Showing papers by "Yasuo Terauchi published in 2015"
TL;DR: It is suggested that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes and that GKAs also have the effect of stimulating the proliferation of β‐cells.
Abstract: Glucokinase is one of four members of the hexokinase family of enzymes. Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the β-cells, it results in insulin release. Studies of glucokinase-linked genetically-modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole-body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Since 2003, many glucokinase activators (GKAs) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, we and others have shown in mouse models that GKAs also have the effect of stimulating the proliferation of β-cells. However, the results of recent phase II trials have shown that GKAs lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with GKAs frequently developed dyslipidemia. A better understanding of the role of glucokinase in metabolic effects is required to resolve several issues identified in clinical trials.
83 citations
TL;DR: Empagliflozin monotherapy for 52 weeks led to sustained reductions in HbA1c, FPG, weight and BP and was well tolerated in Japanese patients with T2DM.
Abstract: The aim of this randomized, double-blind, parallel-group study was to investigate the safety and efficacy of empagliflozin monotherapy for 52 weeks in Japanese patients with type 2 diabetes (T2DM). In a 12-week dose-finding period, patients [N = 547; mean baseline glycosylated hemoglobin (HbA1c) 7.92–8.02%] received empagliflozin (5, 10, 25, or 50 mg) or placebo. In a 40-week extension period, patients on empagliflozin 10 or 25 mg continued the same treatment and patients on other doses were reallocated to empagliflozin 10 or 25 mg. Outcomes at week 52 included changes from baseline in HbA1c, fasting plasma glucose (FPG), weight and blood pressure (BP) in patients who received empagliflozin 10 or 25 mg in both the initial 12 weeks and the extension and safety in patients treated with ≥1 dose of empagliflozin 10 or 25 mg. Adjusted mean ± SE changes in HbA1c from baseline at week 52 were –0.67 ± 0.09% and −0.86 ± 0.09%, in FPG were −24.7 ± 3.2 mg/dL and −31.3 ± 3.4 mg/dL, and in body weight were −3.1 ± 0.4 kg and −3.1 ± 0.4 kg, with empagliflozin 10 and 25 mg, respectively. Both doses reduced systolic and diastolic BP. Adverse events were reported in 70.8% and 66.8% of patients on empagliflozin 10 and 25 mg, respectively. Confirmed hypoglycemic adverse events (plasma glucose ≤70 mg/dL and/or requiring assistance) were reported in one patient per group. Empagliflozin monotherapy for 52 weeks led to sustained reductions in HbA1c, FPG, weight and BP and was well tolerated in Japanese patients with T2DM. Boehringer Ingelheim and Eli Lilly and Company.
45 citations
TL;DR: Comparison of glycemic control parameters, laboratory values, and adverse events revealed significant improvement of HbA1c, casual postprandial plasma glucose, and fasting plasma glucose in each age group with no change in body weight and Serum creatinine increased significantly in all age groups.
Abstract: There have only been a few reports about use of dipeptidyl peptidase 4 (DPP-4) inhibitors in elderly patients with type 2 diabetes mellitus (T2DM), suggesting that the safety of these agents has not been sufficiently demonstrated. We performed a comparative review of the efficacy and safety of sitagliptin for Japanese patients with T2DM managed in the real-world clinical setting. An age-stratified analysis was performed of 831 patients who were treated with sitagliptin for 2 years. Parameters assessed included the hemoglobin A1c (HbA1c), body weight, serum creatinine, and adverse events. HbA1c and the incidence of hypoglycemia were also evaluated in patients treated with sitagliptin and a sulfonylurea (SU), who were divided into three age groups (<65 years, 65–74 years, and ≥75 years). Comparison of glycemic control parameters, laboratory values, and adverse events revealed significant improvement of HbA1c, casual postprandial plasma glucose, and fasting plasma glucose in each age group with no change in body weight. Serum creatinine increased significantly in all age groups. Hypoglycemia only occurred in patients who received combined treatment with an SU and sitagliptin, and there was no age-related difference in its incidence. HbA1c was improved by 2 years of sitagliptin therapy in all three age groups, and age did not seem to influence the incidence of hypoglycemic events. These results confirm the efficacy and safety of sitagliptin in patients ≥ 75 years old, suggesting that it is also useful for treating elderly patients with T2DM.
36 citations
TL;DR: A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.
Abstract: Although many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet. eNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed. Lipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet. A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.
33 citations
TL;DR: Once weekly dulaglutide 0.75 mg in combination with a single OHA was overall well tolerated and improved glycemic control in Japanese patients with T2D.
Abstract: The goal of this study was to assess the safety and efficacy of 0.75 mg of dulaglutide, a once weekly glucagon-like peptide-1 receptor agonist, in Japanese patients with type 2 diabetes (T2D) on a single oral hypoglycemic agent (OHA). In this phase 3, nonrandomized, open-label, parallel-group, 52-week study, safety and efficacy of once weekly dulaglutide 0.75 mg were assessed in Japanese patients with T2D on a single OHA (sulfonylureas [SU], biguanides [BG], α-glucosidase inhibitors [AGI], thiazolidinedione [TZD], or glinides [GLN]). A total of 394 patients were treated with study drug, and 92.9% completed the 52-week treatment period. The most frequent treatment-emergent adverse events were nasopharyngitis and gastrointestinal disorders, including constipation, diarrhea, and nausea. Incidences of hypoglycemia varied across the combination therapy groups: incidence was greater in patients receiving SU compared with other combinations. No severe hypoglycemic episodes occurred during the study. Increases from baseline in pancreatic and total amylase, lipase, and pulse rate were observed in all 5 combination therapy groups. Significant reductions from baseline in HbA1c were observed in all 5 combination therapy groups (-1.57% to -1.69%, p < 0.001 for all). Mean body weight changes from baseline varied across the combination therapy groups: a significant increase was observed in combination with TZD, there were no significant changes in combination with SU or GLN, and significant reductions were observed in combination with BG or AGI. Once weekly dulaglutide 0.75 mg in combination with a single OHA was overall well tolerated and improved glycemic control in Japanese patients with T2D.
29 citations
TL;DR: iNOS-derived NO may play a protective role against the progression to NASH during an HFD by preventing fibrosis and inflammation, which are mediated by NF-kB activation in Kupffer cells.
Abstract: Although many of the factors and molecules closely associated with non-alcoholic steatohepatitis (NASH) have been reported, the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) on the progression of NASH remains unclear. We therefore investigated the role of iNOS-derived NO in NASH pathogenesis with a long-term follow-up study using systemic iNOS-knockout mice under high-fat diet (HFD) conditions. iNOS-knockout and wild-type mice were fed a basal or HFD for 10 or 48 weeks. Lipid accumulation, fibrosis, and inflammation were evaluated, and various factors and molecules closely associated with NASH were analyzed. Marked fibrosis and inflammation (indicators of NASH) were observed in the livers of iNOS-knockout mice compared to wild-type mice after 48 weeks of a HFD; however, lipid accumulation in iNOS-knockout mice livers was less than in the wild-type. Increased expressions of various cytokines that are transcriptionally controlled by NF-kB in iNOS-deficient mice livers were observed during HFD conditions. iNOS-derived NO may play a protective role against the progression to NASH during an HFD by preventing fibrosis and inflammation, which are mediated by NF-kB activation in Kupffer cells. A lack of iNOS-derived NO accelerates progression to NASH without excessive lipid accumulation.
28 citations
TL;DR: The objective was to evaluate the efficacy and tolerability of sitagliptin in subjects with impaired glucose tolerance (IGT) and to establish an experimental protocol for this study.
Abstract: Aims
To evaluate the efficacy and tolerability of sitagliptin in subjects with impaired glucose tolerance (IGT).
Methods
In a double-blind, parallel-group study, 242 Japanese subjects with IGT, determined by a 75-g oral glucose tolerance test (OGTT) at week −1, were randomized (1 : 1 : 1) to placebo (n = 83), sitagliptin 25 mg (n = 82) or 50 mg (n = 77) once daily for 8 weeks. Glycaemic variables were assessed using another OGTT at week 7 and meal tolerance tests (MTTs) at weeks 0 and 8. Primary and secondary endpoints were percent change from baseline in glucose total area under the curve 0–2 h (AUC0–2 h) during the MTT and OGTT, respectively.
Results
Least squares mean percent change from baseline in glucose AUC0–2 h during the MTT were −2.4, −9.5 and −11.5%, and during the OGTT were −3.7, −21.4 and −20.1% with placebo, sitagliptin 25 mg once daily, and 50 mg once daily, respectively (p < 0.001 for either sitagliptin dose vs placebo in both tests). Sitagliptin treatment enhanced early insulin response during the OGTT and decreased total insulin response, assessed as the total AUC0–2 h during the MTT. Sitagliptin treatment also suppressed glucagon response during the MTT. The incidence of adverse events, including hypoglycaemia, was low and generally similar in all treatment groups.
Conclusions
Treatment with sitagliptin significantly reduced glucose excursions during both an MTT and an OGTT; this effect was associated with an increase in early insulin secretion after oral glucose loading as well as a blunted glucagon response during an MTT. Sitagliptin was generally well tolerated in subjects with IGT.
21 citations
TL;DR: No significant change in LDL-C, a tendency of decrease in TC and non-high-density lipoprotein cholesterol (non-HDL-C) after treatment of anagliptin for 1 month is shown.
Abstract: Objective: The mechanism responsible for the lipid-lowering effect of dipeptidyl peptidase-4 (DPP-4) inhibitors remains unknown in humans. We evaluated the effect of anagliptin on serum lipid profiles, including cholesterol synthesis and absorption markers, in Japanese patients with type 2 diabetes.Methods: Thirty patients with type 2 diabetes (20 – 70 years old, low-density lipoprotein cholesterol (LDL-C) level over 120 mg/dl, and no history of treatment with antidiabetic or antihyperlipidemic drugs) were enrolled. One hundred milligrams of anagliptin were administered twice a day for a month.Results: After treatment of anagliptin, the LDL-C and total cholesterol (TC) levels did not decrease overall, but the TC level decreased significantly in 28 patients whose HbA1c levels decreased. Lathosterol decreased significantly, whereas no changes in campesterol, sitosterol or cholestanol were observed.Conclusion: These results of our study show no significant change in LDL-C, a tendency of decrease in TC and no...
21 citations
TL;DR: It is found that the measured HbA1c values were lower than the eHbA 1c values in each of the groups.
Abstract: Background
Glycated hemoglobin (HbA1c) and glycated albumin (GA) are frequently used as glycemic control markers. However, these markers are influenced by alterations in hemoglobin and albumin metabolism. Thus, conditions such as anemia, chronic renal failure, hypersplenism, chronic liver diseases, hyperthyroidism, hypoalbuminemia, and pregnancy need to be considered when interpreting HbA1c or GA values. Using data from patients with normal albumin and hemoglobin metabolism, we previously established a linear regression equation describing the GA value versus the HbA1c value to calculate an extrapolated HbA1c (eHbA1c) value for the accurate evaluation of glycemic control. In this study, we investigated the difference between the measured HbA1c and the eHbA1c values for patients with various conditions.
20 citations
TL;DR: The results suggest that creatinine elevation is associated with activation of incretin, most possibly with up-regulation of diuretic activity of GLP-1.
12 citations
TL;DR: It is concluded that early liraglutide treatment potentially improves β-cell function and subsequently glycemic control in patients with T2D, preventing further diabetic complications.
Abstract: Preclinical studies on liraglutide have suggested related improvements in β-cell function Therefore, we investigated these effects in patients with type 2 diabetes (T2D) using the glucagon stimulation test (GST) We conducted a retrospective cohort study of 73 insulin-treated patients with T2D who had their treatment switched to liraglutide monotherapy Their β-cell function was measured using a 1-mg intravenous GST at baseline and 24 weeks after treatment The effect of liraglutide treatment on β-cell function was assessed by the change in the area under the curve (AUC) of serum C-peptide immunoreactivity during the GST (AUC-CPR) The AUC-CPR increased after 24 weeks of liraglutide treatment (980 ± 055 ng/mL⋅min to 1150 ± 052 ng/mL⋅min, p = 0001) In the univariate and adjusted multivariate regression analyses, a negative relationship between the change in the AUC-CPR and T2D duration was noted (β = -022, 95% confidence interval [CI] = -035 to -009, R(2) = 014, p = 0001 and β = -020, 95% CI = -034 to -005, R2 = 023, p = 0008, respectively) In the analysis using T2D duration tertiles, early liraglutide treatment (T2D duration ≤10 years) significantly improved the AUC-CPR ( 10 years: -033 ± 115 ng/mL⋅min, p = 078) We conclude that early liraglutide treatment potentially improves β-cell function and subsequently glycemic control in patients with T2D, preventing further diabetic complications
TL;DR: Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetic patients with hypertension, whereas trichLormetiazide was moreeffective for reducing albuminuria than azelnidipines.
Abstract: Objective
This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension.
TL;DR: Bazedoxifene may improve bone resorption markers and LDL-C without affecting glucose metabolism in Japanese postmenopausal women with T2DM.
Abstract: Background: Selective estrogen receptor modulators (SERMs) decrease homocysteine and cross-linking of pentosidine and reduce low-density lipoprotein cholesterol (LDL-C), and they are expected to improve bone quality and atherosclerosis. Therefore, the potential effects of bazedoxifene on bone (bone resorption, bone formation, and bone quality), as well as on glucose and lipid metabolism markers, were examined in Japanese postmenopausal women with type 2 diabetes mellitus (T2DM). Methods: Eligible patients received 20 mg of bazedoxifene tablets once daily and were followed up for 12 weeks. Bone resorption markers including tartrate-resistant acid phosphatase 5b (TRACP-5b), bone formation markers and bone quality markers such as homocysteine and serum pentosidine, total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and HbA1c were all measured. Results: Twenty patients completed this study. All bone resorption markers decreased significantly 4 weeks after bazedoxifene treatment. In particular, TRACP-5b decreased significantly at 12 weeks (median percent change: -20.6%), and the minimum significant change (MSC) achievement rate of TRACP-5b was 65%. Bazedoxifene also decreased bone formation markers. However, bazedoxifene did not improve bone quality markers. LDL-C, HDL-C, and non-HDL-C were decreased, but TG was unchanged. Glucose metabolism was not changed after bazedoxifene treatment. In a subgroup analysis, the group of patients in whom the percent change in TRACP-5b exceeded the MSC had no change in pentosidine levels at 12 weeks. However, in the group of patients in whom the percent change in TRACP-5b did not exceed the MSC, pentosidine levels tended to increase. Conclusions: Bazedoxifene may improve bone resorption markers and LDL-C without affecting glucose metabolism in Japanese postmenopausal women with T2DM. J Clin Med Res. 2015;7(10):762-769 doi: http://dx.doi.org/10.14740/jocmr2278w
TL;DR: Glucose-dependent suppression of glucagon secretion by sitagliptin may be useful in patients with impaired insulin secretion as well as concomitantly with insulin irrespective of the insulin regimen, duration of insulin treatment, and concomitant medications.
Abstract: Background: It is unclear whether dipeptidyl peptidase-4 inhibitors decrease hemoglobin A 1c (HbA 1c ) in a glucose-dependent manner in patients on insulin therapy who have impaired insulin secretion. This study investigated factors influencing the efficacy of sitagliptin when used concomitantly with insulin to treat type 2 diabetes mellitus (T2DM) in the real-world setting. Methods: A retrospective study was conducted of 1,004 T2DM patients at 36 Japanese clinics associated with the Diabetes Task Force of the Kanagawa Physicians Association. Eligible patients had been on insulin for at least 6 months, with a baseline HbA 1c of 7.0% (53 mmol/mol) or higher. Baseline characteristics and laboratory data from 495 patients were subjected to multiple regression analysis to identify factors influencing the change of HbA 1c . Results: Most patients (n = 809) received sitagliptin at a dose of 50 mg. In the 1,004 patients, HbA 1c decreased by 0.74% (6 mmol/mol) and body weight increased by 0.1 kg after 6 months of combination therapy. Multiple regression analysis showed that a higher baseline HbA 1c , older age, and lower body mass index influenced the change of HbA 1c after 6 months. Hypoglycemic symptoms occurred in 7.4%, but none were severe. Conclusions: These results emphasize the importance of a higher HbA 1c at the commencement of sitagliptin therapy in patients on insulin. Glucose-dependent suppression of glucagon secretion by sitagliptin may be useful in patients with impaired insulin secretion. Sitagliptin can be used concomitantly with insulin irrespective of the insulin regimen, duration of insulin treatment, and concomitant medications. J Clin Med Res. 2015;7(8):607-612 doi: http://dx.doi.org/10.14740/jocmr2149w
TL;DR: The administration of teneligliptin every other day had a similar efficacy, patient satisfaction level, and safety compared with its administration every day, and this information will be useful for reducing the economic load without changing the patients' satisfaction and glycemic control.
Abstract: The half life (t1/2 ) of teneligliptin is 24.2 hours. Accordingly, we hypothesized that the administration of teneligliptin every other day might improve glycemic control. In this study, we evaluated the effectiveness of the administration of teneligliptin every other day in Japanese patients with type 2 diabetes. Fifty-one patients were randomly assigned to receive treatment with 20 mg of teneligliptin every day (Group A) or 20 mg of teneligliptin every other day (Group B) for 12 weeks. HbA1c, glycoalbumin (GA), 1,5-anhydroglucitol (1,5-AG), lipid, blood pressure, body weight, urine albumin-to-creatinine ratio, overall treatment satisfaction level, adverse events and drug adherence were all measured. Forty-seven patients completed this study, and the HbA1c, GA, and 1,5-AG levels in group B were found to be decreased to the same extent as those in group A. No distinct differences in the overall treatment satisfaction level, adverse events, or drug adherence were seen between the two groups at 12 weeks. The administration of teneligliptin every other day had a similar efficacy, patient satisfaction level, and safety compared with its administration every day. This information will be useful for reducing the economic load without changing the patients' satisfaction and glycemic control.
TL;DR: Although the mean change difference in HbA1c between both groups was not significant, switching from a basal‐bolus insulin regimen to liraglutide once daily improved patient satisfaction levels without loss of glycemic control.
Abstract: This study aimed to compare the efficacy and safety of liraglutide versus insulin detemir plus sitagliptin in Japanese patients with type 2 diabetes treated with a basal-bolus insulin regimen. In this multicenter, open-label trial, 90 patients whose diabetes had been controlled well or moderately (glycated hemoglobin [HbA1c ] ≤ 7.3%) with basal-bolus insulin regimen were randomly assigned to a liraglutide group or a detemir group and were followed up for 24 weeks. The primary end point was HbA1c change from baseline to 24 weeks. Of the 90 enrolled patients, 82 completed this trial. At 24 weeks, the mean changes in HbA1c from baseline were 0.1% ± 0.9% versus 0.3% ± 0.8% in the liraglutide versus detemir groups, respectively (P = .46). The "overall" satisfaction score for the Diabetes Treatment Satisfaction Questionnaire changed from 25.2 ± 7.4 to 29.9 ± 5.3 (P < .001) and from 26.4 ± 6.1 to 28.3 ± 6.4 (P = .12) in the liraglutide and detemir groups, respectively. Although the mean change difference in HbA1c between both groups was not significant, switching from a basal-bolus insulin regimen to liraglutide once daily improved patient satisfaction levels without loss of glycemic control.
Journal Article•
TL;DR: Trelagliptin is a long acting dipeptidyl peptidase-4(DPP-4) inhibitor and a once-weekly treatment by trelagliptin would improve the drug adherence of patients.
Abstract: Clinical development of novel antidiabetic drugs, such as GK activator, GPR40 agonist, GPR119 agonist, 11β-HSD1 inhibitor and trelagliptin, has been progressing over the world. Especially, GK activator, GPR40 agonist, GPR119 agonist and 112-HSD1 inhibitor have unique action mechanism compared to existing drugs. GK activator potentiates glucose-stimulated insulin secretion from β cells and stimulates glucose uptake into the liver. GPR40 agonists and GPR119 agonist stimulate glucose-dependent insulin secretion from β cells. 11β-HSD1 inhibitor reduces the conversion of cortisone to cortisol. Trelagliptin is a long acting dipeptidyl peptidase-4(DPP-4) inhibitor and a once-weekly treatment by trelagliptin would improve the drug adherence of patients. This article focuses on these new and emerging diabetes agents.