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Background: Older patients with type 2 diabetes mellitus (T2D) have an increased risk of hypoglycaemic episodes when using sulphonylureas or insulin. In the Netherlands, guidelines exist for reducing glucose-lowering medication in older patients. However, evidence is lacking that a medication reduction in older patients can be safely pursued. Here, we will examine if promoting the deprescribing of insulin/sulphonylureas with a deprescribing programme (DPP) in general practice affects T2D-complications in older overtreated patients., Methods: We will perform a 1:1 cluster randomised controlled trial in 86 general practices in the Netherlands. The DPP will consist of education sessions with general practitioners and practice nurses about reducing glucose-lowering medication in older patients (≥ 70 years). Topics of the sessions include the necessity of deprescribing, tools to initiate deprescribing and strategies to discuss deprescribing with patients (shared decision making). The DPP further includes a support programme with practice visits. The study will employ a selection tool to identify possibly overtreated older patients from the electronic medical records of the general practitioner. Eligibility for enrolment in the study will be based on HbA1c targets indicated by the Dutch guidelines, which depend on age, diabetes duration, presence of frailty, and life expectancy. The control group will provide usual care. We aim to include 406 patients. The follow-up period will be 2 years. For the primary outcome, the effect of the DPP on T2D-complications will be assessed by counting the cumulative incidence of events related to under- and overtreatment in T2D as registered in the electronic medical records. We shall perform an intention-to-treat analysis and an analysis including only patients for whom deprescribing was initiated. The implementation of the DPP in general practice will be evaluated quantitatively and qualitatively using the Extended Normalisation Process Theory (ENPT) and the Reach, Efficacy - Adoption, Implementation and Maintenance (RE-AIM) model. Other secondary outcomes include quality of life, cognitive functioning, events related to overtreatment or undertreatment, biomarkers of health, amount of blood glucose-lowering medication prescriptions, and cost-effectiveness., Discussion: This study will provide insight into the safety and feasibility of a programme aimed at deprescribing sulphonylureas/insulin in older people with T2D who are treated in general practice., Trial Registration: ISRCTN Registry, ISRCTN50008265 , registered 09 March, 2023., (© 2024. The Author(s).)

Aims/hypothesis: Only a few studies reported the incidence of type 2 diabetes (T2D). Understanding recent trends in diabetes is vital for planning future diabetes care. This study updated national trends in the prevalence and incidence of type 2 diabetes (T2D) in the Netherlands from 2004-2020., Methods: The DIAbetes, MANagement and Treatment (DIAMANT) cohort was used. A cross-sectional design with yearly measurements for the study period was used. The prevalence was calculated by dividing the total number of people with T2D by the total number of all residents. The incidence was calculated by dividing new cases of T2D by the resident population at risk during the calendar year of interest., Results: Among men, the prevalence of T2D in the Netherlands increased from 2.3% in 2004 to 6.3% in 2020. Women's prevalence increased from 2.3% in 2004 to 5.3% in 2020. During 2005-2009, the incidence rate for both men and women was relatively stable Between 2010 and 2020, the incidence rate fell about 1.5 per 1000 in both men and women., Conclusion: From 2004-2020, the prevalence of T2D in the Netherlands more than doubled, with a decreasing incidence from 2010 onwards., Competing Interests: JO, KS and RH are PHARMO Institute for Drug Outcomes Research employees. This independent research institute performs financially supported studies for the government, related healthcare authorities, and several pharmaceutical companies. GN, MB and PE declare no conflict of interest., (© 2024 Overbeek et al.)

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to reduce the risk of cardiovascular complications, which largely drive diabetes' health and economic burdens. Trial results indicated that SGLT2i are cost effective. However, these findings may not be generalizable to the real-world target population. This study aims to evaluate the cost effectiveness of SGLT2i in a routine care type 2 diabetes population that meets Dutch reimbursement criteria using the MICADO model., Methods: Individuals from the Hoorn Diabetes Care System cohort (N = 15,392) were filtered to satisfy trial inclusion criteria (including EMPA-REG, CANVAS, and DECLARE-TIMI58) or satisfy the current Dutch reimbursement criteria for SGLT2i. We validated a health economic model (MICADO) by comparing simulated and observed outcomes regarding the relative risks of events in the intervention and comparator arm from three trials, and used the validated model to evaluate the long-term health outcomes using the filtered cohorts' baseline characteristics and treatment effects from trials and a review of observational studies. The incremental cost-effectiveness ratio (ICER) of SGLT2i, compared with care-as-usual, was assessed from a third-party payer perspective, measured in euros (2021 price level), using a discount rate of 4% for costs and 1.5% for effects., Results: From Dutch individuals with diabetes in routine care, 15.8% qualify for the current Dutch reimbursement criteria for SGLT2i. Their characteristics were significantly different (lower HbA1c, higher age, and generally more preexisting complications) than trial populations. After validating the MICADO model, we found that lifetime ICERs of SGLT2i, when compared with usual care, were favorable (< €20,000/QALY) for all filtered cohorts, resulting in an ICER of €5440/QALY using trial-based treatment effect estimates in reimbursed population. Several pragmatic scenarios were tested, the ICERs remained favorable., Conclusions: Although the Dutch reimbursement indications led to a target group that deviates from trial populations, SGLT2i are likely to be cost effective when compared with usual care., (© 2023. The Author(s).)

Background: Routinely collected clinical data based on electronic medical records could be used to define frailty., Aim: To estimate the ability of four potential frailty measures that use electronic medical record data to identify older patients who were frail according to their GP., Design and Setting: This retrospective cohort study used data from 36 GP practices in the Dutch PHARMO Data Network., Method: The measures were the Dutch Polypharmacy Index, Charlson Comorbidity Index (CCI), Chronic Disease Score (CDS), and Frailty Index. GPs' clinical judgement of patients' frailty status was considered the reference standard. Performance of the measures was assessed with the area under the receiver operating characteristic curve (AUC). Analyses were done in the total population and stratified by age and sex., Results: Of 31 511 patients aged ≥65 years, 3735 (11.9%) patients were classified as frail by their GP. The CCI showed the highest AUC (0.79, 95% confidence interval [CI] = 0.78 to 0.80), followed by the CDS (0.69, 95% CI = 0.68 to 0.70). Overall, the measures showed poorer performance in males and females aged ≥85 years than younger age groups (AUC 0.55-0.58 in females and 0.57-0.60 in males)., Conclusion: This study showed that of four frailty measures based on electronic medical records in primary care only the CCI had an acceptable performance to assess frailty compared with frailty assessments done by professionals. In the youngest age groups diagnostic performance was acceptable for all measures. However, performance declined with older age and was least accurate in the oldest age group, thereby limiting the use in patients of most interest., (© The Authors.)

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/objective: Prolonged heart rate-corrected QT interval (QTc) on the electrocardiogram (ECG) is maybe associated with the occurrence of cardiovascular diseases (CVD), but the evidence is inconsistent. Therefore, we investigated whether baseline prolongation of the QTc interval is associated with CVD morbidity and mortality and its subtypes and whether glucose tolerance modifies this association in a population-based cohort study with a mean follow-up of 10.8 years., Methods: We analyzed a glucose tolerance stratified sample (N = 487) from the longitudinal population-based Hoorn Study cohort (age 64 ± 7 years, 48% female). Cox regression was used to investigate the association between sex-specific baseline QTc quartiles and CVD morbidity and mortality. The risk was also estimated per 10 ms increase in QTc. All analyses were adjusted for age, sex, smoking status, systolic blood pressure, prevalent CVD, glucose tolerance status, hypertension and total cholesterol. In addition, stratified analyses were conducted for glucose tolerance status., Results: During a mean follow-up of 10.8 years, 351 CVD events were observed. The adjusted hazard ratios (95% CI) for each 10 ms increase in QTc interval were 1.06 (95% CI: 1.02-1.10) for CVD, 1.06 (95% CI: 0.97-1.15) for acute myocardial infarction, 1.07 (95% CI: 1.01-1.13) for stroke, 1.12 (95% CI: 1.06-1.19) for heart failure, 1.04 (95% CI: 0.96-1.12) for peripheral arterial disease and 1.01 (95% CI:0.95-1.08) for coronary heart disease. Glucose tolerance status did not modify the association (P > 0.2)., Conclusion/interpretation: Prolongation of the QTc interval is associated with morbidity and mortality due to general CVD. Glucose tolerance status did not modify these associations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sudden cardiac death is responsible for 10% to 20% of all deaths in Europe. The current study investigates how well the risk of sudden cardiac death can be predicted. To this end, we validated a previously developed prediction model for sudden cardiac death from the Atherosclerosis Risk in Communities study (USA)., Methods: Data from participants of the Copenhagen City Heart Study (CCHS) (n=9988) was used to externally validate the previously developed prediction model for sudden cardiac death. The model's performance was assessed through discrimination (C-statistic) and calibration by the Hosmer-Lemeshow goodness-of-fit (HL) statistics suited for censored data and visual inspection of calibration plots. Additional validation was performed using data from the Hoorn Study (N=2045), employing the same methods., Results: During ten years of follow-up of CCHS participants (mean age: 58.7 years, 56.2% women), 425 experienced SCD (4.2%). The prediction model showed good discrimination for sudden cardiac death risk (C-statistic: 0.81, 95% CI: 0.79-0.83). Calibration was robust (HL statistic: P=0.8). Visual inspection of the calibration plot showed that the calibration could be improved. Sensitivity was 89.8%, and specificity was 60.6%. The positive and negative predictive values were 10.1% and 99.2%. Model performance was similar in the Hoorn Study (C-statistic: 0.81, 95% CI: 0.77-0.85 and the HL statistic: 1.00)., Conclusion: Our study showed that the previously developed prediction model in North American adults performs equally well in identifying those at risk for sudden cardiac death in a general North-West European population. However, the positive predictive value is low., Competing Interests: Conflict of interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: To investigate the association of (changes in) electrocardiogram (ECG) abnormalities with incident major adverse cardiac events (MACE) in people with Type 2 diabetes (T2D) without pre-existing cardiovascular disease (CVD)., Methods and Results: A prospective longitudinal study of 11 993 people with T2D without known CVD from the Hoorn Diabetes Care System cohort. Annually repeated measurements (1998-2018), included cardiovascular risk factors, over 70 000 ECG, and self-reported cardiovascular events. ECG abnormalities were classified according to the Minnesota Classification as prolonged PR duration, prolonged QRS duration, left QRS-axis, QS pattern, ST-segment/T-wave abnormalities, or tall R-wave. The association of ECG abnormalities with MACEs was assessed using time-dependent Cox-regression models, adjusted for time-varying cardiovascular risk factors, and medication use [hazard ratios (HRs) with 95% confidence intervals (CIs)]. During a median follow-up of 6.6 (IQR, 3.1-10.7) years, 5445 (45.4%) of the participants had an ECG abnormality (prevalent or incident) at any of the median 6 (IQR, 3-10) annual ECG recordings, and 905 people (7.5%) had a MACE (529 coronary heart disease (CHD), 250 heart failure (HF), and 126 sudden cardiac arrest (SCA)). After adjustment, most ECG abnormalities were associated with HF: prolonged QRS duration [HR, 4.01 (95% CI, 2.67-6.03)], QS pattern [2.68 (0.85-8.49)], ST-segment/T-wave abnormalities [4.26 (2.67-6.80)], and tall R-wave [2.23 (1.33-3.76)]. Only QS pattern [2.69 (1.20-6.03)] and ST-segment/T-wave abnormalities [2.11 (1.48-3.02)] were associated with CHD. These associations were robust across age, sex, hypertension, or estimated CVD risk subgroups., Conclusion: In people with T2D without pre-existing CVD, ECG abnormalities related to decelerated conduction, ischaemia, and hypertrophy are predominantly early signs of emerging HF, while only abnormalities related to ischaemic disorders are signs of CHD., Competing Interests: Conflicts of interest: The authors had complete autonomy in the design, conduct, and reporting of the manuscript. The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Baseline diabetic retinopathy (DR) and risk of development of microalbuminuria, kidney function decline, and cardiovascular events (CVEs) in type 2 diabetes., Methods: Post-hoc analysis of the PRIORITY study including 1758 persons with type 2 diabetes and normoalbuminuria followed for a median of 2.5 (IQR: 2.0-3.0) years. DR diagnosis included non-proliferative and proliferative abnormalities, macular oedema, or prior laser treatment. Cox models were fitted to investigate baseline DR presence with development of persistent microalbuminuria (urinary albumin-creatinine ratio > 30 mg/g); chronic kidney disease (CKD) G3 (eGFR <60 ml/min/1.73m 2 ); and CVE. Models were adjusted for relevant risk factors., Results: At baseline, 304 (17.3 %) had DR. Compared to persons without DR, they were older (mean ± SD: 62.7 ± 7.7 vs 61.4 ± 8.3 years, p = 0.019), had longer diabetes duration (17.9 ± 8.4 vs. 10.6 ± 7.0 years, p < 0.001), and higher HbA 1c (62 ± 13 vs. 56 ± 12 mmol/mol, p < 0.001). The adjusted hazard ratios of DR at baseline for development of microalbuminuria (n = 197), CKD (n = 166), and CVE (n = 64) were: 1.50 (95%CI: 1.07, 2.11), 0.87 (95%CI: 0.56, 1.34), and 2.61 (95%CI: 1.44, 4.72), compared to without DR., Conclusions: Presence of DR in normoalbuminuric type 2 diabetes was associated with an increased risk of developing microalbuminuria and CVE, but not with kidney function decline., Competing Interests: Declaration of competing interest NT is a full-time employee of Novo Nordisk A/S. TWH has equity in Novo Nordisk A/S. ML has received research support from Boehringer Ingelheim, Bayer and Merck Sharp & Dohme, and lecture fees from AstraZeneca, Bayer and Boehringer Ingelheim. All fees are given to Holbaek hospital. FP has served as a consultant, on advisory boards or as educator for AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Sanofi, Mundipharma, MSD, Novartis, Amgen and has received research grants to institution from Novo Nordisk, Boehringer Ingelheim, Amgen and AstraZeneca. AO has received grants from Sanofi and consultancy or speaker fees or travel support from Advicciene, Astellas, Astrazeneca, Amicus, Amgen, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Menarini, Mundipharma, Kyowa Kirin, Alexion, Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk, Sysmex and Vifor Fresenius Medical Care Renal Pharma and is Director of the Catedra Mundipharma-UAM of diabetic kidney disease and the Catedra Astrazeneca-UAM of chronic kidney disease and electrolytes. HM is the cofounder and co-owner of Mosaiques Diagnostics GmbH. JS and PZ are employees of Mosaiques Diagnostics GmbH. MF-M has received speaker fees or support for medical meetings and research grants from AstraZeneca and Novo Nordisk and speaking fees from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Novartis, Baxter, and Sanofi-Aventis. IR has received honoraria for lectures of AstraZenec, Bayer, Boehringer Ingelheim, and Mundipharma. PR has received research support and personal fees from AstraZeneca, Bayer and Novo Nordisk, and personal fees from Astellas Pharma Inc., Bayer, Boehringer Ingelheim, Eli Lilly and Company, Gilead, Merck, Merck Sharp & Dohme, Mundipharma, Sanofi, and Vifor Pharma. All fees are given to Steno Diabetes Center Copenhagen. All other authors declare no competing interests that could be perceived as affecting the impartiality of the reported results., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Conflicting findings have described the association between prolonged heart rate-corrected QT interval (QTc) and cardiovascular disease., Aims: To identify articles investigating the association between QTc and cardiovascular disease morbidity and mortality, and to summarize the available evidence for the general and type 2 diabetes populations., Methods: A systematic search was performed in PubMed and Embase in May 2022 to identify studies that investigated the association between QTc prolongation and cardiovascular disease in both the general and type 2 diabetes populations. Screening, full-text assessment, data extraction and risk of bias assessment were performed independently by two reviewers. Effect estimates were pooled across studies using random-effect models., Results: Of the 59 studies included, 36 qualified for meta-analysis. Meta-analysis of the general population studies showed a significant association for: overall cardiovascular disease (fatal and non-fatal) (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.33-2.12; I 2 =69%); coronary heart disease (fatal and non-fatal) in women (HR 1.27, 95% CI 1.08-1.50; I 2 =38%; coronary heart disease (fatal and non-fatal) in men (HR 2.07, 95% CI 1.26-3.39; I 2 =78%); stroke (HR 1.59, 95% CI 1.29-1.96; I 2 =45%); sudden cardiac death (HR 1.60, 95% CI 1.14-2.25; I 2 =68%); and atrial fibrillation (HR 1.55, 95% CI 1.31-1.83; I 2 =0.0%). No significant association was found for cardiovascular disease in the type 2 diabetes population., Conclusion: QTc prolongation was associated with risk of cardiovascular disease in the general population, but not in the type 2 diabetes population., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: The increasing number of people with diabetes and the unclear long-term safety and effectiveness of newer and older blood-glucose-lowering treatments emphasize the need for more pharmaco-epidemiological studies in this field. A prospective, regularly updated cohort of people with diabetes would provide quick and up-to-date information regarding prevalence, treatment, safety and effectiveness. The current aim was to describe the design of the DIAbetes MANagement and Treatment (DIAMANT) cohort., Methods: The DIAMANT cohort is a population-based, dynamic, prospective cohort of persons with diabetes. It contains real-world data (RWD) from general practitioners (GP), including diagnoses, symptoms, examinations, communication to/from specialists and medication. Diabetes is defined as a recorded diabetes diagnosis or a prescription of drugs used in diabetes. The cohort is part of the national infrastructure of "Stichting Informatievoorziening voor Zorg en Onderzoek" (STIZON) and is linked to other data sources., Results: Currently, the cohort enables access to information of 89,883 patients in 2004 to 344,914 in 2020 (6% T1D, 84% T2D and 10% unclassified type of diabetes), with 193,931 participants still registered as being present in the GP practice (active) in 2020. The frequency of follow-up of persons with diabetes is practice dependent. The Dutch guidelines advise 2-4 contacts per year with a more extensive yearly check-up. The DIAMANT cohort is updated several times a year. Anonymised data from the DIAMANT cohort are available to researchers., Discussion: The DIAMANT cohort provides the opportunity to gain RWD insights into the treatment and outcomes among people with diabetes in daily general practice. The data can be enriched by established linkages to other data sources (eg, hospital data, the Perinatal Registry, the Cancer Registry). The DIAMANT cohort serves as a start of a national infrastructure to study, manage and provide personalised care in order to ultimately improve care and outcomes for people with diabetes., Competing Interests: J.O., K.S. and R.H. are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related health care authorities and several pharmaceutical companies. The authors report no other conflicts of interest in this work., (© 2022 Overbeek et al.)

Background: Many Muslims with diabetes choose to fast against medical advice during Ramadan, potentially increasing their risk of acute complications. Patients are often reluctant to disclose fasting to their health care providers, and their needs regarding Ramadan are not met in consultations. For healthcare professionals to provide patient-centred care, it is important to gain more insight into patients' decision-making process. This study therefore aims to explore how Muslims with diabetes decide whether to fast during Ramadan., Methods: A qualitative study was conducted consisting of 15 focus groups with Muslims with diabetes within a constructivist paradigm. Convenience sampling was used. All focus groups were transcribed verbatim and analyzed using Braun and Clarke's reflexive thematic analysis., Results: Four themes were found to be important in the decision on whether to fast: (1) values and beliefs concerning Ramadan, (2) experiences and emotions concerning Ramadan, (3) the perception of illness, and (4) advice from health care professionals, imams and family. Many participants indicated fasting against medical advice and trusting their subjective assessments on whether they could fast. Moreover, three main stages in the decision-making process for eventually refraining from fasting were identified: (1) the stage where positive experiences with fasting dominate, (2) the stage where one encounters challenges but their determination to fast prevails and (3) the stage where one decides to refrain from fasting after experiencing too many physical difficulties with fasting., Conclusions: Muslims with diabetes experience autonomy in their decisions on Ramadan fasting. The decision to refrain from fasting often resulted from a difficult and dynamic decision-making process and was often made after participants reached their physical limits. These findings highlight the importance of not only shared decision-making to empower patients to make well-informed decisions on Ramadan fasting but also pre-Ramadan diabetes education to help people with diabetes have a safe Ramadan., Competing Interests: The authors have declared that no competing interests exist.

Frail older people face a range of problems and risks that could undermine their ability to live safely at home. A comprehensive overview of these risks, from a multidimensional perspective, is currently lacking. This study aims to examine the prevalence of risks in multiple domains of life among frail older people living at home. We used cross-sectional data from 824 people aged 65 years and older, who received a comprehensive geriatric assessment (the interRAI Home Care [interRAI-HC]) between 2014 and 2018, as part of routine care from 25 general practices in the region of West-Friesland, the Netherlands. The interRAI-HC identifies amenable risks related to people's clinical conditions, functioning, lifestyle and behaviour, and social and physical environment. Descriptive statistics were used to examine population characteristics (age, gender, marital status, living arrangements and presence of chronic conditions) and prevalence of risks. Most common risks were related to people's clinical conditions (i.e cardio-respiratory health, urinary incontinence, pain), functioning (i.e. limitations in instrumental activities of daily living and mood) and social environment (i.e. limitations in informal care and social functioning). More than 80% of frail older people faced multiple risks, and often on multiple domains of life simultaneously. People experiencing multiple risks per person, and on multiple domains simultaneously, were more often widowed and living alone. The multidimensional character of risks among frail older people living at home implies that an integrated approach to care, comprising both health and social care, is necessary. Insight in the prevalence of these risks can give direction to care allocation decisions., (© 2020 The Authors. Health and Social Care in the Community published by John Wiley & Sons Ltd.)

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).)

Introduction: Although associations of total plasma N- glycome (TPNG) with type 2 diabetes have been reported, little is known on the role of TPNG in type 2 diabetes complications, a major cause of type 2 diabetes-related morbidity and mortality. Here, we assessed TPNG in relation to type 2 diabetes complications in subsamples of two Dutch cohorts using mass spectrometry (n=1815 in DiaGene and n=1518 in Hoorn Diabetes Care System)., Research Design and Methods: Blood plasma samples and technical replicates were pipetted into 96-well plates in a randomized manner. Peptide:N-glycosidase F (PNGase F) was used to release N- glycans, whereafter sialic acids were derivatized for stabilization and linkage differentiation. After total area normalization, 68 individual glycan compositions were quantified in total and were used to calculate 45 derived traits which reflect structural features of glycosylation. Associations of glycan features with prevalent and incident microvascular or macrovascular complications were tested in logistic and Cox regression in both independent cohorts and the results were meta-analyzed., Results: Our results demonstrated similarities between incident and prevalent complications. The strongest association for prevalent cardiovascular disease was a high level of bisection on a group of diantennary glycans (A2FS0B; OR=1.38, p=1.34×10 -11 ), while for prevalent nephropathy the increase in 2,6-sialylation on triantennary glycans was most pronounced (A3E; OR=1.28, p=9.70×10 -6 ). Several other TPNG features, including fucosylation, galactosylation, and sialylation, firmly demonstrated associations with prevalent and incident complications of type 2 diabetes., Conclusions: These findings may provide a glance on how TPNG patterns change before complications emerge, paving the way for future studies on prediction biomarkers and potentially disease mechanisms., Competing Interests: Competing interests: MW is inventor on a patent application on sialic acid derivatization by ethyl esterification. EM is employed by Genos. VD currently works at BioTherapeutics Analytical Development, Janssen Biologics BV. No other potential conflicts of interest relevant to this article were reported., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes., Design: Systematic review and external validation., Data Sources: PubMed and Embase., Eligibility Criteria: Studies describing the development of a model to predict the risk of nephropathy, applicable to people with type 2 diabetes., Methods: Screening, data extraction, and risk of bias assessment were done in duplicate. Eligible models were externally validated in the Hoorn Diabetes Care System (DCS) cohort (n=11 450) for the same outcomes for which they were developed. Risks of nephropathy were calculated and compared with observed risk over 2, 5, and 10 years of follow-up. Model performance was assessed based on intercept adjusted calibration and discrimination (Harrell's C statistic)., Results: 41 studies included in the systematic review reported 64 models, 46 of which were developed in a population with diabetes and 18 in the general population including diabetes as a predictor. The predicted outcomes included albuminuria, diabetic kidney disease, chronic kidney disease (general population), and end stage renal disease. The reported apparent discrimination of the 46 models varied considerably across the different predicted outcomes, from 0.60 (95% confidence interval 0.56 to 0.64) to 0.99 (not available) for the models developed in a diabetes population and from 0.59 (not available) to 0.96 (0.95 to 0.97) for the models developed in the general population. Calibration was reported in 31 of the 41 studies, and the models were generally well calibrated. 21 of the 64 retrieved models were externally validated in the Hoorn DCS cohort for predicting risk of albuminuria, diabetic kidney disease, and chronic kidney disease, with considerable variation in performance across prediction horizons and models. For all three outcomes, however, at least two models had C statistics >0.8, indicating excellent discrimination. In a secondary external validation in GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland), models developed for diabetic kidney disease outperformed those for chronic kidney disease. Models were generally well calibrated across all three prediction horizons., Conclusions: This study identified multiple prediction models to predict albuminuria, diabetic kidney disease, chronic kidney disease, and end stage renal disease. In the external validation, discrimination and calibration for albuminuria, diabetic kidney disease, and chronic kidney disease varied considerably across prediction horizons and models. For each outcome, however, specific models showed good discrimination and calibration across the three prediction horizons, with clinically accessible predictors, making them applicable in a clinical setting., Systematic Review Registration: PROSPERO CRD42020192831., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Dutch Diabetes Research foundation Fund, IMI-RHAPSODY, and ZorgInstitute Netherlands (Dutch Healthcare Institute) for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aim: To validate a previously developed model for prediction of diabetic retinopathy (DR) for personalised retinopathy screening in persons with type 1 diabetes., Methods: Retrospective medical data of persons with type 1 diabetes treated in an academic hospital setting were used for analysis. Sight-threatening retinopathy (STR) was defined as the presence of severe non-proliferative DR, proliferative DR or macular oedema. The presence and grade of retinopathy, onset of diabetes, systolic blood pressure, and levels of haemoglobin A 1c were used to calculate an individual risk estimate and personalised screening interval. In persons with STR, the occurrence was compared with the calculated date of screening. The model's predictive performance was measured using calibration and discrimination techniques., Results: Of the 268 persons included in our study, 24 (9.0%) developed STR during a mean follow-up of 4.6 years. All incidences of STR occurred after the calculated screening date. By applying the model, the mean calculated screening interval was 30.5 months, which is a reduction in screening frequency of 61% compared with annual screening and 21% compared with biennial screening. The discriminatory ability was good (Harrell's C-statistic=0.82, 95% CI 0.74 to 0.90), and calibration showed an overestimation of risk in persons who were assigned to a higher risk for STR., Conclusion: This validation study suggests that a screening programme based on the previously developed prediction model is safe and efficient. The use of a personalised screening frequency could improve cost-effectiveness of diabetic eye care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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

Aims/hypothesis: Approximately 25% of people with type 2 diabetes experience a foot ulcer and their risk of amputation is 10-20 times higher than that of people without type 2 diabetes. Prognostic models can aid in targeted monitoring but an overview of their performance is lacking. This study aimed to systematically review prognostic models for the risk of foot ulcer or amputation and quantify their predictive performance in an independent cohort., Methods: A systematic review identified studies developing prognostic models for foot ulcer or amputation over minimal 1 year follow-up applicable to people with type 2 diabetes. After data extraction and risk of bias assessment (both in duplicate), selected models were externally validated in a prospective cohort with a 5 year follow-up in terms of discrimination (C statistics) and calibration (calibration plots)., Results: We identified 21 studies with 34 models predicting polyneuropathy, foot ulcer or amputation. Eleven models were validated in 7624 participants, of whom 485 developed an ulcer and 70 underwent amputation. The models for foot ulcer showed C statistics (95% CI) ranging from 0.54 (0.54, 0.54) to 0.81 (0.75, 0.86) and models for amputation showed C statistics (95% CI) ranging from 0.63 (0.55, 0.71) to 0.86 (0.78, 0.94). Most models underestimated the ulcer or amputation risk in the highest risk quintiles. Three models performed well to predict a combined endpoint of amputation and foot ulcer (C statistics >0.75)., Conclusions/interpretation: Thirty-four prognostic models for the risk of foot ulcer or amputation were identified. Although the performance of the models varied considerably, three models performed well to predict foot ulcer or amputation and may be applicable to clinical practice.

Introduction: Early recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information., Aim: To describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA., Methods: The RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA., Conclusion: The RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

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.)

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.)

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.

Background: Despite many studies evaluating the effectiveness of integrated care, evidence remains inconsistent. There is increasing commentary pointing out the mismatch between the ability to capture the somewhat 'illusive' impact of integrated care initiatives and programmes, and the most appropriate way to do this. Focusing on methodology, this paper describes and critically reviews the experiences of SUSTAIN, a Horizon 2020 funded project (2015-2019) with the purpose of advancing knowledge and understanding of cross-European integrated care evaluation. SUSTAIN sought to improve integrated care initiatives for older people in seven countries, and to maximise the potential for knowledge transfer and application across Europe. The methods approach drew from implementation research, employing the participative Evidence Integration Triangle (EIT) and incorporating a mixed method, multiple embedded case study design. A core set of qualitative and quantitative indicators, alongside context and process data, were created and tested within four key project domains (person-centredness, prevention-orientation, safety and efficiency). The paper critically discusses the overall approach, highlighting the value of the EIT and case study design, and signalling the challenges of data collection with frail older people and stakeholder involvement at the sites, as well as difficulties developing the core set of indicators., Conclusions: Lessons learned and recommendations for advancing integrated care evaluation are put forward that focus on the status of integrated care as a complex intervention and a process. The use of implementation research methods and case study design are recommended as an additional evaluation approach for researchers to consider, alongside suggested ways of improving methods of data collection with frail populations and cost analysis.

Introduction: While many different factors can undermine older people's ability to live safely at home, safety as an explicit aspect of integrated care for older people living at home is an underexplored topic in research. In the context of a European project on integrated care, this study aims to improve our understanding of how safety is addressed in integrated care practices across Europe., Methods: This multiple case study included thirteen integrated care sites from seven European countries. The Framework Method guided content analyses of the case study reports. Activities were clustered into activities aimed at identifying and managing risks, or activities addressing specific risks related to older people's functioning, behaviour, social environment, physical environment and health and social care receipt., Results: Case studies included a broad range of activities addressing older people's safety. Although care providers felt they sufficiently addressed safety issues, older people were often concerned and insecure about their safety. Attention to the practical and social aspects of safety was often insufficient., Conclusions and Discussion: Integrated care services across Europe address older people's safety in many ways. Further integration of health and social care solutions is necessary to enhance older people's perceptions of safety., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

Context: There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease., Objective: To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D)., Design: 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts., Main Outcome Measures: Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing., Results: In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after., Conclusions: This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Although person-centredness is a key principle of integrated care, successfully embedding and improving person-centred care for older people remains a challenge. In the context of a cross-European project on integrated care for older people living at home, the objective of this paper is to provide insight at an overarching level, into activities aimed at improving person-centredness within the participating integrated care sites. The paper describes experiences with these activities from the service providers' and service users' perspectives., Methods: A multiple embedded case study design was conducted that included thirteen integrated care sites for older people living at home., Results: Service providers were positive about the activities that aimed to promote person-centred care and thought that most activities (e.g. comprehensive needs assessment) positively influenced person-centredness. Experiences of service users were mixed. For some activities (e.g. enablement services), discrepancies were identified between the views of service providers and those of service users., Discussion and Conclusion: Evaluating activities aimed at promoting person-centredness from both the service providers' and service users' perspectives showed that not all efforts were successful or had the intended consequences for older people. Involvement of older people in designing improvement activities could ensure that care and support reflect their needs and preferences, and build positive experiences of care and support., Competing Interests: Nick Goodwin and Mirella Minkman are affiliated with the International Foundation for Integrated Care, which supports the journal publishing this paper., (Copyright: © 2020 The Author(s).)

Aims/hypothesis: The aims of this study were to identify all published prognostic models predicting retinopathy risk applicable to people with type 2 diabetes, to assess their quality and accuracy, and to validate their predictive accuracy in a head-to-head comparison using an independent type 2 diabetes cohort., Methods: A systematic search was performed in PubMed and Embase in December 2019. Studies that met the following criteria were included: (1) the model was applicable in type 2 diabetes; (2) the outcome was retinopathy; and (3) follow-up was more than 1 year. Screening, data extraction (using the checklist for critical appraisal and data extraction for systemic reviews of prediction modelling studies [CHARMS]) and risk of bias assessment (by prediction model risk of bias assessment tool [PROBAST]) were performed independently by two reviewers. Selected models were externally validated in the large Hoorn Diabetes Care System (DCS) cohort in the Netherlands. Retinopathy risk was calculated using baseline data and compared with retinopathy incidence over 5 years. Calibration after intercept adjustment and discrimination (Harrell's C statistic) were assessed., Results: Twelve studies were included in the systematic review, reporting on 16 models. Outcomes ranged from referable retinopathy to blindness. Discrimination was reported in seven studies with C statistics ranging from 0.55 (95% CI 0.54, 0.56) to 0.84 (95% CI 0.78, 0.88). Five studies reported on calibration. Eight models could be compared head-to-head in the DCS cohort (N = 10,715). Most of the models underestimated retinopathy risk. Validating the models against different severities of retinopathy, C statistics ranged from 0.51 (95% CI 0.49, 0.53) to 0.89 (95% CI 0.88, 0.91)., Conclusions/interpretation: Several prognostic models can accurately predict retinopathy risk in a population-based type 2 diabetes cohort. Most of the models include easy-to-measure predictors enhancing their applicability. Tailoring retinopathy screening frequency based on accurate risk predictions may increase the efficiency and cost-effectiveness of diabetic retinopathy care., Registration: PROSPERO registration ID CRD42018089122.

Background: Microalbuminuria is an early sign of kidney disease in people with diabetes and indicates increased risk of cardiovascular disease. We tested whether a urinary proteomic risk classifier (CKD273) score was associated with development of microalbuminuria and whether progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone., Methods: In this multicentre, prospective, observational study with embedded randomised controlled trial (PRIORITY), we recruited people with type 2 diabetes, normal urinary albumin excretion, and preserved renal function from 15 specialist centres in ten European countries. All participants (observational cohort) were tested with the CKD273 classifier and classified as high risk (CKD273 classifier score >0·154) or low risk (≤0·154). Participants who were classified as high risk were entered into a randomised controlled trial and randomly assigned (1:1), by use of an interactive web-response system, to receive spironolactone 25 mg once daily or matched placebo (trial cohort). The primary endpoint was development of confirmed microalbuminuria in all individuals with available data (observational cohort). Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone (trial cohort, intention-to-treat population) and association between CKD273 risk score and measures of impaired renal function based on estimated glomerular filtration rate (eGFR; observational cohort). Adverse events (particularly gynaecomastia and hyperkalaemia) and serious adverse events were recorded for the intention-to-treat population (trial cohort). This study is registered with the EU Clinical Trials Register (EudraCT 20120-004523-4) and ClinicalTrials.gov (NCT02040441) and is completed., Findings: Between March 25, 2014, and Sept 30, 2018, we enrolled and followed-up 1775 participants (observational cohort), 1559 (88%) of 1775 participants had a low-risk urinary proteomic pattern and 216 (12%) had a high-risk pattern, of whom 209 were included in the trial cohort and assigned to spironolactone (n=102) or placebo (n=107). The overall median follow-up time was 2·51 years (IQR 2·0-3·0). Progression to microalbuminuria was seen in 61 (28%) of 216 high-risk participants and 139 (9%) of 1559 low-risk participants (hazard ratio [HR] 2·48, 95% CI 1·80-3·42; p<0·0001, after adjustment for baseline variables of age, sex, HbA 1c , systolic blood pressure, retinopathy, urine albumin-to-creatinine ratio [UACR], and eGFR). Development of impaired renal function (eGFR <60 mL/min per 1·73 m 2 ) was seen in 48 (26%) of 184 high-risk participants and 119 (8%) of 1423 low-risk participants (HR 3·50; 95% CI 2·50-4·90, after adjustment for baseline variables). A 30% decrease in eGFR from baseline (post-hoc endpoint) was seen in 42 (19%) of 216 high-risk participants and 62 (4%) of 1559 low-risk participants (HR 5·15, 95% CI 3·41-7·76; p<0·0001, after adjustment for basline eGFR and UACR). In the intention-to-treat trial cohort, development of microalbuminuria was seen in 35 (33%) of 107 in the placebo group and 26 (25%) of 102 in the spironolactone group (HR 0·81, 95% CI 0·49-1·34; p=0·41). In the safety analysis (intention-to-treat trial cohort), events of plasma potassium concentrations of more than 5·5 mmol/L were seen in 13 (13%) of 102 participants in the spironolactone group and four (4%) of 107 participants in the placebo group, and gynaecomastia was seen in three (3%) participants in the spironolactone group and none in the placebo group. One patient died in the placebo group due to a cardiac event (considered possibly related to study drug) and one patient died in the spironolactone group due to cancer, deemed unrelated to study drug., Interpretation: In people with type 2 diabetes and normoalbuminuria, a high-risk score from the urinary proteomic classifier CKD273 was associated with an increased risk of progression to microalbuminuria over a median of 2·5 years, independent of clinical characteristics. However, spironolactone did not prevent progression to microalbuminuria in high-risk patients., Funding: European Union Seventh Framework Programme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Cardiovascular (CV) disease (CVD) risk is increased in rheumatoid arthritis (RA). However, longterm followup studies investigating this risk are scarce., Methods: The CARRÉ (CARdiovascular research and RhEumatoid arthritis) study is a prospective cohort study investigating CVD and its risk factors in 353 patients with longstanding RA. CV endpoints were assessed at baseline and 3, 10, and 15 years after the start of the study and are compared to a reference cohort (n = 2540), including a large number of patients with type 2 diabetes (DM)., Results: Ninety-five patients with RA developed a CV event over 2973 person-years, resulting in an incidence rate of 3.20 per 100 person-years. Two hundred fifty-seven CV events were reported in the reference cohort during 18,874 person-years, resulting in an incidence rate of 1.36 per 100 person-years. Age- and sex-adjusted HR for CV events were increased for RA (HR 2.07, 95% CI 1.57-2.72, p < 0.01) and DM (HR 1.51, 95% CI 1.02-2.22, p = 0.04) compared to the nondiabetic participants. HR was still increased in RA (HR 1.82, 95% CI 1.32-2.50, p < 0.01) after additional adjustment for CV risk factors. Patients with both RA and DM or insulin resistance had the highest HR for developing CVD (2.21, 95% CI 1.01-4.80, p = 0.046 and 2.67, 95% CI 1.30-5.46, p < 0.01, respectively)., Conclusion: The incidence rate of CV events in established RA was more than double that of the general population. Patients with RA have an even higher risk of CVD than patients with DM. This risk remained after adjustment for traditional CV risk factors, suggesting that systemic inflammation is an independent contributor to CV risk.

Many initiatives integrating health and social care have been implemented in order to provide adequate care and support to older people living at home. Further development of existing initiatives requires iterative processes of developing, implementing and evaluating improvements to current practice. This case study provides insight into the process of improving an existing integrated care initiative in the Netherlands. Using a participatory approach, researchers and local stakeholders collaborated to develop and implement activities to further improve collaboration between health and social care professionals. Improvement activities included interprofessional meetings focussing on reflection and mutual learning and workplace visits. Researchers evaluated the improvement process, using data triangulation of multiple qualitative and quantitative data sources. According to participating professionals, the improvement activities improved their communication and collaboration by establishing mutual understanding and trust. Enabling factors included the safe and informal setting in which the meetings took place and the personal relationships they developed during the project. Different organisational cultures and interests and a lack of ownership and accountability among managers hindered the improvement process, whereas issues such as staff shortages, time constraints and privacy regulations made it difficult to implement improvements on a larger scale. Still, the participatory approach encouraged the development of partnerships and shared goals on the level of both managers and professionals. This case study highlights that improving communication between professionals is an important first step in improving integrated care. In addition, it shows that a participatory approach, in which improvements are co-created and tailored to local priorities and needs, can help in the development of shared goals and trust between stakeholders with different perspectives. However, stakeholders' willingness and ability to participate in such an improvement process is challenged by many factors., (© 2019 The Authors. Health and Social Care in the Community published by John Wiley & Sons Ltd.)

Background: Many older people live at home, often with complex and chronic health and social care needs. Integrated care programs are increasingly being implemented as a way to better address these needs. To support older people living at home, it is also essential to maintain their safety. Integrated care programs have the potential to address a wide range of risks and problems that could undermine older people's ability to live independently at home. The aim of this scoping review is to provide insight into how integrated care programs address safety risks faced by older people living at home - an area that is rather underexplored., Methods: Safety was conceptualised as preventing or reducing the risk of problems, associated with individual functioning and behaviour, social and physical environments, and health and social care management, which could undermine older people's ability to live independently at home. For this scoping review a systematic literature search was performed to identify papers describing integrated care programs where at least one intervention component addressed safety risks. Data were extracted on the programs' characteristics, safety risks addressed, and the activities and interventions used to address them., Results: None of the 11 programs included in this review explicitly mentioned safety in their goals. Nevertheless, following the principles of our conceptual framework, the programs appeared to address risks in multiple domains. Most attention was paid to risks related to older people's functioning, behaviour, and the health and social care they receive. Risks related to people's physical and social environments received less attention., Conclusion: Even though prevention of safety risks is not an explicit goal of integrated care programs, the programs address a wide range of risks on multiple domains. The need to address social and environmental risks is becoming increasingly important given the growing number of people receiving care and support at home. Prioritising a multidimensional approach to safety in integrated care programs could enhance the ability of health and social care systems to support older people to live safely at home.

Purpose: Type 2 diabetes requires patients to make lifestyle changes and perform daily self-care. To determine at what stages patients may need particular self-management support, we examined (1) whether patients' performance of self-care related to their diabetes duration, and (2) whether illness characteristics (treatment and complications) and diabetes-related distress influenced this relationship., Methods: Cross-sectional data from 590 type 2 diabetes patients were analysed through linear and logistic regression analysis. Self-care behaviours were assessed by the revised Summary of Diabetes Self-Care Activities (SDSCA) measure. Diabetes duration (model 1), treatment and complications (model 2), and distress, as assessed by the Problem Areas In Diabetes (PAID) scale (model 3), were stepwise included. Sociodemographic characteristics were added to all models to account for confounding., Results: Patients with a longer history of diabetes were less physically active, but monitored their blood glucose levels more frequently than more recently diagnosed patients. These relationships were mediated by the presence of complications and the use of insulin, with lower levels of physical activity being found among patients with macrovascular complications and higher frequencies of glucose monitoring among patients on insulin. All predictors together explained maximally 5% of the variance in self-care, except for glucose monitoring (37%) and smoking (11%)., Conclusion: Type 2 diabetes patients' self-care activity changes over the course of illness. To provide tailored self-management support, diabetes care providers should take into account patients' phase of illness, including their treatment and complications, as well as their personal characteristics and distress level., Competing Interests: Conflict of interestThe authors have no conflicts of interest to declare., (© Springer Nature Switzerland AG 2019.)

Background: Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration., Materials and Methods: Individuals with type 2 diabetes (n = 6770) from the Hoorn Diabetes Care System cohort were included in this study. The coefficient of variation (CV) was calculated over 5-year sliding intervals. People divided in quintiles based on their CV. Cox proportional hazard models were used to investigate the role of glycemic CV as risk factor in diabetes-related complications and mortality., Results: The coefficient of variation of glucose (FG-CV) increased with time, in contrast to HbA1c (HbA1c-CV). People with a high FG-CV were those with an early age of diabetes onset (Δ Q5-Q1  = - 2.39 years), a higher BMI (Δ Q5-Q1  = + 0.92 kg/m 2 ), an unfavorable lipid profile, i.e. lower levels of HDL-C (Δ Q5-Q1  = - 0.06 mmol/mol) and higher triglycerides (Δ Q5-Q1  =+ 1.20 mmol/mol). People with the highest FG-CV in the first 5-year interval showed an increased risk of insulin initiation, retinopathy, macrovascular complications and mortality independent of mean glycemia, classical risk factors and medication use. For HbA1c, the associations were weaker and less consistent., Conclusions: Individuals with a higher FG-CV have an unfavorable metabolic profile and have an increased risk of developing micro- and macrovascular complications and mortality. The association of HbA1c-CV with metabolic outcomes and complications was less consistent in comparison to FG-CV.

Type 2 diabetes is associated with an increased risk of developing macro and microvascular complications. Nevertheless, there is substantial heterogeneity between people with type 2 diabetes in their risk of developing such complications. Personalised medicine for people with type 2 diabetes may aid in efficient and tailored diabetes care for those at increased risk of developing such complications. Recently, progress has been made in the development of personalised diabetes care in several areas. Particularly for the risk prediction of cardiovascular disease, retinopathy and nephropathy, innovative methods have been developed for prediction and tailored monitoring or treatment to prevent such complications. For other complications or subpopulations of people with type 2 diabetes, such as the frail elderly, efforts are currently ongoing to develop such methods. In this review, we discuss the recent developments in innovations of personalised diabetes care for different complications and subpopulations of people with type 2 diabetes, their performance and modes of application in clinical practice.

Integrated care programmes are increasingly being put in place to provide care to older people living at home. However, knowledge about further improving integrated care is limited. In fourteen integrated care sites in Europe, plans to improve existing ways of working were designed, implemented and evaluated to enlarge the understanding of what works and with what outcomes when improving integrated care. This paper provides insight into the existing ways that the sites were working with respect to integrated care, their perceived difficulties and their plans for working towards improvement. The seven components of the Expanded Chronic Care Model provided a conceptual framework for describing the fourteen sites. Although sites were spread across Europe and differed in basic characteristics and existing ways of working, a number of difficulties in delivering integrated care were similar. Existing ways of working and improvement plans mostly focused on three components of the Expanded Chronic Care Model: delivery system design; decision support; self-management. Two components were represented less frequently in existing ways of working and improvement plans: building healthy public policy; building community capacity. These findings suggest that broadly-based prevention efforts, population health promotion and community involvement remain limited. From the Expanded Chronic Care Model perspective, therefore, opportunities for improving integrated care outcomes may continue to be restricted by the narrow focus of developed improvement plans., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

In many integrated care programs, a comprehensive geriatric assessment (CGA) is conducted to identify older people's problems and care needs. Different ways for conducting a CGA are in place. However, it is still unclear which CGA instruments and procedures for conducting them are used in integrated care programs, and what distinguishes them from each other. Furthermore, it is yet unknown how and to what extent CGAs, as a component of integrated care programs, actually reflect the main principles of integrated care, being comprehensiveness, multidisciplinarity and person-centredness. Therefore, the objectives of this study were to: (a) describe and compare different CGA instruments and procedures conducted within integrated care programs for older people living at home, and (b) describe how the principles of integrated care were applied in these CGAs. A scoping review of the scientific literature on CGAs in the context of integrated care was conducted for the period 2006-2018. Data were extracted on main characteristics of the identified CGA instruments and procedures, and on how principles of integrated care were applied in these CGAs. Twenty-seven integrated care programs were included in this study, of which most were implemented in the Netherlands and the United States. Twenty-one different CGAs were identified, of which the EASYcare instrument, RAI-HC/RAI-CHA and GRACE tool were used in multiple programs. The majority of CGAs seemed to reflect comprehensiveness, multidisciplinarity and person-centredness, although the way and extent to which principles of integrated care were incorporated differed between the CGAs. This study highlights the high variability of CGA instruments and procedures used in integrated care programs. This overview of available CGAs and their characteristics may promote (inter-)national exchange of CGAs, which could enable researchers and professionals in choosing from the wide range of existing CGAs, thereby preventing them from unnecessarily reinventing the wheel., (© 2019 The Authors. Health and Social Care in the Community Published by John Wiley & Sons Ltd.)

Background Drug-related problems (DRP) following hospital discharge may cause morbidity, mortality and hospital re-admissions. It is unclear whether a clinical medication review (CMR) and counseling at discharge is a cost-effective method to reduce DRP. Objective To assess the effect of a CMR on health care utilization and to investigate whether CMR is a cost-effective method to reduce DRP in older polypharmacy patients discharged from hospital. Setting 24 community pharmacies in the Netherlands. Method A cluster-randomized controlled trial with an economic evaluation. Community pharmacies were randomized to those providing a CMR, counseling and follow-up at discharge and those providing usual care. Main outcome measures Change in the number of DRP after 1 year of follow-up and costs of health care utilization during follow-up. In 216 patients the use of health care was prospectively assessed. Missing data on effects and costs were imputed using multiple imputation techniques. Bootstrapping techniques were used to estimate the uncertainty around the differences in costs and incremental cost-effectiveness ratios. Results CMR resulted in a small reduction of DRP. The proportion of patients readmitted to the hospital during 6 months of follow-up was significantly higher in the intervention group than in the control group (46.4 vs. 20.9%; p < 0.05). Health care costs were higher in the intervention group, although not statistically significant. The costs of reducing one DRP by a CMR amounted to €8270. Conclusion A CMR in vulnerable older patients at hospital discharge led to a small reduction in DRP. Because of a significantly higher use of health care and higher number of re-hospitalisations post CMR, the present study data indicate that performing the intervention in this patient population is not cost-effective.

Background Insight into the delivery of interventions is necessary to gain a better understanding of what caused an intervention to succeed or fail. The Cardiovascular medication non-Adherence Tailored Intervention (CATI) study failed to show effectiveness of a patient-tailored, pharmacist-led intervention programme on self-reported adherence to antihypertensive medication. Objective To evaluate the implementation fidelity of the CATI intervention programme. Setting Twenty Dutch community pharmacies. Method The process of a randomised controlled trial was evaluated. Both quantitative and qualitative data were collected and analysed according to Carrolls' Conceptual Framework for Implementation Fidelity. Implementation fidelity is defined as the degree to which the intervention was implemented as intended. Main outcome measure Four key intervention components of the intervention programme (i.e., first consultation: barrier identification, information and advice, written summary, and follow-up consultation). Results For most participants the key intervention components were implemented as intended. The training of pharmacists, intensive monitoring during the study and structured and easy-to-use intervention materials facilitated the implementation of the intervention. The method to select participants for the intervention programme was considered insufficient and pharmacists questioned the eligibility of some participants because of a low degree of intake non-adherence. Conclusion Implementation fidelity was moderate to high for all key intervention components. Therefore, the absence of effectiveness of the CATI intervention programme on self-reported medication adherence cannot be explained by poor implementation of the intervention. However, the limited genuine eligibility of some participants resulted in a limited potential for improvement in medication adherence.

Background: Cardiovascular medications have well-established benefits in the primary and secondary prevention of cardiovascular diseases. Unfortunately, adherence to these medicines is often suboptimal. To develop interventions intended to enhance adherence to cardiovascular medications, more insight is needed into the complex character of medication nonadherence., Objective: The aim of the present study was to identify which factors are associated with nonadherence to cardiovascular medications in a sample of patients from Dutch community pharmacies., Methods: In this cross-sectional study, patients using cardiovascular medications from 23 community pharmacies were included. Patient demographics, medication and disease characteristics, knowledge, quality of life, attitude toward medicines, and satisfaction with information were assessed. Both an adherent sample (n = 146) and a sample of patients nonadherent to prescribed medications (n = 109) during the last 6 months as assessed with pharmacy refill data (proportion of days covered <80%) were selected. Associations with refill nonadherence were assessed using univariate and multivariate logistic regression analyses., Results: In total, 255 patients participated (53.3% men, 71.6 ± 10.9 years). Factors associated with cardiovascular medication nonadherence in multivariate analyses included experiencing difficulties with medication use due to forgetting, having insufficient knowledge on what to do when a dose is forgotten, and having an ambivalent attitude toward medicines (beliefs of high necessity and high concerns)., Conclusions: Intervention strategies to enhance cardiovascular medication nonadherence should be targeted mainly to the unintentional dimension of nonadherence and include information and tools to prevent forgetting. Conversely, the influence of factors that underlie intentional nonadherence, particularly patients' beliefs about medicines, should also be addressed.

Aims: To evaluate the immediate and six-month effectiveness of a group-based self-management support program for people diagnosed with type 2 diabetes (1-3 years post diagnosis) on diabetes self-care, distress and cognitions., Methods: People with type 2 diabetes were randomized into the intervention (four group-based interactive sessions) or the control group (a single educational lecture) with their partners. Outcomes were measured at baseline, immediately after the third course session and six months later using validated questionnaires on diabetes self-care, distress, illness perceptions, diabetes-related attitudes, empowerment and partner support. Multilevel analyses were conducted according to the intention-to-treat principle using the data from 82 intervention and 86 control group participants, to test for differences in changes over time between the two groups., Results: The intervention group showed a significantly higher increase in physical activity and fruit and vegetable intake immediately after the program, whereas the low baseline levels of diabetes distress remained unaffected. Furthermore, the intervention group believed their illness to be more likely to be caused by chance/bad luck, but also felt more empowered to handle their condition and its treatment immediately after the program compared with the control group. Six months later, only the differences in empowerment had persisted., Conclusions: Group-based self-management support results in favorable short-term behavioral changes and more persistent alterations in (perceived) empowerment in people living in the first years of type 2 diabetes. In order to achieve more sustainable behavioral changes, more prolonged support is necessary. This could be achieved by integrating attention to patients' illness perceptions and continuous self-management support in regular diabetes care., Trial Registration: Netherlands Trial Registry NL3158., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To describe how principles of self-regulation and social support could be integrated in a group intervention to improve self-management of people with type 2 diabetes mellitus in the early phase of illness and to pilot its suitability in a primary care setting., Methods: Principles of the Common-Sense Model of Self-Regulation, Social Cognitive Theory of Self-Regulation and social support theories were integrated in the intervention. Based on this, a three-session group course was developed to challenge illness perceptions of participants that discourage adequate self-management, to practice goal-setting and behavioural actions and to create a supportive environment. The intervention was piloted with persons with early-stage (1-3 years post diagnosis) type 2 diabetes mellitus selected in general practice in the Netherlands. Data about the suitability of the intervention were retrieved by means of observation and audio-recording of the sessions, an evaluation form filled in by the participants and an evaluation meeting with the group leaders., Results: In total, 16 type 2 diabetes mellitus patients participated in the pilot, who were divided into a group of single participants (N = 8) and a group (N = 8) who participated with their partner. Discrepancies between perceptions of one's own condition and type 2 diabetes mellitus in general were observed. Goal-setting and developing action plans appeared to be difficult tasks for many participants, whereas others felt these exercises were not useful as they did not feel a need to make changes in living with diabetes. The group-based format was appreciated as was the participation of partners., Conclusion: Challenging the illness perceptions of persons with early-stage type 2 diabetes mellitus by a brief interactive group course is feasible and important, as many of these people tend to underestimate the seriousness of their diabetes. However, motivating persons with early-stage type 2 diabetes mellitus to participate in self-management interventions remains a challenge. Offering the intervention as an integral part of type 2 diabetes mellitus management in primary care is desirable., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To determine the diagnostic accuracy in a real-world primary care setting of a deep learning-enhanced device for automated detection of diabetic retinopathy (DR)., Research Design and Methods: Retinal images of people with type 2 diabetes visiting a primary care screening program were graded by a hybrid deep learning-enhanced device (IDx-DR-EU-2.1; IDx, Amsterdam, the Netherlands), and its classification of retinopathy (vision-threatening [vt]DR, more than mild [mtm]DR, and mild or more [mom]DR) was compared with a reference standard. This reference standard consisted of grading according to the International Clinical Classification of DR by the Rotterdam Study reading center. We determined the diagnostic accuracy of the hybrid deep learning-enhanced device (IDx-DR-EU-2.1) against the reference standard., Results: A total of 1,616 people with type 2 diabetes were imaged. The hybrid deep learning-enhanced device's sensitivity/specificity against the reference standard was, respectively, for vtDR 100% (95% CI 77.1-100)/97.8% (95% CI 96.8-98.5) and for mtmDR 79.4% (95% CI 66.5-87.9)/93.8% (95% CI 92.1-94.9)., Conclusions: The hybrid deep learning-enhanced device had high diagnostic accuracy for the detection of both vtDR (although the number of vtDR cases was low) and mtmDR in a primary care setting against an independent reading center. This allows its' safe use in a primary care setting., (© 2019 by the American Diabetes Association.)

Introduction: Hypertension is considered an important public health issue. Inadequate disease management and non-adherence to antihypertensive medication may result in suboptimal clinical outcomes thereby imposing a financial burden on society. This study evaluates the cost-effectiveness of a patient-tailored, pharmacist-led intervention program aimed to enhance adherence to antihypertensive medication in comparison with usual care. Materials and Methods: An economic evaluation was conducted alongside a pragmatic randomized controlled trial with 9-months follow-up among 170 patients using antihypertensive medication. Effect outcomes included self-reported adherence (MARS-5), beliefs about medicines (BMQ Concern and Necessity scales) and quality-adjusted life-years (QALYs). Costs were measured from a societal perspective. Missing cost and effect data were imputed using multiple imputation. Bootstrapping was used to estimate uncertainty around the cost-differences and the incremental cost-effectiveness ratios. Cost-effectiveness planes and acceptability curves were estimated. Results: There were no significant differences in costs or effects between the intervention program and usual care. The probability of cost-effectiveness of the intervention in comparison with usual care was 0.27 at a willingness-to-pay value of 0 €/unit of effect gained. At a willingness-to-pay value of 20,000 €/unit of effect gained, the probability of cost-effectiveness was 0.70, 0.27, 0.64, 0.87, and 0.36 for the continuous MARS-5 score, dichotomized MARS-5 score, BMQ Concern scale, BMQ Necessity scale and QALYs, respectively. Discussion: In patients with hypertension, the patient-tailored, pharmacist-led intervention program to enhance medication adherence was not considered cost-effective as compared to usual care with regard to self-reported medication adherence, beliefs about medicines and QALYs.

Objective: To investigate whether women with type 2 diabetes (T2D) develop a more advanced stage of breast cancer and whether treatment with insulin (analogs) is associated with specific breast cancer characteristics., Research Design and Methods: For this nested case-control study, women with breast cancer diagnosed in 2002-2014 were selected from the linked Netherlands Cancer Registry-PHARMO Database Network ( N = 33,377). T2D was defined as receiving two or more dispensings of noninsulin blood glucose-lowering drugs prior to breast cancer diagnosis. Women with T2D were matched to women without diabetes. Among women with T2D, insulin users and nonusers were compared. Multivariable ordinal logistic regression was used to investigate the association between T2D/insulin and breast cancer characteristics, including TNM classification (tumor size, lymph node status, metastasis), morphology, grade, estrogen receptor and progesterone receptor (PR), human epidermal growth factor receptor 2, and molecular subtype., Results: Women with T2D ( n = 1,567) were more often diagnosed with a more advanced tumor stage (odds ratio 1.28 [95% CI 13-1.44]) and a higher grade (1.22 [1.08-1.39]) though less often with a PR-negative breast tumor (0.77 [0.67-0.89]) than women without diabetes ( n = 6,267). No associations were found for the other breast cancer characteristics. Women with T2D using insulin ( n = 388) were not diagnosed with different breast cancer characteristics compared with women with T2D not using insulin ( n = 1,179)., Conclusions: Our study suggests that women with T2D are at increased risk to be diagnosed with a more aggressive type of breast cancer than women without diabetes. No evidence was found that the use of insulin (analogs) is associated with developing more advanced breast cancer tumors., (© 2019 by the American Diabetes Association.)

Purpose: The prevalence of colorectal cancer is higher among patients with type 2 diabetes mellitus (T2D) than among patients without diabetes. Furthermore, men are at higher risk for developing colorectal cancer than women in the general population and also subsite-specific risks differ per sex. The aim was to evaluate the impact of T2D on these associations., Methods: A population-based matched cohort study was performed using data from the PHARMO Database Network. Patients with T2D were selected and matched (1:4) to diabetes free controls. Cox proportional hazards models were used to estimate hazard ratios (HRs) for CRC and its subsites. HRs were determined per sex and adjusted for age and socioeconomic status. The ratio of distal versus proximal colon cancer was calculated for people with T2D and controls per sex and stratified by age., Results: Over 55,000 people with T2D were matched to > 215,000 diabetes free controls. Men and women with T2D were 1.3 times more likely to develop colorectal cancer compared to controls. Men with T2D were at higher risk to develop distal colon cancer (hazard ratio (95% confidence interval), 1.42 (1.08-1.88)), and women with T2D were at higher risk for developing proximal colon cancer (hazard ratio (95% confidence interval), 1.58 (1.13-2.19)). For rectal cancer, no statistically significant risk was observed for both men and women., Conclusions: Sex-specific screening strategies and prevention protocols should be considered for people with T2D. More tailored screening strategies may optimize the effectiveness of colorectal cancer screening in terms of reducing incidence and mortality.

Objective: We studied whether blood metabolomic measures in people with type 2 diabetes (T2D) are associated with insufficient glycemic control and whether this association is influenced differentially by various diabetes drugs. We then tested whether the same metabolomic profiles were associated with the initiation of insulin therapy., Methods: A total of 162 metabolomic measures were analyzed using a nuclear magnetic resonance-based method in people with T2D from four cohort studies (n = 2641) and one replication cohort (n = 395). Linear and logistic regression analyses with adjustment for potential confounders, followed by meta-analyses, were performed to analyze associations with hemoglobin A1c levels, six glucose-lowering drug categories, and insulin initiation during a 7-year follow-up period (n = 698)., Results: After Bonferroni correction, 26 measures were associated with insufficient glycemic control (HbA1c >53 mmol/mol). The strongest association was with glutamine (OR, 0.66; 95% CI, 0.61 to 0.73; P = 7.6 × 10-19). In addition, compared with treatment-naive patients, 31 metabolomic measures were associated with glucose-lowering drug use (representing various metabolite categories; P ≤ 3.1 × 10-4 for all). In drug-stratified analyses, associations with insufficient glycemic control were only mildly affected by different glucose-lowering drugs. Five of the 26 metabolomic measures (apolipoprotein A1 and medium high-density lipoprotein subclasses) were also associated with insulin initiation during follow-up in both discovery and replication. The strongest association was observed for medium high-density lipoprotein cholesteryl ester (OR, 0.54; 95% CI, 0.42 to 0.71; P = 4.5 × 10-6)., Conclusion: Blood metabolomic measures were associated with present and future glycemic control and might thus provide relevant cues to identify those at increased risk of treatment failure.