Effect of population screening for type 2 diabetes and cardiovascular risk factors on mortality rate and cardiovascular events: a controlled trial among 1,912,392 Danish adults

$\textit{Aims/hypothesis:}$ Health check programmes for chronic disease have been introduced in a number of countries. However, there are few trials assessing the benefits and harms of these screening programmes at the population level. In a post hoc analysis, we evaluated the effect of population-based screening for type 2 diabetes and cardiovascular risk factors on mortality rates and cardiovascular events. $\textit{Methods:}$ This register-based, non-randomised, controlled trial included men and women aged 40-69 years without known diabetes who were registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes risk score questionnaire. Individuals at moderate-to-high risk were invited to visit their GP for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other general practices in Denmark constituted the retrospectively constructed no-screening (control) group. Outcomes were mortality rate and cardiovascular events (cardiovascular disease death, non-fatal ischaemic heart disease or stroke). The analysis was performed according to the intention-to-screen principle. $\textit{Results:}$ Among the screening group, 27,177 (18%) individuals attended for assessment of diabetes status and cardiovascular risk. Of these, 1,533 were diagnosed with diabetes. During a median follow-up of 9.5 years, there were 11,826 deaths in the screening group and 141,719 in the no-screening group (HR 0.99 [95% CI 0.96, 1.02], p = 0.66). There were 17,941 cardiovascular events in the screening group and 208,476 in the no-screening group (HR 0.99 [0.96, 1.02], p = 0.49). $\textit{Conclusions/interpretation:}$ A population-based stepwise screening programme for type 2 diabetes and cardiovascular risk factors among all middle-aged adults in Denmark was not associated with a reduction in rate of mortality or cardiovascular events between 2001 and 2012.ADDITION-Denmark was supported by the National Health Services in the counties of Copenhagen, Aarhus, Ringkøbing, Ribe and South Jutland in Denmark, the Danish Council for Strategic Research, the Danish Research Foundation for General Practice, Novo Nordisk Foundation, the Danish Centre for Evaluation and Health Technology Assessment, the diabetes fund of the National Board of Health, the Danish Medical Research Council, the Aarhus University Research Foundation. The trial has been supported by unrestricted grants from Novo Nordisk AS, Novo Nordisk Scandinavia AB, Novo Nordisk UK, ASTRA Denmark, Pfizer Denmark, GlaxoSmithKline Pharma Denmark, Servier Denmark AS and HemoCue Denmark AS. RKS was supported by the European Foundation for the Study of Diabetes under an Albert Renold Travel grant to complete part of this work. DRW and RKS are supported by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. RKS is further supported by the Aarhus Institute of Advanced Studies. DRW reports receiving lecture fees from Novo Nordisk A/S and Steno Diabetes Center. DRW and TL hold shares in Novo Nordisk A/S. TL reports receiving a fee for attending an international board meeting for Astra Zeneca on early detection and treatment of diabetes in 2015. AS reports receiving lecture fees for providing continuing medical education to GPs. SJG’s research programme is supported by MRC Epidemiology Unit core funding (MC_UU_12015/4). SJG is an NIHR Senior Investigator and member of the NIHR School for Primary Care Research. SJG receives an honorarium and reimbursement of travel expenses from Eli Lilly associated with membership of an independent data monitoring committee for a randomised trial of a medication to lower glucose. SJG received an honorarium from Janssen for speaking at an educational meeting in 2015. KBJ has no duality of interest associated with this manuscript

Does training of general practitioners for intensive treatment of people with screen-detected diabetes have a spillover effect on mortality and cardiovascular morbidity in ‘at risk’ individuals with normoglycaemia? Results from the ADDITION-Denmark cluster-randomised controlled trial

Aims/hypothesis Within a trial of intensive treatment of people with screen-detected diabetes, we aimed to assess a potential spillover effect of the trial intervention on incident cardiovascular disease (CVD) and all-cause mortality among people who screened positive on a diabetes risk questionnaire but who were normoglycaemic. Methods In the Anglo–Danish–Dutch Study of Intensive Treatment In People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark trial, 175 general practices were cluster-randomised into: (1) screening plus routine care of individuals with screen-detected diabetes (control group); or (2) screening plus training and support in intensive multifactorial treatment of individuals with screen-detected diabetes (intervention group). We identified all individuals who screened positive on a diabetes risk questionnaire in ADDITION-Denmark but were normoglycaemic following biochemical testing for use in this secondary analysis. After a median 8.9 years follow-up, we used data from national registers to compare rates of first CVD events and all-cause mortality in individuals in the routine care group with those in the intensive treatment group. Results In total, 21,513 individuals screened positive for high risk of diabetes but were normoglycaemic on biochemical testing in ADDITION-Denmark practices between 2001 and 2006 (10,289 in the routine care group and 11,224 in the intensive treatment group). During 9 years of follow-up, there were 3784 first CVD events and 1748 deaths. The incidence of CVD was lower among the intensive treatment group compared with the routine care group (HR 0.92 [95% CI 0.85, 0.99]). This association was stronger among individuals at highest CVD risk (heart SCORE ≥ 10; HR 0.85 [95% CI 0.75, 0.96]). There was no difference in mortality between the two treatment groups (HR 1.02 [95% CI 0.92, 1.14]). Conclusions/interpretation Training of general practitioners to provide target-driven intensive management of blood glucose levels and other cardiovascular risk factors showed some evidence of a spillover effect on the risk of CVD over a 9 year period among individuals at high risk of diabetes. The effect was particularly pronounced among those at highest risk of CVD. There was no effect on mortality. Trial registration: ClinicalTrials.gov NCT00237549ADDITION-Denmark was supported by the national health services in the counties of Copenhagen, Aarhus, Ringkøbing, Ribe and South Jutland in Denmark, the Danish Council for Strategic Research, the Danish Research Foundation for General Practice, Novo Nordisk Foundation, the Danish Centre for Evaluation and Health Technology Assessment, the diabetes fund of the National Board of Health, the Danish Medical Research Council and the Aarhus University Research Foundation. The trial has been supported by unrestricted grants from Novo Nordisk A/S, Novo Nordisk Scandinavia AB, Novo Nordisk UK, ASTRA Denmark, Pfizer Denmark, GlaxoSmithKline Pharma Denmark, Servier Denmark AS and HemoCue Denmark AS

Serum neurofilament light chain – A potential biomarker for polyneuropathy in type 2 diabetes?

AimsTo investigate the relationship between neurofilament light chain (NfL) and the presence and severity of diabetic polyneuropathy (DPN).MethodsWe performed cross-sectional analysis of data from 178 participants of the ADDITION-Denmark cohort of people with screen-detected type 2 diabetes and 32 healthy controls. Biobank serum samples were analyzed for NfL using single-molecule array. DPN was defined by Toronto criteria for confirmed DPN. Original and axonal nerve conduction study (NCS) sum z-scores were used as indicators of the severity of DPN and peripheral nerve damage.Results39 (21.9%) participants had DPN. Serum NfL (s-NfL) was significantly higher in participants with DPN (18.8 ng/L [IQR 14.4; 27.9]) than in participants without DPN (15.4 ng/L [IQR 11.7; 20.1]). There were no unadjusted s-NfL differences between controls (17.6 ng/L [IQR 12.7; 19.8]) and participants with or without DPN. Higher original and axonal NCS sum z-scores were associated with 10% higher s-NfL (10.2 and 12.1% [95% CI’s 4.0; 16.8 and 6.6; 17.9] per 1 SD). The AUC of s-NfL for DPN was 0.63 (95% CI 0.52; 0.73).ConclusionsS-NfL is unlikely to be a reliable biomarker for the presence of DPN. S-NfL is however associated to the severity of the nerve damage underlying DPN

Patient‐reported outcomes after 10‐year follow‐up of intensive, multifactorial treatment in individuals with screen‐detected type 2 diabetes: the ADDITION‐Europe trial

AimsTo present the longer‐term impact of multifactorial treatment of type 2 diabetes on self‐reported health status, diabetes‐specific quality of life, and diabetes treatment satisfaction at 10‐year follow up of the ADDITION‐Europe trial.MethodsThe ADDITION‐Europe trial enrolled 3057 individuals with screen‐detected type 2 diabetes from four centres [Denmark, the UK (Cambridge and Leicester) and the Netherlands], between 2001 and 2006. Participants were randomized at general practice level to intensive treatment or to routine care . The trial ended in 2009 and a 10‐year follow‐up was performed at the end of 2014. We measured self‐reported health status (36‐item Short‐Form Health Survey and EQ‐5D), diabetes‐specific quality of life (Audit of Diabetes‐Dependent Quality of Life questionnaire), and diabetes treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire) at different time points during the study period. A mixed‐effects model was applied to estimate the effect of intensive treatment (intention‐to‐treat analyses) on patient‐reported outcome measures for each centre. Centre‐specific estimates were pooled using a fixed effects meta‐analysis.ResultsThere was no difference in patient‐reported outcome measures between the routine care and intensive treatment arms in this 10‐year follow‐up study [EQ‐5D: –0.01 (95% CI –0.03, 0.01); Physical Composite Score (36‐item Short‐Form Health Survey): –0.27 (95% CI –1.11, 0.57), Audit of Diabetes‐Dependent Quality of Life questionnaire: –0.01 (95% CI –0.11, 0.10); and Diabetes Treatment Satisfaction Questionnaire: –0.20 (95% CI –0.70, 0.29)].ConclusionsIntensive, multifactorial treatment of individuals with screen‐detected type 2 diabetes did not affect self‐reported health status, diabetes‐specific quality of life, or diabetes treatment satisfaction at 10‐year follow‐up compared to routine care.</div

A randomised trial of the effect and cost-effectiveness of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with screen-detected type 2 diabetes:The Anglo–Danish–Dutch Study of Intensive treatment in people with screen-detected diabetes in primary care (ADDITION-Europe) study

Background: Intensive treatment (IT) of cardiovascular risk factors can halve mortality among people with established type 2 diabetes but the effects of treatment earlier in the disease trajectory are uncertain.  Objective: To quantify the cost-effectiveness of intensive multifactorial treatment of screen-detected diabetes.  Design: Pragmatic, multicentre, cluster-randomised, parallel-group trial.  Setting: Three hundred and forty-three general practices in Denmark, the Netherlands, and Cambridge and Leicester, UK.  Participants: Individuals aged 40–69 years with screen-detected diabetes.  Interventions: Screening plus routine care (RC) according to national guidelines or IT comprising screening and promotion of target-driven intensive management (medication and promotion of healthy lifestyles) of hyperglycaemia, blood pressure and cholesterol.  Main outcome measures: The primary end point was a composite of first cardiovascular event (cardiovascular mortality/morbidity, revascularisation and non-traumatic amputation) during a mean [standard deviation (SD)] follow-up of 5.3 (1.6) years. Secondary end points were (1) all-cause mortality; (2) microvascular outcomes (kidney function, retinopathy and peripheral neuropathy); and (3) patient-reported outcomes (health status, well-being, quality of life, treatment satisfaction). Economic analyses estimated mean costs (UK 2009/10 prices) and quality-adjusted life-years from an NHS perspective. We extrapolated data to 30 years using the UK Prospective Diabetes Study outcomes model [version 1.3; © Isis Innovation Ltd 2010; see www.dtu.ox.ac.uk/outcomesmodel (accessed 27 January 2016)].  Results: We included 3055 (RC, n = 1377; IT, n = 1678) of the 3057 recruited patients [mean (SD) age 60.3 (6.9) years] in intention-to-treat analyses. Prescription of glucose-lowering, antihypertensive and lipid-lowering medication increased in both groups, more so in the IT group than in the RC group. There were clinically important improvements in cardiovascular risk factors in both study groups. Modest but statistically significant differences between groups in reduction in glycated haemoglobin (HbA1c) levels, blood pressure and cholesterol favoured the IT group. The incidence of first cardiovascular event [IT 7.2%, 13.5 per 1000 person-years; RC 8.5%, 15.9 per 1000 person-years; hazard ratio 0.83, 95% confidence interval (CI) 0.65 to 1.05] and all-cause mortality (IT 6.2%, 11.6 per 1000 person-years; RC 6.7%, 12.5 per 1000 person-years; hazard ratio 0.91, 95% CI 0.69 to 1.21) did not differ between groups. At 5 years, albuminuria was present in 22.7% and 24.4% of participants in the IT and RC groups, respectively [odds ratio (OR) 0.87, 95% CI 0.72 to 1.07), retinopathy in 10.2% and 12.1%, respectively (OR 0.84, 95% CI 0.64 to 1.10), and neuropathy in 4.9% and 5.9% (OR 0.95, 95% CI 0.68 to 1.34), respectively. The estimated glomerular filtration rate increased between baseline and follow-up in both groups (IT 4.31 ml/minute; RC 6.44 ml/minute). Health status, well-being, diabetes-specific quality of life and treatment satisfaction did not differ between the groups. The intervention cost £981 per patient and was not cost-effective at costs ≥ £631 per patient.  Conclusions: Compared with RC, IT was associated with modest increases in prescribed treatment, reduced levels of risk factors and non-significant reductions in cardiovascular events, microvascular complications and death over 5 years. IT did not adversely affect patient-reported outcomes. IT was not cost-effective but might be if delivered at a reduced cost. The lower than expected event rate, heterogeneity of intervention delivery between centres and improvements in general practice diabetes care limited the achievable differences in treatment between groups. Further follow-up to assess the legacy effects of early IT is warranted

A model for the jet-disk connection in BH accreting systems

Based on theoretical arguments and quasi-stationary radiative MHD calculations, a model for an accretion-powered jet is presented. It is argued that accretion disks around BHs consist of 1) a cold, Keplerian-rotating and weakly magnetized mediumin the outer part, 2) a highly advective and turbulent-free plasma inside r_\mm{tr}=10-20 Schwarzschild radii, where magnetic fields are predominantly of large scale topology and in excess of thermal equipartition, and 3) an ion-dominated torus in the vicinity of the hole, where magnetic fields undergo a topological change into a monopole like-configuration. The action of magnetic fields interior to r_\mm{tr} is to initiate torsional {\Alfven} waves that extract angular momentum from the disk-plasma and deposit it into the transition layer (-TL) above the disk, where the plasma is dissipative and tenuous. A significant fraction of the shear-generated toroidal magnetic field reconnects in the TL, thereby heating the plasma up to the virial-temperature and forming a super-Keplerian rotating, and hence centrifugally accelerated outflow. The strong magnetic field in the TL forces the electrons to cool rapidly yielding thereby an ion-dominated outflow. The toroidal magnetic field in the TL is in thermal equipartition with the ions, whereas the poloidal component is in equipartition with the electrons. Such a strong toroidal magnetic field is essential for increasing the jet-disk luminosity in the radio regime.Comment: 27 pages, 10 figure

Studies of the Association of Arg72Pro of Tumor Suppressor Protein p53 with Type 2 Diabetes in a Combined Analysis of 55,521 Europeans

A study of 222 candidate genes in type 2 diabetes reported association of variants in RAPGEF1, ENPP1, TP53, NRF1, SLC2A2, SLC2A4 and FOXC2 with type 2 diabetes in 4,805 Finnish individuals. We aimed to replicate these associations in a Danish case-control study and to substantiate any replicated associations in meta-analyses. Furthermore, we evaluated the impact on diabetes-related intermediate traits in a population-based sample of middle-aged Danes.We genotyped nine lead variants in the seven genes in 4,973 glucose-tolerant and 3,612 type 2 diabetes Danish individuals. In meta-analyses we combined case-control data from the DIAGRAM+ Consortium (n = 47,117) and the present genotyping results. The quantitative trait studies involved 5,882 treatment-naive individuals from the Danish Inter99 study.None of the nine investigated variants were significantly associated with type 2 diabetes in the Danish samples. However, for all nine variants the estimate of increase in type 2 diabetes risk was observed for the same allele as previously reported. In a meta-analysis of published and online data including 55,521 Europeans the G-allele of rs1042522 in TP53 showed significant association with type 2 diabetes (OR = 1.06 95% CI 1.02-1.11, p = 0.0032). No substantial associations with diabetes-related intermediary phenotypes were found.The G-allele of TP53 rs1042522 is associated with an increased prevalence of type 2 diabetes in a combined analysis of 55,521 Europeans

Studies of CTNNBL1 and FDFT1 variants and measures of obesity: analyses of quantitative traits and case-control studies in 18,014 Danes

<p>Abstract</p> <p>Background</p> <p>A genome-wide scan in unrelated US Caucasians identified rs7001819 upstream of farnesyl-diphosphate farnesyltransferase 1 (<it>FDFT1</it>) and multiple variants within catenin (cadherin-associated protein), β-like 1 (<it>CTNNBL1</it>) to associate strongly with body mass index (BMI). The most significantly associating variants within <it>CTNNBL1 </it>including rs6013029 and rs6020846 were additionally confirmed to associate with morbid obesity in a French Caucasian case-control sample. The aim of this study was to investigate the impact of these three variants on obesity, through analyses of obesity-related quantitative traits, and case-control studies in large study samples of Danes.</p> <p>Methods</p> <p>The <it>FDFT1 </it>rs7001819, <it>CTNNBL1 </it>rs6013029 and rs6020846 were genotyped, using TaqMan allelic discrimination, in a combined study sample comprising 18,014 participants ascertained from; the population-based Inter99 cohort (<it>n </it>= 6,514), the ADDITION Denmark screening study cohort (<it>n </it>= 8,662), and a population-based sample (<it>n </it>= 680) and a type 2 diabetic patients group (<it>n </it>= 2,158) from Steno Diabetes Center.</p> <p>Results</p> <p>Both <it>CTNNBL1 </it>variants associated with body weight and height with per allele effect sizes of 1.0 [0.3–0.8] kg and 0.6 [0.2–0.9] cm, respectively, for the rs6020846 G-allele. No association was observed with BMI and waist circumference. In case-control studies neither of the <it>CTNNBL1 </it>variants showed association with overweight, obesity or morbid obesity (rs6013029: Odds Ratio (OR)_overweight= 1.02 [0.90–1.16], OR_obesity= 1.09 [0.95–1.25], OR_{morbidobesity}= 1.26 [0.91–1.74]; rs6020846: OR_overweight= 1.05 [0.93–1.18], OR_obesity= 1.13 [1.00–1.28], OR_{morbidobesity}= 1.17 [0.86–1.61]). However, in meta-analyses of the present and the previous study, both the rs6013029 T-allele and the rs6020846 G-allele increased the risk of developing morbid obesity (rs6013029: OR_combined= 1.36 [1.12–1.64], <it>p </it>= 0.002; rs6020846: OR_combined= 1.26 [1.06–1.51], <it>p </it>= 0.01), and obesity (rs6013029: OR_combined= 1.17 [1.04–1.31], <it>p </it>= 0.007; rs6020846: OR_combined= 1.17 [1.05–1.30], <it>p </it>= 0.004).</p> <p>The <it>FDFT1 </it>rs7001819 C-allele showed no association with obesity-related quantitative measures or dichotomous measures of overweight, obesity and morbid obesity.</p> <p>Conclusion</p> <p><it>CTNNBL1 </it>variants associated with body weight and height, and confer the risk of developing obesity in meta-analyses combining the present and a previous study. <it>FDFT1 </it>rs7001819 showed no association with obesity, neither when analysing quantitative traits nor when performing case-control studies of obesity.</p