Data-driven assessment, contextualisation and implementation of 134 variables in the risk for type 2 diabetes:an analysis of Lifelines, a prospective cohort study in the Netherlands

Aims/hypothesis We aimed to assess and contextualise 134 potential risk variables for the development of type 2 diabetes and to determine their applicability in risk prediction. Methods A total of 96,534 people without baseline diabetes (372,007 person-years) from the Dutch Lifelines cohort were included. We used a risk variable-wide association study (RV-WAS) design to independently screen and replicate risk variables for 5-year incidence of type 2 diabetes. For identified variables, we contextualised HRs, calculated correlations and assessed their robustness and unique contribution in different clinical contexts using bootstrapped and cross-validated lasso regression models. We evaluated the change in risk, or 'HR trajectory', when sequentially assigning variables to a model. Results We identified 63 risk variables, with novel associations for quality-of-life indicators and non-cardiovascular medications (i.e., proton-pump inhibitors, anti-asthmatics). For continuous variables, the increase of 1 SD of HbA(1c), i.e., 3.39 mmol/mol (0.31%), was equivalent in risk to an increase of 0.53 mmol/l of glucose, 19.8 cm of waist circumference, 8.34 kg/m(2) of BMI, 0.67 mmol/l of HDL-cholesterol, and 0.14 mmol/l of uric acid. Other variables required an increase of >3 SD, which is not physiologically realistic or a rare occurrence in the population. Though moderately correlated, the inclusion of four variables satiated prediction models. Invasive variables, except for glucose and HbA(1c), contributed little compared with non-invasive variables. Glucose, HbA(1c) and family history of diabetes explained a unique part of disease risk. Adding risk variables to a satiated model can impact the HRs of variables already in the model. Conclusions Many variables show weak or inconsistent associations with the development of type 2 diabetes, and only a handful can reliably explain disease risk. Newly discovered risk variables will yield little over established factors, and existing prediction models can be simplified. A systematic, data-driven approach to identify risk variables for the prediction of type 2 diabetes is necessary for the practice of precision medicine

Preventive use of nitisinone in alkaptonuria

Abstract Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are joint problems, cardiac valve abnormalities and renal problems. Landmark intervention studies with nitisinone 10 mg daily, suppressing an upstream enzyme activity, demonstrated its beneficial effects in AKU patients with established complications, which usually start to develop in the fourth decade. Lower dose of nitisinone in the range of 0.2–2 mg daily will already reduce urinary homogentisic acid (uHGA) excretion by > 90%, which may prevent AKU-related complications earlier in the course of the disease while limiting the possibility of side-effects related to the increase of plasma tyrosine levels caused by nitisinone. Future preventive studies should establish the lowest possible dose for an individual patient, the best age to start treatment and also collect evidence to which level uHGA excretion should be reduced to prevent complications

Macro-B12 masking B12 deficiency

In clinical practice, the finding of an elevated serum B(12) concentration is often the consequence of supplementation with B(12) in either oral form or injections. Also, elevated serum B(12) may be associated with underlying disorders, like liver diseases or a (haematologic) malignancy. Only a few studies have shown that it may also be the consequence of complex formation of B(12)-vitamin binding proteins with immunoglobulins, the so-called macro-B(12). We describe a young woman who previously was diagnosed with B(12) deficiency, and in whom, after cessation of B(12) injection treatment, neurologic symptoms re-appeared, and despite this, repeatedly elevated serum B(12) concentrations above the upper limit of the assay were found. We demonstrated that this was caused by the presence of macro-B(12), which not only resulted in erroneous and longstanding elevated serum B(12), but also masked her underlying B(12) deficiency

Relationship between serum B12 concentrations and mortality:experience in NHANES

BACKGROUND: There is conflicting evidence in the literature on the association between (elevated) serum B12 concentrations and subsequent disease or mortality. We evaluated in the NHANES general population the association of serum B12 concentrations as well as vitamin B12 supplement intake with all-cause, cardiovascular, and cancer-related mortality, while taking into account demographic and lifestyle factors and significant other diseases which are known to be associated with poorer outcome. METHODS: The main outcomes of our study were all-cause mortality, cardiovascular mortality, and cancer-related mortality. Mortality status and cause of death were determined by NHANES-linked National Death Index public access files through December 31, 2015. The association of serum B12 concentrations and vitamin B12 supplement intake with mortality was assessed with Cox proportional hazard (PH) models, with adjustment for a number of relevant demographic and lifestyle factors and comorbidity. RESULTS: The final study population of 24,262 participants had a mean age of 48 (SD 19) years; 50.1% were males. The median follow-up duration was 109 months (range 1-201 months). On the census day of December 31, 2015, 3023 participants were determined as deceased (12.5%). The fully adjusted Cox PH model indicated that low serum B12 concentrations  700 pmol/l were associated with an increase in cardiovascular mortality only (HR 1.45, 95% CI 1.01-2.06, p = 0.042). Participants with a diagnosis of hypertension, dyslipidemia, CVD, and cancer more frequently used vitamin B12-containing supplements than those without these diagnoses. We could not demonstrate an association between vitamin B12 supplement intake and mortality, when adjusted for comorbidity. CONCLUSIONS: In the general population of NHANES, low serum B12 concentrations were associated with a moderate increase in all-cause mortality. There was a small but significant increase in cardiovascular mortality in the groups with low or high serum B12. High intake of vitamin B12 in the form of supplements was not associated with any adverse effect on mortality and therefore can be regarded as safe

Medication Adherence Affects Treatment Modifications in Patients With Type 2 Diabetes

Background: Low rates of treatment modification in patients with insufficiently controlled risk factors are common in type 2 diabetes. Although adherence problems are often mentioned in surveys as a reason for not intensifying treatment, observational studies have shown inconclusive results. Objective: To assess how medication adherence affects treatment modifications for hypertension and hyperglycemia in patients with type 2 diabetes. Methods: This was a cohort study of 11,268 primary care patients with type 2 diabetes in the Netherlands. Inclusion criteria were diagnosis before 2007, >= 1 prescription to antihypertensive or glucose-regulating medication in the preceding 6 months, and a systolic blood pressure level >= 140 mm Hg or glycosylated hemoglobin >= 7% in 2007. Patients on maximal treatment were excluded. Treatment modifications as observed from prescriptions were classified as none, dose increase, dose decrease, class switch, class addition, or class discontinuation. Refill adherence was assessed as medication possession ratio or length of last gap between refills. We performed multilevel multinomial regression analysis to test for associations. Results: We included 4980 diabetic patients with elevated blood pressure and 2945 diabetic patients with elevated glycosylated hemoglobin levels. Patients with lower adherence for antihypertensive drugs were more likely to have those medications discontinued (odds ratio [OR] for every 10% lower medication possession ratio =1.22; 95% CI, 1.11-1.33) or the dose decreased (OR = 1.14; CI 1.01-1.28). For glucose-regulating medication, dose increases (OR = 0.92; 95% CI, 0.85-0.98) and medication additions (OR = 0.90; 95% CI, 0.82-0.99) were less likely in patients with lower adherence levels. Conclusions: Low adherence inhibits the intensification of glucose-regulating but not antihypertensive medication in type 2 diabetic patients with insufficiently controlled risk factors in the Netherlands. Adherence problems may lead to diminished or even discontinued antihypertensive treatment. (Clin Ther. 2011;33:121-134) (c) 2011 Elsevier HS Journals, Inc

A Pilot Study on the Prevalence of Micronutrient Imbalances in a Dutch General Population Cohort and the Effects of a Digital Lifestyle Program

Maintaining an adequate micronutrient status can be achieved by following a complete, diverse diet. Yet, food trends in Western countries show suboptimal consumption of healthy nutrients. In this study, we explored the prevalence of vitamin and mineral imbalances in a general population cohort of Dutch adults and evaluated the effect of a digital lifestyle program on the nutritional status and nutrition health behaviors of these individuals. A micronutrient panel was measured in 348 participants, alongside a dietary assessment. One hundred users subsequently underwent a remeasurement. We identified at least one nutritional imbalance in 301 individuals (86.5%). A total of 80% improved and normalized B6, 67% improved folate, 70% improved B12, and 86% improved vitamin D. Iron abnormalities were corrected in 75% of the participants. In conclusion, this study found that micronutrient deficiencies of easily obtainable vitamins through diet or supplementation such as B vitamins and vitamin D were more prevalent than expected in a Dutch population. This can partly be explained by insufficient consumption of food groups rich in B vitamins. Our preliminary results in those remeasured after a digitally enabled lifestyle intervention show these imbalances can be corrected with adequate behavioral support complemented with supplementation where needed

Postpartum glucose follow-up and lifestyle management after gestational diabetes mellitus:general practitioner and patient perspectives

BACKGROUND: Incidence of type 2 diabetes is high after gestational diabetes mellitus (GDM). We aimed to evaluate the adherence to follow-up six-weeks postpartum visits in secondary care after GDM and glucose monitoring in primary care longer than 12-14 months after delivery and the years thereafter. In addition, we examined the women's lifestyle after delivery. METHODS: A cross-sectional follow-up survey among women with a history of GDM and their general practitioners (GP). Rates of attendance at the six-weeks postpartum visit and glucose testing were obtained from hospital records, over the period 2011-2012. Rates of annual follow-up postpartum glucose testing were assessed by a survey among their GP's. Lifestyle of the women on diet and exercise was assessed by questionnaire in 2015. RESULTS: In total 197 women were eligible for the study. Of these, 156 (79%) attended the six-weeks postpartum visit at the diabetes outpatient clinic and in 145 (93%) of these women glucose testing was performed. In total 77 (39%) women responded to the invitation to participate in this study and filled in the lifestyle questionnaire. About one third of the women met the recommendations for sufficient physical activity. A majority of them did not fulfil the Dutch guidelines on healthy diet - fruit intake 35.1%, vegetables intake 7.8%. Of the 74 invited GP's, 61 responded (82%), only 12 (20%) reported that they had performed a follow-up glucose testing within >12-14 months postpartum. Of these women, five were tested only in the first year of follow-up, five also in the second year, and two were tested for three consecutive years. CONCLUSIONS: Despite the high attendance rate of six-weeks postpartum visit and glucose testing, we observed low rates of longer-term follow-up regarding postpartum glucose testing. Moreover, we found a suboptimal adherence to healthy lifestyle for women with a history of GDM

The Many Faces of Cobalamin (Vitamin B12) Deficiency

Although cobalamin (vitamin B12) deficiency was described over a century ago, it is still difficult to establish the correct diagnosis and prescribe the right treatment. Symptoms related to vitamin B12 deficiency may be diverse and vary from neurologic to psychiatric. A number of individuals with vitamin B12 deficiency may present with the classic megaloblastic anemia. In clinical practice, many cases of vitamin B12 deficiency are overlooked or sometimes even misdiagnosed. In this review, we describe the heterogeneous disease spectrum of patients with vitamin B12 deficiency in whom the diagnosis was either based on low serum B12 levels, elevated biomarkers like methylmalonic acid and/or homocysteine, or the improvement of clinical symptoms after the institution of parenteral vitamin B12 therapy. We discuss the possible clinical signs and symptoms of patients with B12 deficiency and the various pitfalls of diagnosis and treatment.</p

Differences in lipid and blood pressure measurements between individuals with type 1 diabetes and the general population:a cross-sectional study

OBJECTIVES: Cardiovascular disease (CVD) is a precarious complication of type 1 diabetes (T1D). Alongside glycaemic control, lipid and blood pressure (BP) management are essential for the prevention of CVD. However, age-specific differences in lipid and BP between individuals with T1D and the general population are relatively unknown.DESIGN: Cross-sectional study.SETTING: Six diabetes outpatient clinics and individuals from the Lifelines cohort, a multigenerational cohort from the Northern Netherlands.PARTICIPANTS: 2178 adults with T1D and 146 22 individuals without diabetes from the general population.PRIMARY AND SECONDARY OUTCOME MEASURES: Total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol), systolic BP (SBP) and diastolic BP (DBP), stratified by age group, glycated haemoglobin category, medication use and sex.RESULTS: In total, 2178 individuals with T1D and 146 822 without diabetes were included in this study. Total cholesterol and LDL-cholesterol were lower and SBP and DBP were higher in individuals with T1D in comparison to the background population. When stratified by age and medication use, total cholesterol and LDL-cholesterol were lower and SBP and DBP were higher in the T1D population. Men with T1D achieved lower LDL-cholesterol levels both with and without medication in older age groups in comparison to women. Women with T1D had up to 8 mm Hg higher SBP compared with the background population, this difference was not present in men.CONCLUSIONS: Lipid and BP measurements are not comparable between individuals with T1D and the general population and are particularly unfavourable for BP in the T1D group. There are potential sex differences in the management of LDL-cholesterol and BP.</p