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Motivated by a study measuring diabetes-related risk factors and complications, we postulate an extension to the standard formulation of joint models for longitudinal and survival outcomes, wherein the longitudinal outcome has a cumulative effect on the hazard of the event, weighted by recency. We focus on the relationship between the biomarker HbA1c and the development of sight threatening retinopathy, since the impact of the HbA1c marker on the risk of sight threatening retinopathy is expected to be cumulative, with the evolution of the HbA1c marker over time contributing to progressively greater damage to the vascular structure of the retina. Opting for a parametric approach, we propose the use of the normal and skewed normal probability density functions as weight functions, estimating the relevant parameters directly from the data. The use of the recency-weighted cumulative effect specification allows us to incorporate differences in the development of the longitudinal profile over time in the calculation of hazard ratios between subjects. The proposed functions provide us with parameters with clinically relevant interpretations while retaining a degree of flexibility. In addition, they also allow answering of important clinical questions regarding the relative importance of various segments of the biomarkers history in the estimation of the risk of the event. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Homoarginine is an amino acid that may be involved in nitric oxide and energy metabolism. Previous studies in patient populations showed that low homoarginine levels indicate an increased risk of mortality and cardiovascular disease. We evaluated whether low plasma levels of homoarginine are associated with elevated, overall and cause-specific mortality., Materials and Methods: The Hoorn study is a population-based study among older men and women. We calculated Cox proportional hazard ratios (HRs) for overall and cause-specific mortality according to sex-specific homoarginine quartiles., Results: We included 606 study participants (51·3% women; 70·0 ± 6·6 years). Homoarginine concentrations were higher in men (1·63 ± 0·51 μM), compared with women (1·30 ± 0·44 μM; P < 0·001). After a median follow-up time of 7·8 years, 112 study participants died, including 31 deaths due to cardiovascular diseases and 30 due to cancer. Associations between homoarginine levels and mortality showed a threshold effect with a significant risk increase from the second to the first quartile. Compared with the upper three quartiles, the age-, sex- and BMI-adjusted HR (with 95% CI) in the first quartile was 2·26 (1·52-3·32) for overall mortality, 4·20 (2·03-8·69) for cardiovascular mortality and 1·25 (0·55-2·85) for cancer mortality. These associations remained materially unchanged after multivariate adjustments., Conclusions: Low plasma concentrations of homoarginine are a risk marker for overall mortality and especially for cardiovascular mortality in the older general population. Further studies are warranted to elucidate the underlying pathophysiological mechanisms., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Self-monitoring of blood glucose (SMBG) has been found to be effective for patients with type 1 diabetes and for patients with type 2 diabetes using insulin. There is much debate on the effectiveness of SMBG as a tool in the self-management for patients with type 2 diabetes who are not using insulin., Objectives: To assess the effects of SMBG in patients with type 2 diabetes mellitus who are not using insulin., Search Methods: Multiple electronic bibliographic and ongoing trial databases were searched supplemented with handsearches of references of retrieved articles (date of last search: 07 July 2011)., Selection Criteria: Randomised controlled trials investigating the effects of SMBG compared with usual care, self-monitoring of urine glucose (SMUG) or both in patients with type 2 diabetes who where not using insulin. Studies that used glycosylated haemoglobin A(1c) (HbA(1c)) as primary outcome were eligible for inclusion., Data Collection and Analysis: Two authors independently extracted data from included studies and evaluated the studies' risk of bias. Data from the studies were compared to decide whether they were sufficiently homogeneous to pool in a meta-analysis. Primary outcomes were HbA(1c), health-related quality of life, well-being and patient satisfaction. Secondary outcomes were fasting plasma glucose level, hypoglycaemic episodes, morbidity, adverse effects and costs., Main Results: Twelve randomised controlled trials were included and evaluated outcomes in 3259 randomised patients. Intervention duration ranged from 6 months (26 weeks) to 12 months (52 weeks). Nine trials compared SMBG with usual care without monitoring, one study compared SMBG with SMUG, one study was a three-armed trial comparing SMBG and SMUG with usual care and one study was a three-armed trial comparing less intensive SMBG and more intensive SMBG with a control group. Seven out of 11 studies had a low risk of bias for most indicators. Meta-analysis of studies including patients with a diabetes duration of one year or more showed a statistically significant SMBG induced decrease in HbA(1c) at up to six months follow-up (-0.3; 95% confidence interval (CI) -0.4 to -0.1; 2324 participants, nine trials), yet an overall statistically non-significant SMBG induced decrease was seen at 12 month follow-up (-0.1; 95% CI -0.3 to 0.04; 493 participants, two trials). Qualitative analysis of the effect of SMBG on well-being and quality of life showed no effect on patient satisfaction, general well-being or general health-related quality of life. Two trials reported costs of self-monitoring: One trial compared the costs of self-monitoring of blood glucose with self-monitoring of urine glucose based on nine measurements per week and with the prices in US dollars for self-monitoring in 1990. Authors concluded that total costs in the first year of self-monitoring of blood glucose, with the purchase of a reflectance meter were 12 times more expensive than self-monitoring of urine glucose ($481 or 361 EURO [11/2011 conversion] versus $40 or 30 EURO [11/2011 conversion]). Another trial reported a full economical evaluation of the costs and effects of self-monitoring. At the end of the trial, costs for the intervention were £89 (104 EURO [11/2011 conversion]) for standardized usual care (control group), £181 (212 EURO [11/2011 conversion]) for the less intensive self-monitoring group and £173 (203 EURO [11/2011 conversion]) for the more intensive self-monitoring group. Higher losses to follow-up in the more intensive self-monitoring group were responsible for the difference in costs, compared to the less intensive self-monitoring group.There were few data on the effects on other outcomes and these effects were not statistically significant. None of the studies reported data on morbidity., Authors' Conclusions: From this review, we conclude that when diabetes duration is over one year, the overall effect of self-monitoring of blood glucose on glycaemic control in patients with type 2 diabetes who are not using insulin is small up to six months after initiation and subsides after 12 months. Furthermore, based on a best-evidence synthesis, there is no evidence that SMBG affects patient satisfaction, general well-being or general health-related quality of life. More research is needed to explore the psychological impact of SMBG and its impact on diabetes specific quality of life and well-being, as well as the impact of SMBG on hypoglycaemia and diabetic complications.

Aim: To examine whether reduced cognitive functioning can be observed in early stages of left ventricular (LV) dysfunction and heart failure., Methods and Results: In 313 individuals aged 59-87 years from the longitudinal non-demented population-based Hoorn Study, echocardiography was performed to measure markers of LV systolic and diastolic function at baseline (2000-01) and follow-up (2005-09), together with standardized physical examinations and brain natriuretic peptide (BNP) measurements. Heart failure was assessed echocardiographically at the follow-up examination only. Cognitive tests for information processing speed, memory, and attention and executive functioning were administered at follow-up. Linear regression analyses showed that baseline markers of LV diastolic function, but not LV systolic function, were associated with lower scores on attention and executive functioning at follow-up. Individuals with higher baseline BNP had lower scores on all three cognitive domains: standardized regression coefficients were -0.16 (-0.26 to -0.05), -0.17 (-0.28 to -0.05), and -0.28 (-0.37 to -0.19). Worse LV systolic and diastolic function at follow-up were associated with a worse performance on attention and executive functioning. Furthermore, individuals with heart failure at follow-up had lower scores on attention and executive functioning: -0.21 (-0.41 to -0.00). Higher BNP at follow-up was also associated with worse attention and executive functioning, even after adjustment for baseline BNP., Conclusions: Worse cognitive functioning can already be observed in early stages of LV dysfunction and heart failure. BNP is a target for further investigation as a risk factor for cognitive decline in the general population.

Background: The benefits of intensive and continuous antihyperglycemic drug therapy have been extensively described. Data on long-term patterns and modifications of antihyperglycemic drug use are scarce however. Moreover randomized controlled studies may not reflect actual drug use in daily clinical practice., Objective: The aim of this study is to describe the longitudinal patterns of antidiabetic drug modifications after initiation of oral antidiabetic therapy in a large cohort of type 2 diabetes patients. The study will focus specifically on differences between patients who initiate treatment with metformin compared to patients who initiate treatment with sulfonylureas., Methods: An observational study of longitudinal patterns of use and modification of oral antidiabetic drug therapy in 3323 patients who started with oral antidiabetic treatment between 1999 and 2007. Drug dispensing data were extracted from pharmacy information systems., Results: This study shows that changes in international guidelines recommending metformin as first choice initial drug therapy in all patients were rapidly followed by prescribers. Patients starting diabetes treatment with metformin showed fewer modifications to treatment compared to patients initiating treatment with sulfonylureas. After correction for duration of follow-up, Cox regression analysis showed a hazard ratio of 0.84 for any modification in the metformin group compared to the sulfonylureas group., Conclusions: This study shows that adherence to type 2 diabetes treatment guidelines for initial treatment is implemented on a large scale. Longitudinal patterns show that the majority of patients receive a small number of modifications to their drug regimen. Discontinuation rates were relatively low., (Copyright © 2010 John Wiley & Sons, Ltd.)

Aims: Higher plasma B-type natriuretic peptide (BNP) in a non-heart failure (HF) range predicts HF and cardiovascular disease (CVD) mortality in the general population. Heart failure is highly prevalent in type 2 diabetes mellitus (T2DM), but associations of BNP to left ventricular (LV) mass and function in individuals with a different glucose status have not been compared. We therefore aimed to explore (i) the association of BNP levels in a non-HF range with structural and functional markers of LV function, and (ii) possible effect modification by glucose tolerance categories., Methods and Results: Linear regression analyses were performed to investigate associations of BNP with 2D echocardiographic measures of LV mass index, LV systolic function, and markers of LV diastolic function in a population-based study of men and women with normal glucose metabolism (NGM, n = 197), impaired glucose metabolism (IGM, n = 128), or T2DM (n = 204). Patients were aged between 50 and 87 years, had BNP levels below 50 pmol/L, and no LV wall motion abnormalities. B-type natriuretic peptide levels ranged from 0.4 to 46.1 pmol/L, the median was 4.2 pmol/L. Higher BNP was significantly associated with increased LV mass and deteriorated LV diastolic function, but not with LV systolic function. B-type natriuretic peptide was more strongly associated with LV diastolic function in T2DM compared with NGM and IGM., Conclusion: B-type natriuretic peptide was associated with LV mass and markers of LV diastolic function, and the association of BNP with the latter appeared to be particularly strong in individuals with T2DM. This implies that the presence or absence of T2DM should be taken into account if BNP levels are used to assess CVD risk.

Background: Self-monitoring of blood glucose (SMBG) has been found to be effective for patients with type 1 diabetes and for patients with type 2 diabetes using insulin. There is much debate on the effectiveness of SMBG as a tool in the self-management for patients with type 2 diabetes who are not using insulin., Objectives: The objective of this review was to assess the effects of SMBG in patients with type 2 diabetes mellitus who are not using insulin., Search Strategy: Studies were obtained from searches of multiple electronic bibliographic databases supplemented with hand searches of references of retrieved articles. Date of last search: September 2004., Selection Criteria: We included randomised controlled trails investigating the effects of SMBG compared with usual care and/or with self-monitoring of urine glucose in patients with type 2 diabetes who where not using insulin. Included studies should have used at least one of the following outcome measures: glycaemic control, quality of life, well-being, patient satisfaction, or hypoglycaemic episodes., Data Collection and Analysis: Two reviewers independently extracted data from included studies and assessed study quality. Data from the studies were compared to decide whether they were sufficiently homogeneous to pool in a meta-analysis., Main Results: Six randomised controlled trials were included in the review. Four trials compared SMBG with usual care, one trial compared SMBG with self-monitoring of urine glucose and there was one three-armed trial comparing SMBG with self-monitoring of urine glucose and usual care. Because of the differences in patient characteristics, interventions and outcomes between the studies, it was not possible to perform a meta-analysis. The methodological quality of studies was low. Two of the six studies reported a significant lowering effect of self-monitoring of blood glucose on HbA1c. However, one of these studies had a co-intervention with education on diet and lifestyle. There were few data on the effects of other outcomes and these effects were not statistically significant., Authors' Conclusions: From this review we concluded that self-monitoring of blood glucose might be effective in improving glycaemic control in patients with type 2 diabetes who are not using insulin. To assess the potential beneficial effects of SMBG in these patients a large and well-designed randomised controlled trial is required. This long-term trial should also investigate patient-related outcomes like quality of life, well-being and patient satisfaction, and provide adequate education to the patient to allow SMBG to be effective.

Background: Hyperhomocysteinaemia may constitute an independent risk factor for cardiovascular disease, but it is still unclear by which pathophysiological mechanisms homocysteine (tHcy) may promote atherothrombosis. The aim of this study was firstly to examine whether tHcy is associated with endothelial dysfunction, increased adherence of leukocytes, and/or chronic low-grade inflammation, as estimated from plasma levels of von Willebrand factor (vWf), soluble vascular cell adhesion molecule 1 (sVCAM-1) and C-reactive protein (CRP), respectively. Secondly we investigated whether the presence of type 2 diabetes modifies these associations., Materials and Methods: Six hundred and ten subjects of a general population of middle-aged and elderly subjects, 170 of whom had type 2 diabetes, participated in this cross-sectional study. Linear regression analyses were used to study whether tHcy was associated with vWf, sVCAM-1 and CRP, and whether the presence of diabetes modified these associations., Results: After adjustment for confounders, tHcy was significantly but weakly associated with vWf (beta = 0.15, P = 0.05) and sVCAM-1 (beta = 0.082, P = 0.04). tHcy was not significantly associated with CRP (beta = 0.02, P = 0.91). The presence of diabetes did not significantly modify these associations., Conclusions: This study provides evidence that tHcy is, at most, weakly associated with endothelial dysfunction as estimated from plasma vWf, and with leukocyte adhesion as estimated from plasma sVCAM-1. tHcy was not significantly associated with chronic low-grade inflammation as estimated from plasma CRP. Our data thus suggest that the link between tHcy and atherothrombosis cannot be explained by associations of tHcy with vWf, sVCAM-1 or CRP.

The World Health Organization distinguishes among non-diabetic persons a form of glucose intolerance defined as impaired glucose tolerance (IGT). The main reason for considering IGT as a diagnostic entity is its prognostic value for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, the use of one or two oral glucose tolerance tests (OGTT) for the definition of IGT and the large variability of the 2-h glucose level may explain the wide range of the incidence rates reported for NIDDM in subjects with IGT. It is evident that the pathogenesis of diabetes is still poorly understood. Both insulin resistance and impaired function of the beta-cell are thought to be important contributing factors in the development of diabetes. The 2-h post-load glucose level from the OGTT is most powerful for the prediction of the development of NIDDM. In addition, a fasting hyperinsulinaemia and a low glucose removal rate, both reflecting insulin resistance, were found to be associated with a higher risk for the progression of NIDDM. In the San Antonio Study and in the Hoorn Study high fasting proinsulin levels, reflecting beta-cell dysfunction, were associated with progression to NIDDM. Lipid levels did not predict progression to NIDDM in most studies. A two-step model for the development of NIDDM is hypothesized. The first step, the transition from normal to impaired glucose tolerance, is assumed to depend mainly on the presence of insulin resistance. The second step, progressing from IGT to diabetes, although accompanied by some further worsening of insulin resistance, is thought to be primarily dependent on the development of beta-cell dysfunction.