Pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in individuals with type 2 diabetes.

AIMS: To characterize the pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in type 2 diabetes (T2D). MATERIALS AND METHODS: In an open-label trial, 46 individuals with T2D (18-75 years; body mass index 18.0-38.0 kg/m2 ; glycated haemoglobin ≤75 mmol/mol [≤9%]; basal insulin-treated) received subcutaneous once-weekly icodec for ≥8 weeks at individualized doses, aiming at a pre-breakfast plasma glucose concentration of 4.4 to 7.0 mmol/L (80-126 mg/dL) on the last three mornings of each weekly dosing interval. Frequent blood sampling to assess total serum icodec concentration (ie, albumin-bound and unbound) occurred from first icodec dose until 35 days after last dose. Icodec trough concentrations following initiation of once-weekly dosing were predicted by pharmacokinetic modelling. During the final 3 weeks of icodec treatment, while at steady state, the icodec glucose-lowering effect was assessed in three glucose clamps (target 7.5 mmol/L [135 mg/dL]): 0 to 36, 40 to 64 and 144 to 168 h post-dose, thus covering the initial, middle and last part of the 1-week dosing interval. Glucose-lowering effect during a complete dosing interval was predicted by pharmacokinetic-pharmacodynamic modelling. RESULTS: Model-predicted icodec steady state was attained after 3 to 4 weeks. At steady state, model-predicted daily proportions of glucose-lowering effect on days 1 to 7 of the 1-week dosing interval were 14.1%, 16.1%, 15.8%, 15.0%, 14.0%, 13.0% and 12.0%, respectively. Icodec duration of action was at least 1 week in all participants. Once-weekly icodec was overall safe and well tolerated in the current trial. CONCLUSIONS: The pharmacokinetic and pharmacodynamic characteristics of icodec in individuals with T2D support its potential as a once-weekly basal insulin.

Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial.

Importance: Once-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes. Objective: To evaluate the efficacy and safety of once-weekly icodec vs once-daily insulin degludec in people with insulin-naive type 2 diabetes. Design, Setting, and Participants: Randomized, double-masked, noninferiority, treat-to-target, phase 3a trial conducted from March 2021 to June 2022 at 92 sites in 11 countries in adults with type 2 diabetes treated with any noninsulin glucose-lowering agents with hemoglobin A1c (HbA1c) of 7%-11% (53-97 mmol/mol). Interventions: Participants were randomly assigned in a 1:1 ratio to receive either once-weekly icodec and once-daily placebo (icodec group; n = 294) or once-daily degludec and once-weekly placebo (degludec group; n = 294). Main Outcomes and Measures: The primary end point was change in HbA1c from baseline to week 26 (noninferiority margin, 0.3% percentage points). Secondary end points included change in fasting plasma glucose from baseline to week 26, mean weekly insulin dose during the last 2 weeks of treatment, body weight change from baseline to week 26, and number of level 2 (clinically significant; glucose level <54 mg/dL) and level 3 (severe; requiring external assistance for recovery) hypoglycemic episodes. Results: Among 588 randomized participants (mean [SD] age, 58 [10] years; 219 [37%] women), 564 (96%) completed the trial. Mean HbA1c level decreased from 8.6% (observed) to 7.0% (estimated) at 26 weeks in the icodec group and from 8.5% (observed) to 7.2% (estimated) in the degludec group (estimated treatment difference [ETD], -0.2 [95% CI, -0.3 to -0.1] percentage points), confirming noninferiority (P < .001) and superiority (P = .002). There were no significant differences between the icodec and degludec groups for fasting plasma glucose change from baseline to week 26 (ETD, 0 [95% CI, -6 to 5] mg/dL; P = .90), mean weekly insulin dose during the last 2 weeks of treatment, or body weight change from baseline to week 26 (2.8 kg vs 2.3 kg; ETD, 0.46 [95% CI, -0.19 to 1.10] kg; P = .17). Combined level 2 or 3 hypoglycemia rates were numerically higher in the icodec group than the degludec group from week 0 to 31 (0.31 vs 0.15 events per patient-year exposure; P = .11) and statistically higher in the icodec group from week 0 to 26 (0.35 vs 0.12 events per patient-year exposure; P = .01). Conclusions and Relevance: Among people with insulin-naive type 2 diabetes, once-weekly icodec demonstrated superior HbA1c reduction to once-daily degludec after 26 weeks of treatment, with no difference in weight change and a higher rate of combined level 2 or 3 hypoglycemic events in the context of less than 1 event per patient-year exposure in both groups. Trial Registration: ClinicalTrials.gov Identifier: NCT04795531.

[Information and misinformation about adverse drug reactions].

In this review, we critically discuss the information distributed to patients and doctors regarding adverse drug reactions. A major concern is that frequencies reported in the summary of product characteristics are not adjusted for the occurrence of side effects observed in the placebo group. Previous research has found that the understanding of the health hazards related to pharmacotherapy can be significantly improved by providing information on the frequencies of adverse drug reactions in both the active- and the placebo group.

A poison information centre can provide important assessment and guidance regarding medication errors in nursing homes: A prospective cohort study.

The Danish Poison Information Centre (DPIC) regularly receives inquiries about nursing home residents who have been exposed to a medication error. The aim of this prospective cohort study was to describe and discuss the types and consequences of these errors. Data were collected from 1 March 2018 to 31 March 2019. Registered data included characteristics of caller and resident, data related to the suspected medication error, risk assessment and recommendation. Consequences and clinical outcomes were assessed by follow-up telephone calls. Over the study period, the DPIC was consulted about 145 medication errors occurring at Danish nursing homes. The median number of substances administered by error was two (interquartile range 1-5). Hospitalization was recommended in 21% of cases. In one-third of the cases where consultation with the DPIC was done with the resident either on his/her way to or in hospital, hospitalization was found unnecessary, and the resident could have stayed in accustomed surroundings for observation. Follow-up demonstrated that very few medication errors had a severe outcome. This prospective study illustrates that consulting with a poison information centre can qualify risk assessment and potentially reduce hospital admissions following medication errors in a nursing home setting.

Glycemic control and use of glucose-lowering medications in hospital-admitted type 2 diabetes patients over 80 years.

Treatment guidelines for type 2 diabetes (T2D) recommend avoidance of hypoglycemia and less stringent glycemic control in older patients. We examined the relation of glycemic control to glucose-lowering medications use in a cohort of patients aged>80 years with a diagnosis of T2D and a hospital admission in the Capital Region of Denmark in 2012-2016. We extracted data on medication use, diagnoses, and biochemistry from the hospitals' records. We identified 5,172 T2D patients with high degree of co-morbidity and where 17% had an HbA1c in the range recommended for frail, comorbid, older patients with type 2 diabetes (58-75 mmol/mol (7.5-9%)). Half of the patients (n = 2,575) had an HbA1c <48 mmol/mol (<6.5%), and a majority of these (36% of all patients) did not meet the diagnostic criteria for T2D. Of patients treated with one or more glucose-lowering medications (n = 1,758), 20% had HbA1c-values <42 mmol/mol (<6%), and 1% had critically low Hba1c values <30 mmol/mol (<4.9%), In conclusion, among these hospitalized T2D patients, few had an HbA1c within the generally recommended glycemic targets. One third of patients did not meet the diagnostic criteria for T2D, and of the patients who were treated with glucose-lowering medications, one-fifth had HbA1c-values suggesting overtreatment.

[Limited evidence for effect and safety of propranolol for exam-related anxiety].

Propranolol is often prescribed to younger people with exam-related performance anxiety. Evidence for effect as well as safety is, however, sparse for this non-approved indication. Furthermore, only relatively large pack sizes are available in Denmark. This may spur an unnecessary, permanent overuse and increase the risk of overdosing and poisoning. The aim of this review is to examine the evidence for the effect as well as safety of propranolol for exam-related performance anxiety and to discuss, whether the use of this drug for this unapproved indication is rational.

Full journal publication of abstracts presented at the Nordic Congress of General Practice in 2009 and 2011.

OBJECTIVE: To determine the overall publication rates for abstracts presented at two consecutive Nordic Congresses of General Practice and to evaluate determinants for these publication rates. DESIGN: Prospective study. SETTING: MEDLINE (PubMed) and Google Scholar were searched for relevant publications from 1 January 2009 up until 31 August 2014. METHODS: Abstracts accepted for oral or poster presentation were identified from the original congress booklets from the Nordic Congresses of General Practice in 2009 and 2011. Based on PubMed and Google Scholar searches, we subsequently identified full journal publications within a 36-month follow-up from both congresses. In cases of doubt, the first author was contacted directly. MAIN OUTCOME MEASURES: Full journal publication within 36 months after the congress. RESULTS: A total of 200 abstracts were analyzed. Of these, 85 (42.5%) were identified with a full publication within 36 months after the congress. More abstracts from the 2011 congress were published compared to the 2009 congress odds ratio (OR) 1.97, 95% confidence interval (CI) (1.10; 3.50). Abstracts accepted for oral presentation were more often published OR 1.94, 95% CI (1.08; 3.50) than accepted poster abstracts. In the multivariate analysis, a university affiliation for both first and last author increased the probability for publication OR 4.23, 95% CI (1.71; 10.42), as well as more than two authors. An optimal number, based on the highest OR, seems to be 3-4 authors with OR 2.43, 95% CI (1.07; 5.54). Qualitative studies were published at the same frequency as quantitative studies OR 1.36, 95% CI (0.57; 3.24). CONCLUSION: Less than half of the abstracts accepted for oral or poster presentation at two consecutive Nordic Congresses of General Practice were published as full text articles within 36 months. Key points Congress abstracts accepted for Nordic Congress of General Practice are not indexed in international search databases. Less than half of the abstracts accepted for oral or poster presentation at two consecutive Nordic Congresses of General Practice were published as full text articles within 36 months. Future congress committees could address this aspect in order to increase the visibility of and accessibility to research within the field of general practice.

An adverse drug event manager facilitates spontaneous reporting of adverse drug reactions.

INTRODUCTION: Spontaneous reporting of adverse drug reactions (ADRs) is used for continuous risk-benefit evaluation of marketed pharmaceutical products and for signal detection. The Adverse Drug Event Manager (ADEM) is a service offered to clinicians employed at hospitals in the Capital Region of Denmark. The ADEM assists healthcare professionals in reporting suspected ADRs to the Danish Health Authority. The aim of this retrospective observational study was to quantify and describe ADRs reported via the ADEM in 2014. METHODS: All ADR reports handled by the ADEM in 2014 were recorded anonymously and analysed descriptively. RESULTS: A total of 484 ADRs were reported through the ADEM in 2014 (the median number of reports per month was 37; range: 17-78). The majority of the reports came from departments of internal medicine (61%), psychiatry (14%) and dermatology, ophthalmology or otorhinolaryngology (11%). The drugs most frequently reported were lisdexamphetamine (n = 40), rivaroxaban (n = 16) and warfarin (n = 15) (vaccines excluded). In 13 out of 484 reports, the ADR was associated with a fatal outcome. CONCLUSION: The findings of this study indicate that an ADEM promotes and facilitates spontaneous ADR reporting and helps raise awareness about ADRs, including how and why they should be reported. Hopefully, this will assist national and European spontaneous reporting systems in their work to increase patient safety nationally and abroad. FUNDING: none. TRIAL REGISTRATION: not relevant. .

[Pharmaceutical drugs containing lactose can as a rule be used by persons with lactose intolerance]. / Laktoseholdige lægemidler kan som hovedregel indtages af personer med laktoseintolerans.

Lactose is often used as an excipient in pharmaceutical drugs. Current evidence indicates that the amount of lactose in most drugs is not sufficient to cause symptoms in persons with lactose intolerance, although interindividual differences in sensitivity probably exist. Patient preferences and/or suboptimal treatment adherence could be reasons for considering lactose-free drug alternatives.

Dispersed publication of editorial research.

INTRODUCTION: There seems to be no dedicated journals available for publication of editorial research in the biomedical sciences; that is research into editorial or publication process issues involving the scientific approach to writing, reviewing, editing and publishing. It is unknown where papers concerning these issues are typically published. We therefore set out to study the distribution of such papers in the biomedical literature. METHODS: In this pilot study, we conducted a MEDLINE search for papers on editorial research published in the year 2012. RESULTS: We found 445 articles published in 311 journals with a median of one article per journal (range: 1-17). CONCLUSION: The publication of papers on editorial research seems to be dispersed. In order to increase the visibility of this research field, it may be reasonable to establish well-defined platforms such as dedicated journals or journal sections in which such research could preferably be published.

Authorship issues in multi-centre clinical trials: the importance of making an authorship contract.

Discussions about authorship often arise in multi-centre clinical trials. Such trials may involve up to hundreds of contributors of whom some will eventually co-author the final publication. It is, however, often impossible to involve all contributors in the manuscript process sufficiently for them to qualify for authorship as defined by the International Committee of Medical Journal Editors. Therefore, rules for authorship in multi-centre trials are strongly recommended. We propose two contracts to prevent conflicts regarding authorship; both are freely available for use without pay but with reference to the original source.

[The fate of scientific articles when errors and scientific misconduct are detected]. / [Videnskabelige artiklers skæbne ved erkendt fusk og sjusk]

When a minor error is noted in a scientific article, the publishing journal should issue a correction. Issuing an expression of concern is relevant when scientific misconduct is suspected. If the suspicion proves to be well founded, the journal should retract the article. The number of retractions is increasing, and this emphasizes the need for unequivocal concepts and guidelines. The reason a given article is corrected or retracted should be unambiguous and articles as well as notices should be indexed properly.

[Peer review is not based on evidence, but on tradition and good intentions]. / Peer review er ikke baseret på evidens, men på traditioner og gode intentioner.

Ideally, peer review is a method for guaranteeing and improving scientific work, but in terms of evidence we do not know much about what peer review is, what it does or how it could do better. There have been several attempts to improve the current system, but neither blinding, anonymisation, nor training of reviewers seem to make a big difference. The traditional "pre-publication" system seems to be based on tradition and good intentions rather than evidence. "Post-publication" review, which allows all members of the biomedical community to evaluate a certain work, may be an effective supplement to the current system.

Same review quality in open versus blinded peer review in "Ugeskrift for Læger".

INTRODUCTION: Research into the peer review process has previously been conducted in English-language journals. This study deals with a Danish general medical journal with a relatively small pool of both reviewers and readers. The aim of the study was to compare the quality of reviews produced by identifiable and anonymous reviewers, and further to characterize authors' and reviewers' attitudes towards different peer review systems. MATERIAL AND METHODS: The study was conducted as a blinded, randomised controlled trial. Each manuscript was reviewed by an identifiable and an anonymous reviewer. Review quality was subsequently assessed by two blinded editors, using the validated Review Quality Instrument. Reviewers' and authors' attitudes towards different peer review systems were characterized using questionnaires. RESULTS: The study included 364 reviews. There was no statistically significant difference in quality between anonymous and identifiable reviewers' evaluations. 55% of the authors preferred the evaluation produced by the identifiable reviewer (p < 0.05). 26% of the identifiable reviewers found it unpleasant that authors knew their identities; 43% of the anonymous reviewers found it reassuring that authors did not know their identities. Regarding reviewers' preferences for different peer review systems, 38% preferred a double-blinded, 34% preferred a single-blinded and 28% preferred an open system. For authors, the corresponding proportions were 43%, 19% and 37%. CONCLUSION: Implementing open peer review will not affect review quality, but lack of anonymity may cause reviewers, already limited in number, to decline when asked to review. Even though this would be a serious implication for a national journal like the Ugeskrift for Læger, the implementation of an open system should be discussed. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Appearance of ghost and gift authors in Ugeskrift for Læger and Danish Medical Journal.

INTRODUCTION: Authorship should establish accountability and transparency, but previous research into authorship has demonstrated that authors do not always meet the International Committee of Medical Journal Editors' (ICMJE) authorship criteria. Yet, these studies have mainly focused on international, high-impact journals. The aim of the present study was to assess Danish authors' general authorship experiences and views on authorship and authorship criteria. MATERIAL AND METHODS: Corresponding authors of articles published in Ugeskrift for Læger and Danish Medical Journal in 2010 received a web-based questionnaire about the sampled article, co-authors and contributors, general authorship experiences and views on authorship and authorship criteria. RESULTS: A total of 470 authors received the questionnaire and 292 responded (response rate 62%). 29% had experienced that "somebody" (the respondent himself/herself or an acquaintance/colleague) had been excluded from the author byline. 17% had been offered illegitimate authorship. 16% of the respondents had offered illegitimate authorship to somebody else. 25% of the respondents did not agree that legitimate authorship requires fulfilment of all three current ICMJE authorship criteria. Some contributions/functions not part of the current ICMJE criteria were also considered relevant for authorship, e.g. co-author supervision, statistical assistance and research group leadership. CONCLUSION: Illegitimate authorship is prevalent also in low-impact, national journals. In order to promote legitimate authorship, mandatory contribution statements should be considered, but education and information about existing criteria for authorship may be even more important. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

[Lack of clear guidelines for authorship in multicentre studies]. / Der mangler klare anvisninger for forfatterskab i multicenterstudier.

Determining authorship in multicentre studies can be difficult because of the large number of contributors and collaborators. Different experiences and recommendations regarding authorship and byline listing emphasize the importance of transparency and communication before, during, and after manuscript preparation. More specifically, written publication policies, regular meetings, and different scoring systems can be considered. It is important to reduce potential disincentives for engaging in multicentre studies. Therefore, clear guidelines for authorship assignment are necessary.

Authorship trends over the past fifty years in the Journal of the Danish Medical Association (Danish: Ugeskrift for Læger).

INTRODUCTION: Internationally, the number of authors per scientific article is increasing. The objective of this study was to determine authorship trends over the past fifty years in Ugeskrift for Læger (UfL). MATERIAL AND METHODS: From 1960 to 2010, ten volumes of the UfL, 5,962 articles in total, were studied. For each article, category and number of authors were recorded. RESULTS: The median number of authors per article (all categories) was one in 1960 (range 1-3), two in 1985 (range 1-9) and three in 2010 (range 1-14). The proportion of articles published by three or more authors constituted 1% in 1960 and 68% in 2010. For original articles, the median number of authors per article was two in 1960 (range 1-3), three in 1985 (range 1-9) and three in 2010 (range 1-9). For reviews, the median number of authors per article was one in 1960 (range 1-2), two in 1985 (range 1-5) and three in 2010 (range 1-14). For case reports, the median number of authors per article was one in 1960 (range 1-2), two in 1985 (range 1-5) and three in 2010 (range 1-6). CONCLUSION: The number of authors per article increased for all types of articles published in the UfL. This could reflect increases in "gift authorship", but "multiple authorship" could also be fully legitimate. Replacing or supplementing authorship criteria with contribution statements would provide some transparency and accountability. Yet, questions about credit assessment and overall responsibility need to be clarified. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Fate of manuscripts rejected by a non-English-language general medical journal: a retrospective cohort study.

OBJECTIVE: The objective of this study was to determine whether, where and when manuscripts were published following rejection by the Journal of the Danish Medical Association, a general medical journal published in Danish. Similar previous studies have focused on specialty/subspecialty journals published in English. DESIGN: Manuscripts rejected during a 4-year period were searched for in PubMed and Embase in order to assess the percentage of manuscripts subsequently published in other journals. In addition, characteristics of both the published manuscripts and the journals in which they were evaluated. RESULTS: Of 198 rejected manuscripts, 21 (10.6%) were eventually published after a median of 685 days (range 209-1463). The majority of these were original research, published in English-language specialty/subspecialty journals. The median number of citations per article was 2-3 (IQR 0.5-9.5, depending on the database searched). CONCLUSIONS: 10.6% of the rejected manuscripts were eventually published in other journals, mainly English-language specialty journals. This proportion was considerably lower than that for other journals that have studied the fate of rejected manuscripts. Manuscript translation could be a barrier for resubmitting to English-language journals with larger readerships, thus hindering the dissemination of knowledge to the international community.