Open-label randomized non-inferiority trial of a fixed-dose combination of glimepiride and atorvastatin for the treatment of people whose Type 2 diabetes is uncontrolled on metformin.

AIMS: To evaluate, in a randomized, open-label study, the non-inferiority of a bioequivalent fixed-dose combination of glimepiride and atorvastatin vs. separately co-administered tablets in people with Type 2 diabetes mellitus. METHODS: Participants with HbA1c ≥ 53 to < 80 mmol/mol (≥ 7.0 to < 9.5%), average fasting blood glucose > 7.0 mmol/l, who were on metformin for ≥ 3 months, were randomized to combination (n = 215) or co-administered glimepiride and atorvastatin (n = 212) once daily for 20 weeks. Up-titration of glimepiride (1-4 mg) and atorvastatin (10-20 mg) were based on average fasting blood glucose and LDL cholesterol, respectively. Co-primary endpoints were change from baseline to week 20 in HbA1c and LDL cholesterol. RESULTS: Non-inferiority was demonstrated for both co-primary endpoints: the upper limits of 95% CIs for differences (combination-reference) were less than the prespecified margins of 3.3 mmol/mol (0.3%) for change from baseline in HbA1c [difference 0.1 mmol/mol (95% CI -1.6, 1.9); 0.01% (95% CI -0.15, 0.17)] and 6% for percentage change from baseline in LDL cholesterol [difference 0.87% (95% CI -2.47, 4.21)]. Similar proportions of participants on combination and reference had treatment-emergent adverse events (64 vs. 61%). More participants on combination had hypoglycaemia (21 vs. 13%); most events were considered by the treating physician to be unrelated to study drug. CONCLUSIONS: The combination was non-inferior to separately co-administered tablets and the safety profile was consistent with the known profiles of glimepiride and atorvastatin. The observed increase in hypoglycaemia on the combination cannot be explained, but may be attributable to non-systematic collectiof glucose readings and may have been influenced by reporting bias in this open-label trial.

Lobeglitazone and pioglitazone as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension.

We aimed to compare the efficacy and safety of lobeglitazone and pioglitazone as add-ons to metformin in patients with type 2 diabetes. Patients who were inadequately controlled by metformin were randomized and treated once daily with either lobeglitazone (0.5 mg, n = 128) or pioglitazone (15 mg, n = 125) for 24 weeks, with a 28-week extension trial of lobeglitazone treatment in patients who consented. The primary endpoint was the change in glycated haemoglobin (HbA1c) concentration from baseline to week 24. At week 24, the mean change from baseline in HbA1c was -0.74% for the lobeglitazone group and -0.74% for the pioglitazone group, with a mean difference of 0.01% [95% confidence interval (CI) of difference, -0.16 to 0.18]. The effects of lobeglitazone on lipid variables and the adverse events associated with lobeglitazone were similar to those observed with pioglitazone. Lobeglitazone was not inferior to pioglitazone as an add-on to metformin in terms of their efficacy and safety.

Anagliptin and sitagliptin as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, active-controlled, phase III clinical trial with a 28-week extension.

We conducted a 24-week, multicentre, double-blind, randomized study with a 28-week extension to compare the efficacy and safety of anagliptin and sitagliptin as an add-on to metformin in patients with type 2 diabetes. Patients inadequately controlled on metformin were randomized to either anagliptin (100 mg twice daily, n = 92) or sitagliptin (100 mg once daily, n = 88). The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. The mean changes in HbA1c were -0.85 ± 0.70% (p < 0.0001) for anagliptin and -0.83 ± 0.61% (p < 0.0001) for sitagliptin, with a mean difference of -0.02% (95% confidence interval of difference, -0.22 to 0.18%). In both groups, the fasting proinsulin : insulin ratio significantly decreased from baseline, with improved insulin secretion. Safety profiles were similar in each group. In conclusion, the non-inferiority of the efficacy of anagliptin to sitagliptin as an add-on therapy was established with regard to efficacy and safety.

Slewing Mirror Telescope optics for the early observation of UV/optical photons from Gamma-Ray Bursts.

We report on design, manufacture, and testing of a Slewing Mirror Telescope (SMT), the first of its kind and a part of Ultra-Fast Flash Observatory-pathfinder (UFFO-p) for space-based prompt measurement of early UV/optical light curves from Gamma-Ray Bursts (GRBs). Using a fast slewing mirror of 150 mm diameter mounted on a 2 axis gimbal stage, SMT can deliver the images of GRB optical counterparts to the intensified CCD detector within 1.5~1.8 s over ± 35 degrees in the slewing field of view. Its Ritchey-Chrétien telescope of 100 mm diameter provides a 17 × 17 arcmin² instantaneous field of view. Technical details of design, construction, the laboratory performance tests in space environments for this unique SMT are described in conjunction with the plan for in-orbit operation onboard the Lomonosov satellite in 2013.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor gemigliptin compared with sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.

AIMS: This study was designed to assess the efficacy and safety of a dipeptidyl peptidase-4 inhibitor, gemigliptin versus sitagliptin added to metformin in patients with type 2 diabetes. METHODS: We conducted a double-blind, randomized, active-controlled trial in 425 Asian patients with inadequately controlled type 2 diabetes being treated with metformin alone. Eligible patients were randomized into three groups: 50 mg gemigliptin qd, 25 mg gemigliptin bid or sitagliptin 100 mg qd added to ongoing metformin treatment for 24 weeks. Haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) were measured periodically, and oral glucose tolerance tests were performed at baseline and 24 weeks after starting the treatment regimen. RESULTS: Twenty-four weeks later, adding gemigliptin (50 mg/day) to ongoing metformin therapy significantly improved glycaemic control. Reduction in HbA1c caused by 50 mg gemigliptin qd (-0.77% ± 0.8) was non-inferior to that caused by 100 mg sitagliptin qd (-0.8% ± 0.85). Proportion of patients achieving HbA1c <7% while taking 25 mg gemigliptin bid (50%) or 50 mg gemigliptin qd (54.07%) was comparable to the results with 100 mg sitagliptin qd (48.87%). There were significant decreases in FPG, postprandial glucose and AUC0-2 h glucose, as well as increases in GLP-1 and ß cell sensitivity to glucose (supported by homeostasis model assessment of ß-cell function, postprandial 2-h c-peptide and insulinogenic index) in patients receiving gemigliptin treatment with their metformin therapy. There was no increased risk of adverse effects with this dose of gemigliptin compared with sitagliptin 100 mg qd. CONCLUSIONS: Addition of gemigliptin 50 mg daily to metformin was shown to be efficacious, well tolerated and non-inferior to sitagliptin in patients with type 2 diabetes mellitus.

A multicentre, multinational, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (LC15-0444) in patients with type 2 diabetes.

AIM: This study was designed to assess the efficacy and safety of the dipeptidyl peptidase IV inhibitor gemigliptin (LC15-0444) 50 mg versus placebo in patients with type 2 diabetes. METHODS: We conducted a 24-week, randomized, double-blind, placebo-controlled phase III trial in 182 patients (74 from Korea and 108 from India) with type 2 diabetes. After an initial 2 weeks of a diet and exercise programme followed by 2 weeks of a single-blind placebo run-in period, eligible patients were randomized to gemigliptin 50 mg or placebo, receiving the assigned treatment for 24 weeks. HbA1c and fasting plasma glucose (FPG) were measured periodically, and oral glucose tolerance test was performed at baseline and weeks 12 and 24. RESULTS: At week 24, gemigliptin treatment led to significant reductions in HbA1c measurements compared to placebo (adjust mean after subtracting the placebo effect size: -0.71%, 95% confidence interval: -1.04 to -0.37%). A significantly greater proportion of patients achieved an HbA1c <7% with gemigliptin than with placebo. The placebo-subtracted FPG change from baseline at week 24 was -19.80 mg/dl. The overall incidence rates for adverse events were similar in the gemigliptin and placebo groups. CONCLUSIONS: This study showed the efficacy and safety of gemigliptin 50 mg administered once daily as a monotherapy for type 2 diabetes patients.

Efficacy and safety of glimepiride/metformin sustained release once daily vs. glimepiride/metformin twice daily in patients with type 2 diabetes.

AIMS: The study investigated the clinical equivalence in reducing haemoglobin A1c (A1C) between glimepiride/metformin sustained release (GM-SR) 2/500 mg, a fixed-dose combination, once daily and glimepiride/metformin (GM) 1/250 mg, a fixed-dose combination, twice daily in patients with type 2 diabetes (T2D). METHODS: A multicentre, randomised, double-blind, double-dummy study was conducted in 14 hospitals in Korea. Inclusion criteria were age 30-75 years, T2D diagnosis no longer than 10 years previously, A1C between 7% and 10%, and body mass index <40 kg/m(2) . A total of 207 subjects were randomised into the GM-SR group (n=101) or the GM group (n=106). Participants were assessed at baseline, 8 weeks and 16 weeks after treatment. RESULTS: After 16 weeks treatment, no difference in baseline-adjusted changes of A1C (primary efficacy variable) was observed between the two groups (-0.59% for GM-SR group vs. -0.61% for GM group, 95% CI: -0.17 to 0.21; p=0.84). In addition, there were no significant differences in secondary efficacy parameters between the two groups, including changes in A1C up to week 8, changes in fasting plasma glucose (FPG) and 2-h-postprandial plasma glucose up to week 8 and week 16, response rate, drug compliance and hypoglycaemic events. However, there was a difference in baseline-adjusted changes of FPG between the two groups (-1.01 mmol/l for GM-SR group vs. -1.52 mmol/l for GM group, p=0.01 in the intention to treat set). CONCLUSIONS: GM-SR 2/500 mg once daily was as effective as GM 1/250 mg twice daily in lowering A1C. In addition, no difference was noted in hypoglycaemic events between the two groups.

Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia).

AIMS: To assess the efficacy and safety of once-daily lixisenatide versus placebo in Asian patients with type 2 diabetes insufficiently controlled on basal insulin ± sulfonylurea. METHODS: In this 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicentre study, participants (mean baseline HbA(1c) 8.53%) from Japan, Republic of Korea, Taiwan and the Philippines received lixisenatide (n = 154) or placebo (n = 157) in a stepwise dose increase to 20 µg once daily. The primary endpoint was HbA(1c) change from baseline to week 24. RESULTS: Once-daily lixisenatide significantly improved HbA(1c) versus placebo (LS mean difference vs. placebo = -0.88% [95%CI= -1.116, -0.650]; p < 0.0001), and allowed more patients to achieve HbA(1c) <7.0% (35.6 vs. 5.2%) and ≤ 6.5% (17.8 vs. 1.3%). Lixisenatide also significantly improved 2-h postprandial plasma glucose and glucose excursion, average 7-point self-monitored blood glucose and fasting plasma glucose. Lixisenatide was well tolerated; 86% of patients on lixisenatide completed the study versus 92% on placebo. Ten (6.5%) lixisenatide and 9 (5.7%) placebo patients experienced serious adverse events. More lixisenatide patients [14 (9.1%)] discontinued for adverse events versus placebo [5 (3.2%)], mainly with gastrointestinal causes. Nausea and vomiting were reported in 39.6 and 18.2% of patients on lixisenatide versus 4.5 and 1.9% on placebo. Symptomatic hypoglycaemia was more frequent with lixisenatide (42.9%) versus placebo (23.6%), but was similar between groups (32.6 vs. 28.3%, respectively), in those not receiving sulfonylureas. No severe hypoglycaemia was reported. CONCLUSIONS: In an Asian type 2 diabetes population insufficiently controlled by basal insulin ± sulfonylurea, once-daily lixisenatide significantly improved glycaemic control, with a pronounced postprandial effect, and was well tolerated.

The effects of total energy expenditure from all levels of physical activity vs. physical activity energy expenditure from moderate-to-vigorous activity on visceral fat and insulin sensitivity in obese Type 2 diabetic women.

AIMS: We examined the effects of physical activity with or without dietary restriction for 3 months on regional fat and insulin sensitivity and compared the effect of total energy expenditure from all levels of physical activity with that of physical activity energy expenditure from moderate-to-vigorous exercise in obese women with Type 2 diabetes. METHODS: In this randomized, controlled trial, we assessed change of body weight, abdominal visceral fat area, subcutaneous fat area and insulin sensitivity, expressed as K(ITT), and monitored total energy expenditure and physical activity energy expenditure using an accelerometer during a 12-week intervention in four groups: control, diet, exercise and diet plus exercise. RESULTS: The mean body mass index was 28.0 +/- 2.7 kg/m(2) and the mean duration of diabetes was 8 +/- 6 years. Both the diet and diet plus exercise groups showed significant body weight loss compared with the control group (P < 0.05). However, the visceral fat area was reduced only in the diet and exercise group (P = 0.017) and the subcutaneous fat area was reduced only in the diet group (P = 0.009). Mean energy intake was an independent determinant of the change in subcutaneous fat area (P = 0.020) and mean total anergy expenditure was an independent determinant of visceral fat area (P = 0.002). Insulin sensitivity K(ITT) was associated with physical activity energy expenditure (P = 0.006), energy intake (P = 0.047) and the change in fructosamine level (P = 0.016) but not with changes in body weight, subcutaneous fat area, visceral fat area or adipokine level. CONCLUSIONS: Exercise had an additive effect to dietary restriction on visceral fat reduction. Visceral fat area was associated with total energy expenditure, but insulin sensitivity was associated with physical activity energy expenditure.

A multicenter, randomized, placebo-controlled, double-blind phase II trial evaluating the optimal dose, efficacy and safety of LC 15-0444 in patients with type 2 diabetes.

AIM: The objective of this study was to evaluate the optimal dose, efficacy and safety of a novel dipeptidyl peptidase-4 (DPP-IV) inhibitor, LC15-0444, in Korean subjects with type 2 diabetes mellitus treated by diet and exercise. METHODS: This study was a double-blind, randomized, multicenter and parallel-group, dose-range finding study. We enrolled 145 patients (91 men and 54 women) with a median age of 53 years and a median body mass index of 25.1 kg/m(2) . The median baseline fasting plasma glucose (FPG) was 8.1 mmol/l, the median HbA1c was 7.9% and the median time since the diagnosis of diabetes was 3 years. After 2 weeks of an exercise/diet programme followed by 2 weeks of a placebo period, the subjects were randomized to one of the four following groups for a 12-week active treatment period: placebo and 50, 100 or 200 mg of LC15-0444. RESULTS: All three doses of LC15-0444 significantly reduced the HbA1c from baseline compared to the placebo group (-0.06 vs. -0.98, -0.74 and -0.78% in the placebo and 50, 100 and 200 mg groups, respectively), without a significant difference between the doses. Subjects with a higher baseline HbA1c (≥8.5%) had a greater reduction in HbA1c. Insulin secretory function, as assessed using homeostasis model assessment-beta cell, C-peptide and the insulinogenic index, improved significantly with LC15-0444 treatment. Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12 weeks of treatment. The 50 and 200 mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12 weeks compared to the placebo group. No dosage of LC15-0444 affected weight or waist circumference. The incidences of adverse events were similar in all study subjects. CONCLUSIONS: LC15-0444 monotherapy (50 mg for 12 weeks) improved the HbA1c, FPG level, oral glucose tolerance test results, ß-cell function and insulin sensitivity measures, and was well tolerated in Korean subjects with type 2 diabetes.

Resistance exercise did not alter intramuscular adipose tissue but reduced retinol-binding protein-4 concentration in individuals with type 2 diabetes mellitus.

Lipid accumulation in muscle is associated with diminished insulin sensitivity. It was hypothesized that resistance exercise decreases muscular adipose tissue and reduces the level of retinol-binding protein-4 (RBP4), which is linked to adipose tissue and insulin sensitivity in diabetics. Forty-four women with type 2 diabetes were randomly assigned to three groups for a period of 12 weeks: control (asked to maintain a sedentary lifestyle); resistance exercise (elastic band exercise at moderate intensity five times per week); and aerobic exercise (walking for 60 min at moderate intensity five times per week). Subcutaneous (SCAT), subfascial (SFAT) and intramuscular (IMAT) adipose tissues at mid-thigh level were assessed using computed tomography, and RBP4 level and insulin sensitivity (fractional disappearance rate of insulin, k(ITT)) were assessed before and after intervention. Changes in SCAT, SFAT, IMAT, RBP4 and k(ITT) were similar among the three groups. Within-group analysis revealed that body mass index and waist circumference decreased significantly in both exercise groups, but RBP4 decreased significantly only with resistance exercise. Resistance exercise did not alter muscular adipose tissue or improve insulin sensitivity.

Valsartan increases circulating adiponectin levels without changing HOMA-IR in patients with type 2 diabetes mellitus and hypertension.

Evaluating increasing circulating adiponectin levels is becoming an important strategy in the prevention of diabetes mellitus and cardiovascular events. This study was designed to investigate the effect of the angiotensin II receptor blocker valsartan on blood adiponectin levels and insulin sensitivity in patients with type 2 diabetes and mild-to-moderate hypertension. A total of 91 Korean patients were treated with 80 mg/day valsartan for 4 weeks followed by 160 mg/day for a further 8 weeks. Blood pressure, adiponectin levels and metabolic parameters were measured before and after treatment. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as an insulin sensitivity index. Valsartan significantly decreased mean blood pressure and increased circulating adiponectin levels. There were no differences in metabolic parameters, including HOMA-IR, glycosylated haemoglobin and lipid levels before and after treatment. These results indicated that valsartan increases circulating adiponectin levels, but does not change insulin sensitivity in patients with type 2 diabetes and mild-to-moderate hypertension.

Parallel propagating electromagnetic waves in magnetized quantum electron plasmas with finite temperature.

We studied parallel propagating electromagnetic waves in a magnetized quantum electron plasma of finite temperature, as an extension of our previous study on a zero temperature plasma. We obtained simple analytic dispersion relations in the long wavelength limit that included the thermal effect as correction terms to the zero temperature results. As in the zero temperature case, the lower branch of the R wave showed significant damping and became ill-defined at short wavelengths. Quantum effects seemed to give qualitative changes, such as the appearance of anomalous dispersion regions, to the classical dispersion relations when v_{F}/v_{th}≤0.2 for a set of exemplary parameters of v_{F}=0.1c and ω_{ce}/ω_{pe}=0.05 was used. We also noted that introduction of the Planck constant in the quantum Vlasov equation changed the shape of the anomalous dispersion region qualitatively, by forming a normal dispersion region in the middle of the original single broad anomalous dispersion region.

Expression of cyclooxygenase-2 in breast carcinogenesis and its relation to HER-2/neu and p53 protein expression in invasive ductal carcinoma.

The purpose of this study was to evaluate cyclooxygenase-2 (COX-2) expression in the successive steps of breast carcinogenesis and to determine its correlation with HER-2/neu and p53 expression in invasive ductal carcinomas of the breast. Immunohistochemical staining with anti-COX-2 antibody was performed in normal breast tissue, usual hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Expression of COX-2 in invasive ductal carcinoma was correlated with immunohistochemical expression of HER-2/neu and p53 protein. COX-2 expression was found to be progressively elevated along the continuum from normal breast tissue to invasive ductal carcinoma (P<0.001). COX-2 expression significantly correlated with p53 and HER-2/neu protein expression (P<0.05 and P<0.001). On multivariate analysis, only TNM stage and elevated COX-2 expression correlated with survival. Our results suggest that COX-2 may be involved in the carcinogenesis of the breast and may be an independent prognostic indicator in patients with invasive ductal carcinoma. HER-2/neu and p53 are likely to be involved in the regulation of COX-2 expression in invasive ductal carcinomas of the breast.

Cellular F-actin levels as a marker for cellular transformation: correlation with bladder cancer risk.

Previous findings in cultured cells that differentiated cells had markedly higher F-actin levels than undifferentiated cells (Cancer Res., 50: 2215-2220, 1990) suggested that quantitative F-actin measurements in urinary cells might provide diagnostic or prognostic information by identifying those individuals with cells tending towards a lower degree of differentiation. The feasibility of such an approach was investigated using a risk stratification schema. Bladder wash samples were obtained from 163 symptomatic patients being evaluated for bladder cancer and 41 asymptomatic controls without hematuria or other symptoms consistent with bladder cancer. F-actin levels were evaluated by flow cytometry using a fluorescent phalloidin probe. The risk of bladder cancer was stratified according to biopsy, either DNA ploidy by flow cytometry or quantitative fluorescence image analysis cytology, previous bladder cancer history, and hematuria. A strong correlation between the presence of cells with abnormally low F-actin content in cells obtained by bladder wash from 38 patients and biopsy-proved bladder transitional cell carcinoma (P less than 0.001) was observed. A strong correlation was also observed between the presence of cells with low F-actin content and risk of bladder cancer assessed by either stratification schema (P less than 0.0001). The correlation was more consistent with the stratification by quantitative fluorescence image analysis cytology because of the 37% false-positive rate of ploidy analysis by flow cytometry among the control patients. Further evidence that low F-actin was correlated with cellular abnormality was obtained from simultaneously labeling cells for F-actin and with M344 antibody, a monoclonal antibody against a low-grade bladder tumor-related antigen. These studies showed that the F-actin content of the M344-positive cells was lower than that of the M344-negative cells. These results suggest that F-actin could be an early and sensitive marker for bladder cancer detection and risk prognostication.

NAG-1/GDF15 accumulates in the nucleus and modulates transcriptional regulation of the Smad pathway.

Protein dynamics, modifications and trafficking are all processes that can modulate protein activity. Accumulating evidence strongly suggests that many proteins have distinctive roles dependent on cellular location. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a transforming growth factor-ß (TGF-ß) superfamily protein that has a role in cancer, obesity and inflammation. NAG-1 is synthesized and cleaved into a mature peptide, which is ultimately secreted into the extracellular matrix (ECM). In this study, we have found that full-length NAG-1 is expressed in not only the cytoplasm and ECM, but also in the nucleus. NAG-1 is dynamically moved to the nucleus, exported into cytoplasm and further transported into the ECM. We have also found that nuclear NAG-1 contributes to inhibition of the Smad pathway by interrupting the Smad complex. Overall, our study indicates that NAG-1 is localized in the nucleus and provides new evidence that NAG-1 controls transcriptional regulation in the Smad pathway.

Mammary pseudoangiomatous stromal hyperplasia presenting as an axillary mass.

Pseudoangiomatous stromal hyperplasia (PASH) of the breast is characterized by interanastomosing slit-like spaces lined with spindle-shaped cells in an abundant fibrous stroma. PASH is a relatively common incidental finding in the breast tissue removed for other reasons and rarely presents as a localized mass. The etiology of PASH is unknown, but hormonal factors are thought to be involved. Accessory breast tissue is subject to all pathologic changes found in the normal breast. We report a case of PASH that presented as a palpable axillary mass in a 43-year-old woman. To our knowledge, PASH has not previously been reported in the axillary accessory breast tissue. The spindle stromal cells in our patient showed immunophenotypic characteristics of myofibroblastic differentiation. Immunoreactivity for progesterone receptor was noted in the spindle cells. These findings support the hypothesis that endogenous hormones are involved in the development of PASH.