To understand humans' requirements for magnesium and the effect of magnesium on health, it is important to identify sensitive and populationspecific biomarkers of magnesium status. Thus, we assessed the effectiveness of different magnesium status biomarkers through a systematic review of published magnesium supplementation and depletion trials in healthy humans. The methods used in this study included a structured search on Ovid MEDLINE, EMBASE (Ovid) and Cochrane databases up to September 2008, followed by the use of formal inclusion/exclusion criteria, data extraction, validity assessment, and meta-analysis. A total of 20 potential biomarkers of magnesium status were assessed from 21 included publications. The majority of studies included were magnesium supplementation studies. Fewer magnesium depletion studies were identified. Available data analysis suggests that serum/plasma magnesium concentration, red blood cell (RBC) concentration and urinary magnesium excretion responded to dietary manipulation. For other biomarkers with available data, it was not possible to draw any conclusions about their usefulness as magnesium status biomarkers. The lack of data prevented detailed subgroup analysis. In conclusion, although limited data were available, serum/plasma magnesium concentration, RBC magnesium concentration and urinary magnesium excretion appear to be useful biomarkers of magnesium status in the general population. Further high-quality studies are needed to assess the effectiveness of existing and newly developed biomarkers, especially in populations that are vulnerable to magnesium deficiency.Magnesium (Mg 2+ ) is the second most abundant cation within the cell. Magnesium plays an essential role in a wide range of fundamental biochemical reactions and cellular functions, including cell cycle, channel regulation, membrane and nucleic acid stability and is a cofactor for hundreds of enzymes [1]. Therefore, it is not surprising that many clinical disorders are associated with magnesium deficiency [2,3]. Recommendations for magnesium intake are pro-This manuscript does not necessarily reflect the views of the Commission of the European Communities and in no way anticipates their future policy in this area.To cite this article: Witkowski M, Hubert J, Mazur A. Methods of assessment of magnesium status in humans: a systematic review.

IntroductionOnce-weekly semaglutide is a new glucagon-like peptide-1 (GLP-1) analogue administered at a 1.0 or 0.5 mg dose. As head-to-head trials assessing once-weekly semaglutide as an add-on to 1–2 oral anti-diabetic drugs (OADs) vs other GLP-1 receptor agonists (GLP-1 RAs) are limited, a network meta-analysis (NMA) was performed. The objective was to assess the relative efficacy and safety of once-weekly semaglutide vs GLP-1 RAs in patients with type 2 diabetes (T2D) inadequately controlled on 1–2 OADs.MethodsA systematic literature review (SLR) was conducted in order to identify trials of GLP-1 RAs in patients inadequately controlled on 1–2 OADs. Data at 24 ± 4 weeks were extracted for efficacy and safety outcomes (feasible for analysis in a NMA), which included the key outcomes of change from baseline in glycated hemoglobin (HbA1c), systolic blood pressure (SBP), and weight, as well as discontinuation due to adverse events (AEs). Data were synthesized using a NMA and a Bayesian framework.ResultsIn total, 26 studies were included across the base case analyses. Once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA1c and weight vs all GLP-1 RA comparators. Once-weekly semaglutide 0.5 mg also achieved significantly greater reductions in HbA1c and weight compared with the majority of other GLP-1 RAs. Both doses of once-weekly semaglutide were associated with similar odds of discontinuation due to AEs compared with other GLP-1 RAs.ConclusionOverall, once-weekly semaglutide 1.0 mg as an add-on to 1–2 OADs is the most efficacious GLP-1 RA in terms of the reduction of HbA1c and weight from baseline after 6 months of treatment. In addition, the analysis suggests that once-weekly semaglutide is well tolerated and not associated with an increase in discontinuations due to AEs compared with other GLP-1 RAs.FundingNovo Nordisk.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0424-2) contains supplementary material, which is available to authorized users.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by platelet destruction and reduced platelet production resulting in decreased platelet level and an increased risk of bleeding. Based on the immunologic mechanism of ITP, frontline standard therapy consists of corticosteroids and intravenous immunoglobulins (IVIG). If patients do not respond to the first-line treatment, or if continuous therapy is required, the disorder is called refractory ITP, and second-line therapy is indicated.This treatment may consist of rituximab, thrombopoietin receptor agonists, splenectomy, or cytotoxic drugs. Despite significant advances, many patients do not respond to any the treatments listed below, and new treatment options need to be developed for this relapsed and refractory group. Recent clinical studies have indicated promising outcomes for novel drugs, either as single agents or in combination with traditional drugs. This review discusses the latest and the most promising novel drugs for ITP in adults. K E Y W O R D Savatrombopag, eltrombopag, immune thrombocytopenia, indirubin, receptor antagonist, rituximab, romiplostim, rozanolixizumab, rozrolimupab, thrombopoietin

IntroductionOnce-weekly semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is currently available as 1.0 mg and 0.5 mg dose for the treatment of type 2 diabetes (T2D). Currently, no head-to-head trial investigating once-weekly semaglutide as an add-on to basal insulin vs other GLP-1 receptor agonists (GLP-1 RAs) is available. The aim of this study was to conduct a network meta-analysis (NMA) to assess the efficacy and safety of once-weekly semaglutide vs other GLP-1 RAs in patients with T2D inadequately controlled on basal insulin.MethodsA systematic literature review was performed to identify all trials of GLP-1 RAs as an add-on to basal insulin in patients with T2D. Data at 24 ± 4 weeks were extracted for efficacy and safety outcomes (feasible for analysis in an NMA), including the change from baseline in glycated hemoglobin (HbA1c), body weight, and systolic blood pressure, and the incidence of nausea, vomiting, and diarrhea. Data were synthesized using a NMA and a Bayesian framework.ResultsIn total, eight studies were included across the base-case analyses. The results demonstrate that once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA1c (− 0.88% to − 1.39% vs comparators) and weight (− 1.49 to − 4.69 kg vs comparators) and similar odds of experiencing nausea, vomiting, or diarrhea vs all GLP-1 RA comparators. Once-weekly semaglutide 1.0 mg was also equally effective at reducing systolic blood pressure compared with liraglutide 1.8 mg. Once-weekly semaglutide 0.5 mg significantly reduced HbA1c vs the majority of other GLP-1 RAs, except liraglutide 1.8 mg QD. The odds of experiencing nausea were significantly lower with once-weekly semaglutide 0.5 mg compared with all GLP-1 RA comparators.ConclusionOnce-weekly semaglutide 1.0 mg as an add-on to basal insulin is likely to be the most efficacious GLP-1 RA for reducing HbA1c and weight from baseline after 6 months of treatment. The efficacy of once-weekly semaglutide is not associated with a significant increase in the incidence of gastrointestinal side-effects vs other GLP-1 RAs.FundingNovo Nordisk.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0428-y) contains supplementary material, which is available to authorized users.

IntroductionSemaglutide once-weekly (QW) is a novel glucagon-like peptide-1 (GLP-1) analogue administered at a 0.5 or 1.0 mg dose. In the absence of head-to-head trials between semaglutide QW and other GLP-1 receptor agonists (GLP-1 RAs) in a Japanese population, a network meta-analysis (NMA) was performed. The objective was to assess the relative efficacy and safety of semaglutide QW vs GLP-1 RAs in Japanese patients with type 2 diabetes (T2DM), with a specific focus on the comparison between semaglutide 0.5 mg QW and dulaglutide 0.75 mg QW.MethodsA systematic review (SR) and supplementary Japanese searches were conducted to identify trials of GLP-1 RAs in Japanese patients on diet and exercise, who have previously received 0–1 oral antidiabetic drugs (OADs). Data at 52–56 weeks were extracted for the following outcomes (feasible for analysis in an NMA): glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), weight, systolic blood pressure (SBP), and overall hypoglycemia. The data were synthesized using an NMA and a Bayesian framework.ResultsFour trials, identified from the SR and Japanese-specific searches, were relevant for inclusion in the NMA. When compared to dulaglutide 0.75 mg QW, semaglutide 0.5 mg QW was shown to provide significant reductions in HbA1c [− 0.61% (12.3 mmol/mol)], weight (− 1.45 kg), SBP (− 5.03 mmHg), and FPG (− 1.26 mmol/L). No significant differences in the proportion of patients achieving a HbA1c level < 7% (53 mmol/mol) or the risk of overall hypoglycemia were observed between semaglutide 0.5 mg QW and dulaglutide 0.75 mg QW.ConclusionOverall, semaglutide 0.5 mg QW was associated with significant reductions from baseline in HbA1c, weight, SBP, and FPG compared with dulaglutide 0.75 mg QW in Japanese patients with T2DM. These data may provide valuable evidence for clinical decision-making, cost-effectiveness analyses, and health technology appraisal (HTA) requirements.FundingNovo Nordisk Pharma Ltd.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0397-1) contains supplementary material, which is available to authorized users.

BackgroundThe global prevalence of non-alcoholic steatohepatitis (NASH) is increasing, such that NASH is predicted to become the leading cause of liver transplantation (LT) in the US by 2025. Despite this, data on the economic burden of NASH are limited. Objectives This systematic literature review aimed to summarise and critically evaluate studies reporting on the economic burden of NASH and identify evidence gaps for subsequent research. Methods Medline, EMBASE, the Cochrane Library and EconLit were searched up to 6 January 2021 for English language articles published from January 2010 to January 2021 inclusive that reported economic outcomes of a NASH population or subpopulation. Evidence was presented and synthesised using narrative data analysis, and quality was assessed by two reviewers using an 11-item checklist developed for economic evaluations and adapted to cost of illness. Results Fourteen studies were included, of which five presented data on costs and resource use, four on costs only and five on resource use only. Overall, NASH is associated with a significant and increasing economic burden in terms of healthcare resource utilisation (HCRU) and direct and indirect costs. This burden was higher among NASH patients with advanced (fibrosis stage 3-4) versus early (fibrosis stage 0-2) disease, symptomatic versus asymptomatic disease and for patients with complications or comorbidities versus those without. In LT patients, those with NASH as the primary indication had greater HCRU and higher costs compared with non-NASH indications such as hepatitis B and C viruses. Considerable variability in HCRU and costs was seen across the US and Europe, with the highest costs seen in the US. The quality of the included studies was variable, and the studies themselves were heterogeneous in terms of study methodology, patient populations, comorbidities, follow-up time and outcomes measured. Conclusions This review highlights a general scarcity of NASH-specific economic outcomes data. Despite this, the identified studies show that NASH is associated with a significant economic burden in terms of increased HCRU, and high direct medical and non-medical costs and societal burden that increases with disease severity or when patients have complications or comorbidity. More national-level NASH prevalence data are needed to generate accurate forecasts of HCRU and costs in the coming decades.

The use of non-vitamin K antagonist oral anticoagulants (NOACs) has become a breakthrough in anticoagulant treatment and it is expected to rise significantly in upcoming years. The use of conventional anticoagulants have several limitations: subcutaneous administration of heparin, or close monitoring of INR during application of vitamin K antagonists. In the last decade, target-specific oral anticoagulants (TSOAC) including dabigatran, rivaroxaban, apixaban, edoxaban have been marketed for prophylaxis and treatment. Therefore, it is crucial to understand the potential uses, side effects, and management of these agents in routine practice. NOACs have major pharmacologic advantages, including a rapid onset and offset of action, fewer drug interactions than conventional anticoagulants, and predictable pharmacokinetics. These agents are gaining popularity among both physicians and patients because of their easiness of administration and the eliminating the requirement for regular coagulation monitoring. In this review, we focus on discussing practical recommendations for the use of NOACs and the risks and benefits of incorporating them into routine practice.

Background Deficiency of antithrombin increases risk of venous thromboembolism. We hypothesized that antithrombin deficiency affects fibrin clot structure and function. Methods We evaluated 148 patients (age: 38 [32–50] years; 70% women) with genetically confirmed antithrombin deficiency and 50 healthy controls. Fibrin clot permeability (Ks) and clot lysis time (CLT) along with thrombin generation capacity were assessed before and after antithrombin activity normalization in vitro. Results Antithrombin-deficient patients had lower antithrombin activity (−39%) and antigen levels (−23%) compared with controls (both p < 0.01). Prothrombin fragment 1 + 2 levels were 26.5% higher in patients with antithrombin deficiency than in controls along with 94% increased endogenous thrombin potential (ETP) and 108% higher peak thrombin (all p < 0.01). Antithrombin deficiency was associated with 18% reduced Ks and 35% prolonged CLT (both p < 0.001). Patients with type I (n = 65; 43.9%) compared with type II antithrombin deficiency (n = 83; 56.1%) had 22.5% lower antithrombin activity (p < 0.001) and despite similar fibrinogen levels, 8.4% reduced Ks, 18% prolonged CLT, and 30% higher ETP (all p < 0.01). Reduced Ks was associated with lower antithrombin antigen level (β = − 6.1, 95% confidence interval [CI]: −1.7 to −10.5), while prolonged CLT was associated with lower antithrombin antigen (β = − 69.6, 95% CI: −9.6 to −129.7), activity (β = − 2.4, 95% CI: −0.3 to −4.5), higher PAI-1 (β = 12.1, 95% CI: 7.7–16.5), and thrombin-activatable fibrinolysis inhibitor levels (β = 3.8, 95% CI: 1.9–5.7). Addition of exogenous antithrombin reduced ETP (−42%) and peak thrombin (−21%), and improved Ks (+8%) and CLT (−12%; all p < 0.01). Conclusions Our study suggests that enhanced thrombin generation and prothrombotic plasma fibrin clot phenotype can contribute to increased risk of thrombosis in patients with antithrombin deficiency.