<20 kg/m 2 in 2.1%); 63.0% were male and most had comorbidities (renal impairment in ~62%). Median treatment duration was 36.5 months. ADRs occurred in 1024 (12.91%) patients overall (serious ADRs in 2.09%) and 120 patients aged ≥75 years (14.46%). ADRs of special interest included hypoglycemia (0.44% of patients), urinary tract infections (1.07%), genital infections (0.66%), volume depletion (0.50%), diabetic ketoacidosis (0%), and lower limb amputation (0.04%). Overall mean change in HbA1c from baseline was -0.75%., Conclusions: Empagliflozin is effective and generally well tolerated in Japanese patients, and ADRs are consistent with its known safety profile.

Aims: A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA-REG OUTCOME trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus., Methods and Results: This ongoing study is a prospective, randomized, open-label, multicentre investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are conducted using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non-linear least squares method for square analysis. The primary endpoint is the change in the low-frequency (0.04-0.15 Hz)/high-frequency (0.15-0.4 Hz) ratio from baseline to 24 weeks., Conclusions: This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Introduction: The present interim report of the STELLA-LONG TERM study aimed to examine the safety and effectiveness of ipragliflozin in real-word clinical practice in Japan using data up to 12 months. We also evaluated the effect of ipragliflozin on aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in patients with normal vs. abnormal liver function., Methods: This is an ongoing 3-year post-marketing surveillance study. We analyzed data from Japanese type 2 diabetes mellitus (T2DM) patients who were first prescribed ipragliflozin between 17 July 2014 and 16 October 2015 at participating centers in Japan, and whose data were locked by 16 January 2018. The incidence of adverse drug reactions (ADRs) was evaluated for safety. Changes in glycemic control and body weight were evaluated for effectiveness. The effect on liver function was evaluated by changes in the fatty liver index, and changes in AST and ALT were evaluated in patients with normal and abnormal liver function., Results: The safety analysis set comprised 11,051 patients and the efficacy analysis set comprised 8788 patients. The incidence rates of ADRs and serious ADRs were 14.6% (1616/11,051) and 0.97% (107/11,051), respectively. Significant reductions (all P < 0.001 vs. baseline, paired t test) in glycated hemoglobin (- 0.8%), fasting plasma glucose (- 31.9 mg/dL), body weight (- 2.9 kg), and fatty liver index (- 8.7) were observed. In patients with normal liver function at baseline, no clinically significant changes in AST and ALT were observed. In patients with abnormal liver function at baseline, clinically and statistically significant decreases (P < 0.05 vs. baseline, two-sample t test) in AST (- 9.0 U/L) and ALT (- 14.7 U/L) levels were observed., Conclusion: Ipragliflozin was effective and well tolerated in Japanese patients with T2DM over 12 months in the real-world clinical setting. Improvements in liver function parameters (AST and ALT) were observed in T2DM patients with abnormal liver function., Trial Registration: ClinicalTrials.gov identifier, NCT02479399., Funding: Astellas Pharma Inc., Japan.

Aims/introduction: Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of drugs for the treatment of type 2 diabetes mellitus that improve control of plasma glucose and bodyweight, giving great hope for the clinical utility of these agents. However, it is unclear for which patients SGLT2 inhibitors will be useful., Materials and Methods: We analyzed data from long-term tofogliflozin monotherapy in an open-label, randomized controlled trial in Japanese patients with type 2 diabetes mellitus. Patients were divided into tertiles by baseline insulin level: group low (L): insulin ≤5.6 μU/mL, group medium (M): 5.6< insulin ≤10 μU/mL and group high (H): insulin >10 μU/mL., Results: Glycated hemoglobin and fasting plasma glucose levels, along with bodyweight, were significantly reduced from the baseline in all groups. The changes in levels of plasma glucose area under the curve for 2 h, C-peptide index area under the curve for 2 h during the meal tolerance tests and the insulin secretion index were the largest in the H group. The incidence of drug-related adverse events was not different among the three groups., Discussion: Although tofogliflozin was effective regardless of baseline insulin level, it showed the highest efficacy in the H group., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Introduction: Canagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, improves various cardiometabolic parameters. Although canagliflozin was originally discovered in Japan, no comprehensive summary of its effects in Japanese patients has been reported. As differences exist in the pathologic features of diabetes between Japanese and non-Japanese populations, it is important to consolidate Japanese data for canagliflozin. Areas covered: The authors summarize Japanese clinical trial and post-marketing surveillance data for canagliflozin, and make comparisons with non-Japanese data. They also consider the therapeutic potential of canagliflozin in Japanese patients by presenting results from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. Expert opinion: In Japanese patients, canagliflozin 100 mg, administered as monotherapy or combination therapy, improved blood glucose, body weight, and blood pressure, and was well tolerated; the efficacy and safety profiles were comparable to previous clinical studies in other countries. In the CANVAS Program, canagliflozin reduced major cardiovascular events, and although Japan was not included in this program, canagliflozin may have cardiovascular benefits in Japanese patients, in whom control of multiple risk factors is important for preventing diabetic complications. Patients with high cardiovascular risk often have multiple comorbidities, so it is important to consider the risk-benefit balance of using SGLT2 inhibitors in individual patients.

Aims/introduction: The aim of the present study was to evaluate the safety and efficacy of luseogliflozin added to liraglutide monotherapy in Japanese individuals with type 2 diabetes., Materials and Methods: This 52-week, multicenter, open-label, single-arm clinical study enrolled Japanese patients who had inadequate glycemic control with diet/exercise and liraglutide monotherapy. Major efficacy end-points included the changes from baseline in glycated hemoglobin, fasting plasma glucose and bodyweight. Body composition was also assessed in individuals who had access to bioelectrical impedance analysis. Safety assessments included adverse events, clinical laboratory tests, vital signs and 12-lead electrocardiograms., Results: Of 76 patients who received luseogliflozin, 62 completed the study. The changes from baseline in glycated hemoglobin, fasting plasma glucose, and bodyweight (mean ± SE) were -0.68 ± 0.10%, -32.1 ± 3.6 mg/dL and -2.71 ± 0.24 kg at week 52, respectively (all, P < 0.001 vs baseline). Luseogliflozin was associated with greater reductions in fat mass than lean mass at all measuring points (n = 22): fat vs lean mass changes (mean ± SE) at week 52 were -2.49 ± 0.45 kg (P < 0.001 vs baseline) and -0.44 ± 0.26 kg (P = 0.107 vs baseline), respectively. Insulin secretion and Matsuda Index were also improved at weeks 12 and 52 compared with baseline. Adverse events and adverse drug reactions occurred in 65.8 and 27.6% of patients, respectively. The overall safety profile, including frequency of hypoglycemia, was found to be consistent with those of previous studies and there were no new safety concerns., Conclusions: Luseogliflozin added to liraglutide was well tolerated, and improved glycemic control with bodyweight and fat mass reductions in Japanese type 2 diabetes patients., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: This study examined the effects of short-term administration of the sodium glucose cotransporter 2 (SGLT-2) inhibitor, dapagliflozin, on visceral fat area (VFA) in Japanese patients with type 2 diabetes., Research Design and Methods: In this randomized, crossover, controlled clinical trial, overweight patients with type 2 diabetes were randomized to treatment with 5 mg dapagliflozin for the first (n = 27) or second 12-week study period (n = 29). The parameters evaluated at baseline and after 12 and 24 weeks included blood pressure, hemoglobin A1c (HbA1c), body composition, VFA, and subcutaneous fat area (SFA)., Results: In both groups, dapagliflozin administration improved the levels of HbA1c, body weight, blood pressure, total fat mass, and VFA. Cessation of dapagliflozin, however, reversed the improvements in HbA1c, blood pressure, body weight, and SFA levels, whereas reductions in VFA and total fat mass levels were somewhat maintained even after 12 weeks without treatment., Conclusions: Dapagliflozin led to decreases in VFA and, consequently, body weight after a short treatment period. However, these effects were largely reversed by the cessation of dapagliflozin, suggesting that this agent should be administered continuously to maintain clinical usefulness in overweight patients with type 2 diabetes.

Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5-80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20-40 mg) in 30 Japanese subjects. Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t 1/2 of 5-6 h. Exposure increased dose-proportionally up to 320 mg. Body weight-corrected exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4% of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased C max by approximately 30% but did not change AUC 0-inf . Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE 0-24h ), but food intake condition at administration did not affect it. The exposure-response relationship between plasma average concentration of tofogliflozin (C avg ) and UGE 0-24h fitted E max model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia. Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL C avg corresponding to the dose of between 20 and 40 mg leads to almost maximum effect of tofogliflozin., Competing Interests: Conflict of Interest: N.K., T.S., Y.Ohba, S.S., K.T., Y.T., and S.I. are employees of Chugai Pharmaceutical Co., Ltd. T.I. is on loan to our associate company, Chugai Clinical Research Center Co. H.F., Y.Ogama, N.N. and Y.K. declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

The terminal elimination half-life (t1/2) of empagliflozin is 13.1 hours. Accordingly, we hypothesized that the administration of empagliflozin every other day might improve glycemic control in patients with type 2 diabetes mellitus, not being inferior to the therapy every day. We investigated the clinical effects and safety of the addition of empagliflozin every day or every other day to type 2 diabetic patients with a poor control in glycemia. Thirteen Japanese patients diagnosed as type 2 diabetes mellitus recruited to this study. Subjects were divided into two groups; one was treatment with 10 mg of empagliflozin every day (Group A), the other was 10 mg of empagliflozin every other day (Group B). The comparable study of multiple clinical indexes between the 2 groups was made before and 8, 16, and 24 weeks after the treatment. After the treatment for 24 weeks, the HbA1c level was decreased both in group A (from 7.5%±1.1% to 6.5%±0.8%) and in group B (from 7.6%±0.8% to 7.2%±0.5%). This pilot trial suggested the possibility of 10-mg every other day administration with empagliflozin for Japanese patients with type 2 diabetes mellitus. J. Med. Invest. 64: 50-57, February, 2017.

Background: In patients with type 2 diabetes mellitus (T2DM), dapagliflozin improves glycemic control and has a safety profile typically related to its mechanism of action. Hypersensitivity adverse events (AEs) have been reported in some patients with sodium-glucose cotransporter 2 (SGLT2) inhibitors, including a recent report of dermatological AEs in Japan., Methods: We investigated the frequency and characteristics of hypersensitivity AEs, including potentially hypersensitivity-related skin AEs, across 21 phase IIb/III trials of dapagliflozin (N = 5936) versus active or placebo comparators (N = 3403), including the subpopulation of Asian patients (N = 1563)., Results: Overall, AEs and serious AEs (SAEs) of hypersensitivity were infrequent and were reported in a similar proportion of patients with dapagliflozin versus active or placebo comparators (AEs: 4.5 vs. 4.3 %; SAEs: 0.2 vs. 0.1 %, respectively). The most common events affected the skin or subcutaneous tissue: rash (dapagliflozin: 1.1 %, comparator: 1.1 %), eczema (0.6, 0.8 %), dermatitis (0.5, 0.4 %), and urticaria (0.5, 0.2 %). Few patients discontinued as a result of hypersensitivity AEs (≤0.2 %). In patients of Asian descent, a lower frequency of hypersensitivity AEs was observed with dapagliflozin versus comparators (2.0 vs. 4.5 %). In the subset of placebo-controlled trials, hypersensitivity AEs were slightly more frequent with dapagliflozin than with placebo across the overall population (4.7 vs. 3.8 %), and less frequent with dapagliflozin in Asian patients (1.5 vs. 5.0 %)., Conclusions: The findings of this post hoc analysis indicate that dapagliflozin does not lead to an increased risk of serious hypersensitivity reactions or potentially hypersensitivity-related skin events among patients with T2DM, including Asian patients. Long-term outcome studies and postmarketing surveillance will provide further information on hypersensitivity reactions with SGLT2 inhibitors. CLINICALTRIALS., Gov Identifiers: NCT01042977, NCT01031680, NCT00855166, NCT00984867, NCT01294423, NCT00673231, NCT00972244, NCT00680745, NCT00660907, NCT01095653, NCT00831779, NCT00976495, NCT00859898, NCT00736879, NCT00683878, NCT00663260, NCT00643851, NCT00528879, NCT00528372, NCT00357370, NCT00263276.

Introduction: Sodium glucose cotransporter 2 (SGLT2) inhibitors have been available for the treatment of type 2 diabetes (T2DM) in Japan since April 2014. The prescription rate in Japan is low in comparison to Western countries. We summarize the results obtained from the phase 3 clinical trials and clinical studies involving Japanese T2DM patients. We also discuss the current situation and the future prospects of SGLT2 inhibitors in Japan., Areas Covered: Unexpected adverse events, such as cerebral infarction and diabetic ketoacidosis have been reported from clinics shortly after the initiation of SGLT2 inhibitor treatment. However, the reductions in blood glucose levels and body weight have been demonstrated in phase 3 trials using 6 types of SGLT2 inhibitors, while observational studies of Japanese T2DM patients, which were performed in the clinical setting, showed that the incidence of adverse drug reactions, such as severe hypoglycemia, was low., Expert Opinion: SGLT2 inhibitors are also considered to be effective for treating Japanese patients with T2DM. When prescribing SGLT2 inhibitors, it is necessary to ensure that they are used appropriately because the Japanese T2DM patient population has a high proportion of elderly individuals and a high incidence of cerebrovascular disease.

Aims/introduction: The influence of overweight/obesity on the clinical efficacy and safety of sodium-glucose co-transporter 2 inhibitors is unclear. We carried out a pooled analysis to examine the impact of body mass index on the efficacy and safety of ipragliflozin., Materials and Methods: Patient-level data were pooled for five Japanese double-blind trials (NCT00621868, NCT01057628, NCT01135433, NCT01225081 and NCT01242215) in which patients were randomized to ipragliflozin or a placebo as monotherapy, or in combination with metformin, pioglitazone or a sulfonylurea. Outcomes included the changes in hemoglobin A1c, fasting plasma glucose, bodyweight and treatment-emergent adverse events. Patients were divided into four body mass index categories., Results: Hemoglobin A1c, fasting plasma glucose and bodyweight decreased significantly in the ipragliflozin group compared with the placebo group in all body mass index categories, and in the total cohort (all P < 0.001). Hemoglobin A1c did not improve in 11.2 and 69.2% of patients in the ipragliflozin and placebo groups, respectively. The change in hemoglobin A1c was weakly correlated with the change in bodyweight in all patients (r = 0.136, P = 0.002). Regarding laboratory variables, the placebo-subtracted difference tended to be greater in patients with higher body mass index for aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase and uric acid. The incidences of treatment-emergent adverse events were similar between the ipragliflozin and placebo groups in all patients combined and in the four body mass index categories., Conclusions: These results show that the efficacy and safety of ipragliflozin are not influenced by obesity/overweight in Japanese patients., (© 2015 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Introduction: We investigated the impact of reduced renal function on 24-h glucose variability in Japanese patients with type 2 diabetes mellitus (T2DM) treated with luseogliflozin., Methods: In this double-blind, placebo-controlled, crossover study, 37 Japanese patients with T2DM [glycated hemoglobin (HbA1c) 7.0-10.0%] and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m(2) were randomized into two groups in which patients first received luseogliflozin then placebo, or vice versa, for 7 days each. Twenty-four-hour glucose variability was measured on day 7 in each period and was compared among patients divided into three groups according to their baseline eGFR (mL/min/1.73 m(2)): normal (≥90; n = 13; normal group), normal-to-mildly reduced renal function (≥75 to <90; n = 12; normal-mild group), and mild-to-moderately reduced renal function (<75; n = 9; mild-moderate group)., Results: The mean [95% confidence interval (CI)] placebo-subtracted 24-h cumulative urinary glucose excretion (g) was 82.1 (72.7, 91.5), 82.5 (73.4, 91.5), and 62.2 (51.2, 73.3); the placebo-subtracted 24-h mean glucose concentration (mg/dL) was -24.39 (-32.53, -16.26), -28.28 (-39.35, -17.22), and -11.53 (-23.93, 0.86); and the placebo-subtracted peak postprandial glucose (mg/dL) was -26.9 (-46.9, -6.9), -38.1 (-59.6, -16.6), and 1.5 (-25.5, 28.4) in the normal, normal-mild, and mild-moderate groups, respectively. The mean lowest glucose concentrations (placebo vs. luseogliflozin, mg/dL) decreased to similar levels in the normal (115.4 vs. 93.4), normal-mild (121.0 vs. 97.9), and mild-moderate (104.0 vs. 91.1) groups., Conclusion: This post hoc subanalysis revealed that although mild-to-moderately reduced renal function attenuated the glucose-lowering effects of luseogliflozin on peak postprandial glucose, it did not attenuate the effects of luseogliflozin on fasting glucose. These findings may explain the smaller increase in urinary glucose excretion in these patients relative to patients with normal renal function or normal-to-moderately reduced renal function. Further studies may be needed to examine these findings in large populations of patients with T2DM and reduced renal function., Trial Registration: JapicCTI-142548., Funding: Taisho Pharmaceutical Co., Ltd.

Introduction: Luseogliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, promotes urinary glucose excretion (UGE) and reduces plasma glucose concentrations. Luseogliflozin was approved for use in Japan after favorable pharmacokinetic, pharmacodynamic, and safety profiles were reported in healthy Japanese subjects and patients with type 2 diabetes mellitus (T2DM) in clinical development studies. We aimed to investigate the pharmacokinetics, pharmacodynamics, and safety of multiple doses of luseogliflozin administered once daily for 7 days in Japanese patients with T2DM., Methods: We conducted a randomized, placebo-controlled, single-blind, parallel-group, clinical pharmacology study at the P-One Clinic, Keikokai Medical Corporation (Tokyo, Japan) between August 2009 and November 2009. Forty Japanese patients with T2DM were randomly assigned to receive once-daily 0.5, 1, 2.5 or 5 mg luseogliflozin or placebo for 7 days. We assessed the pharmacokinetics, pharmacodynamics (including changes in UGE and plasma glucose concentrations), and safety of luseogliflozin., Results: The plasma concentrations of luseogliflozin and its active metabolite, M2, were dose proportional, without accumulation. 24-h UGE was greater in all luseogliflozin groups versus placebo. Least-squares mean differences in 24-h UGE on Day 7 increased dose dependently in the luseogliflozin groups, with values of 49.2, 66.5, 89.4, and 101 g/day at 0.5, 1, 2.5, and 5 mg, respectively. On Day 7, the areas under the concentration-time curves for post-meal plasma glucose and the mean plasma glucose for 0-16 h were significantly lower in all luseogliflozin groups versus placebo. Seven patients had mild adverse events (AEs); all were resolved. No AEs led to study discontinuation., Conclusion: Once-daily administration of luseogliflozin for 7 days increased 24-h UGE in a dose-dependent manner, reduced plasma glucose concentrations, and was well tolerated in Japanese patients with T2DM. The pharmacokinetic and pharmacodynamic profile of luseogliflozin observed in this study supports its once-daily dosing regimen., Funding: Taisho Pharmaceutical Co., Ltd.

It remains to be seen whether pancreatic β cell dysfunction in type 2 diabetic patients can be ameliorated just by correcting hyperglycemia. The current pilot study investigated β cell function after a four-week treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus. Ten participants (age, 51±13 years; hemoglobin A1c levels, 9.4±1.0%) took 50 mg of ipragliflozin L-proline for four weeks and thereafter discontinued the agent for one week. A 75-g oral glucose tolerance test (OGTT) was performed at 0 (baseline), 4 (end of medication), and 5 weeks (end of washout). The β cell function was evaluated using the disposition index, which was calculated as the product of the ΔIns₀₋₁₂₀/ΔGlu₀₋₁₂₀ and the Matsuda index, where ΔIns₀₋₁₂₀/ΔGlu₀₋₁₂₀ represents the ratio of the incremental concentrations of insulin to those of glucose during the 0- to 120-min time period of the OGTT. The fasting glucose level was 182±34 mg/dL at 0 week, 137±20 mg/dL at 4 weeks (p<0.001), and 154±31 mg/dL at 5 weeks (p=0.001). Compared to baseline, the disposition index was significantly elevated not only at 4 weeks (p<0.001) but also at 5 weeks (p=0.008). In conclusion, the current pilot study showed that the β cell function assessed by the OGTT-derived disposition index was significantly improved after a four-week treatment with ipragliflozin in Japanese patients with type 2 diabetes mellitus.

Purpose: The purpose of this study was to assess the effect of renal impairment on the pharmacokinetic, pharmacodynamic, and safety profiles of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in Japanese patients with type 2 diabetes mellitus (T2DM)., Methods: In an open-label, parallel-group study, 32 Japanese patients with T2DM and different degrees of renal function (n = 8 per renal function category: normal renal function, estimated glomerular filtration rate [eGFR; Japanese equation] ≥90 mL/min/1.73 m(2); mild renal impairment, eGFR of 60-<90 mL/min/1.73 m(2); moderate renal impairment, eGFR of 30-<60 mL/min/1.73 m(2); and severe renal impairment, eGFR of 15-<30 mL/min/1.73 m(2)) received a single 25 mg dose of empagliflozin., Findings: Empagliflozin exposure increased with increasing renal impairment. Maximum empagliflozin plasma concentrations were similar among all renal function groups. Adjusted geometric mean ratios for extent of exposure (AUC0-∞) to empagliflozin versus normal renal function were 128.8% (95% CI, 106.0-156.6%), 143.8% (95% CI, 118.3-174.8%), and 152.3% (95% CI, 125.3-185.2%) for patients with mild, moderate, and severe renal impairment, respectively. Decreases in renal clearance of empagliflozin correlated with eGFR. Urinary glucose excretion decreased with increasing renal impairment and correlated with eGFR (adjusted mean [SE] change from baseline: 75.0 [4.84] g, 62.6 [5.75] g, 57.9 [4.86] g, and 23.7 [5.24] g for patients with normal renal function and mild, moderate, and severe renal impairment, respectively). Only 2 patients (6%) had adverse events; both were mild., Implications: Pharmacokinetic data suggest that no dose adjustment of empagliflozin is necessary in Japanese patients with T2DM and renal impairment because increases in exposure were <2-fold. Urinary glucose excretion decreased with increasing renal impairment. ClinicalTrials.gov identifier: NCT01581658., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)

Ipragliflozin (Suglat(®)) is a potent and selective inhibitor of sodium-glucose cotransporter-2 that was recently launched in Japan. Its mechanism of action involves the suppression of glucose re-absorption in the kidney proximal tubules, causing excretion of glucose in the urine. The aim of this review is to provide a comprehensive overview of currently available pharmacokinetic and pharmacodynamic data on ipragliflozin, including studies in healthy subjects, patients with type 2 diabetes mellitus and special populations. In single- and multiple-dose studies, the maximum plasma concentration and area under the plasma concentration-time curve (AUC) for ipragliflozin increased in a dose-dependent manner. Although urinary excretion of ipragliflozin is low (approximately 1 %), tubular concentration of free ipragliflozin is adequate to provide pharmacological activities. No clinically relevant effects of age, gender or food on the exposure of ipragliflozin were observed. The AUC for ipragliflozin was 20-30 % greater in patients with moderate renal or hepatic impairment than in patients with normal renal or hepatic function. In drug-drug interaction studies, the pharmacokinetics of ipragliflozin and other oral antidiabetic drugs (metformin, sitagliptin, pioglitazone, glimepiride, miglitol and mitiglinide) were not significantly affected by their co-administration. Urinary glucose excretion (UGE) also increased in a dose-dependent manner, approaching a maximum effect at 50-100 mg dosages in Japanese healthy volunteers and patients with type 2 diabetes. The change in UGE from baseline (ΔUGE) tended to be lower in older subjects and female subjects, compared with younger subjects and male subjects, respectively. ΔUGE tended to decrease with decreasing renal function, especially in patients with type 2 diabetes with moderate or severe renal impairment.