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Acquired hemophilia A is a rare but severe autoimmune bleeding disorder. It is more frequent in the elderly and results from the presence of autoantibodies directed against clotting factor VIII. In this review, we briefly report on the present state of knowledge regarding acquired hemophilia A, analyzing its epidemiology, pathogenesis, diagnostic, and clinical features. We also describe the main characteristics of this disorder according to its association with different conditions and the most important advances in the treatment of bleeding episodes and the eradication of the autoantibody.

Acute kidney injury (AKI) is considered largely reversible based on the capacity of surviving tubular cells to dedifferentiate and replace lost cells via cell division. Here we show by tracking individual tubular cells in conditional Pax8/Confetti mice that kidney function is recovered after AKI despite substantial tubular cell loss. Cell cycle and ploidy analysis upon AKI in conditional Pax8/FUCCI2aR mice and human biopsies identify endocycle-mediated hypertrophy of tubular cells. By contrast, a small subset of Pax2+ tubular progenitors enriches via higher stress resistance and clonal expansion and regenerates necrotic tubule segments, a process that can be enhanced by suitable drugs. Thus, renal functional recovery upon AKI involves remnant tubular cell hypertrophy via endocycle and limited progenitor-driven regeneration that can be pharmacologically enhanced.

OBJECTIVE: Recently, much attention has been paid to the possibility that postprandial hyperglycemia may be a cardiovascular risk factor in diabetes. Oxidative stress has been involved in the pathogenesis of diabetic complications, and increased plasma levels of nitrotyrosine, a product of peroxynitrite action, have been found in the plasma of diabetic subjects. The aim of the present study was to evaluate whether postprandial hyperglycemia is accompanied by nitrotyrosine generation and, if so, to explore a possible direct role of hyperglycemia in such a phenomenon. RESEARCH DESIGN AND METHODS: A total of 23 type 2 diabetic patients and 15 matched normal healthy subjects were recruited for this study. Two different tests were performed in diabetic patients: a standard meal preceded by regular insulin (0.15 units/kg body wt) or insulin aspart (0.15 units/kg body wt) to achieve different levels of postprandial hyperglycemia. The meal test was also performed in healthy control subjects. At 0 min and 1, 2, 4, and 6 h after each meal, blood glucose, triglyceride, and nitrotyrosine levels were measured. RESULTS: Fasting nitrotyrosine was significantly increased in diabetic patients and was further increased during both meal tests in diabetic subjects but not normal subjects. As compared with regular insulin, aspart administration significantly reduced the area under the curve of both glycemia (P < 0.04) and nitrotyrosine (P < 0.03), whereas that of triglycerides was not significantly affected by the treatment. CONCLUSIONS: This study shows a direct correlation between postprandial hyperglycemia and the production of nitrotyrosine, a marker of oxidative stress, in patients with type 2 diabetes.

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXT(S)-(+)-2-(3'-Carboxybicyclo[1.1.1]pentyl)- glycine, a Structurally New Group I Metabotropic Glutamate Receptor AntagonistRoberto Pellicciari, Mariarosa Raimondo, Maura Marinozzi, Benedetto Natalini, Gabriele Costantino, and Christian ThomsenView Author Information Istituto di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo, 1, 06123 Perugia, Italy and Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark Cite this: J. Med. Chem. 1996, 39, 15, 2874–2876Publication Date (Web):July 19, 1996Publication History Received1 April 1996Published online19 July 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/jm960254ohttps://doi.org/10.1021/jm960254orapid-communicationACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views3721Altmetric-Citations137LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Antagonists,Hydrolysis,Monomers,Peptides and proteins,Receptors Get e-Alerts

PURPOSE: There are sparse data defining the dose response of radiation therapy (RT) to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors. We examined the correlation between RT dose to these structures and development of endocrine dysfunction in this population. MATERIALS AND METHODS: Dosimetric and clinical data were collected from children and young adults (< 26 years of age) with brain tumors treated with proton RT on three prospective studies (2003 to 2016). Deficiencies of growth hormone (GH), thyroid hormone, adrenocorticotropic hormone, and gonadotropins were determined clinically and serologically. Incidence of deficiency was estimated using the Kaplan-Meier method. Multivariate models were constructed accounting for radiation dose and age. RESULTS: Of 222 patients in the study, 189 were evaluable by actuarial analysis, with a median follow-up of 4.4 years (range, 0.1 to 13.3 years), with 31 patients (14%) excluded from actuarial analysis for having baseline hormone deficiency and two patients (0.9%) because of lack of follow-up. One hundred thirty patients (68.8%) with medulloblastoma were treated with craniospinal irradiation (CSI) and boost; most of the remaining patients (n = 56) received involved field RT, most commonly for ependymoma (13.8%; n = 26) and low-grade glioma (7.4%; n = 14). The 4-year actuarial rate of any hormone deficiency, growth hormone, thyroid hormone, adrenocorticotropic hormone, and gonadotropin deficiencies were 48.8%, 37.4%, 20.5%, 6.9%, and 4.1%, respectively. Age at start of RT, time interval since treatment, and median dose to the combined hypothalamus and pituitary were correlated with increased incidence of deficiency. CONCLUSION: Median hypothalamic and pituitary radiation dose, younger age, and longer follow-up time were associated with increased rates of endocrinopathy in children and young adults treated with radiotherapy for brain tumors.

OBJECTIVE: Through the Australian and New Zealand Haemostasis Registry, we report on the Australian and New Zealand experience with recombinant activated factor VII (rFVIIa) in obstetric patients. METHODS: The role of rFVIIa for off-label indications, including trauma, cardiac surgery, and severe postpartum hemorrhage, remains controversial. The Haemostasis Registry established by Monash University in Melbourne, Australia monitors off-label use of rFVIIa across Australia and New Zealand. The purpose of this study was to summarize Registry data for all obstetric hemorrhage patients treated with rFVIIa at participating hospitals between January 2002 and July 2008. The primary outcome measures were reduction or cessation of bleeding (positive therapeutic response), mortality, and hysterectomy rate. RESULTS: During the study period, the Registry received data for 2128 patients. This included 110 cases of administration of rFVIIa in obstetric patients from 38 hospitals, comprising 5% of the total Registry population, 105 of whom were treated for acute hemorrhage. Women received median (interquartile range) individual doses of 92 microg/kg (73-100) of rFVIIa (median total dose 92 microg/kg [58-108]), and 78% of patients received a single dose. The positive response rate to rFVIIa was 76% with 64% responding to the first dose. Ninety-one percent of women were alive at 28 days. Forty-three women (41%) underwent hysterectomy before receiving rFVIIa and, of those remaining, 13 (21%) required hysterectomy after rFVIIa therapy. Two thromboembolic events (1 pulmonary embolism and 1 deep venous thrombosis) and 1 case of hypoxic-ischemic encephalopathy resulting from severe anoxia were reported. CONCLUSIONS: The reported effect of rFVIIa in many, but not all, obstetric cases was positive. There was no mortality as a result of thromboembolic complications. Randomized, controlled trials are required to confirm its safety and efficacy and to assess the possibility that use at an earlier stage in treatment of severe postpartum hemorrhage may avoid the need to resort to postpartum hysterectomy for control of bleeding, thus preserving fertility.

OBJECTIVE: Recently, much attention has been focused on the possibility that the post-prandial state may be a cardiovascular risk factor in diabetes. The aim of the present study was to evaluate whether the post-prandial state is associated with endothelial dysfunction in patients with diabetes and to explore the effect on this aspect of managing post-prandial hyperglycaemia by insulin aspart. RESEARCH DESIGN AND METHODS: Twenty-three patients with Type 2 diabetes and 10 normal controls were recruited. In the diabetic patients two different tests were performed in each subject: a standard meal preceded by subcutaneous injection of soluble insulin (0.15 U/kg body weight) or of short-acting insulin aspart (0.15 U/kg body weight). These tests were designed to achieve different levels of post-prandial hyperglycaemia. Controls received a single standard meal test. Immediately before, and 1, 2, 4 and 6 h after each meal, blood glucose, triglycerides, free fatty acids and flow-mediated vasodilation were measured. RESULTS: Compared with regular insulin, insulin aspart significantly reduced the area under the curve for post-prandial hyperglycaemia (58.3 +/- 17.6 vs. 68.1 +/- 17.7; P<0.04), and preserved flow-mediated vasodilation, which was decreased in the post-prandial state (39.4 +/- 2.9 vs. 34.1 +/- 2.2; P<0.01). Triglyceride and free fatty acid levels were not differentially affected by the treatment. In normal controls the meal did not affect flow-mediated vasodilation. CONCLUSION: This study shows that the post-prandial state is accompanied by endothelial dysfunction in Type 2 diabetic patients and that insulin aspart improved endothelial function.

BACKGROUND AND OBJECTIVES: Factor VII (FVII) deficiency is a rare coagulation disorder, historically treated with prothrombin complex concentrates or plasma-derived FVII concentrates. We treated such patients (n = 17) with a recombinant, activated FVII preparation. MATERIALS AND METHODS: Twenty-seven spontaneous bleeding episodes were treated and 7 major and 13 minor surgical interventions were carried out. The dosages employed ranged from 8.08 to 70.5 Ig/kg body weight. RESULTS: A mean dose between 22 and 26 Ig/kg was sufficient to normalise the prothrombin time. Fifteen haemarthroses were treated with single doses and results were excellent in 13 cases. In 5/6 bleeding episodes of other types, the treatment gave either excellent or at least effective results. Haemostasis was secured in the 7 major and 13 minor surgical interventions. One patient developed antibodies 4-5 weeks after an extremely high dose. Otherwise, there were no side effects and no evidence of a thrombotic tendency. CONCLUSION: This recombinant concentrate is efficacious in FVII-deficient patients. It is safe since any risk of transmission of blood-borne viruses is eliminated.

Abstract Background and Objectives: Factor VII (FVII) deficiency is a rare coagulation disorder, historically treated with prothrombin complex concentrates or plasma‐derived FVII concentrates. We treated such patients (n=17) with a recombinant, activated FVII preparation. Materials and Methods: Twenty‐seven spontaneous bleeding episodes were treated and 7 major and 13 minor surgical interventions were carried out. The dosages employed ranged from 8.08 to 70.5 μg/kg body weight. Results: A mean dose between 22 and 26 μg/kg was sufficient to normalise the prothrombin time. Fifteen haemarthroses were treated with single doses and results were excellent in 13 cases. In 5/6 bleeding episodes of other types, the treatment gave either excellent or at least effective results. Haemostasis was secured in the 7 major and 13 minor surgical interventions. One patient developed antibodies 4–5 weeks after an extremely high dose. Otherwise, there were no side effects and no evidence of a thrombotic tendency. Conclusion: This recombinant concentrate is efficacious in FVII‐deficient patients. It is safe since any risk of transmission of blood‐borne viruses is eliminated.

INTRODUCTION: Insulin degludec (degludec) is a basal insulin with an ultra-long, stable action profile and reduced pharmacodynamic variability. Seven phase 3a trials compared degludec with insulin glargine (glargine). Patient-level meta-analyses were performed to obtain a comprehensive overview of differences between the insulin preparations, possible because consistent outcome definitions were utilized. METHODS: Three categories of trials were analyzed: basal-bolus-treated type 1 diabetes mellitus (T1DMB/B), insulin-naïve type 2 diabetes mellitus (T2DMinsulin-naïve), and basal-bolus-treated T2DM (T2DMB/B). Regression models were adjusted for baseline characteristics. Endpoints analyzed were glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), insulin dose and hypoglycemic rates analyzed in mutually exclusive groups: non-severe nocturnal, non-severe daytime, and severe. RESULTS: As with previous treat-to-target trials, reductions in HbA1c were similar between degludec and glargine. Reductions in FPG were significantly greater with degludec in T1DMB/B and T2DMinsulin-naïve. Total daily insulin dose was significantly lower with degludec in T1DMB/B and T2DMinsulin-naïve. Estimated hypoglycemia rate ratios for degludec/glargine were as follows for T1DMB/B, T2DMinsulin-naïve and T2DMB/B, respectively: non-severe nocturnal 0.83, 0.64, 0.75 (all P < 0.05); non-severe daytime 1.14 [not significant (ns)], 0.89 (ns), and 0.83 (P < 0.05). Rate ratios for severe events were 1.12 (ns) (T1DMB/B); 0.14 (P < 0.05) (T2DMinsulin-naïve); and not analyzed (T2DMB/B) due to too few events. CONCLUSIONS: Compared with glargine, degludec is associated with equivalent HbA1c control and significantly lower nocturnal hypoglycemia rates. In T1DMB/B and T2DMinsulin-naïve, degludec is also associated with significantly greater reductions in FPG and lower total doses of insulin versus glargine.

All 16 2-(2‘-carboxy-3‘-phenylcyclopropyl)glycine (PCCGs) stereoisomers 32−47 have been prepared from the corresponding racemic aldehydes 12−15 following an enantiodivergent synthetic protocol. Compounds 32−47 were evaluated by a number of binding and functional experiments as potential ligands for several classes of excitatory amino acid receptors, including metabotropic glutamate receptors (mGluR1a, mGluR2, mGluR4) and ionotropic glutamate receptors (NMDA, KA, AMPA) as well as sodium-dependent and calcium/chloride-dependent glutamate transport systems. The stereolibrary of compounds 32−47 appears to be endowed with a peculiar pharmacological profile. PCCG-2 (33) and PCCG-3 (34) displaced labeled kainate at low micromolar concentration; PCCG-9 (40) and PCCG-11 (42) weakly interacted with the NMDA site; PCCG-5 (36), PCCG-10 (41), and PCCG-12 (43) showed to be potent inhibitors of Ca2+/Cl--dependent glutamate transport system. Most interestingly, PCCG-4 (35) has been shown to be able to antagonize (IC50 = 8 μM) the effects of glutamate on forskolin-stimulated cAMP formation in BHK cells expressing mGluR2. Uneffective at mGluR1, 35 is a weak mGluR4 agonist (EC50 = 156 μM) and has no effect on either ionotropic receptors or glutamate transport systems, thus demonstrating to be a novel selective mGluR2 antagonist with a 6-fold increase in potency over previously reported antagonists.

PURPOSE: Hypoglycemia is a frequent side effect induced by insulin treatment of type 1 (T1DM) and type 2 diabetes (T2DM). Limited data exist on the associated healthcare resource use and patient impact of hypoglycemia, particularly at a country-specific level. This study investigated the effects of self-reported non-severe hypoglycemic events (NSHE) on use of healthcare resources and patient wellbeing. METHODS: Patients with T1DM or insulin-treated T2DM diabetes from seven European countries were invited to complete four weekly questionnaires. Data were collected on patient demographics, NSHE occurrence in the last 7 days, hypoglycemia-related resource use, and patient impact. NSHE were defined as events with hypoglycemia symptoms, with or without blood glucose measurement, or low blood glucose measurement without symptoms, which the patient could manage without third-party assistance. RESULTS: Three thousand, nine hundred and fifty-nine respondents completed at least one wave of the survey, with 57% completing all four questionnaires; 3827 respondents were used for data analyses. Overall, 2.3% and 8.9% of NSHE in patients with T1DM and T2DM, respectively, resulted in healthcare professional contact. Across countries, there was a mean increase in blood glucose test use of 3.0 tests in the week following a NSHE. Among respondents who were employed (48%), loss of work-time after the last hypoglycemic event was reported for 9.7% of NSHE. Overall, 10.2% (daytime) and 8.0% (nocturnal) NSHE led to work-time loss, with a mean loss of 84.3 (daytime) and 169.6 (nocturnal) minutes among patients reporting work-time loss. Additionally, patients reported feeling tired, irritable, and having negative feelings following hypoglycemia. LIMITATIONS: Direct comparisons between studies must be interpreted with caution because of different definitions of hypoglycemia severity, duration of the studies, and methods of data collection. CONCLUSIONS: NSHE were associated with use of extra healthcare resources and work-time loss in all countries studied, suggesting that NSHE have considerable impact on patients/society.

AIMS: This randomized, multi-centre, double-blind, stratified, two period, cross-over trial was undertaken to assess the pharmacokinetics and pharmacodynamics of insulin aspart injected immediately before compared with regular human insulin injected 30 min before a Mediterranean-style meal in 37 (23 M, 14 F) patients with Type 2 diabetes. METHODS: Insulin aspart or regular human insulin was given subcutaneously (0.15 U/kg) in random sequence, using a double-dummy technique (at one visit: human regular insulin at t=-30 min and placebo at t=0; at the other visit: placebo at t=-30 min and aspart insulin at t=0). Serum glucose and insulin concentrations (15 points) were measured after each meal for 240 min. RESULTS: Post-prandial glycaemic excursions were 20% lower with insulin aspart (IAsp) compared with regular human insulin (HI) treatment [ratio (Iasp/HI)=0.80, CI=(0.66-0.98), P=0.034]. The maximum serum glucose (SG) concentration was similar for the two treatments (P=NS). The (median) time to maximum SG was 25 min shorter for IAsp compared with HI (P=0.048). Maximum serum insulin concentration was higher after IAsp compared with HI (P=0.023) as well as the area under the 4-h serum insulin curve (P=0.006). Furthermore, the time to maximum serum insulin concentration was 27 min shorter after IAsp (P=0.039), even though IAsp was injected 30 min after HI. No adverse events occurred during the trial. CONCLUSIONS: In patients with Type 2 diabetes a more favourable insulin profile and a better glycaemic control were found with IAsp injected immediately before compared with HI injected 30 min before a Mediterranean-style meal.

Abstract We illustrate a case study of a saline tracer test in a shallow, highly heterogeneous aquifer, monitored by means of surface time-lapse ERT. The test was aimed at identifying the system's hydraulic properties. Some of the expected limitations of the method — particularly caused by the strong decrease in ERT resolution with depth — and the consequent problems with mass balance and moment calculation could be partly balanced by the use of direct measurements of groundwater electrical conductivity and tracer concentration at one selected location. The vast heterogeneity of the system, ranging in lithology from clay to gravel at a scale of meters to tens of meters, reflects itself in the tracer migration and distribution over time: The tracer is trapped in the low-permeability regions and from these it is slowly released over time. High-resolution surface ERT proves effective at picturing this system behavior over time. The extreme heterogeneity is also a challenge in the attempt to translate bulk electrical conductivity into estimates of groundwater electrical conductivity and, hence, solute concentration because surface conductivity in fine sediments has an important role. The test results could be used to identify some of the key parameters for solute transport, namely, mean groundwater velocity and aquifer dispersivity at the scale of the test by means of transport model calibration.

UNLABELLED: Aims/Introduction: We compared the safety and efficacy of liraglutide vs glibenclamide in patients with poorly controlled (HbA1c, 7.4-10.4%) type 2 diabetes. MATERIALS AND METHODS: Subjects were randomly assigned at a 1:2 ratio to receive 1-year treatment with glibenclamide 1.25-2.5 mg/day or liraglutide 0.9 mg/day. Other oral anti-diabetic drugs (OAD) were prohibited during the trial. Adverse events (AE) were monitored. RESULTS: A total of 400 patients (liraglutide group, n = 268; glibenclamide group, n = 132) were randomized and exposed to trial products. At week 52 vs baseline, HbA1c in the liraglutide and glibenclamide groups was reduced from 9.3 to 7.8% and from 9.2 to 8.2%, respectively. Treatment difference (liraglutide - glibenclamide) at the end of the study was -0.49 (95% CI, -0.71 to -0.27). In the liraglutide and glibenclamide groups, Japan Diabetes Society target HbA1c < 6.9% was achieved by 22.1 and 8.5% of patients, respectively. Fasting plasma glucose fell from 202.8 and 202.1 mg/dL, respectively, to 145.3 and 156.7 mg/dL, respectively. Mean plasma glucose and mean postprandial plasma glucose increment were lower in the liraglutide group. Mean bodyweight was reduced by -0.8 kg in the liraglutide group and increased by 1.0 kg in the glibenclamide group. The proportion of patients reporting at least one treatment-emergent AE (TEAE) in the liraglutide and glibenclamide groups was 91.4 and 91.7%, respectively. Most TEAE were mild in severity. No major hypoglycemic episode was observed. CONCLUSIONS: Once-daily administration of liraglutide 0.9 mg for 52 weeks provides more favorable metabolic control and safety profile compared with glibenclamide. Patients on liraglutide lost bodyweight, whereas those on glibenclamide gained weight. This trial was registered with ClinicalTrial.gov (no. NCT00393718). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00128.x, 2011).

Ligand-based virtual screening approaches were applied to search for new chemotype KCOs activating Kir6.2/SUR1 KATP channels. A total of 65 208 commercially available compounds, extracted from the ZINC archive, served as database for screening. In a first step, pharmacokinetic filtering via VolSurf reduced the initial database to 1913 compounds. Afterward, six molecules were selected as templates for similarity searches: similarity scores, obtained toward these templates, were calculated with the GRIND, FLAP, and TOPP approaches, which differently encode structural information into potential pharmacophores. In this way, we obtained 32 hit candidates, 16 via GRIND and eight each via FLAP and TOPP. For biological testing of the hit candidates, their effects on membrane potentials in HEK 293 cells expressing Kir6.2/SUR1 were studied. GRIND, FLAP, and TOPP all yielded hits, but no method top-ranked all the actives. Thus, parallel application of different approaches probably improves hit detection.

We study the impact of female board representation as well as citizenship on corporate performance based on a sample of the largest listed firms in the Nordic countries as well as Germany. We also seek to determine the variation of board structures using factor analysis. We find no support for any performance impact relating to female board representation. However, we find an impact of board citizenship on performance showing that board members with a background from common law have a significant positive influence on corporate performance measured as ROA, ROE and ROCE. Consistent with other studies we also document that large boards impact corporate performance negatively. Moreover we also show that data set on boards can be explained by four underlying factors. This article adds insight to board determinants of corporate performance as well as the classification of board variation. Specifically, our results support the view that increasing the proportion of board members from common law countries would be beneficial for the largest German and Nordic listed companies.

BACKGROUND: In the context of the DAWN-2 initiatives, the BENCH-D Study aims to test a model of regional benchmarking to improve not only the quality of diabetes care, but also patient-centred outcomes. METHODS/DESIGN: As part of the AMD-Annals quality improvement program, 32 diabetes clinics in 4 Italian regions extracted clinical data from electronic databases for measuring process and outcome quality indicators. A random sample of patients with type 2 diabetes filled in a questionnaire including validated instruments to assess patient-centred indicators: SF-12 Health Survey, WHO-5 Well-Being Index, Diabetes Empowerment Scale, Problem Areas in Diabetes, Health Care Climate Questionnaire, Patients Assessment of Chronic Illness Care, Barriers to Medications, Patient Support, Diabetes Self-care Activities, and Global Satisfaction for Diabetes Treatment. Data were discussed with participants in regional meetings. Main problems, obstacles and solutions were identified through a standardized process, and a regional mandate was produced to drive the priority actions. Overall, clinical indicators on 78,854 patients have been measured; additionally, 2,390 patients filled-in the questionnaire. The regional mandates were officially launched in March 2012. Clinical and patient-centred indicators will be evaluated again after 18 months. A final assessment of clinical indicators will take place after 30 months. DISCUSSION: In the context of the BENCH-D study, a set of instruments has been validated to measure patient well-being and satisfaction with the care. In the four regional meetings, different priorities were identified, reflecting different organizational resources of the different areas. In all the regions, a major challenge was represented by the need of skills and instruments to address psychosocial issues of people with diabetes. The BENCH-D study allows a field testing of benchmarking activities focused on clinical and patient-centred indicators.

This study evaluates the effects of insulin versus glibenclamide on lipoprotein metabolism at comparable levels of blood glucose control, in particular on the concentration and distribution of VLDL subfractions and lipolytic enzyme activities in nine NIDDM men (aged 56 +/- 3 years, BMI 26.5 +/- 0.9 kg/m2) (means +/- SE) participating in a crossover study. After a 3-week washout period, patients were randomly assigned to 2-month treatment periods (insulin or glibenclamide); thereafter, each patient crossed to the other treatment. At the end of each period, mean daily blood glucose (MDBG), HbA1e, plasma lipids, lipoproteins (VLDL, LDL, HDL), lipoprotein subfractions (VLDL1, 2, 3; HDL2, HDL3), and post-heparin lipase activities (lipoprotein lipase [LPL], hepatic lipase [HL]) were evaluated. Although glucose control was similar at the end of both periods (MDBG 8.3 +/- 0.3 vs. 7.9 +/- 0.3 mmol/l; HbA1c 7.4 +/- 0.3 vs. 7.0 +/- 0.2%, insulin versus glibenclamide), insulin compared with glibenclamide induced a significant reduction in plasma triglycerides (0.9 +/- 0.1 vs. 1.1 +/- 0.1 mmol/l, P < 0.05), VLDL triglycerides (50.1 +/- 12.2 vs. 63.6 +/- 12.3 mg/dl, P < 0.02), VLDL1 lipid concentration (24.9 +/- 7.5 vs. 39.9 +/- 9.5 mg/dl, P < 0.006), and increased HDL2 cholesterol (25.2 +/- 1.6 vs. 20.3 +/- 1.3 mg/dl, P < 0.03). In terms of VLDL percentage subfraction distribution, with insulin, there was a decrease in the larger subfractions (VLDL1 26.5 +/- 3.0 vs. 37.8 +/- 3.4%, P < 0.02) and an increase in the smallest (VLDL3 47.3 +/- 3.8 vs. 37.3 +/- 3.3%, P < 0.05). Moreover, HL activity was significantly lower after insulin than after glibenclamide (HL 247.2 +/- 22.3 vs. 263.5 +/- 22.6 mU/ml, P < 0.05). In conclusion, compared with glibenclamide, insulin treatment (independent of variations in glucose control) is able to decrease significantly plasma triglycerides, to increase HDL2 cholesterol, and to reduce only the concentration of the larger VLDL subfractions, with a consequent redistribution of their profile.

UNLABELLED: Aims/Introduction: Sulfonylurea (SU) agents are the most effective drugs at lowering blood glucose when used alone. However, their effectiveness declines after a certain period. The addition of liraglutide to existing SU therapy might reverse some of the known drawbacks of SU. MATERIALS AND METHODS: This multicenter, randomized, 52-week study assessed the long-term efficacy and safety of adding liraglutide at 0.6 or 0.9 mg/day to existing SU therapy in Japanese patients with inadequately controlled type 2 diabetes. RESULTS: In total, 264 patients were enrolled and received treatment. At week 52, HbA1c in the liraglutide 0.6 mg, liraglutide 0.9 mg and placebo groups was reduced from 9.00 to 7.91%, from 8.61 to 7.33%, and from 8.85 to 8.79%, respectively. The mean difference of HbA1c (95% CI) in the liraglutide 0.6 and 0.9 mg groups vs the placebo group was 0.96 (-1.25 to -0.67) and -1.33 (-1.62 to -1.04), respectively. For the liraglutide 0.6 mg, 0.9 mg and placebo groups, the Japanese Diabetes Society target HbA1c of <6.9% was achieved by 15.1, 39.1 and 4.5% of patients, respectively. Mean fasting plasma glucose at week 52 was lower in the liraglutide groups compared with the placebo group, and mean bodyweight remained unchanged in the liraglutide groups. Most subjects in all three treatment groups reported mild adverse events. No major hypoglycemic episode was reported. CONCLUSIONS: Once-daily administration of liraglutide in combination with SU for 52 weeks provided favorable metabolic control, a safety profile and did not alter bodyweight. This trial was registered with ClinicalTrial.gov (no. NCT00395746). (J Diabetes Invest,doi: 10.1111/j.2040-1124.2011.00103.x, 2011).