Cultural competency of GP trainees and GP trainers: a cross-sectional survey study.

OBJECTIVE: To assess the cultural competence (CC) of GP trainees and GP trainers.Design and setting: A cross-sectional survey study was conducted at the GP Training Institute of Amsterdam UMC. SUBJECTS: We included 92 GP trainees and 186 GP trainers. MAIN OUTCOME MEASURES: We measured the three domains of cultural competency: 1) knowledge, 2) culturally competent attitudes and 3) culturally competent skills. Regression models were used to identify factors associated with levels of CC. Participants rated their self-perceived CC at the beginning and end of the survey, and the correlation between self-perceived and measured CC was assessed. RESULTS: Approximately 94% of the GP trainees and 81% of the GP trainers scored low on knowledge; 45% and 42%, respectively, scored low on culturally competent attitudes. The level of culturally competent skills was moderate (54.3%) or low (48.4%) for most GP trainees and GP trainers. The year of residency and the GP training institute were significantly associated with one or more (sub-)domains of CC in GP trainees. Having >10% migrant patients and experience as a GP trainer were positively associated with one or more (sub-) domains of cultural competence in GP trainers. The correlation between measured and self-perceived CC was positive overall but very weak (Spearman correlation coefficient ranging from -0.1-0.3). CONCLUSION: The level of cultural competence was low in both groups, especially in the knowledge scores. Cultural competence increased with experience and exposure to an ethnically diverse patient population. Our study highlights the need for cultural competence training in the GP training curricula.

General practitioner (GP) trainees find cross-cultural consultations stressful due to a self-perceived lack of cultural competence (CC). The level of CC in general practice is as yet unknown.On average, the level of CC was low for the majority of GP trainees and GP trainers, especially for the scores on knowledge.CC increased with experience and exposure to an ethnically diverse patient population.GP trainees and trainers perceived a lack of covered education on various topics related to the care of migrants.Our study highlights the need for cultural competence training in the GP training curricula.

Performance of prediction models for nephropathy in people with type 2 diabetes: systematic review and external validation study.

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.

Serum Magnesium Is Inversely Associated With Heart Failure, Atrial Fibrillation, and Microvascular Complications in Type 2 Diabetes.

OBJECTIVE: We investigated whether serum magnesium (Mg2+) was prospectively associated with macro- or microvascular complications and mediated by glycemic control (hemoglobin A1c [HbA1c]), in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We analyzed in 4,348 participants the association of serum Mg2+ with macrovascular disease and mortality (acute myocardial infarction [AMI], coronary heart disease [CHD], heart failure [HF], cerebrovascular accident [CVA], and peripheral arterial disease [PAD]), atrial fibrillation (AF), and microvascular complications (chronic kidney disease [CKD], diabetic retinopathy, and diabetic foot) using Cox regression, adjusted for confounders. Mediation analysis was performed to assess whether HbA1c mediated these associations. RESULTS: The average baseline serum Mg2+ concentration was 0.80 ± 0.08 mmol/L. During 6.1 years of follow-up, serum Mg2+ was inversely associated with major macrovascular, 0.87 (95% CI 0.76; 1.00); HF, 0.76 (95% CI 0.62; 0.93); and AF, 0.59 (95% CI 0.49; 0.72). Serum Mg2+ was not associated with AMI, CHD, CVA, and PAD. During 5.1 years of follow-up, serum Mg2+ was inversely associated with overall microvascular events, 0.85 (95% CI 0.78; 0.91); 0.89 (95% CI 0.82; 0.96) for CKD, 0.77 (95% CI 0.61; 0.98) for diabetic retinopathy, and 0.85 (95% CI 0.78; 0.92) for diabetic foot. HbA1c mediated the associations of serum Mg2+ with HF, overall microvascular events, diabetic retinopathy, and diabetic foot. CONCLUSIONS: Serum Mg2+ concentration is inversely associated with the risk to develop HF and AF and with the occurrence of CKD, diabetic retinopathy, and foot complications in T2D. Glycemic control partially mediated the association of serum Mg2+ with HF and microvascular complications.

The interobserver agreement of ECG abnormalities using Minnesota codes in people with type 2 diabetes.

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.

A personalised screening strategy for diabetic retinopathy: a cost-effectiveness perspective.

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.

Phenotypic and lifestyle determinants of HbA1c in the general population-The Hoorn Study.

AIM: To investigate the relative contribution of phenotypic and lifestyle factors to HbA1c, independent of fasting plasma glucose (FPG) and 2h post-load glucose (2hPG), in the general population. METHODS: The study populations included 2309 participants without known diabetes from the first wave of the Hoorn Study (1989) and 2619 from the second wave (2006). Multivariate linear regression models were used to analyze the relationship between potential determinants and HbA1c in addition to FPG and 2hPG. The multivariate model was derived in the first wave of the Hoorn Study, and replicated in the second wave. RESULTS: In both cohorts, independent of FPG and 2hPG, higher age, female sex, larger waist circumference, and smoking were associated with a higher HbA1c level. Larger hip circumference, higher BMI, higher alcohol consumption and vitamin C intake were associated with a lower HbA1c level. FPG and 2hPG together explained 41.0% (first wave) and 53.0% (second wave) of the total variance in HbA1c. The combination of phenotypic and lifestyle determinants additionally explained 5.7% (first wave) and 3.9% (second wave). CONCLUSIONS: This study suggests that, independent of glucose, phenotypic and lifestyle factors are associated with HbA1c, but the contribution is relatively small. These findings contribute to a better understanding of the low correlation between glucose levels and HbA1c in the general population.

Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas.

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).

Moderate and heavy alcohol consumption are prospectively associated with decreased left ventricular ejection fraction: The Hoorn Study.

BACKGROUND AND AIMS: Data on the prospective relationship of alcohol consumption at more moderate levels with systolic and diastolic function are scarce. We aimed to examine the prospective association of alcohol consumption with echocardiographic measures of cardiac structure and function, in individuals with and without type 2 diabetes (T2DM). METHODS AND RESULTS: We included 778 participants from the Hoorn Study (aged 68.4 ± 7.2 years, 49% women), a population-based prospective cohort study, oversampled for people with impaired glucose metabolism or T2DM. Self-reported alcohol consumption was collected at baseline with a validated food-frequency questionnaire and categorized into: none (0/week), light (>0-≤30 g/week), light-to-moderate (>30-≤70 g/week), moderate (>70-≤140 g/week), and heavy drinkers (>140 g/week). Echocardiography was performed at baseline (N = 778) and after 8 years follow-up (N = 404). Multiple linear regression was used to study the association between alcohol consumption and echocardiographic measures (left ventricular ejection fraction (LVEF), left atrial volume index (LAVI) and left ventricular mass index (LVMI)), adjusted for confounders. Moderate and heavy alcohol consumption were associated with a decreased LVEF of -3.91% (CI: -7.13;-0.69) for moderate and -4.77% (-8.18;-1.36) for heavy drinkers compared to light drinkers. No associations were found between alcohol consumption, LVMI and LAVI. Modified Poisson regression showed a trend that higher alcohol consumption amounts were associated with a higher risk of incident systolic dysfunction (LVEF≤50%) (P-for-trend 0.058). CONCLUSION: The findings provide longitudinal evidence that moderate and heavy alcohol consumption are associated with decreased LVEF and trend towards a higher risk of incident LV systolic dysfunction, compared to light drinkers.

Cost-effectiveness of a clinical medication review in vulnerable older patients at hospital discharge, a randomized controlled trial.

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.

Type 2 Diabetes, but Not Insulin (Analog) Treatment, Is Associated With More Advanced Stages of Breast Cancer: A National Linkage of Cancer and Pharmacy Registries.

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.

Sex- and site-specific differences in colorectal cancer risk among people with type 2 diabetes.

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.

Blood Metabolomic Measures Associate With Present and Future Glycemic Control in Type 2 Diabetes.

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.

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 Collaboration's 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.

HbA1c is associated with altered expression in blood of cell cycle- and immune response-related genes.

AIMS/HYPOTHESIS: Individuals with type 2 diabetes are heterogeneous in their glycaemic control as tracked by blood HbA1c levels. Here, we investigated the extent to which gene expression levels in blood reflect current and future HbA1c levels. METHODS: HbA1c levels at baseline and 1 and 2 year follow-up were compared with gene expression levels in 391 individuals with type 2 diabetes from the Hoorn Diabetes Care System Cohort (15,564 genes, RNA sequencing). The functions of associated baseline genes were investigated further using pathway enrichment analysis. Using publicly available data, we investigated whether the genes identified are also associated with HbA1c in the target tissues, muscle and pancreas. RESULTS: At baseline, 220 genes (1.4%) were associated with baseline HbA1c. Identified genes were enriched for cell cycle and complement system activation pathways. The association of 15 genes extended to the target tissues, muscle (n = 113) and pancreatic islets (n = 115). At follow-up, expression of 25 genes (0.16%) associated with 1 year HbA1c and nine genes (0.06%) with 2 year HbA1c. Five genes overlapped across all time points, and 18 additional genes between baseline and 1 year follow-up. After adjustment for baseline HbA1c, the number of significant genes at 1 and 2 years markedly decreased, suggesting that gene expression levels in whole blood reflect the current glycaemic state and but not necessarily the future glycaemic state. CONCLUSIONS/INTERPRETATION: HbA1c levels in individuals with type 2 diabetes are associated with expression levels of genes that link to the cell cycle and complement system activation.

External Validation of a Tool Predicting 7-Year Risk of Developing Cardiovascular Disease, Type 2 Diabetes or Chronic Kidney Disease.

BACKGROUND: Chronic cardiometabolic diseases, including cardiovascular disease (CVD), type 2 diabetes (T2D) and chronic kidney disease (CKD), share many modifiable risk factors and can be prevented using combined prevention programs. Valid risk prediction tools are needed to accurately identify individuals at risk. OBJECTIVE: We aimed to validate a previously developed non-invasive risk prediction tool for predicting the combined 7-year-risk for chronic cardiometabolic diseases. DESIGN: The previously developed tool is stratified for sex and contains the predictors age, BMI, waist circumference, use of antihypertensives, smoking, family history of myocardial infarction/stroke, and family history of diabetes. This tool was externally validated, evaluating model performance using area under the receiver operating characteristic curve (AUC)-assessing discrimination-and Hosmer-Lemeshow goodness-of-fit (HL) statistics-assessing calibration. The intercept was recalibrated to improve calibration performance. PARTICIPANTS: The risk prediction tool was validated in 3544 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). KEY RESULTS: Discrimination was acceptable, with an AUC of 0.78 (95% CI 0.75-0.81) in men and 0.78 (95% CI 0.74-0.81) in women. Calibration was poor (HL statistic: p < 0.001), but improved considerably after intercept recalibration. Examination of individual outcomes showed that in men, AUC was highest for CKD (0.85 [95% CI 0.78-0.91]) and lowest for T2D (0.69 [95% CI 0.65-0.74]). In women, AUC was highest for CVD (0.88 [95% CI 0.83-0.94)]) and lowest for T2D (0.71 [95% CI 0.66-0.75]). CONCLUSIONS: Validation of our previously developed tool showed robust discriminative performance across populations. Model recalibration is recommended to account for different disease rates. Our risk prediction tool can be useful in large-scale prevention programs for identifying those in need of further risk profiling because of their increased risk for chronic cardiometabolic diseases.

Extension of the association structure in joint models to include weighted cumulative effects.

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.

Self-reported hypoglycaemia in patients with type 2 diabetes treated with insulin in the Hoorn Diabetes Care System Cohort, the Netherlands: a prospective cohort study.

BACKGROUND: Our aim was to study the prevalence of self-reported hypoglycaemic sensations and its association with mortality in patients with type 2 diabetes (T2D) treated with insulin in usual care. METHODS: Demographics, clinical characteristics and mortality data were obtained from 1667 patients with T2D treated with insulin in the Hoorn Diabetes Care System Cohort (DCS), a prospective cohort study using clinical care data. Self-reported hypoglycaemic sensations were defined as either mild: events not requiring help; or severe: events requiring help from others (either medical assistance or assistance of others). The association between hypoglycaemic sensations and mortality was analysed using logistic regression analysis. RESULTS: At baseline, 981 patients (59%) reported no hypoglycaemic sensations in the past year, 612 (37%) reported only mild sensations and 74 (4%) reported severe hypoglycaemic sensations. During a median follow-up of 1.9 years, 98 patients (5.9%) died. Reporting only mild hypoglycaemic sensations was associated with a lower mortality risk (OR 0.48, 95% CI 0.28 to 0.80), while reporting severe sensations was not significantly associated with mortality (OR 0.76, 95% CI 0.33 to 1.80), compared with reporting no hypoglycaemic sensations, and adjusting for demographic and clinical characteristics. Sensitivity analyses showed an OR of 1.38 (95% CI 0.31 to 6.11) for patients reporting severe hypoglycaemic sensations requiring medical assistance. CONCLUSIONS: Self-reported hypoglycaemic sensations are highly prevalent in our insulin-treated T2D population. Patients reporting hypoglycaemic sensations not requiring medical assistance did not have an increased risk of mortality, suggesting that these sensations are not an indicator of increased short-term mortality risk in patients with T2D.

Time to insulin initiation and long-term effects of initiating insulin in people with type 2 diabetes mellitus: the Hoorn Diabetes Care System Cohort Study.

OBJECTIVE: The aim of this study was to assess the time to insulin initiation in type 2 diabetes mellitus (T2DM) patients treated with oral glucose-lowering agents and to determine the baseline characteristics associated with time to insulin initiation. This was evaluated in T2DM patients with HbA1c levels consistently ≥7.0% during total follow up and in those with fluctuating HbA1c levels around 7.0%. DESIGN AND METHODS: Prospective, observational study was performed, comprising 2418 persons with T2DM aged ≥40 years who entered the Diabetes Care System between 1998 and 2012 with a minimum follow up of at least 3 years, following the first HbA1c level ≥7.0%. Cox regression analyses were performed to assess the determinants of time to insulin initiation. Data related to long-term effects of insulin initiation were studied at baseline and at the end of follow up using descriptive summary statistics. RESULTS: Two-thirds of the patients initiated insulin during follow up. The time to insulin varied from 1.2 years (range 0.3-3.1) in patients with HbA1c levels consistently ≥7.0% to 5.4 years (range 3.0-7.5) in patients with fluctuating HbA1c levels around 7.0%. Longer diabetes duration (hazard ratio (HR) 1.04 95% CI 1.03-1.05) and lower age (HR 1.00 95% CI 0.99-1.00) at baseline were associated with a shorter time to initiation. More insulin initiators had retinopathy compared with patients that remained on oral glucose-lowering agents during follow up. CONCLUSION: The time to insulin initiation was short, and most of the patients with HbA1c levels consistently ≥7.0% were initiating insulin. Longer diabetes duration and younger age shortened the time to insulin.

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 140 mmHg) 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.

Distinct HbA1c trajectories in a type 2 diabetes cohort.

AIMS: The aim of this study was to identify subgroups of type 2 diabetes mellitus patients with distinct hemoglobin A1c (HbA1c) trajectories. Subgroup characteristics were determined and the prevalence of microvascular complications over time was investigated. STUDY DESIGN AND SETTING: Data from a cohort of 5,423 type 2 diabetes patients from a managed primary care system were used [mean follow-up 5.7 years (range 2-9 years)]. Latent class growth modeling was used to identify subgroups of patients with distinct HbA1c trajectories. Multinomial logistic regression analyses were conducted to determine which characteristics were associated with different classes. RESULTS: Four subgroups were identified. The first and largest subgroup (83 %) maintained good glycemic control over time (HbA1c ≤53 mmol/mol), the second subgroup (8 %) initially showed severe hyperglycemia, but reached the recommended HbA1c target within 2 years. Patients within this subgroup had significantly higher baseline HbA1c levels but were otherwise similar to the good glycemic control group. The third subgroup (5 %) showed hyperglycemia and a delayed response without reaching the recommended HbA1c target. The fourth subgroup (3.0 %) showed deteriorating hyperglycemia over time. Patients within the last two subgroups were significantly younger, had higher HbA1c levels and a longer diabetes duration at baseline. These subgroups also showed a higher prevalence of retinopathy and microalbuminuria. CONCLUSION: Four subgroups with distinct HbA1c trajectories were identified. More than 90 % reached and maintained good glycemic control (subgroup one and two). Patients within the two subgroups that showed a more unfavorable course of glycemic control were younger, had higher HbA1c levels and a longer diabetes duration at baseline.