Introduction Cette étude multicentrique de phase 3 de 24 semaines, randomisée, en double aveugle, contrôlée versus placebo en 2 bras parallèles a évalué l’efficacité et la tolérance du lixisenatide ...chez des patients asiatiques ayant un DT2 non équilibré sous insuline basale ± SU. Matériels et méthodes 311 patients (âge moyen : 58,4 ans, durée de diabète : 13,9 ans, IMC : 25,3 kg/m2 , du Japon, de Corée du Sud, de Taïwan ou des Philippines). Ces patients antérieurement traités par insuline basale ± SU ont été séparés par randomisation en 2 groupes, un groupe lixisenatide 20 ∞g en 1 prise (n = 154) et un groupe placebo (n = 157). Les groupes étaient globalement comparables à l’inclusion. Après l’inclusion et 1 semaine de placebo en simple aveugle, les patients entraient dans une phase de 24 semaines de traitement en double aveugle, contrôlée versus placebo. Le critère principal était la variation d’HbA1c entre l’inclusion et 24 semaines. Résultats Le lixisenatide une fois par jour a amélioré significativement l’HbA1c vs le placebo (différence moyenne LS (Least Square = moindres carrés) : −0,9 %). Davantage de patients sous lixisenatide ont atteint une HbA1c − 6,5 % (17,8 %) et < 7,0 % (35,6 %) vs placebo (1,3 % et 5,2 %; p < 0,0001). Le lixisenatide a également diminué significativement la GPP à 2 heures, les pics glycémiques et la moyenne glycémique lors de cycles d’auto surveillance glycémique (ASG) en 7 points. Le lixisenatide a été bien toléré et 86 % des patients sous lixisenatide ont terminé l’étude vs 92 % des patients sous placebo. 9 patients sous placebo (5,7 %) et 10 sous lixisenatide (6,5 %) ont eu un EI grave attribué au traitement. Davantage de patients sous lixisenatide (14 9,1 %) par rapport aux patients sous placebo (5 3,2 %) ont stoppé le traitement en raison d’un EI lié au traitement, il s’agissait essentiellement d’EI digestifs. Des nausées et des vomissements ont été rapportés chez 39,6 % et 18,2 % des patients sous lixisenatide vs 4,5 % et 1,9 % dans le groupe placebo. Comme cela était attendu dans une population traitée par insuline ± SU, le % de patients ayant présenté une hypoglycémie symptomatique était supérieur sous lixisenatide (42,9 %) vs placebo (23,6 %), mais le taux baissait à 32,6 % sous lixisenatide vs 28,3 % sous placebo chez ceux qui ne recevaient pas de SU. Il n’y a eu aucune hypoglycémie sévère. Conclusion Dans cette population asiatique de patients DT2 mal équilibrés sous insuline basale ± SU, le lixisenatide en une prise quotidienne a significativement amélioré l’équilibre glycémique avec un effet prononcé sur la GJ et la GPP et a été bien toléré.
We search for the dark photon dark matter (DPDM) using a cryogenic millimeter-wave receiver. DPDM has a kinetic coupling with electromagnetic fields with a coupling constant of χ and is converted ...into ordinary photons at the surface of a metal plate. We search for signal of this conversion in the frequency range 18-26.5 GHz, which corresponds to the mass range 74-110 μeV/c^{2}. We observed no significant signal excess, allowing us to set an upper bound of χ<(0.3-2.0)×10^{-10} at 95% confidence level. This is the most stringent constraint to date and tighter than cosmological constraints. Improvements from previous studies are obtained by employing a cryogenic optical path and a fast spectrometer.
A synchrotron X-ray powder diffraction pattern was measured for a lithium superionic conductor, Li7P3S11, which has a high conductivity of 3.2X10-3Scm-1 at room temperature and a low activation ...energy of 12kJmol-1 Mizuno et al., Solid State Ionics, vol. 177 (2006) 2721. The crystal structure was solved by a direct space global optimization technique and refined by the Rietveld method. The compound crystallizes in a triclinic cell, space group P-1, a=12.5009(3) A, b=6.03160(17) A, c=12.5303(3) A, alpha=102.845(3) deg , beta=113.2024(18) deg , gamma=74.467(3) deg . PS4 tetrahedra and P2S7 ditetrahedra are contained in the structure and Li ions are situated between them.
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) control glucose homeostasis through well-defined actions on the islet beta cell via ...stimulation of insulin secretion and preservation and expansion of beta cell mass. We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r(-/-), Gipr(-/-), and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor-1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist D-Ala(2)GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the beta cell via control of adipokine secretion and energy expenditure.
Axion Like Particles (ALPs) with a sub-keV range mass are searched by using the light-shining-through-a-wall technique. A novel system is developed in which injected X rays are converted and ...reconverted by the Laue-case conversion within a silicon single crystal with dual blades. The resonant ALPs mass of the conversion is scanned by varying the X-ray injection angle to the crystal. No significant signals are observed, and 90% C. L. upper limits on the ALP-two photon coupling constant are obtained as follows,(1)gaγγ<4.2×10−3GeV−1(ma<10eV),(2)gaγγ<5.0×10−3GeV−1(46eV<ma<1020eV). These are the most stringent laboratory-based constraints on ALPs heavier than 300 eV.
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 HbA1c 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 HbA1c change from baseline to week 24.
Results
Once‐daily lixisenatide significantly improved HbA1c versus placebo (LS mean difference vs. placebo = −0.88% 95%CI= −1.116, −0.650; p < 0.0001), and allowed more patients to achieve HbA1c <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.
Abstract
Objective:
Liraglutide is a once-daily human glucagon-like peptide-1 (GLP-1) analogue developed for the treatment of type 2 diabetes mellitus (T2DM). In Phase 2 and Phase 3 trials, largely ...conducted in populations of European descent, liraglutide has been shown to lower HbA1C, weight and systolic blood pressure with a low risk of hypoglycaemia. This Phase 3, 24-week, multi-centre, double-blind, double dummy, randomised parallel-group trial compared the efficacy and safety of liraglutide and glibenclamide monotherapy in Japanese subjects with T2DM, inadequately controlled with diet therapy or oral antidiabetic drug (OAD) monotherapy.
Research design and methods:
A total of 411 Japanese subjects were randomised 2:1 to liraglutide (n = 272) or glibenclamide (n = 139). Liraglutide was administered at a maximum planned dose of 0.9 mg once daily. Glibenclamide was administered once or twice daily at a planned maximum dose of 2.5 mg/day, before or after meals.
Clinical trial registration:
NCT00393718.
Results:
After 24 weeks, glycaemic control with liraglutide was non-inferior/superior to glibenclamide, with HbA1C at 24 weeks of 6.99% (SE 0.07) with liraglutide and 7.50% ( 0.09) with glibenclamide (difference, −0.5%; 95% CI −0.70 to 0.30; p < 0.0001). Mean fasting plasma glucose (FPG) levels at 24 weeks were significantly lower with liraglutide (7.6 mmol/l SE 0.1) vs glibenclamide (8.3 mmol/l 0.1; difference, −0.72 mmol/l; 95% CI −1.0 to −0.4; p < 0.0001). Weight was reduced by −0.92 kg from a baseline of 65.2 kg in liraglutide-treated patients, compared with weight gain of +0.99 kg from a baseline of 64.8 kg with glibenclamide (difference, −1.91 kg; 95% CI −2.34 to −1.48; p < 0.0001). A significantly lower rate of minor hypoglycaemic episodes was achieved with liraglutide compared with glibenclamide (p < 0.0001), and no major hypoglycaemic episodes were reported in either treatment group. The most common gastrointestinal AEs were diarrhoea (liraglutide, 6.3%; glibenclamide, 3.8%) and constipation (liraglutide, 5.6%; glibenclamide, 3.8%). Nausea was infrequent (liraglutide, 4.5%; glibenclamide, 1.5%).
Conclusions:
Liraglutide monotherapy, administered once daily for 24 weeks in Japanese subjects with T2DM, was well tolerated. Compared with glibenclamide monotherapy, liraglutide achieved superior glycaemic control and weight outcome, and a significantly lower incidence of hypoglycaemia. Future studies, comprising a greater proportion of true therapy-naïve Japanese patients, will be beneficial in order to establish the true add-on efficacy of liraglutide monotherapy in patients with T2DM.
Aims
To evaluate the efficacy and safety of alogliptin added to metformin versus metformin monotherapy in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on metformin ...(500 or 750 mg/day) + diet/exercise.
Methods
In a randomized, double‐blind trial, 288 patients with type 2 diabetes mellitus T2DM received either 12.5 or 25 mg alogliptin once daily + metformin or placebo + metformin for 12 weeks. Thereafter, 276 patients continued on one of the two alogliptin dosages + metformin in an open‐label extension for 40 weeks. The primary efficacy endpoint in the randomized, double‐blind phase was the change in HbA1c from baseline (week 0) to the end of treatment (week 12). The primary endpoint during the long‐term extension phase was adverse events.
Results
After 12 weeks both dosages of alogliptin + metformin produced significantly greater changes from baseline in HbA1c than placebo (metformin monotherapy: with changes in LS means − 0.55 and − 0.64% vs. 0.22%, respectively; p < 0.0001). Incidences of adverse effects were comparable between groups, with no increases in hypoglycaemia. Over 52 weeks, there were no safety or tolerability concerns with alogliptin when added to metformin.
Conclusions
Alogliptin 12.5 and 25 mg once daily was safe and effective when added to metformin (500 or 750 mg/day) in Japanese patients with inadequately controlled type 2 diabetes on metformin alone.
Aim: Sulphonylureas (SUs) are often used as first-line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. ...Methods: The efficacy and safety of the once-daily human glucagon-like peptide-1 (GLP-1) analogue liraglutide were compared in 264 Japanese subjects mean body mass index (BMI) 24.9 kg/m²; mean glycated haemoglobin (HBA1c) 8.4% randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24-week, double-blind, parallel-group trial. Results: The mean change in HBA1c from baseline to week 24 (LOCF) was -1.56 (s.d. 0.84) and -1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and -0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference -1.47 mmol/l and -1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: -0.37 kg), while mean body weight decreased in subjects receiving placebo (-1.12 kg). Conclusions: The addition of liraglutide to SU treatment for 24 weeks dose-dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.
Abstract
Quantum electrodynamics predicts X-ray diffractions under a high-intensity laser field via virtual charged particles, and this phenomenon is called vacuum diffraction (VD). In this paper, we ...derive a new formula to describe VD in a head-on collision geometry of an X-ray free-electron laser (XFEL) pulse and a laser pulse. The wavefront curvature of the XFEL pulse is newly considered in this formula. With this formula, we also discuss the curvature effect on VD signals based on realistic parameters at the SACLA XFEL facility.
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