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Context: The role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes (T2D) and obesity is not fully understood., Objective: We investigate the association of cardiometabolic, diet, and lifestyle parameters on fasting and postprandial GLP-1 in people at risk of, or living with, T2D., Methods: We analyzed cross-sectional data from the two Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohorts, cohort 1 (n = 2127) individuals at risk of diabetes; cohort 2 (n = 789) individuals with new-onset T2D., Results: Our multiple regression analysis reveals that fasting total GLP-1 is associated with an insulin-resistant phenotype and observe a strong independent relationship with male sex, increased adiposity, and liver fat, particularly in the prediabetes population. In contrast, we showed that incremental GLP-1 decreases with worsening glycemia, higher adiposity, liver fat, male sex, and reduced insulin sensitivity in the prediabetes cohort. Higher fasting total GLP-1 was associated with a low intake of wholegrain, fruit, and vegetables in people with prediabetes, and with a high intake of red meat and alcohol in people with diabetes., Conclusion: These studies provide novel insights into the association between fasting and incremental GLP-1, metabolic traits of diabetes and obesity, and dietary intake, and raise intriguing questions regarding the relevance of fasting GLP-1 in the pathophysiology T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: In 2018, a grant was provided for an evidence-based guideline on osteoporosis and fracture prevention based on 10 clinically relevant questions., Methods: A multidisciplinary working group was formed with delegates from Dutch scientific and professional societies, including representatives from the patient's organization and the Dutch Institute for Medical Knowledge. The purpose was to obtain a broad consensus among all participating societies to facilitate the implementation of the updated guideline., Results: Novel recommendations in our guideline are as follows: - In patients with an indication for DXA of the lumbar spine and hips, there is also an indication for VFA. - Directly starting with anabolic drugs (teriparatide or romosozumab) in patients with a very high fracture risk; - Directly starting with zoledronic acid in patients 75 years and over with a hip fracture (independent of DXA); - Directly starting with parenteral drugs (denosumab, teriparatide, zoledronic acid) in glucocorticoid-induced osteoporosis with very high fracture risk; - A lifelong fracture risk management, including lifestyle, is indicated from the start of the first treatment., Conclusion: In our new multidisciplinary guideline osteoporosis and fracture prevention, we developed 5 "relatively new statements" that are all a crucial step forward in the optimization of diagnosis and treatment for fracture prevention. We also developed 5 flowcharts, and we suppose that this may be helpful for individual doctors and their patients in daily practice and may facilitate implementation., (© 2024. The Author(s).)

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX., Introduction: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD)., Methods: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted β-coefficients., Results: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination., Conclusion: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Aims/hypothesis: Inflammation is important in the development of type 2 diabetes complications. The N-glycosylation of IgG influences its role in inflammation. To date, the association of plasma IgG N-glycosylation with type 2 diabetes complications has not been extensively investigated. We hypothesised that N-glycosylation of IgG may be related to the development of complications of type 2 diabetes., Methods: In three independent type 2 diabetes cohorts, plasma IgG N-glycosylation was measured using ultra performance liquid chromatography (DiaGene n = 1815, GenodiabMar n = 640) and mass spectrometry (Hoorn Diabetes Care Study n = 1266). We investigated the associations of IgG N-glycosylation (fucosylation, galactosylation, sialylation and bisection) with incident and prevalent nephropathy, retinopathy and macrovascular disease using Cox- and logistic regression, followed by meta-analyses. The models were adjusted for age and sex and additionally for clinical risk factors., Results: IgG galactosylation was negatively associated with prevalent and incident nephropathy and macrovascular disease after adjustment for clinical risk factors. Sialylation was negatively associated with incident diabetic nephropathy after adjustment for clinical risk factors. For incident retinopathy, similar associations were found for galactosylation, adjusted for age and sex., Conclusions: We showed that IgG N-glycosylation, particularly galactosylation and to a lesser extent sialylation, is associated with a higher prevalence and future development of macro- and microvascular complications of diabetes. These findings indicate the predictive potential of IgG N-glycosylation in diabetes complications and should be analysed further in additional large cohorts to obtain the power to solidify these conclusions., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Background: Premature atrial contractions (PACs) are potential markers for imminent onset of both atrial fibrillation (AF) and brain ischemia (BI; transient ischemic attack [TIA] or ischemic stroke). We investigated the association of PACs with incident AF and BI events separately, and of incident AF with BI events in people with type 2 diabetes (T2D) without pre-existing AF or cerebrovascular disease., Methods: A prospective longitudinal study of 12,242 people with T2D without known AF or cerebrovascular disease from the Hoorn Diabetes Care System cohort. Annual measurements (1998-2018) included cardiovascular risk factors, over 85,000 ECGs, and self-reported cardiovascular events. We assessed the association of PACs with incident AF and BI events and of incident AF with BI events using time-dependent Cox-regression models, adjusted for time-varying cardiovascular risk factors and medication use (Hazard Ratios with 95%CIs)., Results: The baseline mean age was 62.2 ± 11.9 years. During a median follow-up of 7.0 (IQR 3.4-11.0) years, 1031 (8.4 %) participants had PACs, and 566 (4.6 %) had incident AF at any of the median 6 (IQR 3-10) annual ECG recordings. BI events occurred in 517 (4.2 %) people (304 TIAs, 213 ischemic strokes). After adjustment, PACs were associated with incident AF (Hazard Ratio, 1.96 (95%CI, 1.53-2.50)), but not with overall BI events (1.09 (0.76-1.56)), or with TIA (0.91 (0.57-1.46)) or ischemic stroke (1.50 (0.88-2.54)) separately. AF was not associated with BI events (0.95 (0.55-1.63))., Conclusions: In people with T2D without a history of AF or BI events, PACs are associated with a two-fold increased risk of incident AF., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Microvascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association., Methods: We recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified., Results: Mean age was 67 ± 6y, mean HbA1c 7.6 ± 1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34-165 vs. 46, 27-117 pg/ml) and E/E'(13.3 ± 4.3 vs. 11.4 ± 3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers., Conclusions: Impaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The COVID-19 pandemic has a large impact worldwide and is known to particularly affect the older population. This paper outlines the protocol for external validation of prognostic models predicting mortality risk after presentation with COVID-19 in the older population. These prognostic models were originally developed in an adult population and will be validated in an older population (≥ 70 years of age) in three healthcare settings: the hospital setting, the primary care setting, and the nursing home setting., Methods: Based on a living systematic review of COVID-19 prediction models, we identified eight prognostic models predicting the risk of mortality in adults with a COVID-19 infection (five COVID-19 specific models: GAL-COVID-19 mortality, 4C Mortality Score, NEWS2 + model, Xie model, and Wang clinical model and three pre-existing prognostic scores: APACHE-II, CURB65, SOFA). These eight models will be validated in six different cohorts of the Dutch older population (three hospital cohorts, two primary care cohorts, and a nursing home cohort). All prognostic models will be validated in a hospital setting while the GAL-COVID-19 mortality model will be validated in hospital, primary care, and nursing home settings. The study will include individuals ≥ 70 years of age with a highly suspected or PCR-confirmed COVID-19 infection from March 2020 to December 2020 (and up to December 2021 in a sensitivity analysis). The predictive performance will be evaluated in terms of discrimination, calibration, and decision curves for each of the prognostic models in each cohort individually. For prognostic models with indications of miscalibration, an intercept update will be performed after which predictive performance will be re-evaluated., Discussion: Insight into the performance of existing prognostic models in one of the most vulnerable populations clarifies the extent to which tailoring of COVID-19 prognostic models is needed when models are applied to the older population. Such insight will be important for possible future waves of the COVID-19 pandemic or future pandemics., (© 2023. The Author(s).)

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures., Introduction: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors., Methods: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible., Results: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed., Conclusions: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266))., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Objective: Area-level socioeconomic factors are known to associate with chances to survive out-of-hospital cardiac arrest (OHCA survival). However, the relationship between individual-level socioeconomic factors and OHCA survival in men and women is less established. This study investigated the association between individual-level income and OHCA survival in men and women, as well as its contribution to outcome variability and mediation by resuscitation characteristics., Methods: A cross-sectional cohort study using data from a Dutch community-based OHCA registry was performed. We included 5395 patients aged≥25 years with OHCA from a presumed cardiac cause. Household income, derived from Statistics Netherlands, was stratified into quartiles. The association between survival to hospital discharge and household income was analysed using multivariable logistic regression adjusting for age, sex and resuscitation characteristics., Results: Overall women had lower household income than men (median €18 567 vs €21 015), and less favourable resuscitation characteristics. Increasing household income was associated with increased OHCA survival in both men and women in a linear manner (Q4 vs Q1: OR 1.63 95% CI (1.24 to 2.16) in men, and 2.54 (1.43 to 4.48) in women). Only initial rhythm significantly changed the ORs for OHCA survival with>10% in both men and women. Household income explained 3.8% in men and 4.3% in women of the observed variance in OHCA survival., Conclusion: Both in men and women, higher individual-level household income was associated with a 1.2-fold to 2.5-fold increased OHCA survival to hospital discharge, but explained only little of outcome variability. A shockable initial rhythm was the most important resuscitation parameter mediating this association. Our results do not support the need for immediate targeted interventions on actionable prehospital resuscitation care characteristics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Aims: Valid health economic models are essential to inform the adoption and reimbursement of therapies for diabetes mellitus. Often existing health economic models are applied in other countries and settings than those where they were developed. This practice requires assessing the transferability of a model developed from one setting to another. We evaluate the transferability of the MICADO model, developed for the Dutch 2007 setting, in two different settings using a range of adjustment steps. MICADO predicts micro- and macrovascular events at the population level., Methods: MICADO simulation results were compared to observed events in an Italian 2000-2015 cohort (Casale Monferrato Survey [CMS]) and in a Dutch 2008-2019 (Hoorn Diabetes Care Center [DCS]) cohort after adjusting the demographic characteristics. Additional adjustments were performed to: (1) risk factors prevalence at baseline, (2) prevalence of complications, and (3) all-cause mortality risks by age and sex. Model validity was assessed by mean average percentage error (MAPE) of cumulative incidences over 10 years of follow-up, where lower values mean better accuracy., Results: For mortality, MAPE was lower for CMS compared to DCS (0.38 vs. 0.70 following demographic adjustment) and adjustment step 3 improved it to 0.20 in CMS, whereas step 2 showed best results in DCS (0.65). MAPE for heart failure and stroke in DCS were 0.11 and 0.22, respectively, while for CMS was 0.42 and 0.41., Conclusions: The transferability of the MICADO model varied by event and per cohort. Additional adjustments improved prediction of events for MICADO. To ensure a valid model in a new setting it is imperative to assess the impact of adjustments in terms of model accuracy, even when this involves the same country, but a new time period., (© 2022. The Author(s).)

Introduction: Benefits and risks of preventive medication change over time for ageing patients and deprescribing of medication may be needed. Deprescribing of cardiovascular and antidiabetic drugs can be challenging and is not widely implemented in daily practice., Objective: The aim of this study was to identify barriers and enablers of deprescribing cardiometabolic medication as seen by healthcare providers (HCPs) of different disciplines, and to explore their views on their specific roles in the process of deprescribing., Methods: Three focus groups with five general practitioners, eight pharmacists, three nurse practitioners, two geriatricians, and two elder care physicians were conducted in three cities in The Netherlands. Interviews were recorded and transcribed verbatim. Directed content analysis was performed on the basis of the Theoretical Domains Framework. Two researchers independently coded the data., Results: Most HCPs agreed that deprescribing of cardiometabolic medication is relevant but that barriers include lack of evidence and expertise, negative beliefs and fears, poor communication and collaboration between HCPs, and lack of resources. Having a guideline was considered an enabler for the process of deprescribing of cardiometabolic medication. Some HCPs feared the consequences of discontinuing cardiovascular or antidiabetic medication, while others were not motivated to deprescribe when the patients experienced no problems with their medication. HCPs of all disciplines stated that adequate patient communication and involving the patients and relatives in the decision making enables deprescribing. Barriers to deprescribing included the use of medication initiated by specialists, the poor exchange of information, and the amount of time it takes to deprescribe cardiometabolic medication. The HCPs were uncertain about each other's roles and responsibilities. A multidisciplinary approach including the pharmacist and nurse practitioner was seen as the best way to support the process of deprescribing and address barriers related to resources., Conclusion: HCPs recognized the importance of deprescribing cardiometabolic medication as a medical decision that can only be made in close cooperation with the patient. To successfully accomplish the process of deprescribing they strongly recommended a multidisciplinary approach., (© 2022. The Author(s).)

The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments., Competing Interests: The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. M.I.C. has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global; has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly; and has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.C. is an employee of Genentech and a holder of Roche stock. S.B. is holder of stock in Intomics, Hoba Therapeutics, Novo Nordisk, and Lundbeck and holds managing board memberships in Proscion and Intomics., (© 2021 The Authors.)

This study aimed to evaluate the diagnostic performance of echocardiographic markers of heart failure with preserved ejection fraction (HFpEF) and left ventricular diastolic dysfunction (LVDD) in comparison with the gold standard of cardiac catheterization. Diagnosing HFpEF is challenging, as symptoms are non-specific and often absent at rest. A clear need exists for sensitive echocardiographic markers to diagnose HFpEF. We systematically searched for studies testing the diagnostic value of novel echocardiographic markers for HFpEF and LVDD. Two investigators independently reviewed the studies and assessed the risk of bias. Results were meta-analysed when four or more studies reported a similar diagnostic measure. Of 353 studies, 20 fulfilled the eligibility criteria. The risk of bias was high especially in the patients' selection domain. The highest diagnostic performance was demonstrated by a multivariable model combining echocardiographic, clinical and arterial function markers with an area under the curve of 0.95 (95% CI, 0.89-0.98). A meta-analysis of four studies indicated a reasonable diagnostic performance for left atrial strain with an AUC of 0.83 (0.70-0.95), a specificity of 93% (95% CI, 90-97%) and a sensitivity of 77% (95% CI, 59-96%). Moreover, the addition of exercise E/e' improved the sensitivity of HFpEF diagnostic algorithms up to 90%, compared with 60 and 34% of guidelines alone. Despite the heterogeneity of the included studies, this review supported the current multivariable-based approach for the diagnosis of HFpEF and LVDD and showed a potential diagnostic role for exercise echocardiography and left atrial strain. Larger well-designed studies are needed to evaluate the incremental value of novel diagnostic tools to current diagnostic algorithms., (© 2020. The Author(s).)

Aim: This study aimed to determine whether patients suffering from out-of-hospital cardiac arrest (OHCA) with a pre-OHCA diagnosis of heart disease have higher survival chances than patients without such a diagnosis and to explore possible underlying mechanisms., Methods: A retrospective cohort study in 3760 OHCA patients from the Netherlands (2010-2016) was performed. Information from emergency medical services, treating hospitals, general practitioner, resuscitation ECGs and civil registry was used to assess medical histories and the presence of pre-OHCA diagnosis of heart disease. We used multivariable regression analysis to calculate associations with survival to hospital admission or discharge, immediate causes of OHCA (acute myocardial infarction (AMI) vs non-AMI) and initial recorded rhythm., Results: Overall, 48.1% of OHCA patients had pre-OHCA heart disease. These patients had higher odds to survive to hospital admission than patients without pre-OHCA heart disease (OR 1.25 (95%CI 1.05 to 1.47)), despite being older and more often having cardiovascular risk factors and some non-cardiac comorbidities. These patients also had higher odds of shockable initial rhythm (SIR) (OR 1.60 (1. 36 to 1.89)) and a lower odds of AMI as immediate cause of OHCA (OR 0.33 (0.25 to 0.42)). Their chances of survival to hospital discharge were not significantly larger (OR 1.16 (0.95 to 1.42))., Conclusion: Having pre-OHCA diagnosed heart disease is associated with better odds to survive to hospital admission, but not to hospital discharge. This is associated with higher odds of a SIR and in a subgroup with available diagnosis a lower proportion of AMI as immediate cause of OHCA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic ( N = 12,828), metabolomic ( N = 2,945), lipidomic ( N = 2,593), and proteomic ( N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease., (© 2021 by the American Diabetes Association.)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors include a relatively new class of glucose-lowering drugs that reduce plasma glucose concentrations by inhibiting proximal tubular reabsorption of glucose in the kidney, while increasing its excretion in urine. Recent large randomised controlled trials have demonstrated that many of these agents reduce the occurrence of major adverse cardiovascular events, hospitalisation for heart failure, cardiovascular death and/or chronic kidney disease progression in patients with and without type 2 diabetes mellitus (DM2). Given their unique insulin-independent mode of action and favourable efficacy and adverse-event profile, SGLT2 inhibitors are promising and they offer an interesting therapeutic approach for the cardiologist to incorporate into routine practice. However, despite accumulating data supporting this class of therapy, cardiologists infrequently prescribe SGLT2 inhibitors, potentially due to a lack of familiarity with their use and the reticence to change DM medication. Here, we provide an up-to-date practical guide highlighting important elements of treatment initiation based on real-world evidence and expert opinion. We describe how to change DM medication, including insulin dosing when appropriate, and how to anticipate any adverse events based on real-world experience in patients with DM2 in the Meander Medical Centre in Amersfoort, the Netherlands. This includes a simple algorithm showing how to initiate SGLT2 inhibitor treatment safely, while considering the consequence of the glucosuric effects of these inhibitors for the individual patient., (© 2021. The Author(s).)

Objective: Out-of-hospital cardiac arrest (OHCA) occurrence has been shown to exhibit a circadian rhythm, following the circadian rhythm of acute myocardial infarction (AMI) occurrence. Diabetes mellitus (DM) is associated with changes in circadian rhythm. We aimed to compare the temporal variation of OHCA occurrence over the day and week between OHCA patients with DM and those without., Methods: In two population-based OHCA registries (Amsterdam Resuscitation Studies [ARREST] 2010-2016, n  = 4163, and Danish Cardiac Arrest Registry [DANCAR], 2010-2014, n  = 12,734), adults (≥18y) with presumed cardiac cause of OHCA and available medical history were included. Single and double cosinor analysis was performed to model circadian variation of OHCA occurrence. Stratified analysis of circadian variation was performed in patients with AMI as immediate cause of OHCA., Results: DM patients (22.8% in ARREST, 24.2% in DANCAR) were older and more frequently had cardiovascular risk factors or previous cardiovascular disease. Both cohorts showed 24 h-rhythmicity, with significant amplitudes in single and double cosinor functions ( P -range < 0.001). In both registries, a morning peak (10:00-11:00) and an evening peak (20:00-21:00) was observed in both DM and non-DM patients. No septadian variation was observed in either DM or non-DM patients ( P -range 0.13-84)., Conclusions: In these two population-based OHCA registries, we observed a similar circadian rhythm of OHCA occurrence in DM and non-DM patients., (© 2021 The Authors.)

Objectives: To assess the interobserver agreement in categories of electrocardiogram (ECG) abnormalities using the Minnesota Code criteria., Methods: We used a random sample of 180 ECGs from people with type 2 diabetes. ECG abnormalities were classified and coded using the Minnesota ECG Classification. Each ECG was independently rated on several abnormalities by an experienced rater (rater 1) and by two cardiologists (raters 2 and 3) trained to apply the Minnesota codes on four Minnesota codes; 1-codes as an indication for myocardial infarction, 4 en 5-codes as an indication for ischemic abnormalities, 3-codes as an indication for left ventricle hypertrophy, 7-1-codes as an indication for ventricular conduction abnormalities, and 8-3-codes as an indication for atrial fibrillation / atrial flutter. After all pairwise tables were summed, the overall agreement, the specific positive and negative agreement were calculated with a 95% confidence interval (CI) for each abnormality. Also, Kappa's with a 95% CI were calculated., Results: The overall agreement (with 95% CI) were for myocardial infarction, ischemic abnormalities, left ventricle hypertrophy, conduction abnormalities and atrial fibrillation/atrial flutter respectively: 0.87 (0.84-0.91), 0.79 (0.74-0.84), 0.81 (0.76-0.85), 0.93 (0.90-0.95), 0.96 (0.93-0.97)., Conclusion: This study shows that the overall agreement of the Minnesota code is good to excellent., Competing Interests: No authors have competing interests

Objective: To explore factors that potentially impact external validation performance while developing and validating a prognostic model for hospital admissions (HAs) in complex older general practice patients., Study Design and Setting: Using individual participant data from four cluster-randomised trials conducted in the Netherlands and Germany, we used logistic regression to develop a prognostic model to predict all-cause HAs within a 6-month follow-up period. A stratified intercept was used to account for heterogeneity in baseline risk between the studies. The model was validated both internally and by using internal-external cross-validation (IECV)., Results: Prior HAs, physical components of the health-related quality of life comorbidity index, and medication-related variables were used in the final model. While achieving moderate discriminatory performance, internal bootstrap validation revealed a pronounced risk of overfitting. The results of the IECV, in which calibration was highly variable even after accounting for between-study heterogeneity, agreed with this finding. Heterogeneity was equally reflected in differing baseline risk, predictor effects and absolute risk predictions., Conclusions: Predictor effect heterogeneity and differing baseline risk can explain the limited external performance of HA prediction models. With such drivers known, model adjustments in external validation settings (eg, intercept recalibration, complete updating) can be applied more purposefully., Trial Registration Number: PROSPERO id: CRD42018088129., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To describe the prevalence and characteristics of polypharmacy in a Dutch cohort of individuals with type 2 diabetes., Methods: We included people with type 2 diabetes from the Diabetes Pearl cohort, of whom 3886 were treated in primary care and 2873 in academic care (secondary/tertiary). With multivariable multinomial logistic regression analyses stratified for line of care, we assessed which sociodemographic, lifestyle and cardiometabolic characteristics were associated with moderate (5-9 medications) and severe polypharmacy (≥10 medications) compared with no polypharmacy (0-4 medications)., Results: Mean age was 63 ± 10 years, and 40% were women. The median number of daily medications was 5 (IQR 3-7) in primary care and 7 (IQR 5-10) in academic care. The prevalence of moderate and severe polypharmacy was 44% and 10% in primary care, and 53% and 29% in academic care respectively. Glucose-lowering and lipid-modifying medications were most prevalent. People with severe polypharmacy used a relatively large amount of other (i.e. non-cardiovascular and non-glucose-lowering) medication. Moderate and severe polypharmacy across all lines of care were associated with higher age, low educational level, more smoking, longer diabetes duration, higher BMI and more cardiovascular disease., Conclusions: Severe and moderate polypharmacy are prevalent in over half of people with type 2 diabetes in primary care, and even more in academic care. People with polypharmacy are characterized by poorer cardiometabolic status. These results highlight the significance of polypharmacy in type 2 diabetes., (© 2020 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aim: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration., Methods: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months., Results: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (β = 0.36, 95% CI 0.13-0.58), Subgroup 3 (β = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (β = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months., Conclusions: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified., (© 2020 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Objective: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D)., Research Design and Methods: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA 1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression., Results: Faster HbA 1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles ( R 2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role., Conclusions: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression., (© 2020 by the American Diabetes Association.)

Aims: The American Diabetes Association, and the joint European Society of Cardiology and European Association for the Study of Diabetes guidelines recommend a resting ECG in people with type 2 diabetes with hypertension or suspected cardiovascular disease (CVD). However, knowledge on the prevalence of ECG abnormalities is incomplete. We aimed to analyse the prevalence of ECG abnormalities and their cross-sectional associations with cardiovascular risk factors in people with type 2 diabetes., Methods: We used data of the Diabetes Care System cohort obtained in 2018. ECG abnormalities were defined using the Minnesota Classification and categorised into types of abnormalities. The prevalence was calculated for the total population (n = 8068) and the subgroup of people without a history of CVD (n = 6494). Logistic regression models were used to asses cross-sectional associations., Results: Approximately one-third of the total population had minor (16.0%) or major (13.1%) ECG abnormalities. Of the participants without a CVD history, approximately one-quarter had minor (14.9%) or major (9.1%) ECG abnormalities, and for those with hypertension or very high CVD risk, the prevalence was 27.5% and 39.6%, respectively. ECG abnormalities were significantly and consistently associated with established CVD risk factors., Conclusions: Resting ECG abnormalities are common in all people with type 2 diabetes (29.1%), including those without a history of CVD (24.0%), and their prevalence is related to traditional cardiovascular risk factors such as older age, male sex, hypertension, lower HDL cholesterol, higher BMI, and smoking behaviour., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A low vitamin D and K status has been associated with increased cardiovascular disease (CVD) risk but the evidence of their combined effect on cardiovascular health is limited., Objectives: Our study aimed to investigate the prospective association of vitamin D and K status with subclinical measures of cardiovascular health and all-cause mortality among a population of Dutch Caucasians., Methods: We performed an observational prospective study on 601 participants of the Hoorn Study (mean ± SD age: 70 ± 6 y, 50.4% women, BMI: 27.2 ± 4.0 kg/m2), of whom 321 underwent an echocardiogram in 2000-2001 and 2007-2009. Vitamin D and K status was assessed at baseline by serum 25-hydroxyvitamin D [25(OH)D] and plasma desphospho-uncarboxylated matrix-gla protein (dp-ucMGP)-high concentrations indicate low vitamin K status. Vital status was assessed from baseline until 2018. We studied the association of categories of 25(OH)D (stratified by the clinical cutoff of 50 mmol/L) and dp-ucMGP (stratified by the median value of 568 pmol/L) with echocardiographic measures using linear regression and with all-cause mortality using Cox regression, adjusted for confounders., Results: Compared with markers of normal vitamin D and K status, markers of low vitamin D and K status were prospectively associated with increased left ventricular mass index (5.9 g/m2.7; 95% CI: 1.8, 10.0 g/m2.7). Participants with low vitamin D and K status were also at increased risk of all-cause mortality with an HR of 1.64 (95% CI: 1.12, 2.39) compared with normal vitamin D and K status., Conclusions: A combination of low vitamin D and K status is associated with adverse cardiac remodeling and increased risk of all-cause mortality in men and women. Future studies should investigate whether vitamin D and K supplementation could help to improve cardiovascular health and to decrease CVD risk., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Society for Nutrition.)

Aim: Subclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D., Methods: The study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders., Results: At baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1-3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18-1.92) for subgroup 2 and 1.88 (-0.08-3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose., Conclusions: Different glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk., Competing Interests: The authors have read the journal’s policy and have the following competing interests: IP is employed by Eli Lilly Regional Operations GmbH, Vienna, Austria and BJ and HR are employees of Sanofi-Aventis Deutschland GmbH, R&D, Frankfurt am Main, Germany. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Aims/hypothesis: In this study we examined the cost-effectiveness of three different screening strategies for diabetic retinopathy: using a personalised adaptive model, annual screening (fixed intervals), and the current Dutch guideline (stratified based on previous retinopathy grade)., Methods: For each individual, optimal diabetic retinopathy screening intervals were determined, using a validated risk prediction model. Observational data (1998-2017) from the Hoorn Diabetes Care System cohort of people with type 2 diabetes were used (n = 5514). The missing values of retinopathy grades were imputed using two scenarios of slow and fast sight-threatening retinopathy (STR) progression. By comparing the model-based screening intervals to observed time to develop STR, the number of delayed STR diagnoses was determined. Costs were calculated using the healthcare perspective and the societal perspective. Finally, outcomes and costs were compared for the different screening strategies., Results: For the fast STR progression scenario, personalised screening resulted in 11.6% more delayed STR diagnoses and €11.4 less costs per patient compared to annual screening from a healthcare perspective. The personalised screening model performed better in terms of timely diagnosis of STR (8.8% less delayed STR diagnosis) but it was slightly more expensive (€1.8 per patient from a healthcare perspective) than the Dutch guideline strategy., Conclusions/interpretation: The personalised diabetic retinopathy screening model is more cost-effective than the Dutch guideline screening strategy. Although the personalised screening strategy was less effective, in terms of timely diagnosis of STR patients, than annual screening, the number of delayed STR diagnoses is low and the cost saving is considerable. With around one million people with type 2 diabetes in the Netherlands, implementing this personalised model could save €11.4 million per year compared with annual screening, at the cost of 658 delayed STR diagnoses with a maximum delayed time to diagnosis of 48 months.

Purpose: In this study, we investigated the association between adherence to the Dutch Healthy Diet index 2015 (DHD15-index) and incidence of prediabetes (preT2D) and Type 2 Diabetes (T2D) in a representative sample for the general Dutch population., Methods: Two prospective cohort studies, The Hoorn and The New Hoorn Study, were used for data analyses. In total, data from 2951 participants without diabetes at baseline (mean age 56.5 ± 7.5 years; 49.6% male) were harmonized. Baseline dietary intake was assessed with validated Food Frequency Questionnaires and adherence to the DHD15-index was calculated (range 0-130). PreT2D and T2D were classified according to the WHO criteria 2011. Poisson regression was used to estimate prevalence ratios between participant scores on the DHD15-index and preT2D and T2D, adjusted for follow-up duration, energy intake, socio-demographic, and lifestyle factors. Change in fasting plasma glucose levels (mmol/L) over follow-up was analysed using linear regression analyses, additionally adjusted for baseline value., Results: During a mean follow-up of 6.3 ± 0.7 years, 837 participants developed preT2D and 321 participants developed T2D. The highest adherence to the DHD15-index was significantly associated with lower T2D incidence [model 3, PR T3vsT1 : 0.70 (0.53; 0.92), p trend  = 0.01]. The highest adherence to the DHD15-index pointed towards a lower incidence of preT2D [PR T3vsT1 : 0.87 (0.74; 1.03), p trend  = 0.11]. Higher adherence to the DHD15-index was not associated with change in fasting plasma glucose levels [β 10point : - 0.012 (- 0.034; 0.009)mmol/L]., Conclusion: The present study showed that the highest compared to the lowest adherence to the DHD15-index was associated with a lower T2D incidence, and pointed towards a lower incidence of preT2D. These results support the benefits of adhering to the guidelines in T2D prevention.

Aims: This study aimed to establish whether higher levels of glycated haemoglobin (HbA1c) are associated with increased sudden cardiac arrest (SCA) risk in non-diabetic individuals., Methods and Results: Case-control study in non-diabetic individuals (HbA1c < 6.5%) in the Netherlands. Cases were SCA patients with electrocardiogram (ECG)-documented ventricular fibrillation (VF, the predominant cause of SCA) and HbA1c measurements immediately after VF, prospectively included in September 2009-December 2012. Controls (up to 10 per case) were age/sex-matched non-SCA individuals, included in July 2006-November 2007. We studied 306 cases (56.4 ± 6.8 years, 79.1% male) and 1722 controls (54.0 ± 6.8 years, 64.8% male). HbA1c levels were higher in cases than in controls (5.8 ± 0.3% vs. 5.4 ± 0.3%, P < 0.001). The proportion of increased HbA1c (≥5.7%) was 63.1% in cases and 19.3% in controls (P < 0.001). Multivariate regression models indicated that increased HbA1c was associated with a > six-fold increased VF risk [adjusted odds ratio (ORadj) 6.74 (5.00-9.09)] and that 0.1% increase in HbA1c level was associated with 1.4-fold increase in VF risk, independent of concomitant cardiovascular risk factors. Increased VF risk at higher HbA1c is associated with acute myocardial infarction (MI) as cause of VF [OR 1.14 (1.04-1.24)], but the association between HbA1c and VF was similar in non-MI patients [OR 1.32 (1.21-1.44)] and MI patients [OR 1.47 (1.37-1.58)]., Conclusion: Among non-diabetic individuals, risk of VF increased with rising HbA1c levels, independent of concomitant cardiovascular disease. Future studies should establish whether HbA1c level may be used as biomarker to recognize individuals at risk for VF., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

This systematic review and meta-analysis showed a significant reduction of (major) osteoporotic fractures and hip fractures after screening using fracture risk assessment and bone densitometry compared with usual care. The results indicate that screening is effective for fracture risk reduction, especially hip fractures. To perform a systematic review and meta-analysis of population screening for high fracture risk on fracture prevention compared with usual care. MEDLINE and Embase were searched for studies published until June 20th 2019. Randomized studies were selected that screened for high fracture risk using at least bone densitometry, screened in a general population, provided subsequent treatment with anti-osteoporosis medication, had a usual care group as comparator, and had at least one fracture-related outcome (all fractures, (major) osteoporotic fractures, or hip fractures). The primary assessment was the hazard ratio (HR) for fracture-related outcomes. All-cause mortality was a secondary outcome. Random-effects models were used to estimate pooled HRs. We identified 1186 potentially eligible articles and included three randomized studies: the ROSE study, the SCOOP study, and the SOS with a total number of N = 42,009 participants. Respectively, 11%, 15%, and 18% of the participants in the intervention group started medication. Meta-analysis showed a statistically significant and clinically relevant reduction of osteoporotic fractures (HR = 0.95, 95% confidence interval (CI) = 0.89-1.00), major osteoporotic fractures (HR = 0.91; 95%CI = 0.84-0.98), and hip fractures (HR = 0.80; 95%CI = 0.71-0.91), but no reduction of all fractures (HR = 0.95; 95%CI = 0.89-1.02). The pooled HR for the secondary outcome all-cause mortality was 1.04 (95% CI = 0.95-1.14). Numbers needed to screen to prevent one fracture were 247 and 272 for osteoporotic fractures and hip fractures, respectively (corresponding to 113 and 124 performed bone densitometry examinations, and 25 and 28 persons being treated). This meta-analysis showed that population screening is effective to reduce osteoporotic fractures and hip fractures. Implementation of screening in older women should be considered as serious option to prevent osteoporotic fractures, especially hip fractures.

Introduction: The role of insufficient glucagon suppression after an oral load in the development of type 2 diabetes mellitus is unclear. The aim of this study was to examine the association between glucagon responses at baseline and fasting glucose levels 7 years later., Methods: Data of the Hoorn Meal Study were used, an observational cohort study among 121 persons without diabetes with a mean age of 61.1 ± 6.7 years and 50% being female. The glucagon response to an oral glucose tolerance test and mixed meal test was expressed as early and late incremental area under the curve. The association with change in fasting glucose levels at follow-up was assessed by linear regression analysis., Results: The early glucagon response following the mixed meal test was associated with an increase in fasting glucose levels of 0.18 mmol/L (95%-CI: 0.04-0.31, P = 0.01), per unit increase in the incremental area under the curve of glucagon, adjusted for confounders. No significant associations were observed for the late response after the mixed meal test or oral glucose tolerance test., Conclusions: Within a population without diabetes, relative lack of glucagon suppression early after a meal was associated with increased glucose levels over time, suggesting a role of insufficient glucagon suppression in the deterioration of glycaemic control., (© 2019 John Wiley & Sons Ltd.)

Objective: Social jetlag, a form of chronic circadian misalignment, has previously been associated with obesity in adults. We aimed to investigate the association between social jetlag and obesity-related characteristics in Dutch adolescents over a 1-year period., Methods: We analysed data of 83 adolescents, who were recruited from a Dutch cohort born between the years 1990 and 1993. At the age of 16 and 17y, we determined anthropometric measurements, body composition, physical activity, hours of television use, and self-reported sleep duration. Using linear regression models, we assessed the association between social jetlag, defined as more than a 1-hour difference between the midpoint of sleep during weekdays and weekend days, and body mass index (BMI), body fat percentage, and waist circumference at baseline and after one year. We corrected the analysis for sex, sleep, physical activity, and hours of television use., Results: At age 16y, we observed that social jetlag was highly prevalent, with only 13% of the adolescents reporting no social jetlag (≤1 h), whereas 29% and 58% reported a social jetlag of >1-2 h and ≥2 h. In a cross-sectional analysis, we observed at age 16y a significant higher BMI in the group with no social jetlag, compared to the group with >1- to 2-hour and ≥2-hour social jetlag after adjustment for sex (-0.81 kg/m 2 , 95% confidence interval = -3.1 to 1.4; and -2.09 kg/m 2 , 95% confidence interval = -4.1 to -0.1). This association remained significant after correction for the other possible confounders. No significant associations were observed between social jetlag at age 16y and changes in obesity-related characteristics over one year., Conclusion: Our pilot data showed that social jetlag is highly prevalent in adolescents, with social jetlag associated with a lower BMI; however, in this small group, social jetlag was not associated with changes in obesity-related characteristics over time., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We developed an externally validated simple prediction model to predict serum 25(OH)D levels < 30, < 40, < 50 and 60 nmol/L in older women with risk factors for fractures. The benefit of the model reduces when a higher 25(OH)D threshold is chosen., Introduction: Vitamin D deficiency is associated with increased fracture risk in older persons. General supplementation of all older women with vitamin D could cause medicalization and costs. We developed a clinical model to identify insufficient serum 25-hydroxyvitamin D (25(OH)D) status in older women at risk for fractures., Methods: In a sample of 2689 women ≥ 65 years selected from general practices, with at least one risk factor for fractures, a questionnaire was administered and serum 25(OH)D was measured. Multivariable logistic regression models with backward selection were developed to select predictors for insufficient serum 25(OH)D status, using separate thresholds 30, 40, 50 and 60 nmol/L. Internal and external model validations were performed., Results: Predictors in the models were as follows: age, BMI, vitamin D supplementation, multivitamin supplementation, calcium supplementation, daily use of margarine, fatty fish ≥ 2×/week, ≥ 1 hours/day outdoors in summer, season of blood sampling, the use of a walking aid and smoking. The AUC was 0.77 for the model using a 30 nmol/L threshold and decreased in the models with higher thresholds to 0.72 for 60 nmol/L. We demonstrate that the model can help to distinguish patients with or without insufficient serum 25(OH)D levels at thresholds of 30 and 40 nmol/L, but not when a threshold of 50 nmol/L is demanded., Conclusions: This externally validated model can predict the presence of vitamin D insufficiency in women at risk for fractures. The potential clinical benefit of this tool is highly dependent of the chosen 25(OH)D threshold and decreases when a higher threshold is used.

Background Implementation of clinical medication reviews in daily practice is scarcely evaluated. The Opti-Med intervention applied a structured approach with external expert teams (pharmacist and physician) to conduct medication reviews. The intervention was effective with respect to resolving drug related problems, but did not improve quality of life. Objective The objective of this process evaluation was to gain more insight into the implementation fidelity of the intervention. Setting Process evaluation alongside a cluster randomized trial in 22 general practices and 518 patients of 65 years and over. Method A mixed methods design using quantitative and qualitative data and the conceptual framework for implementation fidelity was used. Implementation fidelity is defined as the degree to which the various components of an intervention are delivered as intended. Main outcome measure Implementation fidelity for key components of the Opti-Med intervention. Results Patient selection and preparation of the medication analyses were carried out as planned, although mostly by the Opti-Med researchers instead of practice nurses. Medication analyses by expert teams were performed as planned, as well as patient consultations and patient involvement. 48% of the proposed changes in the medication regime were implemented. Cooperation between expert teams members and the use of an online decision-support medication evaluation facilitated implementation. Barriers for implementation were time constraints in daily practice, software difficulties with patient selection and incompleteness of medical files. The degree of embedding of the intervention was found to influence implementation fidelity. The total time investment for healthcare professionals was 94 min per patient. Conclusion Overall, the implementation fidelity was moderate to high for all key components of the Opti-Med intervention. The absence of its effectiveness with respect to quality of life could not be explained by insufficient implementation fidelity.

Both CC and CXC-class chemokines drive inflammatory disease. Tick salivary chemokine-binding proteins (CKBPs), or evasins, specifically bind subsets of CC- or CXC-chemokines, and could precisely target disease-relevant chemokines. Here we have used yeast surface display to identify two tick evasins: a CC-CKBP, P1243 from Amblyomma americanum and a CXC-CKBP, P1156 from Ixodes ricinus. P1243 binds 11 CC-chemokines with K d  < 10 nM, and 10 CC-chemokines with K d between 10 and 100 nM. P1156 binds two ELR + CXC-chemokines with K d  < 10 nM, and four ELR + CXC-chemokines with K d between 10 and 100 nM. Both CKBPs neutralize chemokine activity with IC 50  < 10 nM in cell migration assays. As both CC- and CXC-CKBP activities are desirable in a single agent, we have engineered "two-warhead" CKBPs to create single agents that bind and neutralize subsets of CC and CXC chemokines. These results show that tick evasins can be linked to create non-natural proteins that target subsets of CC and CXC chemokines. We suggest that "two-warhead" evasins, designed by matching the activities of parental evasins to CC and CXC chemokines expressed in disease, would achieve precision targeting of inflammatory disease-relevant chemokines by a single agent.

Aims: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA 1c levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA 1c levels in people with Type 2 diabetes in the Netherlands., Methods: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication., Results: In total, 3257 participants (59.8% men, mean 62.2±9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA 1c levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or -0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA 1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level., Conclusions: Partner's occupational status provided additional information on the association between socio-economic status and HbA 1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association., (© 2017 Diabetes UK.)

Non-adherence to antihypertensive medication is the most important cause of uncontrolled blood pressure and is influenced by multiple interrelating factors. Understanding the complexity of medication non-adherence and its associated factors is important to determine intervention strategies. Therefore, a systematic review was performed aimed to identify factors associated with antihypertensive medication non-adherence. Different databases were searched for observational studies reporting on factors associated with non-adherence to antihypertensive medication. Titles, abstracts and full texts were reviewed by three researchers. Subsequently, the methodological quality of each study was assessed. Factors that were extracted from the included studies were categorised as factors with consistent or inconsistent evidence to put their potential importance into perspective. Forty-four studies were included. Higher co-payment, side effects and a poor patient-provider relationship were identified as factors with consistent evidence since consistent significant relationships were found for these factors whenever studied. The relationships between non-adherence and multiple other factors were inconsistent among the reviewed studies. However, some of these factors deserve some consideration. Since multiple potentially relevant factors were identified, patient-tailored interventions focussing on identifying and addressing patients' specific barriers to adherence are needed. Further research should clarify the influence of inconsistent factors on adherence and their potential to be addressed in interventions.

Background: Several drugs have become available for the treatment of osteoporosis. However, screening and treatment of patients with a high fracture risk is currently not recommended in the Netherlands, because the effectiveness of bone sparing drugs has not been demonstrated in the general primary care population. Here we describe the design of the SALT Osteoporosis study, which aims to examine whether the screening and treatment of older, female patients in primary care can reduce fractures, in comparison to usual care., Methods: A randomised pragmatic trial has been designed using a stepwise approach in general care practices in the Netherlands. Women aged ≥65 years, who are not prescribed bone sparing drugs or corticosteroids are eligible for the study. First, women with at least one clinical risk factor for fractures, as determined by questionnaires, are randomly assigned to the intervention or control group. Second, women in the intervention group having a high fracture risk according to our screening program, including an adapted fracture risk assessment (FRAX) tool, combined with dual-energy x-ray absorptiometry (DXA), and instant vertebral assessment (IVA), are offered a structured treatment program. The women in the control group receive care as usual and will undergo the same screening as the intervention group at the end of the trial. The follow-up duration will be three years and the primary outcome is time to first incident fracture and the total number of fractures., Discussion: The results of the current study will be very important for underpinnings of the prevention strategy of the osteoporosis guidelines., Trial Registration: ID NTR2430 . Registered 26 July 2010.

Purpose: People with type 2 diabetes (T2D) have a doubled morbidity and mortality risk compared with persons with normal glucose tolerance. Despite treatment, clinical targets for cardiovascular risk factors are not achieved. The Hoorn Diabetes Care System cohort (DCS) is a prospective cohort representing a comprehensive dataset on the natural course of T2D, with repeated clinical measures and outcomes. In this paper, we describe the design of the DCS cohort., Participants: The DCS consists of persons with T2D in primary care from the West-Friesland region of the Netherlands. Enrolment in the cohort started in 1998 and this prospective dynamic cohort currently holds 12 673 persons with T2D., Findings to Date: Clinical measures are collected annually, with a high internal validity due to the centrally organised standardised examinations. Microvascular complications are assessed by measuring kidney function, and screening feet and eyes. Information on cardiovascular disease is obtained by 1) self-report, 2) electrocardiography and 3) electronic patient records. In subgroups of the cohort, biobanking and additional measurements were performed to obtain information on, for example, lifestyle, depression and genomics. Finally, the DCS cohort is linked to national cancer and all-cause mortality registers. A selection of published findings from the DCS includes identification of subgroups with distinct development of haemoglobin A1c, blood pressure and retinopathy, and their predictors; validation of a prediction model for personalised retinopathy screening; the assessment of the role of genetics in development and treatment of T2D, providing options for personalised medicine., Future Plans: We will continue with the inclusion of persons with newly diagnosed T2D, follow-up of persons in the cohort and linkage to morbidity and mortality registries. Currently, we are involved in (inter)national projects on, among others, biomarkers and prediction models for T2D and complications and we are interested in collaborations with external researchers., Trial Registration: ISRCTN26257579., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective . With depression being present in approximately 20% of people with type 2 diabetes mellitus (T2DM), we expect equally frequent prescription of antidepressants, anxiolytics, and hypnotics. Nevertheless, prescription data in people with T2DM is missing and the effect of depression on glycaemic control is contradictory. The aim of this study was to assess the prevalence of antidepressants, anxiolytics, and/or hypnotics use in a large, managed, primary care system cohort of people with T2DM and to determine the sociodemographic characteristics, comorbidities, T2DM medication, and metabolic control associated with its use. Method . The prevalence of antidepressants, anxiolytics, and/or hypnotics use in the years 2007-2012 was assessed in the Hoorn Diabetes Care System Cohort from the Netherlands. Results . From the 7016 people with T2DM, 500 people (7.1%) used antidepressants only, 456 people (6.5%) used anxiolytics and/or hypnotics only, and 254 people (3.6%) used a combination. Conclusion . We conclude that in our managed, primary care system 17% of all people with T2DM used antidepressants, anxiolytics, and/or hypnotics. Users of antidepressants, anxiolytics, and/or hypnotics were more often female, non-Caucasian, lower educated, and more often treated with insulin., Competing Interests: The authors declare that there are no competing interests regarding the publication of this paper.

Aims: To identify HbA1c trajectories after the start of insulin treatment and to identify clinically applicable predictors of the response to insulin therapy., Methods: The study population comprised 1203 people with Type 2 diabetes included in the Hoorn Diabetes Care System (n = 9849). Inclusion criteria were: age ≥ 40 years; initiation of insulin during follow-up after failure to reach HbA1c levels ≤ 53 mmol/mol (7%) with oral glucose-lowering agents; and a follow up ≥ 2 years after initiating insulin. Latent class growth modelling was used to identify trajectories of HbA1c . Subjects considered to be 'off target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during one-third or more of the follow-up time, and those considered to be 'on target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during less than one-third of the follow-up time., Results: Four HbA1c trajectories were identified. Most people (88.7%) were classified as having a stable HbA1c trajectory of ~57 mmol/mol (7.4%). Only 24.4% of the people were on target in response to insulin; this was associated with lower HbA1c levels and a higher age at the start of insulin treatment., Conclusions: Using latent class growth modelling, four HbA1c trajectories were identified. A quarter of the people starting insulin were on target. Low HbA1c levels and advanced age at the start of insulin therapy were associated with better response to insulin therapy. Initiating insulin earlier improves the likelihood of achieving and sustaining glycaemic control., (© 2016 Diabetes UK.)

Objectives: The objectives of this study were to determine the prevalence of carriage of ESBL-producing Enterobacteriaceae (ESBL-E) in a representative sample of the general adult Dutch community, to identify risk factors and to gain understanding of the epidemiology of these resistant strains., Methods: Adults enrolled in five general practices in Amsterdam were approached by postal mail and asked to fill in a questionnaire and to collect a faecal sample. Samples were analysed for the presence of ESBL-E. ESBL genes were characterized by PCR and sequencing. Strains were typed using MLST and amplified fragment length polymorphism (AFLP) and plasmids were identified by PCR-based replicon typing. Risk factors for carriage were investigated by multivariate analysis., Results: ESBL-E were found in 145/1695 (8.6%) samples; 91% were Escherichia coli. Most ESBL genes were of the CTX-M group (blaCTX-M-1 and blaCTX-M-15). MLST ST131 was predominant and mainly associated with CTX-M-15-producing E. coli. One isolate with reduced susceptibility to ertapenem produced OXA-48. In multivariate analyses, use of antimicrobial agents, use of antacids and travel to Africa, Asia and Northern America were associated with carriage of ESBL-E, in particular strains with blaCTX-M-14/15., Conclusions: This study showed a high prevalence of ESBL-E carriage in the general Dutch community. Also, outside hospitals, the use of antibiotics was a risk factor; interestingly, use of antacids increased the risk of carriage. A major risk factor in the general population was travel to countries outside Europe, in particular to Asia, Africa and Northern America., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Objective: To investigate the nature and prevalence of drug related problems (DRPs) in older patients with polypharmacy identified by community pharmacists in daily practice through means of a clinical medication review (CMR) and assess the implementation rate of proposed interventions to solve DRPs., Design: A cross-sectional study METHOD: We analysed the CMR data of 3,807 older patients (≥ 65 years) with polypharmacy (≥ 5 drugs) completed in January-August 2012. Using the "Service Apotheek Medicatie Review Tool" (SAMRT, Service Pharmacy Medication Review Tool), pharmacists in 258 community pharmacies registered the patients' year of birth, gender, dispensing data, DRPs, and proposed and implemented interventions., Results: Pharmacists identified a median of two DRPs (interquartile range 1-4; mean 3.0) per patient. The DRP categories overtreatment (25.5 %) and undertreatment (15.9 %) were found to occur most frequently. On average, 46.2 % of the proposed interventions to address DRPs were implemented as proposed. In 22.4 % of cases the intervention differed from the proposal, whereas in 31.3 % of cases no intervention was implemented., Conclusion: In daily practice, community pharmacists identified a mean of three DRPs in older patients with polypharmacy, a number comparable to that found in controlled studies. Over- or undertreatment caused nearly half of the identified DRPs. The majority (69.9%) of the proposed interventions led to an intervention for the patient.

Background: The role of the general practitioner (gp) in the treatment of severe psychiatric disorders, including bipolar disorder (bd), is under discussion., Aim: To investigate how many patients with a recognised bd are being treated for their illness exclusively in the setting of primary care and to find out how many patients are registrated as having bd on their gp's file., Method: We made an exploratory study in a gp's database containing data for 14,254 Dutch adult patients in the Amsterdam over a period of 3.5 years (2010-2013)., Results: We found that the gp was in charge of the treatment of bd in less than one patient per practice. The percentage of patients officially recognised as having bd in the database we studied was 0.15%, a percentage that is much lower than the percentage of bd in the Dutch population as a whole. There are several possible explanations for this discrepancy., Conclusion: Given these low numbers, it is unlikely that the gps can have adequate experience of giving their bd patients the latest type of treatment. In view of the increasing role played by gps in the treatment of bd, it is important that there is strong collaboration with specialised mental health care, and that a low threshold prevails for consultation and referral.

Objective: To describe the implementation and feasibility of the national healthcare guidelines on childhood obesity in a region with a high prevalence of overweight and obesity in children., Design: Descriptive, implementation study., Method: The implementation of the guidelines took place in the borough Amsterdam West. In total, 17 general practitioners (GP) from the Academic General Practice Network (ANH) of the VU University Medical Center, Amsterdam, participated in the study, along with 19 child healthcare practitioners and 3 paediatricians. A number of measures were taken to promote implementation. Feasibility was evaluated using both qualitative and quantitative methods., Results: The participating healthcare providers found the training in application of the guidelines and case study discussions useful. GPs found that their role as central caregiver was not feasible. All participants expressed a preference for child healthcare practitioners as the central caregiver. A total of 327 obese children were invited to attend the GP's surgery; only 65 of them participated in the study and only 28 children were monitored for a whole year. Collaboration agreements between involved healthcare providers were rarely fulfilled., Conclusion: Implementation of the national healthcare guidelines on childhood obesity in the current form appears not to be feasible in Amsterdam West, despite the many implementation-enhancing measures that were applied. It is questionable whether the national healthcare guidelines on childhood obesity in its current form can contribute to addressing the societal problem of overweight and obesity in children.

Background: In order to improve and optimize future behavioral family lifestyle intervention programs, more information on the perceptions of obese children and their parents of these programs is needed. As such, the aim of this qualitative study is 1) to explore the expectations of obese children and their parents in relation to lifestyle interventions; 2) to identify barriers to making lifestyle changes that parents and children face within their social context (within the family, at school and amongst friends and peers) as well as the things that facilitate these changes and 3) to identify the needs of obese children and their parents in the context of a lifestyle intervention., Methods: A qualitative study using semi-structured interviews was conducted. Interviewees were participants in a lifestyle intervention program in the Netherlands., Results: Eighteen children (mean age 10 years) and 24 parents were interviewed. The respondents expected to lose weight by being physically active or by eating healthily. Parents struggled with adopting and adhering to new rules and the absence of support of family members. Children struggled with inconsistent parenting and a lack of support from their parents. Bullying experienced at school impeded the children in their ability to make the necessary changes. Support from peers, on the other hand, stimulated their progress. Parents identified the need for the general practitioner to discuss overweight in a non-offensive way and to show an interest in the process of weight loss., Conclusions: Participants in a lifestyle behavior intervention program benefit from parental support and help from their (extended) family, peers and friends. They would also profit from the sustained involvement of their general practitioner in assisting in the maintenance of lifestyle behavior changes.

Unlabelled: The probability of initiating with anti-osteoporosis therapy increased from 7 % in 2000 to 46 % in 2010. This improvement was greater for patients over the age of 75 years. Men, those overweight, having dementia or exposed to antipsychotics, sedatives/hypnotics or opioid analgesics were significantly less likely to receive anti-osteoporosis drugs., Introduction: The objective of this study was to examine trends and determinants of anti-osteoporosis drug prescribing after hip fracture in the UK between 2000 and 2010., Methods: Data were extracted from the UK Clinical Practice Research Datalink for patients ≥50 years who had a first hip fracture between 2000 and 2010 and who did not currently (≤6 months prior) receive anti-osteoporosis drugs (bisphosphonates, strontium ranelate, parathyroid hormone, calcitonin and raloxifene) (n = 27,542). The cumulative incidence probability of being prescribed anti-osteoporosis drugs within 1 year after hip fracture was estimated by Kaplan-Meier life-table analyses. Determinants for treatment initiation were estimated by Cox proportional hazards models., Results: The probability of being prescribed any anti-osteoporosis drug after hip fracture increased from 7 % in 2000 to 46 % in 2010. This trend was more marked in patients ≥75 years. The increase in prescribing of anti-osteoporosis drugs was complemented by a similar increase in vitamin D/calcium provision. Cumulative incidence of receiving anti-osteoporosis therapy was greater at any given point in time in women (8 % in 2000, 51 % in 2010) compared to men (4 % in 2000, 34 % in 2010). In addition to male gender, multivariable Cox regression identified reduced likelihood of receiving anti-osteoporosis drugs for those being overweight, having dementia and exposed to psychotropic drugs (antipsychotics, sedatives/hypnotics) or opioid analgesics., Conclusion: Although the prescribing of anti-osteoporosis drugs after hip fracture has increased substantially since 2000, the overall rate remained inadequate, particularly in men. With the continuing increase in the absolute number of hip fractures, further research should be made into the barriers to optimise osteoporosis management.