Evidence review : liraglutide for the treatment of type 2 diabetes

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of liraglutide in the treatment of type 2 diabetes mellitus, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The manufacturer proposed the use of liraglutide as a second or third drug in patients with type 2 diabetes whose glycaemic control was unsatisfactory with metformin, with or without a second oral glucose-lowering drug. The submission included six manufacturer-sponsored trials that compared the efficacy of liraglutide against other glucose-lowering agents. Not all of the trials were relevant to the decision problem. The most relevant were Liraglutide Effects and Actions in Diabetes 5 (LEAD-5) (liraglutide used as part of triple therapy and compared against insulin glargine) and LEAD-6 [liraglutide in triple therapy compared against another glucagon-like peptide-1 agonist, exenatide]. Five of the six trials were published in full and one was then unpublished. Two doses of liraglutide, 1.2 and 1.8 mg, were used in some trials, but in the two comparisons in triple therapy, against glargine and exenatide, only the 1.8-mg dose was used. Liraglutide in both doses was found to be clinically effective in lowering blood glucose concentration [glycated haemoglobin (HbA1c)], reducing weight (unlike other glucose-lowering agents, such as sulphonylureas, glitazones and insulins, which cause weight gain) and also reducing systolic blood pressure (SBP). Hypoglycaemia was uncommon. The ERG carried out meta-analyses comparing the 1.2- and 1.8-mg doses of liraglutide, which suggested that there was no difference in control of diabetes, and only a slight difference in weight loss, insufficient to justify the extra cost. The cost-effectiveness analysis was carried out using the Center for Outcomes Research model. The health benefit was reported as quality-adjusted life-years (QALYs). The manufacturer estimated the cost-effectiveness to be £15,130 per QALY for liraglutide 1.8 mg compared with glargine, £10,054 per QALY for liraglutide 1.8 mg compared with exenatide, £10,465 per QALY for liraglutide 1.8 mg compared with sitagliptin, and £9851 per QALY for liraglutide 1.2 mg compared with sitagliptin. The ERG conducted additional sensitivity analyses and concluded that the factors that carried most weight were: in the comparison with glargine, the direct utility effects of body mass index (BMI) changes and SBP, with some additional contribution from HbA1c in the comparison with exenatide, HbA1c, with some additional effects from cholesterol and triglycerides in the comparison with sitagliptin, HbA1c and direct utility effects of BMI changes. The European Medicines Agency has approved liraglutide in dual therapy with other oral glucose-lowering agents. NICE guidance recommends the use of liraglutide 1.2 mg in triple therapy when glycaemic control remains or becomes inadequate with a combination of two oral glucose-lowering drugs. The use of liraglutide 1.2 mg in a dual therapy is indicated only in patients who are intolerant of, or have contraindications to, three oral glucose-lowering drugs. The use of liraglutide 1.8 mg was not approved by NICE. The ERG recommends research into the (currently unlicensed) use of liraglutide in combination with long-acting insulin

An overview of the research evidence on ethnicity and communication in healthcare

• The aim of the present study was to identify and review the available research evidence on 'ethnicity and communication' in areas relevant to ensuring effective provision of mainstream services (e.g. via interpreter, advocacy and translation services); provision of services targeted on communication (e.g. speech and language therapy, counselling, psychotherapy); consensual/ participatory activities (e.g. consent to interventions), and; procedures for managing and planning for linguistic diversity

Metabolic modeling and analysis of the metabolic switch in Streptomyces coelicolor

Background The transition from exponential to stationary phase in Streptomyces coelicolor is accompanied by a major metabolic switch and results in a strong activation of secondary metabolism. Here we have explored the underlying reorganization of the metabolome by combining computational predictions based on constraint-based modeling and detailed transcriptomics time course observations. Results We reconstructed the stoichiometric matrix of S. coelicolor, including the major antibiotic biosynthesis pathways, and performed flux balance analysis to predict flux changes that occur when the cell switches from biomass to antibiotic production. We defined the model input based on observed fermenter culture data and used a dynamically varying objective function to represent the metabolic switch. The predicted fluxes of many genes show highly significant correlation to the time series of the corresponding gene expression data. Individual mispredictions identify novel links between antibiotic production and primary metabolism. Conclusion Our results show the usefulness of constraint-based modeling for providing a detailed interpretation of time course gene expression data

First observation of Bs0 → D*s2+Xμ-ν decays

Using data collected with the LHCb detector in proton–proton collisions at a centre-of-mass energy of 7 TeV, the semileptonic decays B0s→D+sXμ−ν and B0s→D0K+Xμ−ν are detected. Two structures are observed in the D0K+ mass spectrum at masses consistent with the known Ds1(2536)+ and D∗s22573)+ mesons. The measured branching fractions relative to the total B0s semileptonic rate are B(B0s→D∗+s2Xμ−ν)/B(B0s→Xμ−ν) = (3.3±1.0±0.4)%, and B(B0s→D+s1Xμ−ν)/B(B0s→Xμ−ν) = (5.4±1.2±0.5)%, where the first uncertainty is statistical and the second is systematic. This is the first observation of the D∗+s2 state in B0s decays; we also measure its mass and width

An international longitudinal registry of patients with atrial fibrillation at risk of stroke (GARFIELD) : the UK protocol

Background Atrial fibrillation (AF) is an independent risk factor for stroke and a significant predictor of mortality. Evidence-based guidelines for stroke prevention in AF recommend antithrombotic therapy corresponding to the risk of stroke. In practice, many patients with AF do not receive the appropriate antithrombotic therapy and are left either unprotected or inadequately protected against stroke. The purpose of the Global Anticoagulant Registry in the FIELD (GARFIELD) is to determine the real-life management and outcomes of patients newly diagnosed with non-valvular AF. Methods/design GARFIELD is an observational, international registry of newly diagnosed AF patients with at least one additional investigator-defined risk factor for stroke. The aim is to enrol 55,000 patients at more than 1000 centres in 50 countries worldwide. Enrolment will take place in five independent, sequential, prospective cohorts; the first cohort includes a retrospective validation cohort. Each cohort will be followed up for 2 years. The UK stands to be a significant contributor to GARFIELD, aiming to enrol 4,582 patients, and reflecting the care environment in which patients with AF are managed. The UK protocol will also focus on better understanding the validity of the two main stroke risk scores (CHADS2 and CHA2DS2VASC) and the HAS-BLED bleeding risk score, in the context of a diverse patient population. Discussion The GARFIELD registry will describe how therapeutic strategies, patient care, and clinical outcomes evolve over time. This study will provide UK-specific comprehensive data that will allow a range of evaluations both at a national level and in relation to global data and contribute to a better understanding of AF management in the UK

Ethnicity : UK colorectal cancer screening pilot : final report

27. In summary, the overall evaluation of the UK Pilot has demonstrated that key parameters of test and programme performance observed in randomised studies of FOBt screening can be repeated in population-based pilot programmes. However, our study provides strong evidence of very low CRC screening uptake for ethnic groups in the Pilot area. This is coupled with a very low uptake of colonoscopy for individuals from ethnic groups with a positive FOBt result. 28. It has long been acknowledged that a diverse population may require diverse responses. Following the implementation of the Race Relations Amendment Act 2000, there has been a statutory duty laid upon all NHS agencies to ‘have due regard to the need to eliminate unlawful discrimination’, and to make explicit consideration of the implications for racial equality of every action or policy. 29. Because the observed overall outcomes in the UK Pilot generally compare favourably with the results of previous randomised trials of FOBt screening, the main Evaluation Group has concluded that benefits observed in the trials should be repeatable in a national roll-out. 30. However, our study indicates that any national colorectal cancer screening programme would need to very carefully consider the implications of ethnicity for roll-out, and develop a strategic plan on how best to accommodate this at both a national and local level. Based on our findings, consideration will clearly need to be given to improved access and screening service provision for ethnic minorities. 31. In order to ensure adequate CRC screening provision for a diverse UK population, and to address the explicit implications for racial equality highlighted by our findings, interventions now urgently need to be evaluated to improve access for ethnic minorities. This work should be undertaken as part of the second round of CRC screening currently underway in the English Pilot

Is protocolised weaning that includes early extubation onto non-invasive ventilation more cost effective than protocolised weaning without non-invasive ventilation? Findings from the Breathe Study

Background Optimising techniques to wean patients from invasive mechanical ventilation (IMV) remains a key goal of intensive care practice. The use of non-invasive ventilation (NIV) as a weaning strategy (transitioning patients who are difficult to wean to early NIV) may reduce mortality, ventilator-associated pneumonia and intensive care unit (ICU) length of stay. Objectives Our objectives were to determine the cost effectiveness of protocolised weaning, including early extubation onto NIV, compared with weaning without NIV in a UK National Health Service setting. Methods We conducted an economic evaluation alongside a multicentre randomised controlled trial. Patients were randomised to either protocol-directed weaning from mechanical ventilation or ongoing IMV with daily spontaneous breathing trials. The primary efficacy outcome was time to liberation from ventilation. Bivariate regression of costs and quality-adjusted life-years (QALYs) provided estimates of the incremental cost per QALY and incremental net monetary benefit (INMB) overall and for subgroups [presence/absence of chronic obstructive pulmonary disease (COPD) and operative status]. Long-term cost effectiveness was determined through extrapolation of survival curves using flexible parametric modelling. Results NIV was associated with a mean INMB of £620 ($US885) (cost-effectiveness threshold of £20,000 per QALY) with a corresponding probability of 58$US6594 per QALY gained). Conclusions The probability of NIV being cost effective relative to weaning without NIV ranged between 57 and 59% overall and between 82 and 87% for the COPD subgroup

A model-independent Dalitz plot analysis of B±→DK± with D→K0Sh+h− (h=π,K) decays and constraints on the CKM angle γ

A binned Dalitz plot analysis of B ±→DK ± decays, with D→KS0π+π- and D→KS0K+K-, is performed to measure the CP-violating observables x ± and y ± which are sensitive to the CKM angle γ. The analysis exploits 1.0 fb -1 of data collected by the LHCb experiment. The study makes no model-based assumption on the variation of the strong phase of the D decay amplitude over the Dalitz plot, but uses measurements of this quantity from CLEO-c as input. The values of the parameters are found to be x -=(0.0±4.3±1.5±0.6)×10 -2, y -=(2.7±5.2±0.8±2.3)×10 -2, x +=(-10.3±4.5±1.8±1.4)×10 -2 and y +=(-0.9±3.7±0.8±3.0)×10 -2. The first, second, and third uncertainties are the statistical, the experimental systematic, and the error associated with the precision of the strong-phase parameters measured at CLEO-c, respectively. These results correspond to γ=(44-38+43)°, with a second solution at γ→γ+180°, and r B=0.07±0.04, where r B is the ratio between the suppressed and favoured B decay amplitudes

Measurement of the Bs0-Bs0 oscillation frequency δms in Bs0→Ds-(3)π decays

The Bs0-Bs0 oscillation frequency δms is measured with 36 pb-1 of data collected in pp collisions at s=7TeV by the LHCb experiment at the Large Hadron Collider. A total of 1381 Bs0→Ds-π+ and Bs0→Ds-π+π-π + signal decays are reconstructed, with average decay time resolutions of 44 fs and 36 fs, respectively. An oscillation signal with a statistical significance of 4.6σ is observed. The measured oscillation frequency is δm s=17.63±0.11(stat)±0.02(syst)ps -1

Chronic Headache Education and Self-management Study (CHESS) : Statistical Analysis Plan [v1.1]

Background and rationale Chronic headaches present a major problem both for the individual and society. Previous studies on supportive self-management interventions in this population have largely been small studies with short term follow-up, they often did not report clinically relevant outcomes, or were conducted in different healthcare systems therefore difficult to translate into an NHS setting. These studies also did not necessarily focus on chronic headache but rather looked at headache with no frequency specified. Based on the results of our systematic review there may be potential for large gain through a combination of self-management education and appropriate use of prophylaxis and management of medication overuse headache in a chronic headache population. In order to develop the evidence base needed for self-management intervention for chronic headache there needs to be a carefully developed, piloted and evaluated intervention package which has been supported by good qualitative work on understanding outcomes of interest. There is therefore the need for a robust clinical and cost-effectiveness trial within an NHS setting. Objectives The objective is to answer the question: Amongst adults with chronic headache arising from migraine, chronic tension type headache or medication overuse headache, is the provision of a self-management support programme in addition to best usual NHS care clinically and cost effective? ISRCTN number: 7970810