G. Nijpels

Vitamin D in Relation to Myocardial Structure and Function after Eight Years of Follow-Up: The Hoorn Study

Background and Aims: To investigate associations between baseline serum 25-hydroxyvitamin D [25(OH)D] levels and myocardial structure and function after 8 years of follow-up in older Dutch subjects. Methods: We included 256 subjects of the Hoorn Study, a population-based cohort. They underwent a standardized 2-dimensional echocardiogram at baseline between 2000 and 2001, and again between 2007 and 2009. We studied the association of 25(OH)D quartiles with echocardiographic measures of the left ventricular mass index (LVMI), left ventricular systolic function and markers of diastolic function using linear regression analyses. Results: At baseline, subjects had a mean age of 67.4 ± 5.2 years and 41.4% had prior cardiovascular disease (CVD). Low serum 25(OH)D levels were only associated with higher LVMI at 8-year follow-up in subjects without prior CVD and in subjects with low kidney function (median estimated glomerular filtration rate ≤77.5 ml/min/1.73m2). The associations attenuated after adjustments for parathyroid hormone (PTH), which was associated with higher LVMI (g/m2.7) in subjects with low kidney function (regression coefficient highest quartile 6.3, 95% CI: 0.2, 12.5). Conclusion: This study showed no strong associations of 25(OH)D with myocardial structure and function. However, PTH - a possible modifiable mediator in the relation between 25(OH)D and myocardial structure - was positively associated with LVMI in subjects with low kidney function.

Neuropeptide Y polymorphism significantly magnifies diabetes and cardiovascular disease risk in obesity: the Hoorn Study.

The leucine7 to proline7 (Leu7Pro) polymorphism in preproneuropeptide Y (preproNPY) has been associated with accelerated atherosclerosis and type II diabetes, both of which are obesity-related diseases. The current study evaluated the impact of obesity on the disease risk linked to the Leu7Pro polymorphism of preproNPY in 393 elderly subjects. In 6 years follow-up, the polymorphism alone did not change the risk for abnormal glucose regulation, while obesity was associated with a significant 3-fold risk (odds ratio (OR) 2.95; 95% confidence interval (CI) 1.81–4.81, P<0.001) and the Leu7Pro polymorphism–obesity interaction, with a remarkable 12-fold risk (OR 12.33; 95% CI 1.18–128.35, P<0.05). The Leu7Pro polymorphism modified significantly the 10-year incidence of cardiovascular events, causing a 7.6-fold increase in the hazard ratio (HR 7.58; 95% CI 2.87–20.03, P<0.001) in the obese but not in the nonobese subjects. The results indicate that obesity may be a pivotal factor in multiplying the disease risk associated with the Leu7Pro polymorphism in preproNPY.

Different Type of Carotid Arterial Wall Remodeling in Rheumatoid Arthritis Compared with Healthy Subjects: A Case-Control Study

Objective. Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) risk, but mechanisms behind this increased risk have not been fully elucidated. Carotid arterial remodeling is the change of structural properties in response to hemodynamic or metabolic factors aimed at keeping wall stress within certain limits. This process might become maladaptive when stress on the arterial wall increases beyond these limits. We investigated whether maladaptive carotid arterial remodeling is present in RA compared with control subjects. Methods. The 2 cohorts were 96 patients with RA and 274 healthy subjects, who were investigated cross-sectionally. Carotid intima-media thickness (cIMT) and interadventitial diameter (IAD) were assessed by B-mode carotid ultrasonography. Lumen diameter (LD), circumferential wall stress (CWS), and circumferential wall tension (CWT) were calculated. Linear regression analyses were used to investigate the association between presence of RA and carotid arterial remodeling. Results. Compared with healthy subjects, RA was associated with a 0.40 mm (9.3%) greater LD, 0.41 mm (7.8%) greater IAD, 10% higher CWS, and 8% higher CWT. The groups had comparable cIMT. Associations remained similar after exclusion of patients with prior CV disease and after adjustment for demographic factors and CV risk factors. Conclusion. RA is associated with maladaptive outward carotid arterial remodeling. These results are relevant because maladaptive outward remodeling is associated with plaque instability and rupture. These results indicate an alternative pathway, beyond the traditional CV risk factors, in RA that amplifies the CV risk.

Prevalence and Correlates of Sexual Dysfunction in Men and Women With Type 2 Diabetes

This study aimed to assess the prevalence and correlates of sexual dysfunction in a sample of Dutch men and women with type 2 diabetes. Patients with type 2 diabetes who were between the ages of 40 and 75 years from 4 Dutch diabetes centers were asked to complete self-report questionnaires covering sociodemographic characteristics, medical characteristics, clinical depression (Center for Epidemiological Studies), and sexual dysfunction (in men: International Index of Erectile Function; in women: Female Sexual Function Index). In total, 158 type 2 diabetes patients (68% men) completed the cross-sectional survey. On the basis of predefined criteria, 69% of men and 70% of women were classified with some degree of sexual dysfunction. Univariable logistic regression analyses revealed that sexual dysfunctions were associated with higher age, clinical depression (Center for Epidemiological Studies score ≥16), and one or more diabetes-related complications in both men and women. Multivariable logistic regression analyses revealed that clinical depression was most strongly associated with both male (OR = 6.87, 95% CI [1.77, 26.63]) and female (OR = 9.33, 95% CI [1.03, 84.87]) sexual dysfunction. In conclusion, sexual dysfunction is highly prevalent in men and women with type 2 diabetes and is associated with higher age, clinical depression, and diabetes-related complications. These results suggest that addressing sexual dysfunction in diabetes care is important.

Real-world evidence of suboptimal blood pressure control in patients with type 2 diabetes

Aims: In order to eventually improve blood pressure (BP) management, the aim of this study was to identify subgroups of type 2 diabetes mellitus (T2DM) patients with distinct trajectories of SBP levels. Identifying subgroups with distinct SBP trajectories helps to better understand the course of SBP levels in T2DM patients and its associated consequences. Subgroup characteristics were determined and the prevalence of complications and mortality rates over time in the different subgroups was investigated. Methods: Five thousand, seven hundred and eleven T2DM patients with at least two SBP follow-up measurements were selected from a prospective T2DM cohort of 9849 T2DM patients. The mean follow-up period was 5.7 years (range 2–9 years). Latent Class Growth Modeling, as currently the most flexible cluster analysis available, was performed to identify subgroups of patients with distinct SBP trajectories. Subgroup characteristics were determined by multinomial logistic regression analyses. Results: Four subgroups with distinct SBP trajectories were identified. The largest subgroup (85.6%) showed adequate SBP control (at or around 140u200ammHg) over time. The second subgroup (5.6%) were hypertensive in the first years, responded slowly to BP management and eventually reached SBP control. The third subgroup (3.4%) showed deteriorating hypertension during the first 4 years, then showed insufficient response to BP management. The fourth subgroup (5.4%) showed deteriorating hypertension over time. Patients within subgroups 2–4 were significantly older, comprised more women, used more antihypertensive medication and had a higher prevalence of retinopathy, microalbuminuria and cardiovascular disease (CVD) mortality. Conclusion: More than 85% reached and maintained adequate SBP control. Subgroups with a more unfavourable course of SBP control also showed higher rates of microvascular complications and CVD mortality over time. This study identified important subgroups to target in order to improve BP management in T2DM patients.

The Hoorn Diabetes Care System (DCS) cohort. A prospective cohort of persons with type 2 diabetes treated in primary care in the Netherlands

Purpose People with type 2 diabetes (T2D) have a doubled morbidity and mortality risk compared with persons with normal glucose tolerance. Despite treatment, clinical targets for cardiovascular risk factors are not achieved. The Hoorn Diabetes Care System cohort (DCS) is a prospective cohort representing a comprehensive dataset on the natural course of T2D, with repeated clinical measures and outcomes. In this paper, we describe the design of the DCS cohort. Participants The DCS consists of persons with T2D in primary care from the West-Friesland region of the Netherlands. Enrolment in the cohort started in 1998 and this prospective dynamic cohort currently holds 12u2009673 persons with T2D. Findings to date Clinical measures are collected annually, with a high internal validity due to the centrally organised standardised examinations. Microvascular complications are assessed by measuring kidney function, and screening feet and eyes. Information on cardiovascular disease is obtained by 1) self-report, 2) electrocardiography and 3) electronic patient records. In subgroups of the cohort, biobanking and additional measurements were performed to obtain information on, for example, lifestyle, depression and genomics. Finally, the DCS cohort is linked to national cancer and all-cause mortality registers. A selection of published findings from the DCS includes identification of subgroups with distinct development of haemoglobin A1c, blood pressure and retinopathy, and their predictors; validation of a prediction model for personalised retinopathy screening; the assessment of the role of genetics in development and treatment of T2D, providing options for personalised medicine. Future plans We will continue with the inclusion of persons with newly diagnosed T2D, follow-up of persons in the cohort and linkage to morbidity and mortality registries. Currently, we are involved in (inter)national projects on, among others, biomarkers and prediction models for T2D and complications and we are interested in collaborations with external researchers. Trial registration ISRCTN26257579

The Use of Antidepressants, Anxiolytics, and Hypnotics in People with Type 2 Diabetes and Patterns Associated with Use: The Hoorn Diabetes Care System Cohort

Objective. With depression being present in approximately 20% of people with type 2 diabetes mellitus (T2DM), we expect equally frequent prescription of antidepressants, anxiolytics, and hypnotics. Nevertheless, prescription data in people with T2DM is missing and the effect of depression on glycaemic control is contradictory. The aim of this study was to assess the prevalence of antidepressants, anxiolytics, and/or hypnotics use in a large, managed, primary care system cohort of people with T2DM and to determine the sociodemographic characteristics, comorbidities, T2DM medication, and metabolic control associated with its use. Method. The prevalence of antidepressants, anxiolytics, and/or hypnotics use in the years 2007–2012 was assessed in the Hoorn Diabetes Care System Cohort from the Netherlands. Results. From the 7016 people with T2DM, 500 people (7.1%) used antidepressants only, 456 people (6.5%) used anxiolytics and/or hypnotics only, and 254 people (3.6%) used a combination. Conclusion. We conclude that in our managed, primary care system 17% of all people with T2DM used antidepressants, anxiolytics, and/or hypnotics. Users of antidepressants, anxiolytics, and/or hypnotics were more often female, non-Caucasian, lower educated, and more often treated with insulin.

Modelling integrated care for diabetes based on observational data: the MICADO model

Background and aims: TCF7L2 is both an activator and an inhibitor of transcription and the most highly associated type 2 diabetes gene known to date. It influences beta cell survival and function, i.e. incretin hormonal effects, insulin processing and secretion. However, its target genes in pancreatic islets are not fully described and the molecular mechanism whereby it propagates its effects on islet function is not known. The aim of this study is to identify the molecular mechanisms through which TCF7L2 influence beta cell survival and function. Materials and methods: Wister rat primary islets and INS-1 (832/13) cells were incubated with siRNA against Tcf7l2, both Tcf7l2 and TP53INP1 or both TCF7L2 and TP53 in 5.5 mM and 14.3 mM glucose. TCF7L2 activity, p53 activity and target gene expression (using qPCR) were measured after siRNA treatment. INS-1 cell apoptosis was measured by DNA degradation levels, caspase-3/7 levels and by using antibodies against Annexin V, and 7-AAD, visualized using confocal microscopy. Rat islet viability was estimated measuring metabolic rate. Rat islet apoptosis was estimated by measuring Caspase-3/7 level. Results: The type 2 diabetes associated genes TP53INP1, FTO, GIPR and ADAMTS9 were identified as TCF7L2 potential target gene using chromatin immunoprecipitation on microarrays. In INS-1 cells, siRNA mediated Tcf7l2 knock down (69.5 %) resulted in decreased TCF7L2 activity (91%) and differential expression of the target genes: Tp53 (14.5% increase), TP53INP1 (65.9% increase) and ADAMTS9 (82.8% decrease). TCF7L2 knockdown also lead to reduced cell viability (65%) and increased apoptosis (113%). The TCF7L2 induced cell death was replicated in rat primary islets. When restoring (decreasing) the Tp53inp1 expression level in TCF7L2 depleted islets, the decrease in cell viability and increase in apoptosis were prevented, suggesting that the Tcf7l2 effect is mediated via Tp53inp1. Furthermore, p53 depletion prohibited TCF7L2 down regulation induced cell death and elevation of Tp53inp1 expression in both INS-1 cells and rat primary islets. Conclusion: The type 2 diabetes associated genes TP53INP1 and ADAMTS9 are target genes of TCF7L2 in pancreatic islets. TCF7L2 induced apoptosis and decreased cell viability are mediated through activation of p53 and increased p53INP1 expression.

Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: A systematic review and meta-analysis

The long‐term impact of dipeptidyl peptidase‐4 (DPP‐4) inhibition is unknown, and there are concerns about the influence of DPP‐4 inhibition on carcinogenesis of the pancreas and thyroid. As DPP‐4 is a rather unselective enzyme present in many tissues, we focused on all specific cancer types. PubMed and EMBASE were searched between January 2005 and April 2017 to identify studies comparing DPP‐4 inhibitors with either placebo or active drugs on cancer risk. Studies were included if they reported on at least one specific cancer outcome and had a follow‐up of at least 1 year after start of drug use. Methodological quality of the studies was assessed by the Cochrane Collaborations tool and the Newcastle‐Ottawa Scale. Twenty‐five studies met the inclusion criteria (12 randomized controlled trials and 13 observational studies). Sample sizes of the DPP‐4 inhibitor groups ranged from 29 to 8212 patients for randomized controlled trials and from 2422 to 71 137 patients for observational studies. Mean age ranged from 51 to 76 years, and mean follow‐up was 1.5 years. None of the pooled (sensitivity) analyses, except the observational studies studying breast cancer (hazard ratio [95% CI]: 0.76 [0.60‐0.96]), showed evidence for an association between DPP‐4 inhibitors and site‐specific cancer. Also for pancreatic and thyroid cancer, no statistically significant risk was found. Based on the current literature, it is not possible to conclude whether DPP‐4 inhibitors were associated with an increased risk of site‐specific cancer. Future studies should address the methodological limitations and follow patients for a longer period to determine the long‐term cancer risk of DPP‐4 inhibitors.

Screening for sexual dissatisfaction among people with type 2 diabetes in primary care

AIMSnThe identification and discussion of sexual care needs in people with type 2 diabetes mellitus (T2DM) in primary care is currently insufficient. The objective of this study was to determine the prevalence of sexual dissatisfaction, sexual problems and need for help by using a screening instrument among people with T2DM in primary care.nnnMETHODSnData were collected in 45 general practices in the Netherlands from January 2015 to February 2016. The Brief Sexual Symptom Checklist (BSSC) was used to screen among 40-75 year old men and women.nnnRESULTSnIn total, 786 people with T2DM (66.5% men) were screened. The prevalence of sexual dissatisfaction was 36.6%, significantly higher among men than among women (41.1% vs. 27.8%). Sexually dissatisfied men most often reported erectile dysfunction (71.6%); for sexually dissatisfied women, low sexual desire (52.8%) and lubrication problems (45.8%) were most common. More than half of all dissatisfied people had a need for care (61.8%), significantly more men than women (66.8% vs. 47.2%).nnnCONCLUSIONSnOne third of people with T2DM is sexually dissatisfied and more than half of these people report a need for help. The BSSC could be used a tool to proactively identify sexually dissatisfied people in primary care.