Objectif Comparer le risque de maladie C V, de mortalité toutes causes et d'hypoglycémie sévère chez des patients DT2 initiant en 2e ligne un SU ou iDPP4. Matériels et Méthodes Des patients DT2 ...traités par 1 antidiabétique non insulinique (NIAD) recevant un 2e hypoglycémiant entre 2006-2013 ont été identifiés dans le Registre suédois des médicaments puis reliés aux Registres nationaux patients et causes de décès. Date de délivrance 2e antidiabétique définie date index. Risques d'événements pendant suivi estimés par modèles de survie de Cox, ajustés sur âge, sexe, durée traitement de 1re ligne, maladies CV antérieures, et fragilité. Définition maladie CV : hospitalisation angor instable, IDM, AVC embolique, décès CV ; hypoglycémie sévère définie par hospitalisation. Résultats 68 351 patients ont initié une bithérapie, metformine + SH (64 %), metformine + iDPP4 (15 %). Les patients sous metformine + SU, plus âgés (65 vs 61 ans), plus d'hommes (59 % vs 62 %) vs patients sous metformine + iDPP4. ATCD maladies CV (32 % vs 28 %) et microvasculaires (18 % vs 15 %) similaires entre groupes. Traitements antihypertenseurs, hypolipémiants et aspirine faible dose similaires entre groupes. L'association d'un SU en 2e intention est associée à un risque accru de maladies CV fatale/non fatale, de mortalité toutes causes et d'hypoglycémie sévère vs iDPP4 ; (ICà95 %) : 1,11 (1,00 – 1,22), 1,20 (1,07-1,33) et 1,62 (1,11 – 2,36) respectivement. Conclusions Chez des patients DT2, en 2e ligne les SU sont associés à un risque accru d'événements C V, de mortalité toutes causes, et d'hypoglycémie sévère vs iDPP4.
Aims/hypothesis
This study aimed to determine whether lifestyle intervention lasting for 4 years affected diabetes incidence, body weight, glycaemia or lifestyle over 13 years among individuals at ...high risk of type 2 diabetes.
Methods
Overweight, middle-aged men (
n
= 172) and women (
n
= 350) with impaired glucose tolerance were randomised in 1993–1998 to an intensive lifestyle intervention group (
n
= 265), aiming at weight reduction, dietary modification and increased physical activity, or to a control group (
n
= 257) that received general lifestyle information. The primary outcome was a diagnosis of diabetes based on annual OGTTs. Secondary outcomes included changes in body weight, glycaemia, physical activity and diet. After active intervention (median 4 years, range 1–6 years), participants still free of diabetes and willing to continue their participation (200 in the intervention group and 166 in the control group) were further followed until diabetes diagnosis, dropout or the end of 2009, with a median total follow-up of 9 years and a time span of 13 years from baseline.
Results
During the total follow-up the adjusted HR for diabetes (intervention group vs control group) was 0.614 (95% CI 0.478, 0.789;
p
< 0.001). The corresponding HR during the post-intervention follow-up was 0.672 (95% CI 0.477, 0.947;
p
= 0.023). The former intervention group participants sustained lower absolute levels of body weight, fasting and 2 h plasma glucose and a healthier diet. Adherence to lifestyle changes during the intervention period predicted greater risk reduction during the total follow-up.
Conclusions/interpretation
Lifestyle intervention in people at high risk of type 2 diabetes induces sustaining lifestyle change and results in long-term prevention of progression to type 2 diabetes.
Trial registration
ClinicalTrials.gov NCT00518167
Funding
The DPS study has been financially supported by the Academy of Finland (128315, 129330), Ministry of Education, Novo Nordisk Foundation, Yrjö Jahnsson Foundation, Juho Vainio Foundation, Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, Unilever, and Competitive Research Funding from Tampere, Kuopio and Oulu University Hospitals. The study sponsors had no role in the design and conduct of the study; the collection, analysis and interpretation of the data; or the preparation, review or approval of the manuscript.
•The impact of small alkali halide additions on the corrosivity was investigated.•The effect of minor impurity additions on deposit melting behavior was addressed.•Already small impurity additions ...change the corrosivity of a synthetic deposit.•The melting behavior of a deposit is affected by corrosion products.
The impact of small alkali halide additions on the melting behavior and corrosivity of a synthetic sulfate deposit at 500, 550, and 600 °C was investigated. Three differently alloyed commercial heat-transfer materials; low-alloyed 10CrMo9-10, stainless AISI 347, and high-alloyed Sanicro 28, were studied. The samples were exposed for 168 h in a tube furnace to a K2SO4 + Na2SO4 mixture containing 0.85 mol% KCl, KBr, or KF. The extent of material degradation was determined by weight loss measurements, while the morphology, thickness, and composition of the formed oxide scale were characterized with SEM-EDS. Additionally, the melting behavior of the mixtures was studied with TG-DTA. It could be concluded that already small amounts of reactive alkali halides in an otherwise inert K2SO4 + Na2SO4 mixture change significantly the corrosion and melting behavior of the mixture.
Background Low birthweight has been consistently shown to be associated with coronary heart disease (CHD) and its biological risk factors. The effects of low birthweight are increased by slow infant ...growth and rapid weight gain in childhood. To quantify the importance of developmental processes in the genesis of CHD it is necessary to establish the impact of fetal, infant and childhood growth on major pathological events in later life—death, hospital treatment and the need for medication. Methods Longitudinal study of 13 517 men and women who were born in Helsinki University Hospital during 1924–1944, whose body sizes at birth and during childhood were recorded, and in whom deaths, hospital admissions, and prescription of medication for chronic disease are documented. Results The combination of small size at birth and during infancy, followed by accelerated weight gain from age 3 to 11 years, predicts large differences in the cumulative incidence of CHD, type 2 diabetes and hypertension. Conclusions Coronary heart disease and type 2 diabetes may originate through two widespread biological phenomena—developmental plasticity and compensatory growth.
It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The ...possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.
Abstract Increasing levels of physical inactivity is a global burden for mankind and is also an emerging problem in companion dogs. In both humans and dogs, insufficient physical activity is ...associated with increased risk for noncommunicable diseases and impaired quality of life (QoL). The aim of the current pilot study was to evaluate effects of a joint outdoor exercise program for dog owners (n = 22) and dogs (n = 22) with focus on QoL and body measurements. Results indicate that an eight-week exercise intervention alone, with a target distance of at least 2 km twice a week, may be sufficient to significantly increase self-reported QoL and acceptance of bodily appearance in dog owners despite no reductions in body measurements. In dogs, a significantly reduced body condition score (BCS) was registered, despite no considerable changes in feeding. The increased owner motivation for continued joint exercise suggests potential for lifestyle changes, which could be investigated in future studies including control groups and long-term follow-ups. The importance of the human-animal bond as a success factor for increased mutual physical activity and health benefits in both dog owners and dogs is recommended to be studied in a more in-depth manner.
The detection of cell-bound proteins that are produced due to aberrant gene expression in malignant tumors can provide important diagnostic information influencing patient management. The use of ...small radiolabeled targeting proteins would enable high-contrast radionuclide imaging of cancers expressing such antigens if adequate binding affinity and specificity could be provided. Here, we describe a HER2-specific 6 kDa Affibody molecule (hereinafter denoted Affibody molecule) with 22 pmol/L affinity that can be used for the visualization of HER2 expression in tumors in vivo using gamma camera. A library for affinity maturation was constructed by re-randomization of relevant positions identified after the alignment of first-generation variants of nanomolar affinity (50 nmol/L). One selected Affibody molecule, Z(HER2:342) showed a >2,200-fold increase in affinity achieved through a single-library affinity maturation step. When radioiodinated, the affinity-matured Affibody molecule showed clear, high-contrast visualization of HER2-expressing xenografts in mice as early as 6 hours post-injection. The tumor uptake at 4 hours post-injection was improved 4-fold (due to increased affinity) with 9% of the injected dose per gram of tissue in the tumor. Affibody molecules represent a new class of affinity molecules that can provide small sized, high affinity cancer-specific ligands, which may be well suited for tumor imaging.
To compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA).
Patients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour ...necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS). Data were collected through 31 December 2011. Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003-2005/2006-2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy).
During 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events). Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40). These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods). The discontinuation rate was higher for starters in 2006-2009 than 2003-2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20). The composition of 1-year discontinuations also changed from 2003-2005 vs 2006-2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001).
Discontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year. Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy.
Abstract Objective: To determine how growth during infancy and childhood modifies the increased risk of coronary heart disease associated with small body size at birth. Design: Longitudinal study. ...Setting: Helsinki, Finland. Subjects: 4630 men who were born in the Helsinki University Hospital during 1934–44 and who attended child welfare clinics in the city. Each man had on average 18.0 (SD 9.5) measurements of height and weight between birth and age 12 years. Main outcome measures: Hospital admission or death from coronary heart disease. Results: Low birth weight and low ponderal index (birth weight/length3) were associated with increased risk of coronary heart disease. Low height, weight, and body mass index (weight/height2) at age 1 year also increased the risk. Hazard ratios fell progressively from 1.83 (95% confidence interval 1.28 to 2.60) in men whose body mass index at age 1 year was below 16 kg/m2 to 1.00 in those whose body mass index was >19 (P for trend=0.0004). After age 1 year, rapid gain in weight and body mass index increased the risk of coronary heart disease. This effect was confined, however, to men with a ponderal index <26 at birth. In these men the hazard ratio associated with a one unit increase in standard deviation score for body mass index between ages 1 and 12 years was 1.27 (1.10 to 1.47; P=0.001). Conclusion: Irrespective of size at birth, low weight gain during infancy is associated with increased risk of coronary heart disease. After age 1 year, rapid weight gain is associated with further increase in risk, but only among boys who were thin at birth. In these boys the adverse effects of rapid weight gain on later coronary heart disease are already apparent at age 3 years. Improvements in fetal, infant, and child growth could lead to substantial reductions in the incidence of coronary heart disease. What is already known on this topic Coronary heart disease is associated with low birth weight One study has shown that irrespective of size at birth, low weight gain in infancy is also associated with increased risk of the disease among men Rapid weight gain after age 6 years is associated with further increase in risk What this study adds The association with low weight gain in infancy is confirmed The adverse effects of rapid childhood weight gain on risk of coronary heart disease are already apparent at age 3 years and occur only in boys who were thin at birth
Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal ...impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment.
This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30-59 mL/min per 1·73 m
, and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA
(primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete.
Between Sept 20, 2016, and Sept 29, 2017, of 721 patients screened, 324 were eligible and randomly assigned to oral semaglutide (n=163) or placebo (n=161). Mean age at baseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the placebo group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA
(estimated mean change of -1·0 percentage point (SE 0·1; -11 mmol/mol SE 0·8) vs -0·2 percentage points (SE 0·1; -2 mmol/mol SE 0·8); estimated treatment difference ETD: -0·8 percentage points, 95% CI -1·0 to -0·6; p<0·0001) and bodyweight (estimated mean change of -3·4 kg SE 0·3 vs -0·9 kg SE 0·3; ETD, -2·5, 95% CI -3·2 to -1·8; p<0·0001) by the treatment policy estimand. Significant differences were seen for the trial product estimand: mean change in HbA
-1·1 percentage points (SE 0·1; -12 mmol/mol SE 0·8 versus -0·1 percentage points (SE 0·1; -1 mmol/mol SE 0·8; ETD -1·0 percentage points, 95% CI -1·2 to -0·8; p<0·0001); mean change in bodyweight -3·7 kg (SE 0·3) versus -1·1 kg (SE 0·3; ETD -2·7 kg, 95% CI -3·5 to -1·9; p<0·0001). More patients taking oral semaglutide than placebo had adverse events (120 74% of 163 vs 105 65% of 161), and discontinued treatment as a result (24 15% vs eight 5%). Gastrointestinal events, mainly mild-to-moderate nausea, were more common with oral semaglutide than with placebo. Three deaths occurred during the treatment period that were not condsidered to be treatment related, one in the semaglutide group and two in the placebo group.
Oral semaglutide was effective in patients with type 2 diabetes and moderate renal impairment, potentially providing a new treatment option for this population. Safety, including renal safety, was consistent with the GLP-1 receptor agonist class.
Novo Nordisk A/S.
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