[Show abstract][Hide abstract] ABSTRACT: Hyperglycaemia during hospital admission is common in patients who are not known to have diabetes and is associated with adverse outcomes. The risk of subsequently developing type 2 diabetes, however, is not known. We linked a national database of hospital admissions with a national register of diabetes to describe the association between admission glucose and the risk of subsequently developing type 2 diabetes.
PLoS Medicine 08/2014; 11(8):e1001708. DOI:10.1371/journal.pmed.1001708 · 15.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Design Mendelian randomisation meta-analysis of 56 epidemiological studies. Participants 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. Main outcome measures Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. Results Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P= 0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). Conclusions Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
[Show abstract][Hide abstract] ABSTRACT: Background
Statin therapy is widely used in the prevention and treatment of cardiovascular events and is associated with significant risk reductions. However, there is considerable variation in response to statin therapy both in terms of LDL cholesterol reduction and clinical outcomes. It has been hypothesized that genetic variation contributes importantly to this individual drug response.
Methods and results
We investigated the interaction between genetic variants and pravastatin or placebo therapy on the incidence of cardiovascular events by performing a genome-wide association study in the participants of the PROspective Study of Pravastatin in the Elderly at Risk for vascular disease–PHArmacogenetic study of Statins in the Elderly at risk (PROSPER/PHASE) study (n = 5244). We did not observe genome-wide significant associations with a clinically meaningful differential cardiovascular event reduction by pravastatin therapy. In addition, SNPs with p-values lower than 1 × 10−4 were assessed for replication in a case-only analysis within two randomized placebo controlled pravastatin trials, CARE (n = 711) and WOSCOPS (n = 522). rs7102569, on chromosome 11 near the ODZ4 gene, was replicated in the CARE study (p = 0.008), however the direction of effect was opposite. This SNP was not associated in WOSCOPS. In addition, none of the SNPs replicated significantly after correcting for multiple testing.
We could not identify genetic variation that was significantly associated at genome-wide level with a clinically meaningful differential event reduction by pravastatin treatment in a large prospective study. We therefore assume that in daily practice the use of genetic characteristics to personalize pravastatin treatment to improve prevention of cardiovascular disease will be limited.
[Show abstract][Hide abstract] ABSTRACT: To compare the relationship between adiposity and prevalent diabetes across ethnic groups in the UK Biobank cohort and to derive ethnic-specific obesity cutoffs that equate to those developed on white populations in terms of diabetes prevalence.RESEARCH DESIGN AND METHODS: UK Biobank recruited 502,682 U.K. residents aged 40-69 years. We used baseline data on the 490,288 participants from the four largest ethnic subgroups: 471,174 (96.1%) white, 9,631 (2.0%) South Asian, 7,949 (1.6%) black, and 1,534 (0.3%) Chinese. Regression models were developed for the association between anthropometric measures (BMI, waist circumference, percentage body fat, and waist-to-hip ratio) and prevalent diabetes, stratified by sex and adjusted for age, physical activity, socioeconomic status, and heart disease.RESULTS: Nonwhite participants were two- to fourfold more likely to have diabetes. For the equivalent prevalence of diabetes at 30 kg/m(2) in white participants, BMI equated to the following: South Asians, 22.0 kg/m(2); black, 26.0 kg/m(2); Chinese women, 24.0 kg/m(2); and Chinese men, 26.0 kg/m(2). Among women, a waist circumference of 88 cm in the white subgroup equated to the following: South Asians, 70 cm; black, 79 cm; and Chinese, 74 cm. Among men, a waist circumference of 102 cm equated to 79, 88, and 88 cm for South Asian, black, and Chinese participants, respectively.CONCLUSIONS: Obesity should be defined at lower thresholds in nonwhite populations to ensure that interventions are targeted equitably based on equivalent diabetes prevalence. Furthermore, within the Asian population, a substantially lower obesity threshold should be applied to South Asian compared with Chinese groups.
Diabetes Care 06/2014; 37(9). DOI:10.2337/dc13-2966 · 8.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As is well known, diabetes rates continue to escalate worldwide, adding cost and disease burden to all health-care institutions. Over the last few years, however, a number of diabetes paradigms have been challenged, not least on the best methods to lessen or delay the development of co-morbidities, in particular cardiovascular disease (CVD) (i.e. targeting blood pressure, cholesterol, and smoking will do more than intensive glucose control). In addition, recent research has offered some hope to potentially reverse diabetes in motivated individuals, with resultant larger and longer trials of such interventions about to commence. This brief review summarizes these important recent developments and suggests that, while many new drugs are being added to the diabetes therapeutic armory, more could and should be done to target sustainable weight change in our patients for multiple health benefits.
[Show abstract][Hide abstract] ABSTRACT: We investigated microvascular event risk in people with type 2 diabetes and assessed whether N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTnT) improved prediction.RESEARCH DESIGN AND METHODS: We performed a case-cohort study, including 439 incident cases of microvascular events (new or worsening nephropathy or retinopathy) and 2,946 noncase subjects identified from participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. NT-proBNP and hsTnT were measured in stored plasma samples using automated commercial assays.RESULTS: After adjustment for age, sex, and randomized treatment, the hazard ratios for microvascular events per 1-SD increase in the log-transformed hsTnT and NT-proBNP were 1.67 (95% CI 1.51-1.85) and 1.63 (1.44-1.84), respectively. After further adjustment for classical and diabetes-related cardiovascular disease risk factors, the hazard ratios attenuated to 1.40 (1.24-1.58) and 1.41 (1.24-1.60), respectively. While the C statistic did not improve on addition of hsTnT or NT-proBNP for the total microvascular end point, a combination of both markers improved the prediction of nephropathy (P = 0.033) but not retinopathy (P = 0.72). The corresponding net reclassification indices in a three-risk category model (<10%, 10-15%, and >15% 5-year risk) for all microvascular events were 7.31% (95% CI 2.24-12.79) for hsTNT addition, 6.23% (1.74-11.5) for NT-proBNP addition, and 7.1% (1.5-12.9) for both markers together.CONCLUSIONS: These data suggest that cardiac biomarkers moderately improve microvascular event risk prediction, in particular the risk of nephropathy. Further studies examining the value of this approach for trial design and clinical use are warranted.
Diabetes Care 05/2014; 37(8). DOI:10.2337/dc13-2625 · 8.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Excess body fat is associated with an increase in risk of type 2 diabetes and hypertension in adulthood and these risks can adversely affect progression of arterial disease. We aimed to assess the impact of lifelong patterns of adiposity on cardiovascular risk factors and carotid intima media thickness (cIMT) in later life in participants in the 1946 British birth cohort study.
[Show abstract][Hide abstract] ABSTRACT: Statin therapy reduces the risk of myocardial infarction, stroke, and cardiovascular death by 25% to 30% in primary as well as secondary prevention patients. Thus, statins are the pharmacologic therapy of choice for the management of high blood cholesterol levels. Prompted by examination of clinical trial data suggesting a modest, but statistically significant, increase in the incidence of new-onset type 2 diabetes mellitus with statin use, the US Food and Drug Administration in 2012 added a statement to the labels of statin medications indicating that increases in glycated hemoglobin (HbA1C) and fasting glucose levels have been reported with statin use. This labeling change has raised questions among clinicians regarding the relative benefits and risks of statin use, both among patients with diabetes mellitus and among those with diabetes risk factors. This 2014 report from the Diabetes Subpanel of the National Lipid Association Expert Panel on Statin Safety reviews the published evidence relating statin use to the hazard for diabetes mellitus or worsening glycemia, examines potential mechanisms that may mediate the relationship between statin use and diabetes mellitus risk, and suggests future research efforts. Given the well-established benefits of statin therapy in the primary and secondary prevention of cardiovascular events among those with indications for treatment, no changes to clinical practice are recommended other than the measurement of HbA1C or fasting glucose in those deemed to also be at elevated diabetes risk after initiating statin therapy, and potentially before initiation in selected patients considered to be at elevated risk of developing diabetes. The panel advocates following recommendations from the American Diabetes Association, or other relevant guidelines if outside the United States, for screening and diagnosis as well as lifestyle modification for prevention or delay of diabetes mellitus in those with prediabetes or other risk factors.
[Show abstract][Hide abstract] ABSTRACT: Increased physical activity is beneficial in type 2 diabetes mellitus (T2DM) but whether individuals change activity levels after T2DM diagnosis is unknown. The NAVIGATOR trial, conducted in participants with impaired glucose tolerance at high cardiovascular risk, assessed ambulatory activity annually using research-grade pedometers. Oral glucose tolerance tests were performed annually and repeated to confirm T2DM diagnosis. This observational analysis used general linear models to compare step counts before and after T2DM diagnosis in the 2,816 participants with the requisite data. Participants were relatively inactive at baseline taking a median of 5,488 (interquartile range 3,258-8,361) steps/day, which decreased after T2DM diagnosis on average by 258 (standard error [SE] 64) steps/day (p < 0.0001). However, after adjusting for background trend for activity, step count after T2DM diagnosis was unchanged (103 [SE 87] fewer steps/day; p = 0.23). Awareness of T2DM diagnosis had no impact on the trajectory of activity established before diagnosis.
[Show abstract][Hide abstract] ABSTRACT: Adiposity is a key risk factor for NAFLD. Few studies have examined prospective associations of infant and childhood adiposity with subsequent NAFLD risk. We examined associations of weight-for-height trajectories from birth to age 10 with liver outcomes in adolescence, and assessed the extent to which associations are mediated through fat mass at the time of outcome assessment.
Individual trajectories of weight and height were estimated for participants in the Avon Longitudinal Study of Parents and Children using random-effects linear-spline models. Associations of birthweight (adjusted for birth length) and weight change (adjusted for length/height change) from 0-3 months, 3 months-1y, 1-3y, 3-7y and 7-10y with ultrasound scan (USS) determined liver fat and stiffness, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) at mean age 17.8y were assessed with linear and logistic regressions. Mediation by concurrent fat mass was assessed with adjustment for fat mass at mean age 17.8y.
Birth weight was positively associated with liver stiffness and negatively with ALT and AST. Weight change from birth to 1y was not associated with outcomes. Weight change from 1-3, 3-7 and 7-10y was consistently positively associated with USS and blood-based liver outcomes. Adjusting for fat mass at mean age 17.8y attenuated associations toward the null, suggesting associations are largely mediated by concurrent body fatness.
Greater rates of weight-for-height change between 1 and 10y are consistently associated with adverse liver outcomes in adolescence. These associations are largely mediated through concurrent fatness.
Journal of Hepatology 04/2014; 61(3). DOI:10.1016/j.jhep.2014.04.018 · 10.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that fetuin-A may be a potential biomarker of cardiometabolic disease. However, few studies have investigated preanalytical factors that might impact the measurement of fetuin-A in the circulation. This pilot study aimed to investigate the preanalytical variables of sample type, timing of sample centrifugation and the impact of freeze-thaw cycles on the concentration of fetuin-A in serum or EDTA-plasma.
Blood samples were taken from 19 male or female healthy volunteers, aged 18-70 years, and left at ambient room temperature for 2 h or 48 h. The tubes were then centrifuged, serum and EDTA-plasma separated, and fetuin-A concentrations measured using a commercially available enzyme-linked immunosorbent assay (ELISA).
There was no significant difference between the concentrations of fetuin-A in EDTA-plasma and serum following separation from whole blood at 2 h postcollection (P = 0.78). The median (interquartile range) concentrations of fetuin-A in EDTA-plasma separated at 2 h and 48 h postcollection were 589 µg/mL (484-703 µg/mL) and 767 µg/mL (687-942 µg/mL), respectively (P < 0.0005). For serum, equivalent concentrations were 606 µg/mL (501-669 µg/mL) at 2 h and 607 µg/mL (564-757 µg/mL) at 48 h postcollection (P = 0.06). Fetuin-A concentrations measured in EDTA-plasma and serum showed no significant change following three freeze-thaw cycles in samples separated at 2 h postcollection (EDTA-plasma P = 0.16; serum P = 0.89).
This small pilot study has shown that serum is preferable to EDTA-plasma for the measurement of fetuin-A. It has also shown that fetuin-A appears to be as stable after three freeze-thaw cycles as it is after one.
[Show abstract][Hide abstract] ABSTRACT: The genetic contribution to the variation in human lifespan is approximately 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality.We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16121 younger controls (< 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases≥90 years.We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR=1.10, P =1.74 x 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR=0.72, P=3.40 x 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n=34103) the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR=0.95, P=0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure.We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
Human Molecular Genetics 03/2014; 23(16). DOI:10.1093/hmg/ddu139 · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain.
To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk.
Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment.
Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥7.5%) risk.
During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels.
In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.
JAMA The Journal of the American Medical Association 03/2014; 311(12):1225-33. DOI:10.1001/jama.2014.1873 · 30.39 Impact Factor