The Institute for Adult Diseases

Chūō-ku, Japan

The Institute for Adult Diseases

Chūō-ku, Japan
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Araki E.,Kumamoto University | Onishi Y.,The Institute for Adult Diseases | Asano M.,Astrazeneca | Kim H.,Astrazeneca | Yajima T.,Astrazeneca
Diabetes, Obesity and Metabolism | Year: 2017

Aims: To evaluate the efficacy and safety of dapagliflozin as add-on to insulin in Japanese patients with type 2 diabetes. Materials and methods: Insulin-treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16-week double-blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36-week open-label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs. Results: The changes in HbA1c from baseline to weeks 16 and 52 were −0.62% and −0.74%, respectively, in the dapagliflozin group, vs −0.08% and −0.83%, respectively, in the placebo–dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open-label dapagliflozin in the placebo–dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in ≤5% of patients. Conclusion: This trial showed that administration of dapagliflozin as an add-on to insulin therapy was effective, was well tolerated and had insulin-sparing effects in Japanese patients with type 2 diabetes. © 2016 John Wiley & Sons Ltd


Ji L.,Peking University | Onishi Y.,The Institute for Adult Diseases | Ahn C.W.,Gangnam Severance Hospital | Agarwal P.,Hormone Care and Research Center | And 4 more authors.
Journal of Diabetes Investigation | Year: 2013

Aims/Introduction: To compare safety and efficacy of the extended-release formulation exenatide once weekly (EQW) vs exenatide twice daily (EBID) for 26 weeks in type 2 diabetes patients from China, India, Japan, South Korea and Taiwan. Materials and Methods: A randomized, comparator-controlled, open-label study included 681 patients with type 2 diabetes inadequately controlled (hemoglobin A1c [HbA1c] ≥7 and ≤11%) with oral antihyperglycemic medications (OAMs). Patients added 2 mg EQW or 10 μg EBID to current OAMs. Safety was re-evaluated 10 weeks after last treatment. Results: EQW was superior to EBID on HbA1c measures at week 26 (Least-squares mean treatment difference: -0.31% [95% confidence interval -0.49, -0.14%]). More EQW-treated patients achieved target HbA1c ≤7.0% (P = 0.003), ≤6.5% (P < 0.001), or ≤6.0% (P = 0.003). Fasting serum glucose reductions were greater among EQW-treated patients (P < 0.001). Blood glucose profiles improved in both treatment groups (P < 0.001). Weight loss occurred with both treatments, but was greater with EBID. Adverse events (≥10%, either group) were nausea, injection-site induration, dyslipidemia and vomiting. Injection-site induration was more frequent with EQW, whereas nausea, vomiting and hypoglycemia were less frequent. One episode each of major hypoglycemia (EBID) and pancreatitis (EQW) were reported. Conclusion: In this population, EQW and EBID showed efficacious glucose and weight control; safety and tolerability were consistent with observations in non-Asian patients. This trial was registered with ClinicalTrials.gov (no. NCT00917267). © 2012 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.


Onishi Y.,The Institute for Adult Diseases | Iwamoto Y.,Tokyo Women's Medical University | Yoo S.J.,Catholic University of Korea | Clauson P.,Novo Nordisk AS | And 2 more authors.
Journal of Diabetes Investigation | Year: 2013

Introduction: Insulin degludec (IDeg) is an ultra-long-acting basal insulin with a consistent action profile of >42 h. This trial compared the efficacy and safety of IDeg with insulin glargine (IGlar) in insulin-naïve Asian patients with type 2 diabetes. Materials and Methods: In this multinational, 26-week, open-label, treat-to-target trial, 435 participants (202 females, 233 males; mean age 58.6 years; mean body mass index 25 kg/m2; mean glycated hemoglobin [HbA1c] 8.5%) were randomized (2:1) to IDeg or IGlar, each administered once daily with ≥1 oral antidiabetic drug(s) (OAD). Results: After 26 weeks, HbA1c had decreased by 1.24 and 1.35% in the IDeg and IGlar groups, respectively (treatment difference [IDeg - IGlar] 0.11%, 95% confidence interval [CI] -0.03 to 0.24), confirming non-inferiority. Rates of overall confirmed hypoglycemia were similar for IDeg and IGlar during the full trial period (3.0 vs 3.7 episodes/patient-year of exposure [PYE]; rate ratio [RR] 0.82, 95% CI 0.60 to 1.11, P = 0.20), but significantly lower (by 37%) for IDeg during the maintenance period (from week 16 onward; RR 0.63, 95% CI 0.42 to 0.94, P = 0.02). No significant difference in the rate of nocturnal confirmed hypoglycemia was found between IDeg and IGlar in the full trial period (0.8 vs 1.2 episodes/PYE; RR 0.62, 95% CI 0.38 to 1.04, P = 0.07) or maintenance period (RR 0.52, 95% CI 0.27 to 1.00, P = 0.05). Adverse event rates were similar between treatments. Conclusions: Initiating insulin therapy with IDeg in Asian patients with type 2 diabetes, inadequately controlled with OADs, provides similar improvements in long-term glycemic control to IGlar, but at a significantly lower rate of overall confirmed hypoglycemia once stable glycemic control and insulin dosing are achieved. This trial was registered with www.clinicaltrials.gov (no. NCT01059799). © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.


Kikuchi M.,The Institute for Adult Diseases | Haneda M.,Asahikawa Medical College | Koya D.,Kanazawa Medical University | Tobe K.,University of Toyama | And 5 more authors.
Diabetes Research and Clinical Practice | Year: 2010

Aim: To investigate the efficacy and tolerability of vildagliptin, a potent and selective dipeptidyl peptidase-4 inhibitor, as add-on to glimepiride in Japanese patients with Type 2 diabetes mellitus (T2DM) who were inadequately controlled. Methods: This 12-week, randomized, double-blind, placebo-controlled study compared vildagliptin 50. mg twice-daily (n=102) with placebo (n=100) when added to a stable dose of glimepiride (≥1. mg/d). Results: Treatment groups were balanced at baseline (glycosylated hemoglobin [HbA1c], 7.9%; fasting plasma glucose, 163.8mg/dL). During treatment HbA1c decreased progressively with vildagliptin, but remained unchanged with placebo. The adjusted mean change (AMΔ) at endpoint was -1.0±0.1 and -0.1±0.1% in vildagliptin- and placebo-treated patients (between-group Δ=-1.0±0.1%, P<0.001). A greater proportion of vildagliptin-treated patients had HbA1c ≤6.5% compared to placebo-treated patients (45% vs 3%, P<0.001). The AMΔ FPG was -20.9±2.8mg/dL with vildagliptin compared to 6.3±2.8mg/dL with placebo (between-group Δ=-27.2±3.9mg/dL, P<0.001). Patients in vildagliptin and placebo groups reported similar incidences of adverse events (AEs) (59.8% vs. 57.0%), serious AEs (0% vs 2.0%), suspected drug-related AEs (21.6% vs. 23.0%), and discontinuation due to AEs (1.0% vs 3.0%). Hypogylcaemia was reported in two (vildagliptin) and one (placebo) patient. Conclusion: Vildagliptin is effective and well tolerated as an add-on to glimepiride in Japanese patients with T2DM. © 2010 Elsevier Ireland Ltd.


Onishi Y.,The Institute for Adult Diseases | Koshiyama H.,Medical Research Institute Kitano Hospital | Imaoka T.,Eli Lilly and Company | Haber H.,inVentiv Health | And 2 more authors.
Journal of Diabetes Investigation | Year: 2013

Aims/Introduction: An initial 26-week, randomized, open-label study compared the efficacy and safety of exenatide 10mcg twice daily with exenatide 2mg once weekly in Asian patients with type 2 diabetes who experienced inadequate glycemic control with oral antidiabetes medications. The aim of this study was to evaluate the safety of exenatide once weekly in Japanese patients, a subset of the initial patient population, who continued into this extension study for an additional 26weeks of therapy on exenatide once weekly, followed by 10weeks without exenatide once weekly. Materials and Methods: Japanese patients initially assigned to exenatide twice daily (n=62) switched to exenatide once weekly for the extended 26weeks, and patients initially assigned to exenatide once weekly (n=74) continued on this regimen for the remainder of the study (total treatment of 52weeks). Results: A total of 68% of patients reported one or more treatment-emergent adverse events during the extension period; the most common of these were nasopharyngitis (14%) and vomiting (6%). No major hypoglycemic episodes were reported. Improvements in glycated hemoglobin, fasting plasma glucose and postprandial glucose were maintained over 52weeks of treatment. At week52, bodyweight remained reduced from baseline. Conclusions: Exenatide once weekly added to oral antidiabetes medication was well tolerated in Japanese patients with type 2 diabetes, and was associated with glycemic control and weight loss through to 52weeks, supporting the use of exenatide once weekly as an adjunctive treatment for type 2 diabetes in this patient population. The initial 26-week portion of this trial was registered with ClinicalTrials.gov (no. NCT00917267). © 2012 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.


PubMed | Novo Nordisk AS, The Institute for Adult Diseases and Kenichi Yamada Internal Medicine Clinic
Type: | Journal: Journal of diabetes investigation | Year: 2016

Insulin degludec/insulin aspart (IDegAsp) is a soluble combination of insulin degludec (70%) and insulin aspart (30%). The present exploratory trial investigated the safety of switching unit-to-unit from twice-daily basal or pre-mix insulin to twice-daily IDegAsp in Japanese patients with type 2 diabetes.In this 6-week, open-label, parallel-group, controlled trial, 66 participants were randomized (1:1) to receive either IDegAsp or biphasic insulin aspart 30 (BIAsp 30) twice daily at the same total daily dose as pre-trial insulin. During the trial, insulin doses were adjusted according to a pre-specified algorithm to achieve pre-breakfast and pre-dinner plasma glucose of 4.4-7.2 mmol/L.No severe hypoglycemic episodes occurred. There were no statistically significant differences in rates of confirmed hypoglycemia (rate ratio IDegAsp/BIAsp 30: 0.63, 95% confidence interval: 0.31-1.30) and confirmed nocturnal hypoglycemia (rate ratio: 0.49, 95% confidence interval: 0.10-2.38) for IDegAsp vs BIAsp 30. The hypoglycemia rate for IDegAsp was constant over the 6 weeks of treatment. IDegAsp and BIAsp 30 were both safe and well tolerated. Reduction in fasting plasma glucose was statistically significantly greater for IDegAsp than for BIAsp 30 (estimated treatment difference, IDegAsp-BIAsp 30: -1.6 mmol/L, 95% confidence interval: -2.4 to -0.8). The apparent decrease in mean postprandial plasma glucose increment (IDegAsp: 4.2-3.8 mmol/L; BIAsp 30: 4.5-2.8 mmol/L) was not statistically significantly different between treatments (estimated treatment difference: 1.0 mmol/L, 95% confidence interval: -0.1 to 2.2).Switching unit-to-unit from basal or pre-mix insulin to IDegAsp seems not to be associated with any concerns related to hypoglycemia or general safety in Japanese patients with type 2 diabetes.


PubMed | Kumamoto University, The Institute for Adult Diseases and Astrazeneca
Type: Journal Article | Journal: Journal of diabetes investigation | Year: 2016

Dapagliflozin treatment when added to insulin therapy in Japanese patients with type 2 diabetes remains to be evaluated.This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate efficacy (at 16 weeks) and long-term safety (at 52 weeks) of dapagliflozin in addition to insulin therapy. The interim analysis was carried out at week 16 to assess the efficacy and safety profiles. The patients receiving insulin (n = 182) were randomized to either dapagliflozin 5 mg or a placebo at a 2:1 ratio. The primary efficacy end-point was the change in hemoglobin A1c (HbA1c) from baseline at week 16.Patients in the dapagliflozin group showed an adjusted decrease in HbA1c of -0.55% from baseline, whereas the placebo showed a marginal increase of 0.05%. The placebo-corrected mean change of HbA1c from baseline to week 16 in dapagliflozin was -0.60% (P < 0.0001). In addition, the placebo-corrected mean change of fasting plasma glucose and bodyweight from baseline to week 16 in the dapagliflozin group was -22.7 mg/dL (P < 0.0001) and -1.21 kg (P < 0.0001), respectively. The placebo-corrected mean daily insulin dose in the dapagliflozin group was numerically decreased (treatment difference: -0.72 IU/day; P = 0.0743). No major episodes or discontinuations as a result of hypoglycemia were reported during the study period.Dapagliflozin used as add-on treatment to insulin therapy showed significantly greater reduction of HbA1c, fasting plasma glucose and bodyweight without severe hypoglycemia compared with the placebo at week 16. These results show the clinical benefit of prescribing dapagliflozin for Japanese patients with insufficient glycemic control even with insulin therapy.


PubMed | The Institute for Adult Diseases
Type: Clinical Trial, Phase III | Journal: Endocrine journal | Year: 2016

The efficacy and tolerability of once weekly dulaglutide 0.75 mg in Japanese patients with type 2 diabetes (T2D) were evaluated by subgroups defined by key demographic characteristics. This post hoc analysis included data from patients who received dulaglutide 0.75 mg for up to 26 weeks in three phase 3 trials (one open-label, randomized; one double-blind and open-label, randomized; one open-label, nonrandomized). Patients were classified into subgroups on the basis of sex (male, female), age (<65, 65 years), body weight (<70, 70 kg), body mass index (BMI; <25, 25 kg/m(2)), duration of diabetes (<7, 7 years), HbA1c (8.5, >8.5%), use of concomitant sulfonylurea (yes, no), and use of concomitant biguanide (yes, no). Efficacy measures analyzed were changes from baseline in HbA1c and body weight and percentages of patients achieving HbA1c <7.0%. Safety measures analyzed were incidence of hypoglycemia and nausea and change from baseline in seated pulse rate. A total of 855 patients were analyzed. Once weekly dulaglutide 0.75 mg improved blood glucose control as measured by HbA1c regardless of patient characteristics; patients with higher baseline HbA1c values had greater improvements compared to patients with lower baseline values. Weight loss was greater in patients with lower baseline HbA1c and in patients taking concomitant biguanides. Concomitant use of sulfonylureas had the greatest effect on the incidence of hypoglycemia. Treatment of T2D with once weekly dulaglutide 0.75 mg for 26 weeks was associated with significant improvement in glycemic control irrespective of age, sex, duration of diabetes, body weight, BMI, or concomitant medication.


PubMed | Hiroshima University, The Institute for Adult Diseases and Kyushu University
Type: | Journal: Nutrition, metabolism, and cardiovascular diseases : NMCD | Year: 2017

Epicatechin (EC) intake has been suggested to be beneficial for the prevention of cardiovascular disorders, and it is well known that adipose tissue inflammation is one of the major risk factors for coronary heart diseases. The purpose of the present study was to determine the invitro and invivo effects of EC on adipose tissue inflammation and obesity.DNA microarray analysis was performed to evaluate the effects of EC on gene expression in adipocytes co-cultured with bacterial endotoxin-stimulated macrophages. To determine the invivo effects of the catechin, C57BL/6 mice were fed either a high-fat diet (HFD) or HFD combined with EC, and metabolic changes were observed EC suppressed the expression of many inflammatory genes in the adipocytes co-cultured with endotoxin-stimulated macrophages. Specifically, EC markedly suppressed chemokine (CC motif) ligand 19 (CCL19) expression. The target cell of EC appeared to macrophages. The invivo study indicated that mice fed the EC-supplemented HFD were protected from diet-induced obesity and insulin resistance. Accordingly, the expression levels of genes associated with inflammation in adipose tissue and in the liver were downregulated in this group of mice.EC exerts beneficial effects for the prevention of adipose tissue inflammation and insulin resistance. Since we previously reported that mice deficient in the CCL19 receptor were protected from diet-induced obesity and insulin resistance, it can be concluded that the beneficial effects of EC could be mediated, at least in part, by marked suppression of CCL19 expression.


PubMed | The Institute for Adult Diseases and Jikei University School of Medicine
Type: | Journal: Journal of diabetes investigation | Year: 2016

We evaluated the impact of postprandial hyperglycemia at clinic visits on the incidence of cardiovascular diseases (CVD) and all-cause mortality independently of mean glycosylated hemoglobin (HbA1c) in type 2 diabetes patients in a real-world setting.This retrospective observational cohort study included 646 type 2 diabetes patients. All of the subjects had their initial consultations at our clinic during the period from 1995-1996, visited the clinic 4 times, had their 2-hour post-breakfast blood glucose (2h-PBBG) levels measured, and were followed-up for 1 year. The 646 patients were followed-up for survival. Of the 646 patients, 618 had no history of CVD at the first visit and had measured 2h-PBBG until the first CVD onset or censorings. These two cohorts were followed-up through June 2012, and subsequently questionnaires were mailed. Risks of the CVD incidence and death were evaluated by multivariate Cox proportional hazard models.CVD occurred in 78 patients and death in 56. The median follow-up periods of the CVD cohort and the mortality cohort were 15.6 years and 15.9 years, respectively. The mean 2h-PBBG is a significant predictor of the CVD incidence and all-cause mortality after adjusting for the mean HbA1c, the number of 2h-PBBG measurements, age, sex and classical risk factors.Postprandial hyperglycemia represented by the mean level of 2h-PBBG at clinic visits is associated with the CVD incidence and all-cause mortality independently of the mean HbA1c level in type 2 diabetes patients. Prospective interventional trials are warranted to confirm our findings. This article is protected by copyright. All rights reserved.

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