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Schernthaner G.,Rudolfstiftung Hospital | Duran-Garcia S.,Hospital Universitario Of Valme | Hanefeld M.,GWT TUD GmbH | Langslet G.,University of Oslo | And 5 more authors.
Diabetes, Obesity and Metabolism | Year: 2015

Aims: To assess the efficacy and safety of adjunctive saxagliptin vs glimepiride in elderly patients with type 2 diabetes (T2D) and inadequate glycaemic control. Methods: In this multinational, randomized, double-blind, phase IIIb/IV study (GENERATION; NCT01006603), patients aged≥65years were randomized (1:1) to receive saxagliptin 5mg/day or glimepiride ≤6mg/day, added to metformin, during a 52-week treatment period. The primary endpoint was achievement of glycated haemoglobin (HbA1c)<7.0% at week52 without confirmed/severe hypoglycaemia. The key secondary endpoint was incidence of confirmed/severe hypoglycaemia. Safety and tolerability were also assessed. Results: Of 720 patients randomized (360 in each treatment group; mean age 72.6years; mean T2D duration 7.6years), 574 (79.8%) completed the study (saxagliptin 80.3%; glimepiride 79.2%). Similar proportions of patients achieved the primary endpoint with saxagliptin and glimepiride (37.9 vs 38.2%; odds ratio 0.99, 95% confidence interval 0.73, 1.34; p=0.9415); however, a significant treatment-by-age interaction effect was detected (p=0.0389): saxagliptin was numerically (but not significantly) superior to glimepiride for patients aged<75years (39.2 vs 33.3%) and numerically inferior for patients aged≥75years (35.9 vs 45.5%). The incidence of confirmed/severe hypoglycaemia was lower with saxagliptin vs glimepiride (1.1 vs 15.3%; nominal p<0.0001). Saxagliptin was generally well tolerated, with similar incidences of adverse events compared with glimepiride. Conclusion: As avoiding hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in patients with T2D aged≥65years. © 2015 John Wiley & Sons Ltd.

Monnier L.,Montpellier University | Hanefeld M.,GWT TUD GmbH | Schnell O.,Helmholtz Center Munich | Colette C.,Montpellier University | Owens D.,University of Swansea
Diabetes and Metabolism | Year: 2013

The relationship between insulin and atherosclerosis is complex. People with type 2 diabetes are affected by three main glycaemic disorders: chronic hyperglycaemia; glycaemic variability; and iatrogenic hypoglycaemia. In addition to this triumvirate, the diabetic condition is characterized by lipid disorders, chronic low-grade inflammation and activation of oxidative stress. All these associated disorders reflect the insulin-resistant nature of type 2 diabetes and contribute to the development and progression of cardiovascular (CV) diseases. By both lowering plasma glucose and improving the lipid profile, insulin exerts beneficial effects on CV outcomes. In addition, insulin has several pleiotropic effects such as anti-inflammatory, antithrombotic and antioxidant properties. Insulin per se exerts an inhibitory effect on the activation of oxidative stress and seems able to counteract the pro-oxidant effects of ambient hyperglycaemia and glycaemic variability. However, insulin actions remain a subject of debate with respect to the risk of adverse CV events, which can increase in individuals exposed to high insulin doses. Evidence from the large-scale, long-term ORIGIN trial suggests that early implementation of insulin supplementation therapy in the course of glycaemic disorders, including type 2 diabetes, has a neutral impact on CV outcomes compared with standard management. Thus, the answer to the question " What impact does insulin have on atherosclerosis?" remains unclear, even though it is logical to deduce that insulin should be initiated as soon as possible and that small doses of insulin early on are better than higher doses later in the disease process. © 2013 Elsevier Masson SAS.

Hanefeld M.,GWT TUD GmbH | Monnier L.,Montpellier University | Schnell O.,Ludwig Maximilians University of Munich | Owens D.,University of Swansea
Diabetes Therapy | Year: 2016

Dysglycemia results from a deficit in first-phase insulin secretion compounded by increased insulin insensitivity, exposing β cells to chronic hyperglycemia and excessive glycemic variability. Initiation of intensive insulin therapy at diagnosis of type 2 diabetes mellitus (T2DM) to achieve normoglycemia has been shown to reverse glucotoxicity, resulting in recovery of residual β-cell function. The United Kingdom Prospective Diabetes Study (UKPDS) 10-year post-trial follow-up reported reductions in cardiovascular outcomes and all-cause mortality in persons with T2DM who initially received intensive glucose control compared with standard therapy. In the cardiovascular outcome trial, outcome reduction with an initial glargine intervention (ORIGIN), a neutral effect on cardiovascular disease was observed in the population comprising prediabetes and T2DM. Worsening of glycemic control was prevented over the 6.7 year treatment period, with few serious hypoglycemic episodes and only moderate weight gain, with a lesser need for dual or triple oral treatment versus standard care. Several other studies have also highlighted the benefits of early insulin initiation as first-line or add-on therapy to metformin. The decision to introduce basal insulin to metformin must, however be individualized based on a risk–benefit analysis. The landmark ORIGIN trial provides many lessons relating to the concept and application of early insulin therapy for the prevention and safe and effective induction and maintenance of glycemic control in type 2 diabetes. Funding: Sanofi. © 2016, The Author(s).

Haas B.J.,The Broad Institute of MIT and Harvard | Papanicolaou A.,CSIRO | Yassour M.,The Broad Institute of MIT and Harvard | Yassour M.,Hebrew University of Jerusalem | And 22 more authors.
Nature Protocols | Year: 2013

De novo assembly of RNA-seq data enables researchers to study transcriptomes without the need for a genome sequence; this approach can be usefully applied, for instance, in research on 'non-model organisms' of ecological and evolutionary importance, cancer samples or the microbiome. In this protocol we describe the use of the Trinity platform for de novo transcriptome assembly from RNA-seq data in non-model organisms. We also present Trinity-supported companion utilities for downstream applications, including RSEM for transcript abundance estimation, R/Bioconductor packages for identifying differentially expressed transcripts across samples and approaches to identify protein-coding genes. In the procedure, we provide a workflow for genome-independent transcriptome analysis leveraging the Trinity platform. The software, documentation and demonstrations are freely available from The run time of this protocol is highly dependent on the size and complexity of data to be analyzed. The example data set analyzed in the procedure detailed herein can be processed in less than 5 h.

Bolli G.B.,University of Perugia | Munteanu M.,Victor Babes University of Medicine and Pharmacy Timisoara | Dotsenko S.,Zaporozhye State Medical University | Niemoeller E.,Sanofi S.A. | And 3 more authors.
Diabetic Medicine | Year: 2014

Aims: To assess the efficacy and safety of one- and two-step dose-increase regimens of lixisenatide once daily in participants with Type 2 diabetes mellitus insufficiently controlled with metformin. Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-centre study enrolling participants with Type 2 diabetes (n = 484) treated with metformin. Participants were randomized to receive either lixisenatide in a one-step dose increase or a two-step dose increase vs. placebo for 24 weeks, followed by a ≥ 52-week variable double blind period. Primary outcome was HbA1c reduction at week 24. Results: Lixisenatide one-/two-step once daily significantly improved HbA1c at week 24 compared with placebo (P < 0.0001) and allowed more participants to achieve HbA1c < 53 mmol/mol (< 7.0%) (P ≤ 0.0005). Improvements were observed in fasting plasma glucose (-0.5/-0.6 vs. +0.1 mmol/l; P < 0.001) and body weight (-2.6/-2.7 vs. -1.6 kg; P < 0.005). At week 24, adverse events were reported by 67.7/70.8/65.6% of participants treated with lixisenatide one-/two-step/placebo, respectively-nausea and vomiting being reported most frequently. Symptomatic hypoglycaemia occurred in 1.9/2.5% of participants on one-/two-step lixisenatide and 0.6% with placebo, with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable double-blind extension period of at least 52 weeks. Conclusions: Lixisenatide one- or two-step dose-increase regimens significantly improved glycaemic control and decreased body weight over 24 weeks and during a long-term extension period without increasing hypoglycaemia. The study confirmed that tolerability in the one-step group was at least similar to the two-step dose increase, with nausea/vomiting and hypoglycaemia frequency being lower in the one-step regimen. © 2013 Diabetes UK.

Hanefeld M.,GWT TUD GmbH | Koehler C.,GWT TUD GmbH | Hoffmann C.,GWT TUD GmbH | Wilhelm K.,Leipziger Institute For Praventivmedizin | And 2 more authors.
Diabetic Medicine | Year: 2010

Aims The purpose of this sub-study of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial was to determine efficacy and safety of targeting normal fasting plasma glucose (FPG) levels in patients with early Type 2 diabetes treated with insulin glargine in comparison with standard care. Methods Participants were randomly allocated to insulin or standard care. Insulin was titrated to reach FPG ≤ 5.3 mmol/l. Two years after randomization in a small subset (43 glargine, 32 standard care), continuous glucose measurement (CGMS® System Gold™), including a test meal, was performed. Sixteen volunteers with normal oral glucose tolerance test (OGTT) served as control subjects. Objectives were glycaemic variability, standard deviation (sd), mean amplitude of glucose excursion (MAGE) with postprandial glucose excursion after the test meal, time spent < 3.0 mmol/l interstitial glucose. Results Participants allocated to insulin and standard care had FPG levels of 5.3 and 6.1 mmol/l (P = 0.019) and glycated haemoglobin (HbA 1c) 5.7% and 5.9%, respectively (P < 0.025). Time (min/24 h) spent at low glucose levels was not significantly different between groups (30.6 ± 83.8 min control subjects, 33.7 ± 75.1 min insulin, 10.6 ± 50.6 min standard care). Standard deviation and MAGE were similar for glargine and standard care, but significantly higher than in control subjects. If FPG was < 5.3 mmol/l, the postprandial glucose excursion was in the range seen in control subjects. Conclusions Treatment to target of FPG < 5.3 mmol/l with insulin glargine was not associated with significantly increased risk of hypoglycaemia. Strict control of FPG with insulin glargine was effective to control postprandial glucose excursion, but had no significant effect on sd and MAGE. © 2010 Diabetes UK.

Panse C.,Friedrich - Schiller University of Jena | Leitsmann R.,Friedrich - Schiller University of Jena | Leitsmann R.,GWT TUD GmbH | Bechstedt F.,Friedrich - Schiller University of Jena
Physical Review B - Condensed Matter and Materials Physics | Year: 2010

The electronic-structure and magnetic properties of hydrogenated silicon nanocrystals doped with pairs of manganese atoms are investigated using spin-density-functional theory. Formation energies and total magnetic moments sensitively depend on the two sites occupied by manganese. Usually pairs at interstitial and substitutional sites with small total moment are energetically favored. Pairs at sites with the same character tend to ferromagnetic spin arrangements which are, however, significantly influenced by their noncollinearity. The resulting magnetic ordering is clearly related to the impurity levels and their occupation. The magnetic coupling is distance dependent, antiferromagnetic for small distances, and almost ferromagnetic for larger Mn-Mn distances. A Rudderman-Kittel-Kasuya-Yoshida-type exchange mechanism may describe the distance dependence but simultaneously not its magnitude. © 2010 The American Physical Society.

Hanefeld M.,GWT TUD GmbH | Ganz X.,GWT TUD GmbH | Nolte C.,Praxis fur Innere Medizin and Kardiologie Epidaurus
Herz | Year: 2014

Hypoglycemia is a common and potentially life-threatening adverse effect of inappropriate diabetes treatment. Typical cardiac complications are ischemia with angina pectoris, myocardial infarction, stroke and arrhythmias, such as atrial fibrillation (AF), ventricular tachycardia and heart failure. Elderly multimorbid patients with type 2 diabetes and polypharmacy and/or cardiac autonomous neuropathy represent a very high risk group for cardiovascular complications associated with hypoglycemia. Targets for glycemic control have to be adapted to the risk of hypoglycemia with a priority of stable glucose homeostasis without rapid fluctuations. Elderly patients with diabetes have a >20% risk of AF. At blood glucose levels of <3 mmol/l with a duration of >30 min, prolongation of QTc time and ventricular tachycardia occur with an increased risk of ventricular fibrillation and sudden death. Ventricular arrhythmias and AF significantly increase mortality in patients with heart failure. Rapid fluctuations with a mean amplitude of glucose excursion (MAGE) >5 mmol/l promote vulnerability of electrical stability of the heart, particularly in frail patients with preexisting coronary heart disease and autonomic neuropathy. Antihyperglycemic agents, such as metformin, acarbose and sodium glucose cotransporter 2 (SGLT2) inhibitors have only a low risk of severe hypoglycemia. Dipeptidyl peptase 4 (DPP-IV) inhibitors and glucagon-like peptide 1 (GLP1) analogues as insulin secretagogues have a lower risk for hypoglycemia than sulfonylurea and insulin. Early basal insulin treatment in patients insufficiently controlled with metformin is efficient, safe and convenient. Targets for glucose control and HbA1c have to be individualized and the choice of drugs must be risk-adjusted. Risk of hypoglycemia should be used as guide in decision-making for safe treatment of diabetes. © 2014 Urban & Vogel.

Stahn A.,Universitatsklinikum Carl Gustav Carus | Pistrosch F.,Universitatsklinikum Carl Gustav Carus | Pistrosch F.,GWT TUD GmbH | Ganz X.,Universitatsklinikum Carl Gustav Carus | And 6 more authors.
Diabetes Care | Year: 2014

OBJECTIVE In patients with type 2 diabetes and cardiovascular diseases (CVDs), intensive treatment with insulin and/or sulfonylurea (SU)may be associated with excessive increased risk of hypoglycemic episodes. To evaluate the risk of critical arrhythmias related to glycemic variability, we carried out an observational study in type 2 diabetes patients with CVD. RESEARCH DESIGN AND METHODS Thirty patients with type 2 diabetes and documented CVD who had been treated with insulin and/or SU underwent 5 days of monitoring with a continuous glucose measurement system along with parallel electrocardiogram recording for monitoring of ventricular arrhythmias. Twelve age-matched patients with documented CVD who received treatment with metformin and/or dipeptidyl peptidase-4 inhibitor served as the control group. Patients were receiving stable treatment, and were instructed to notice symptoms of arrhythmias and hypoglycemia, respectively. RESULTS We observed a high incidence of asymptomatic severe episodes of hypoglycemia (≥3.1 mmol/L) in patients receiving treatment with insulin and/or SU, whereas severe hypoglycemia did not develop in any of the control subjects. Patients with severe hypoglycemia (n = 12) had a higher number of severe ventricular arrhythmias (patients with versus without severe hypoglycemia, respectively: ventricular couplets 41.7 ± 81.8 vs. 5.5 ± 16.7; ventricular tachycardia 1.0 ± 1.9 vs. 0.1 ± 0.3). No direct correlation could be found among different variables of glucose profile, corrected QT interval, and ventricular arrhythmias. CONCLUSIONS Our results suggest that severe episodes of hypoglycemia are associated with an increased risk of severe ventricular arrhythmias. © 2014 by the American Diabetes Association.

Agency: European Commission | Branch: FP7 | Program: CP | Phase: ICT-2007.1.1 | Award Amount: 21.00M | Year: 2008

Key objectives of EUWB are i) to explore the enormous economic potential of the ground-breaking Ultra-Wideband (UWB) radio technology, ii) to extend the UWB concept with advanced cognitive radio, multiband/multimode networking, and multiple antenna system concepts, iii) to enable the introduction of advanced services and competitive applications using the radio spectrum in a sophisticated manner.\nThe advanced scientific and technical project work will be accompanied by activities in European and world wide regulation and standardisation bodies in which EUWB partners are highly committed. As a key for economic success of UWB, the project partners will continue to devote significant efforts to participation in CEPT ECC, IEEE, ITU, ETSI, and ECMA working towards consensus building and iterative improvement of the initial European and world-wide UWB regulation and standardisation.\nUWB technology enables gigabits per second short range communications and inherent precise real-time location tracking. Prominent examples to be implemented in the EUWB project are the Intelligent Home environment, the Public Transport environment, the Automotive environment and the Next Generation of Heterogeneous Public Access Network environment, following a strong demand from the mentioned industry sectors.\nEUWB is an industry-led initiative of 22 highly regarded industrial, consulting, and academic organisations. It builds on previous projects, such as PULSERS, and take into account stakeholders of the whole value chain. Major aim is to consolidate the technology advances in scientific areas related to UWB and to define system concepts for the envisaged four application areas. The results will be materialised in four application platforms built on the open UWB technology developed in EUWB. Besides integration in the AIRBUS plane, the DAIMLER car, the PHILIPS future home, and the TELEFNICA access network, scientific studies will guide industry to gain competitiveness with their UWB system.

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