Effects of 3 months of 10-h per-day time-restricted eating and 3 months of follow-up on bodyweight and cardiometabolic health in Danish individuals at high risk of type 2 diabetes: the RESET single-centre, parallel, superiority, open-label, randomised controlled trial.

BACKGROUND: Time-restricted eating (TRE) has been suggested to be a simple, feasible, and effective dietary strategy for individuals with overweight or obesity. We aimed to investigate the effects of 3 months of 10-h per-day TRE and 3 months of follow-up on bodyweight and cardiometabolic risk factors in individuals at high risk of type 2 diabetes. METHODS: This was a single-centre, parallel, superiority, open-label randomised controlled clinical trial conducted at Steno Diabetes Center Copenhagen (Denmark). The inclusion criteria were age 30-70 years with either overweight (ie, BMI ≥25 kg/m2) and concomitant prediabetes (ie, glycated haemoglobin [HbA1c] 39-47 mmol/mol) or obesity (ie, BMI ≥30 kg/m2) with or without prediabetes and a habitual self-reported eating window (eating and drinking [except for water]) of 12 h per day or more every day and of 14 h per day or more at least 1 day per week. Individuals were randomly assigned 1:1 to 3 months of habitual living (hereafter referred to as the control group) or TRE, which was a self-selected 10-h per-day eating window placed between 0600 h and 2000 h. Randomisation was done in blocks varying in size and was open for participants and research staff, but outcome assessors were masked during statistical analyses. The randomisation list was generated by an external statistician. The primary outcome was change in bodyweight, assessed after 3 months (12 weeks) of the intervention and after 3 months (13 weeks) of follow-up. Adverse events were reported and registered at study visits or if participants contacted study staff to report events between visits. This trial is registered on ClinicalTrials.gov (NCT03854656). FINDINGS: Between March 12, 2019, and March 2, 2022, 100 participants (66 [66%] were female and 34 [34%] were male; median age 59 years [IQR 52-65]) were enrolled and randomly assigned (50 to each group). Of those 100, 46 (92%) in the TRE group and 46 (92%) in the control group completed the intervention period. After 3 months of the intervention, there was no difference in bodyweight between the TRE group and the control group (-0·8 kg, 95% CI -1·7 to 0·2; p=0·099). Being in the TRE group was not associated with a lower bodyweight compared with the control group after subsequent 3-month follow-up (-0·2 kg, -1·6 to 1·2). In the per-protocol analysis, participants who completed the intervention in the TRE group lost 1·0 kg (-1·9 to -0·0; p=0·040) bodyweight compared with the control group after 3 months of intervention, which was not maintained after the 3-month follow-up period (-0·4 kg, -1·8 to 1·0). During the trial and follow-up period, one participant in the TRE group reported a severe adverse event: development of a subcutaneous nodule and pain when the arm was in use. This side-effect was evaluated to be related to the trial procedures. INTERPRETATION: 3 months of 10-h per-day TRE did not lead to clinically relevant effects on bodyweight in middle-aged to older individuals at high risk of type 2 diabetes. FUNDING: Novo Nordisk Foundation, Aalborg University, Helsefonden, and Innovation Fund Denmark.

PaCO2 trajectories in mechanically ventilated patients with COVID-19: A population-based cohort study.

OBJECTIVE: To identify PaCO2 trajectories and assess their associations with mortality in critically ill patients with coronavirus disease 2019 (COVID-19) during the first and second waves of the pandemic in Denmark. DESIGN: A population-based cohort study with retrospective data collection. PATIENTS: All COVID-19 patients were treated in eight intensive care units (ICUs) in the Capital Region of Copenhagen, Denmark, between March 1, 2020 and March 31, 2021. MEASUREMENTS: Data from the electronic health records were extracted, and latent class analyses were computed based on up to the first 3 weeks of mechanical ventilation to depict trajectories of PaCO2 levels. Multivariable Cox regression analyses were used to calculate adjusted hazard ratios (aHRs) for Simplified Acute Physiology Score 3, sex and age with 95% confidence intervals (CIs) for death according to PaCO2 trajectories. MAIN RESULTS: In latent class trajectory models, including 25,318 PaCO2 measurements from 244 patients, three PaCO2 latent class trajectories were identified: a low isocapnic (Class I; n = 130), a high isocapnic (Class II; n = 80), as well as a progressively hypercapnic (Class III; n = 34) trajectory. Mortality was higher in Class II [aHR: 2.16 {1.26-3.68}] and Class III [aHR: 2.97 {1.63-5.40}]) compared to Class I (reference). CONCLUSION: Latent class analysis of arterial blood gases in mechanically ventilated COVID-19 patients identified distinct PaCO2 trajectories, which were independently associated with mortality.

Intracranial Hemorrhage Following Anticoagulant Treatment in Denmark: Spontaneous Adverse Drug Reaction Reports Versus Real-World Data.

INTRODUCTION: In Denmark, physicians are legally obliged to report serious adverse drug reactions (ADRs), such as intracranial hemorrhage (ICH) following anticoagulant (AC) treatment, to the Danish Medicines Agency. We were therefore puzzled to discover a high number of reports concerning ICHs following treatment with the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin. This was surprising, as all DOACs have been found to be associated with a lower risk of ICH compared with warfarin in phase III randomized controlled trials. OBJECTIVES: The primary aim of the study was to estimate the level of underreporting of ICH as an ADR following treatment with warfarin, dabigatran, rivaroxaban, and apixaban. METHODS: This observational study covered a 5-year period (2014-2018). Using nationwide registries held by the Danish Health Data Authority, the number of users, exposure time in person-years, and related ICH events for each of the study drugs were estimated. Data on ADR-ICH reports were extracted from the interactive ADR overviews held by the Danish Medicines Agency. RESULTS: From 2014 to 2018, 97.0% of the identified warfarin-related ICH events were not reported as ADRs. For the DOACs, the level of underreporting ranged from 88.8 to 90.8%. CONCLUSION: We found a heavy and differentiated level of underreporting of ICH as an ADR following treatment with the four study drugs.

Drug-related challenges following primary total hip and knee arthroplasty.

We aimed to characterize the in-hospital analgesic use among total hip or knee arthroplasty (THA or TKA) patients, and to identify possible drug-related challenges. We identified 15 263 patients operated with a THA or TKA between 1 January 2012 and 30 April 2016. The prevalence of analgesic users and patients with potential clinically relevant drug-drug interactions (DDIs), along with the prevalence of readmission among patients with vs. without a DDI, were calculated. A DDI was defined as the combination of (A) a diuretic, an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, and an non-steroidal anti-inflammatory Drug (NSAID); (B) warfarin and an NSAID; and (C) a benzodiazepine or a benzodiazepine-related drug and an opioid. The prevalence of analgesics administered in THA and TKA patients was 99.3% and 99.1% for paracetamol and 93.8% and 98.8% for opioids, respectively. The prevalence of patients who received interaction A, B or C was 8.4%, 2.5% and 40.7%, respectively. Patients with vs. without a DDI had a higher prevalence of 30-day readmission. In conclusion, most THA and TKA patients were administered paracetamol or opioids. The prevalence of 30-day readmission was higher in patients with than in patients without a potential clinically relevant DDI.

Developing and validating COVID-19 adverse outcome risk prediction models from a bi-national European cohort of 5594 patients.

Patients with severe COVID-19 have overwhelmed healthcare systems worldwide. We hypothesized that machine learning (ML) models could be used to predict risks at different stages of management and thereby provide insights into drivers and prognostic markers of disease progression and death. From a cohort of approx. 2.6 million citizens in Denmark, SARS-CoV-2 PCR tests were performed on subjects suspected for COVID-19 disease; 3944 cases had at least one positive test and were subjected to further analysis. SARS-CoV-2 positive cases from the United Kingdom Biobank was used for external validation. The ML models predicted the risk of death (Receiver Operation Characteristics-Area Under the Curve, ROC-AUC) of 0.906 at diagnosis, 0.818, at hospital admission and 0.721 at Intensive Care Unit (ICU) admission. Similar metrics were achieved for predicted risks of hospital and ICU admission and use of mechanical ventilation. Common risk factors, included age, body mass index and hypertension, although the top risk features shifted towards markers of shock and organ dysfunction in ICU patients. The external validation indicated fair predictive performance for mortality prediction, but suboptimal performance for predicting ICU admission. ML may be used to identify drivers of progression to more severe disease and for prognostication patients in patients with COVID-19. We provide access to an online risk calculator based on these findings.

Characteristics of newly diagnosed adults with type 1 diabetes in the UK and evolution of glycaemic control, body mass index and Charlson comorbidity index over the first 5 years after diagnosis.

AIMS: This retrospective, longitudinal study characterised 2430 adults (mean age 40.8±16.1years) with newly diagnosed type 1 diabetes (T1D) over the first 5years of insulin treatment. METHODS: Data from 1year pre- and up to 5 years post-insulin initiation were extracted from the UK Clinical Practice Research Datalink (1990-2013). Baseline HbA1c, BMI and Charlson comorbidity index (CCI) score were compared with data at 1, 2, 3 and 5 years. RESULTS: Mean HbA1c decreased significantly from baseline 95±32.8mmol/mol (10.8±3.0%) to 61±21.9mmol/mol (7.7±2.0%) at 1year, remaining significantly lower at 2, 3 and 5 years (p<0.0001). One year after initiating insulin, only 6.3% of patients had HbA1c <48mmol/mol (<6.5%). There was no further improvement in HbA1c after 1year. Mean BMI increased significantly from baseline 25.3±5.5kg/m2 to 27.2±5.8kg/m2 at 1year; p<0.0001), remaining significantly higher thereafter, with over two-thirds having overweight/obesity by year 5. Mean CCI score increased significantly (1.32, baseline; 1.46, year 1; 1.75, year 5). CCI patterns were similar within BMI and HbA1c strata. CONCLUSIONS: More intensive support to reach and maintain glycaemic targets soon post-diagnosis, while avoiding weight gain, and prevention and optimal management of comorbidities are warranted.

Evaluating the effectiveness of risk minimisation measures: the application of a conceptual framework to Danish real-world dabigatran data.

PURPOSE: For both marketing authorization holders and regulatory authorities, evaluating the effectiveness of risk minimization measures is now an integral part of pharmacovigilance in the European Union. The overall aim of activities in this area is to assess the performance of risk minimization measures implemented in order to ensure a positive benefit-risk balance in patients treated with a medicinal product. METHODS: Following a review of the relevant literature, we developed a conceptual framework consisting of four domains (data, knowledge, behaviour and outcomes) intended for the evaluation of risk minimization measures put into practice in the Danish health-care system. For the implementation of the framework, four classes of monitoring variables can be named and defined: patient descriptors, performance-related indicators of knowledge, behaviour and outcomes. RESULTS: We reviewed the features of the framework when applied to historical, real-world data following the introduction of dabigatran in Denmark for the prophylactic treatment of patients with non-valvular atrial fibrillation. CONCLUSIONS: The application of the framework provided useful graphical displays and an opportunity for a statistical evaluation (interrupted time series analysis) of a regulatory intervention. © 2017 Commonwealth of Australia. Pharmacoepidemiology & Drug Safety © 2017 John Wiley & Sons, Ltd.