Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes.

BACKGROUND: Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP­1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials. METHODS: In a single-dose, first-in-human trial, 135 healthy males received oral semaglutide (2-20 mg semaglutide co-formulated with 150-600 mg SNAC) or placebo with SNAC. In a 10-week, once-daily, multiple-dose trial, 84 healthy males received 20 or 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC, and 23 males with type 2 diabetes (T2D) received 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC. RESULTS: Oral semaglutide was safe and well-tolerated in both trials. The majority of adverse events (AEs) were mild, with the most common AEs being gastrointestinal disorders. In the single-dose trial, semaglutide exposure was highest when co-formulated with 300 mg SNAC. In the multiple-dose trial, semaglutide exposure was approximately twofold higher with 40 versus 20 mg oral semaglutide in healthy males, in accordance with dose proportionality, and was similar between healthy males and males with T2D. The half-life of semaglutide was approximately 1 week in all groups. CONCLUSION: The safety profile of oral semaglutide was as expected for the GLP-1 receptor agonist drug class. Oral semaglutide co-formulated with 300 mg SNAC was chosen for further clinical development. The pharmacokinetic results supported that oral semaglutide is suitable for once-daily dosing. CLINICALTRIALS. GOV IDENTIFIERS: NCT01037582, NCT01686945.

Low levels of vitamin D are associated with increased mortality in patients attending a university hospital in Denmark.

INTRODUCTION: Increased mortality in patients with low serum concentrations of S-25(OH)D has been described, though no causal relationship has been shown. The aim of this cohort study was to investigate the possible association between S-25(OH)D status and all-cause mortality in 5,147 patients attending a university hospital in Denmark from 2003-2008. METHODS: Serum was analyzed for ionized calcium (S-Ca(2+)), parathyroid hormone (S-PTH) and S-25(OH)D. Kaplan-Meier curves were used to analyze the association between S-25(OH)D quartiles, S-PTH-quartiles and all-cause mortality. Cox regression analyzed associations of age, gender, concentrations of ionized calcium, S-PTH and S-25(OH)D with all-cause mortality. RESULTS: Log rank tests for both S-25(OH)D and S-PTH quartiles showed a significant difference across the quartiles. The Cox regression analysis showed a hazard ratio (HR) for death of 1.02 (95% CI: 1.01; 1.03) for S-PTH per pmol/L increase, 1.07 (95% CI: 1.05; 1.10) for S-25(OH)D per 10 nmol/L decrease and 0.54 (95% CI: 0.24; 1.20) for S-Ca(2+) per mmol/L increase. DISCUSSION: This study supports growing evidence, that low serum concentrations of 25(OH)D are associated with an increased all-cause mortality; however the nature of the study prevents the finding of a causal relationship. In the Cox regression analysis S-25(OH)D concentrations in the blood were inversely associated with all-cause mortality. Prospective controlled studies are needed to confirm a causal relationship between low S-25(OH)D concentrations and mortality.

Use of nonsteroidal anti-inflammatory drugs prior to chronic renal replacement therapy initiation: a nationwide study.

PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with severe renal complications, including acute renal failure, reduced glomerular filtration rate and interstitial nephritis. Caution against NSAIDs is therefore recommended in advanced chronic kidney disease. In this study, we examined NSAID use, aetiology and comorbidity among a national cohort of patients before the initiation of chronic renal replacement therapy (RRT). METHODS: Patients initiated on chronic RRT in the period 1997-2006 were identified in the Danish National Registry on Regular Dialysis and Transplantation, including etiological diagnosis. The use of NSAID before the start of RRT was studied by linkage to the National Prescription Register and comorbidity by linkage to the National Patient Registry. RESULTS: A total of 6663 patients were included in the study, and 2407 patients (36.1%) were prescribed NSAID in the 3 years before the start of RRT. These patients were older (mean age = 63.0 vs 61.4 years) and had a significantly higher degree of comorbidity (Charlson score = 2.85 vs 2.61, p < 0.05) compared with patients not treated with NSAIDs. In the 3 years leading up to RRT, the number of patients treated with NSAID each year and the cumulated median length of treatment including all NSAIDs were stable at approximately 20% and 40 days, respectively. CONCLUSIONS: In this study of a nationwide group of patients, we observed a widespread use of NSAID with an unaffected high annual incidence in the 3 years leading up to the initiation of RRT.

[Treatment of severe digoxin intoxication with antidote]. / Brugen af antidot ved digoxinforgiftning.

In the case of severe digoxin intoxication, an antidote digoxin immune Fab (Digibind) is available. Digibind binds and inactivates digoxin. Measuring se-digoxin after administering Digibind (by standard measuring methods) is misleading as Digibind interferes with digitalis immunoassay measurements. The effect of Digibind must be estimated on the basis of the disappearance of the patient's symptoms and cardiac abnormalities. A case involving Fab therapy of a digoxin-overdosed patient is reported.