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Introduction: Maternal demographics have evolved, and more women than ever enter pregnancy with preexisting comorbidity and with potentially complex medication exposure, including polypharmacy (concomitant intake of multiple medications). This study aims to describe the evolution of medication use in pregnancy in Denmark from 1998 to 2018 with special focus on polypharmacy, patterns of use, and underlying demographics. Material and methods: A Danish nationwide historical registry study based on all clinically recognized pregnancies with a gestation ≥10 weeks between 1998 and 2018. Medication use was estimated by redemption of prescriptions during pregnancy. Results: Among a total of 1 402 327 clinically recognized pregnancies, redemption of at least one prescription medication during pregnancy increased from 56.9% in 1998 to 63.3% in 2018, coinciding with an increased use of polypharmacy (from 24.8% in 1998 to 35.2% in 2018). The prevalence of pregnant women who used medications for chronic conditions increased more than the prevalence of women treated for occasional or short‐time conditions. Redemption of one or multiple prescription medications during pregnancy was mostly seen among pregnant women ≥35 years of age. However, pregnant women <25 years old exhibited the largest increase in medication use during the study period. Conclusions: Medication use in general, and polypharmacy in particular, increased from 1998 to 2008, possibly as the result of an increased prevalence of pregnant women with chronic conditions requiring pharmacological treatment. Notably, a marked maternal age‐based discrepancy in usage pattern was observed, highlighting the need for further research in this area. The rise in the prevalence of polypharmacy during pregnancy underscores the need for pharmacovigilance to monitor adverse effects. Future studies should investigate the patterns of polypharmacy and the accompanying maternal and fetal risks. [ABSTRACT FROM AUTHOR]

Objective: To examine the course of cardiovascular autonomic neuropathy (CAN) and related cardiometabolic risk factors in patients with type 2 diabetes.Research Design and Methods: CAN and cardiometabolic risk factors were assessed in the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) at 6-year (n = 777) and 13-year (n = 443) follow-up examinations. Cardiovascular autonomic reflex tests (CARTs)-that is, lying to standing, deep breathing, and the Valsalva maneuver-and 2-min resting heart rate variability (HRV) indices were obtained as the main measures of CAN. Risk factors related to CAN status, as determined by CARTs, were studied by using multivariate logistic regressions. The effects of risk factors on continuous CARTs and HRV indices, and their changes over time, were estimated in linear mixed models.Results: A progressive yet heterogeneous course of CAN occurred between the 6- and 13-year follow-ups. Higher HbA1c, weight, BMI, and triglycerides were associated with prevalent CAN. No significant effect of risk factors on CARTs was found when they were analyzed as continuous variables. CART indices decreased over time, and a trend of decreasing HRV indices was seen. Higher HbA1c and BMI were associated with lower HRV index values, but these differences diminished over time.Conclusions: These data confirm that hyperglycemia, obesity, and hypertriglyceridemia are negatively related to indices of CAN, although these effects diminish over time. The observed heterogeneous course of CAN may challenge the present clinical approach of categorically classifying CARTs to diagnose CAN and the notion of CAN being irreversible. [ABSTRACT FROM AUTHOR]

Objective: To study cardiometabolic risk-factor trajectories (in terms of levels and changes over time) preceding diabetic polyneuropathy (DPN) 13 years after a screen-detected diagnosis of type 2 diabetes.Research Design and Methods: We clinically diagnosed DPN in a nested case-control study of 452 people in the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION). By linear regression models, we estimated preceding risk-factor trajectories during 13 years. Risk of DPN was estimated by multivariate logistic regression models of each individual's risk-factor trajectory intercept and slope adjusting for sex, age, diabetes duration, height, and trial randomization group.Results: Higher baseline levels of HbA1c (odds ratio [OR] 1.76 [95% CI 1.37; 2.27] and OR 1.68 [95% CI 1.33; 2.12] per 1% and 10 mmol/mol, respectively) and steeper increases in HbA1c over time (OR 1.66 [95% CI 1.21; 2.28] and OR 1.59 [95% CI 1.19; 2.12] per 1% and 10 mmol/mol increase during 10 years, respectively) were associated with DPN. Higher baseline levels of weight, waist circumference, and BMI were associated with DPN (OR 1.20 [95% CI 1.10; 1.31] per 5 kg, OR 1.27 [95% CI 1.13; 1.43] per 5 cm, and OR 1.24 [95% CI 1.12; 1.38] per 2 kg/m2, respectively).Conclusions: Both higher levels and slopes of HbA1c trajectories were associated with DPN after 13 years. Our findings indicate that the rate of HbA1c increase affects the development of DPN over and above the effect of the HbA1c level. Furthermore, this study supports obesity as a risk factor for DPN. [ABSTRACT FROM AUTHOR]

Objective: Glucose measurements during an oral glucose tolerance test (OGTT) are useful in predicting diabetes and its complications. However, knowledge of the pathophysiology underlying differences in glucose curve shapes is sparse. We examined the pathophysiological characteristics that create different glucose curve patterns and studied their stability and reproducibility over 3 years of follow-up.Research Design and Methods: We analyzed data from participants without diabetes from the observational cohort from the European Group for the Study of Insulin Resistance: Relationship between Insulin Sensitivity and Cardiovascular Disease study; participants had a five-time point OGTT at baseline (n = 1,443) and after 3 years (n = 1,045). Measures of insulin sensitivity and secretion were assessed at baseline with a euglycemic-hyperinsulinemic clamp and intravenous glucose tolerance test. Heterogeneous glucose response patterns during the OGTT were identified using latent class trajectory analysis at baseline and at follow-up. Transitions between classes were analyzed with multinomial logistic regression models.Results: We identified four different glucose response patterns, which differed with regard to insulin sensitivity and acute insulin response, obesity, and plasma levels of lipids and inflammatory markers. Some of these associations were confirmed prospectively. Time to glucose peak was driven mainly by insulin sensitivity, whereas glucose peak size was related to both insulin sensitivity and secretion. The glucose patterns identified at follow-up were similar to those at baseline, suggesting that the latent class method is robust. We integrated our classification model into an easy-to-use online application that facilitates the assessment of glucose curve patterns for other studies.Conclusions: The latent class analysis approach is a pathophysiologically insightful way to classify individuals without diabetes based on their response to glucose during an OGTT. [ABSTRACT FROM AUTHOR]

Objective: To study incident diabetic polyneuropathy (DPN) prospectively during the first 13 years after a screening-based diagnosis of type 2 diabetes and determine the associated risk factors for the development of DPN.Research Design and Methods: We assessed DPN longitudinally in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION) using the Michigan Neuropathy Screening Instrument questionnaire (MNSIQ), defining DPN with scores ≥4. Risk factors present at the diabetes diagnosis associated with the risk of incident DPN were estimated using Cox proportional hazard models adjusted for trial randomization group, sex, and age.Results: Of the total cohort of 1,533 people, 1,445 completed the MNSIQ at baseline and 189 (13.1%) had DPN at baseline. The remaining 1,256 without DPN entered this study (median age 60.8 years [interquartile range 55.6; 65.6], 59% of whom were men). The cumulative incidence of DPN was 10% during 13 years of diabetes. Age (hazard ratio [HR] 1.03 [95% CI 1.00; 1.07]) (unit = 1 year), weight (HR 1.09 [95% CI 1.03; 1.16]) (unit = 5 kg), waist circumference (HR 1.14 [95% CI 1.05; 1.24]) (unit = 5 cm), BMI (HR 1.14 [95% CI 1.06; 1.23]) (unit = 2 kg/m2), log2 methylglyoxal (HR 1.45 [95% CI 1.12; 1.89]) (unit = doubling), HDL cholesterol (HR 0.82 [95% CI 0.69; 0.99]) (unit = 0.25 mmol/L), and LDL cholesterol (HR 0.92 [95% CI 0.86; 0.98]) (unit = 0.25 mmol/L) at baseline were significantly associated with the risk of incident DPN.Conclusions: This study provides further epidemiological evidence for obesity as a risk factor for DPN. Moreover, low HDL cholesterol levels and higher levels of methylglyoxal, a marker of dicarbonyl stress, are identified as risk factors for the development of DPN. [ABSTRACT FROM AUTHOR]

Objective: We compared the risk of cardiovascular disease (CVD) and all-cause mortality in subgroups of prediabetes defined by fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), or HbA1c.Research Design and Methods: In the Whitehall II cohort, 5,427 participants aged 50-79 years and without diabetes were followed for a median of 11.5 years. A total of 628 (11.6%) had prediabetes by the World Health Organization (WHO)/International Expert Committee (IEC) criteria (FPG 6.1-6.9 mmol/L and/or HbA1c 6.0-6.4%), and 1,996 (36.8%) by the American Diabetes Association (ADA) criteria (FPG 5.6-6.9 mmol/L and/or HbA1c 5.7-6.4%). In a subset of 4,730 individuals with additional measures of 2hPG, 663 (14.0%) had prediabetes by 2hPG. Incidence rates of a major event (nonfatal/fatal CVD or all-cause mortality) were compared for different definitions of prediabetes, with adjustment for relevant confounders.Results: Compared with that for normoglycemia, incidence rate in the context of prediabetes was 54% higher with the WHO/IEC definition and 37% higher with the ADA definition (P < 0.001) but declining to 17% and 12% after confounder adjustment (P ≥ 0.111). Prediabetes by HbA1c was associated with a doubling in incidence rate for both the IEC and ADA criteria. However, upon adjustment, excess risk was reduced to 13% and 17% (P ≥ 0.055), respectively. Prediabetes by FPG or 2hPG was not associated with an excess risk in the adjusted analysis.Conclusions: Prediabetes defined by HbA1c was associated with a worse prognosis than prediabetes defined by FPG or 2hPG. However, the excess risk among individuals with prediabetes is mainly explained by the clustering of other cardiometabolic risk factors associated with hyperglycemia. [ABSTRACT FROM AUTHOR]

The article focuses on a study on assessment of time to glucose peak during an oral glucose tolerance test (OGTT). Topics discussed include understanding of features of the glucose curve through analysis of OGTT, extracting individual-specific parameters from the model with statistical software, and comparing the predictive ability of the binary and the continuous time to glucose peak variables using logistic regression.

: Examining patterns of change in body mass index (BMI) and other cardiometabolic risk factors in individuals during the years before they were diagnosed with diabetes, Kristine Færch and colleagues report that few of them experienced dramatic BMI changes. Please see later in the article for the Editors' Summary [ABSTRACT FROM AUTHOR]

Background Most clinicians acknowledge that type 2 diabetes is multifactorial and has heterogeneous characteristics, but neither prevention nor treatment is systematically stratified. To address the heterogeneity of the disease, we examined whether patients diagnosed on the basis of fasting glucose concentrations, those diagnosed on the basis of 2 h concentrations, and those diagnosed on the basis of both criteria differed in terms of pathogenesis or cardiovascular risks. Methods Retrospectively, we analysed trajectories of cardiometabolic risk factors and 10 year cardiovascular risks in the prospective Whitehall II study cohort by use of multilevel longitudinal modelling. Participants were diagnosed by 75 g oral glucose-tolerance tests. We classified those diagnosed with type 2 diabetes into three subgroups: diagnosed on the basis of fasting glucose concentrations, diagnosed on the basis of 2 h glucose concentrations, and diagnosed on the basis of both concentrations. We also developed a classification tree for identification of individuals who are likely to have high fasting and 2 h glucose concentrations, but for whom only fasting concentrations are available. Results Median follow-up was 14•2 years with 15 826 person-examinations (1991–2009). Of 10 308 individuals, 6843 were included and 6569 remained diabetes free. 274 cases of type 2 diabetes were identified: 55 had high fasting glucose concentrations only, 148 had high 2 h concentrations only, and 71 had high fasting and 2 h concentrations. At diagnosis, participants with high fasting and 2 h glucose concentrations had higher mean body-mass indices (30•9 kg/m² [SD 5•7]) than did those with high fasting concentrations (28•4 kg/m² [4•4]; p=0•0009) or 2 h concentrations (27•9 kg/m² [4•9]; <0•0001). Mean glycated haemoglobin A1c concentrations were also higher in the fasting and 2 h subgroup (7•4% [1•6]) than in the fasting (5•9% [0•5]; <0•0001) or 2 h (5•9% [0•6]; <0•0001) sugroups. Additionally, the fasting and 2 h subgroup had a higher proportion of individuals with moderate or high risk of cardiovascular disease than did the fasting subgroup (p=0•02). A classic pattern of β-cell decompensation before diagnosis was noted only in the fasting and 2 h subgroup. Additionally, glucose concentrations and insulin resistance accelerated more substantially before diagnosis in the fasting and 2 h subgroup than in the fasting subgroup or the 2 h subgroup. Interpretation Patients with type 2 diabetes diagnosed on the basis of increased fasting glucose concentrations or 2 h glucose concentrations, or both, have distinct cardiometabolic risk development before diagnosis. Funding UK Medical Research Council, UK Economic and Social Research Council, British Heart Foundation, UK Health and Safety Executive, UK Department of Health, US National Heart Lung and Blood Institute, US National Institute on Aging, US Agency for Health Care Policy Research, and John D and Catherine T MacArthur Foundation. [ABSTRACT FROM AUTHOR]

Background Most clinicians acknowledge that type 2 diabetes is multifactorial and has heterogeneous characteristics, but neither prevention nor treatment is systematically stratified. To address the heterogeneity of the disease, we examined whether patients diagnosed on the basis of fasting glucose concentrations, those diagnosed on the basis of 2 h concentrations, and those diagnosed on the basis of both criteria differed in terms of pathogenesis or cardiovascular risks. Methods Retrospectively, we analysed trajectories of cardiometabolic risk factors and 10 year cardiovascular risks in the prospective Whitehall II study cohort by use of multilevel longitudinal modelling. Participants were diagnosed by 75 g oral glucose-tolerance tests. We classified those diagnosed with type 2 diabetes into three subgroups: diagnosed on the basis of fasting glucose concentrations, diagnosed on the basis of 2 h glucose concentrations, and diagnosed on the basis of both concentrations. We also developed a classification tree for identification of individuals who are likely to have high fasting and 2 h glucose concentrations, but for whom only fasting concentrations are available. Results Median follow-up was 14-2 years with 15826 person-examinations (1991-2009). Of 10 308 individuals, 6843 were included and 6569 remained diabetes free. 274 cases of type 2 diabetes were identified: 55 had high fasting glucose concentrations only, 148 had high 2 h concentrations only, and 71 had high fasting and 2 h concentrations. At diagnosis, participants with high fasting and 2 h glucose concentrations had higher mean body-mass indices (30.9 kg/m² [SD 5.7]) than did those with high fasting concentrations (28.4 kg/m² [4.4]; p=0.0009) or concentrations (27.9 kg/m² [4.9]; <0.0001). Mean glycated haemoglobin A1c concentrations were also higher in the fasting and 2 h subgroup (7.4% [1.6]) than in the fasting (5.9% [0.5]; <0.0001) or 2 h (5.9% [0.6]; <0.0001) sugroups. Additionally, the fasting and 2 h subgroup had a higher proportion of individuals with moderate or high risk of cardiovascular disease than did the fasting subgroup (p=0 02). A classic pattern of P-cell decompensation before diagnosis was noted only in the fasting and 2 h subgroup. Additionally, glucose concentrations and insulin resistance accelerated more substantially before diagnosis in the fasting and 2 h subgroup than in the fasting subgroup or the 2 h subgroup. Interpretation Patients with type 2 diabetes diagnosed on the basis of increased fasting glucose concentrations or 2 h glucose concentrations, or both, have distinct cardiometabolic risk development before diagnosis. Funding UK Medical Research Council, UK Economic and Social Research Council, British Heart Foundation, UK Health and Safety Executive, UK Department of Health, US National Heart Lung and Blood Institute, US National Institute on Aging, US Agency for Health Care Policy Research, and John D and Catherine T MacArthur Foundation. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to determine the association between different anthropometric parameters and metabolic profile in an overweight, adult, black Kenyan population. Methods: An opportunity sample of 245 overweight adult Kenyans (body mass index (BMI) ≥ 25 kg/m2) was analysed. A score of metabolic profile (metabolic Z-score) was constructed on the basis of levels of plasma lipids, blood pressure, blood glucose and serum insulin. Linear regressions using metabolic Z-score as outcome and six anthropometric variables (waist circumference (WC), hip circumference, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue, arm fat area and arm muscle area) separately as independent variables were carried out. Results: Mean age of study participants was 42.1 years (SD = 9.6) and 26.5% of the participants were men. The median BMI was 28.6 kg/m2 (Q1 = 26.3; Q3 = 31.3). Of the six anthropometric variables tested, WC and VAT thickness had the strongest negative association with the metabolic profile (β = 0.17 (0.09; 0.24) and 0.15 (0.08; 0.23), respectively). Conclusions: WC and VAT thickness were the strongest anthropometric predictors for the metabolic profile in overweight adult Kenyans. WC is useful in clinical practice for the diagnosis of metabolically unhealthy fat accumulation in an African setting. [ABSTRACT FROM AUTHOR]

Abstract: Background: Intake of carbohydrates which elicit a large glycemic response is hypothesized to increase the risk of diabetes. However, studies assessing the relationship between glycemic index (GI) and glycemic load (GL) and diabetes are inconsistent. Only few studies have studied the relationship between GI and GL and markers of glucose metabolism, mostly in western populations. Objective: To determine the relationship between GI and GL and indices of glucose metabolism and prevalence of diabetes in Greenland''s Inuit population. Design: The Inuit Health in Transition Study is a geographically representative cross-sectional study among aged ≥18years. Diet was assessed using a 67-item food frequency questionnaire. Logistic and linear regression was used to assess the association between GI and GL and diabetes, impaired fasting glucose, impaired glucose tolerance, HbA1c, fasting plasma glucose, 2h plasma glucose, HOMA2-IR and HOMA2-%β. Results: No association was found between GI and GL and diabetes. GL was significantly inversely associated with IFG (OR: 0.91 (0.84–0.98)). While GI was positively associated with FPG, GL was positively associated with both HOMA2-IR and HOMA2-%β and inversely associated with IFG. Conclusion: These findings do not support a link between dietary GI or GL and risk of type 2 diabetes among Greenland''s Inuit population. [Copyright &y& Elsevier]

Abstract: Objectives:: To assess whether the validity of endothelial function measurement by flow-mediated dilatation (FMD) is affected by local brachial artery stiffness (distensibility coefficient; DC) and arterial wall thickness (intima-media thickness, IMT). Background:: FMD measurement relies on assessment of arterial diameter change. Increased IMT and decreased DC might physically limit dilatation of the brachial artery in spite of healthy endothelium. Methods:: DC, IMT and FMD of the brachial artery were simultaneously measured in 349 patients with advanced atherosclerosis or cardiovascular risk factors. The relations between FMD and age, and FMD and current smoking were regarded as a proxy for the relation between FMD and true endothelial function. Results:: The relations between FMD and age, and FMD and smoking, were significantly modified by brachial artery DC. No modification was found for IMT. The interaction terms were statistically significant (p =0.03 and 0.04, respectively). The relation between FMD and age, and FMD and smoking was progressively more pronounced in patients with more elastic arteries. Conclusion:: The results of our study indicate that increased arterial stiffness may interfere with valid measurement of FMD and that patients with stiff arteries may be considered for exclusion from analyses involving FMD to ensure its validity. [Copyright &y& Elsevier]

Objectives: The aim of this research was to study whether the relation between endothelial function measured by flow-mediated dilation (FMD) of the brachial artery and cardiovascular risk factors is affected by the baseline cardiovascular risk. Background: Flow-mediated dilation of the brachial artery is widely used as a measure of endothelial function. Relations between FMD and most cardiovascular risk factors have been described. Methods: We performed a meta-regression analysis of 211 selected articles (399 populations) reporting on FMD and cardiovascular risk factors. Mean values of FMD; age; proportion of men; proportion of smokers; blood pressure; lipids; glucose; and the presence of diabetes mellitus, of hyperlipidemia, and of hypertension were retrieved from the articles. The 10-year risk of coronary heart disease (CHD) for each population was estimated based on the Framingham risk score. The relation between FMD and cardiovascular risk factors was assessed within each risk category by linear regression analysis, adjusting for age and gender, and weighted for the study size. Results: A relation between FMD and cardiovascular risk factors was most clear in the category with lowest baseline risk (below 2.8% per decade). In populations with low baseline risk, for each % increase in Framingham risk, FMD decreased by 1.42% (95% confidence interval: 0.65 to 2.19). In medium- and high-risk populations, FMD was not related to risk (−0.02% [−0.27 to 0.22] and 0.06% [−0.02 to 0.13], respectively). These findings were independent of differences in brachial lumen diameter and technical aspects of the FMD measurement. Conclusions: Only in populations at low risk, endothelial function measured by FMD is related to the principal cardiovascular risk factors, and to the estimated 10-year risk of CHD. [Copyright &y& Elsevier]

OBJECTIVE -- To compare screen-detected diabetes prevalence and the degree of diagnostic agreement by ethnicity with the current oral glucose tolerance test (OGTT)-based and newly proposed A1C-based diagnostic criteria. RESEARCH DESIGN AND METHODS-- Six studies (1999-2009) from Denmark, the U.K., Australia, Greenland, Kenya, and India were tested for the probability of an A1C ≥6.5% among diabetic case subjects based on an OGTT. The difference in probability between centers was analyzed by logistic regression adjusting for relevant confounders. RESULTS -- Diabetes prevalence was lower with the A1C-based diagnostic criteria in four of six studies. The probability of an A1C ≥6.5% among OGTT-diagnosed case subjects ranged widely (17.0-78.0%) by study center. Differences in diagnostic agreement between ethnic subgroups in the U.K. study were of the same magnitude as between-country comparisons. CONCLUSIONS-- A shift to an A1C-based diagnosis for diabetes will have substantially different consequences for diabetes prevalence across ethnic groups and populations. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether an important football match increases stress to such an extent that it triggers acute myocardial infarction and stroke.Design: Longitudinal study of mortality around 22June 1996 (the day the Dutch football team was eliminated from the European football championship). Mortality on 22 June was compared with the five days before and after the match and in the same period in 1995 and 1997.Setting: Netherlands.Subjects: Dutch population aged 45 years or over in June 1996.Main outcome measures: All cause mortality and mortality due to coronary heart disease and stroke.Results: Mortality from coronary heart disease and stroke was increased in men on the day of the match (relative risk 1.51, 95% confidence interval 1.08 to 2.09). No clear rise in mortality was observed for women (1.11, 0.80 to 1.56). Among men, about 14 excess cardiovascular deaths occurred on the day of the match.Conclusion: Important sporting events may provoke a sufficient level of stress to trigger symptomatic cardiovascular disease. The difference between men and women requires further investigation. [ABSTRACT FROM AUTHOR]

Background: We aimed to estimate the age-specific and age-standardized incidence rate of diabetes for men and women in Mexico between 2003 and 2015, and to assess the relative change in incidence of diabetes between 2003 and 2015. Methods: We use a partial differential equation describing the illness-death model to estimate the incidence rate (IR) of diabetes for the years 2003, 2009 and 2015 based on prevalence data from National Health Surveys conducted in Mexico, the mortality rate of the Mexican general population and plausible input values for age-specific mortality rate ratios associated with diabetes. Results: The age-standardized IR of diabetes per 1000 person years (pryr) was similar among men (IRm) and women (IRw) in the year 2003 (IRm 6.1 vs. IRw 6.5 1000/pryr), 2009 (IRm: 7.0 vs. IRw: 8.4 1000/pryr), and in 2015 (IRm 8.0 vs. IRw 10.6 1000/pryr). The highest incident rates were observed among men and women in the 60–69 age group. Conclusions: Overall, the incidence rate of diabetes in Mexico between the years 2003 and 2015 remained stable. However, rates were markedly higher among women in the age group 40–49 and 50–59 in the year 2015 compared with rates in 2003. [ABSTRACT FROM AUTHOR]

The microbial communities of the oral cavity are important elements of oral and systemic health. With emerging evidence highlighting the heritability of oral bacterial microbiota, this study aimed to identify host genome variants that influence oral microbial traits. Using data from 16S rRNA gene amplicon sequencing, we performed genome-wide association studies with univariate and multivariate traits of the salivary microbiota from 610 unrelated adults from the Danish ADDITION-PRO cohort. We identified six single nucleotide polymorphisms (SNPs) in human genomes that showed associations with abundance of bacterial taxa at different taxonomical tiers (P < 5 × 10–8). Notably, SNP rs17793860 surpassed our study-wide significance threshold (P < 1.19 × 10–9). Additionally, rs4530093 was linked to bacterial beta diversity (P < 5 × 10–8). Out of these seven SNPs identified, six exerted effects on metabolic traits, including glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, the risk of type 2 diabetes and stroke. Our findings highlight the impact of specific host SNPs on the composition and diversity of the oral bacterial community. Importantly, our results indicate an intricate interplay between host genetics, the oral microbiota, and metabolic health. We emphasize the need for integrative approaches considering genetic, microbial, and metabolic factors. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the longitudinal development of neurofilament light chain (NfL) levels in type 2 diabetes with and without diabetic polyneuropathy (+/−DPN) and to explore the predictive potential of NfL as a biomarker for DPN. RESEARCH DESIGN AND METHODS: We performed retrospective longitudinal case-control analysis of data from 178 participants of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care-Denmark (ADDITION-Denmark) cohort of people with screen-detected type 2 diabetes. Biobank samples acquired at the ADDITION-Denmark 5- and 10-year follow-ups were analyzed for serum NfL (s-NfL) using single-molecule array, and the results were compared with established reference material to obtain NfL z- scores. DPN was diagnosed according to Toronto criteria for confirmed DPN at the 10-year follow-up. RESULTS: s-NfL increased over time in +DPN (N = 39) and −DPN participants (N = 139) at levels above normal age-induced s-NfL increase. Longitudinal s-NfL change was greater in +DPN than in −DPN participants (17.4% [95% CI 4.3; 32.2] or 0.31 SD [95% CI 0.03; 0.60] higher s-NfL or NfL z -score increase in +DPN compared with −DPN). s-NfL at the 5-year follow-up was positively associated with nerve conduction studies at the 10-year follow-up (P = 0.02 to <0.001), but not with DPN risk. Areas under the curve (AUCs) for s-NfL were not inferior to AUCs for the Michigan Neuropathy Screening Instrument questionnaire score or vibration detection thresholds. Higher yearly s-NfL increase was associated with higher DPN risk (odds ratio 1.36 [95% CI 1.08; 1.71] per 1 ng/L/year). CONCLUSIONS: Our findings suggest that preceding s-NfL trajectories differ slightly between those with and without DPN and imply a possible biomarker value of s-NfL trajectories in DPN. [ABSTRACT FROM AUTHOR]

Objective: To examine 18-year trends in early A1C and lipid control among patients initiating first-time glucose-lowering drug therapy (GLD) for type 2 diabetes. Materials and Methods: Population-based sequential cross-sectional study using healthcare databases covering Northern Denmark (∼1.8 million persons). For all 94,175 GLD initiators during 2000-2017, we examined likelihood of A1C and lipid testing, antilipid therapy, and 1-year glycemic and LDL cholesterol target achievement. Results: The proportion of patients with at least one A1C test increased from 53% in 2000 to 95% in 2017 (Figure, Panel A). Lipid testing increased from 82% to 98% and lipid lowering therapy initiation quintupled from 12% to 61%. Mean pre-treatment A1C declined substantially, from 9.2% (77 mmol/mol) to 7.3% (56 mmol/mol) in 2011, then rose to 7.9% (63 mmol/mol) in 2017 (Panel B). Post-treatment A1C decreased less; pre- and post-treatment LDL cholesterol declined similarly. The proportion of patients achieving glycemic and cholesterol targets increased substantially over time (Panel C). Conclusion: Monitoring and treatment of A1C and cholesterol in early type 2 diabetes have improved considerably over the past 18 years, while quality improvement was somewhat flat after the 2011 change in diagnostic criteria. Disclosure: J.S. Knudsen: None. D.R. Witte: None. A. Hulman: None. P.F. Rønn: Research Support; Self; Amgen AB. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Lauritzen: Advisory Panel; Self; AstraZeneca. Board Member; Self; Novo Nordisk A/S. H.T. Sôrensen: None. R.W. Thomsen: None. Funding: Aarhus University [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether diabetic polyneuropathy (DPN) follows the hypothesis for the course of nerve fiber damage reflected by symptoms progressing from pure small through mixed to large nerve fiber symptoms with or without symptoms of loss of function of small nerve fibers.Research Design and Methods: Repeated assessments of nerve fiber-specific symptoms were obtained in 518 participants of the ADDITION-Denmark study from the time of a screening-based diagnosis of type 2 diabetes using specific items of the Michigan Neuropathy Screening Instrument questionnaire. DPN was clinically assessed 13 years after inclusion. The course of symptoms reflecting dysfunction of specific nerve fibers was evaluated, and the association between symptoms and DPN was estimated using logistic regression models.Results: An overall stable, yet heterogeneous course of symptoms was seen. According to the hypothesis of symptom progression, 205 (40%) participants remained free of symptoms and 56 (11%) had stable, 114 (23%) progressing, and 132 (26%) improving symptoms. Cross-sectional estimates showed a higher risk of DPN (odds ratios between 2.1 and 4.1) for participants with mixed or large nerve fiber symptoms with or without symptoms of loss of function of small nerve fibers compared with participants without symptoms.Conclusions: There was no evidence for a progressive development of nerve fiber damage in DPN reflected by symptoms going from pure small through mixed to large nerve fiber symptoms with or without symptoms of loss of function of small nerve fibers. Yet overall, neuropathic symptoms were prospectively associated with a higher risk of DPN. [ABSTRACT FROM AUTHOR]

• More than 3.5 million, or 70% of all Danish adults, had HbA1c measured during 2012 to 2018. • In 2018, the prevalence of HbA1c-defined prediabetes was 7.1% among Danish adults. • Each year, 1.4 out of 100 adult Danes are identified with incident prediabetes. • Within five years, 1 in 5 progresses to type 2 diabetes and more than 1 in 6 dies. • Laboratory databases may aid in identification of prediabetes at an early stage. To estimate the prevalence, incidence, mortality, and risk of progression to type 2 diabetes for individuals with HbA1c-defined prediabetes based on Danish nationwide population-based laboratory databases. We included all HbA1c measurements from general practice and hospitals during 2012 to 2018. We estimated the cumulative incidence of having at least one HbA1c measurement. The prevalence and incidence rates of prediabetes (HbA1c 42–47 mmol/mol) were examined in the adult Danish population. The 5-year cumulative incidence of progression to type 2 diabetes was estimated with death as competing event. Among 4,979,590 adult Danes, 70.8% (95% CI 70.8–70.9) had at least one HbA1c measurement during 2012 to 2018. The prevalence of prediabetes was 7.1% (95% CI 7.1–7.1) in 2018. The incidence rate was 14.2 (95% CI 14.1–14.3) per 1,000 person-years, with median age 66.9 years (IQR 56.7–75.7) and median HbA1c 43 mmol/mol (IQR 42–44) at prediabetes diagnosis. Within five years, 17.5% (95% CI 17.3–17.7) died and the 5-year cumulative incidence of type 2 diabetes was 21.3% (95% CI 21.1–21.5). Out of 100 Danish adults, 1.4 develop prediabetes each year and they can be identified at an early stage in laboratory databases. Within five years, one in five individuals with prediabetes progresses to diabetes and one in six dies. [ABSTRACT FROM AUTHOR]

Purpose Classical regression models might give an incomplete picture of the associations between predictors and outcomes. We investigated associations between gestational weight gain (GWG) and birth weight along the entire birth weight distribution with quantile regression and estimated effects of hypothetical prevention strategies. Methods The GWG–birth weight association was analyzed using quantile and classical regression models on data from a population-based gestational diabetes screening ( n = 4760) at the Szent Imre Teaching Hospital in Budapest, Hungary (2002–2005). Birth weight distributions were modeled based on hypothetical GWG changes. Results At a body mass index of 20 kg/m 2 , a 1-kg difference in GWG was associated with a 14.2 g (95% confidence interval, 10.0–20.9) higher birth weight at the fifth percentile of the birth weight distribution and a 29.0 g (21.3–35.6) higher birth weight at the 95th percentile. The coefficient from linear regression was 20.7 (17.5–24.0). Estimates differed modestly between the two regressions at a body mass index of 30 kg/m 2 . A population-wide 2-kg decrease in GWG would rather affect the risk of macrosomia (−1.8%) than that of low birth weight (+0.4%). In contrast, a 3-kg decrease in GWG among overweight and obese women would lower macrosomia more modestly (−0.8%). Conclusions A population-wide lowering of GWG would lead to greater improvements in the right tail of the birth weight distribution. [ABSTRACT FROM AUTHOR]

Aims: We examined whether social relations are associated with the risk of developing type 2 diabetes mellitus (T2DM) and furthermore, whether social relations modify the association between depressive symptoms and incident T2DM. We hypothesized that the risk of developing T2DM would be lower for individuals with stronger social relations compared to those with weaker social relations, and that the association between depressive symptoms and incident T2DM would be attenuated for those with stronger social relations.Methods: Non-diabetic participants (n=7662) of the "English Longitudinal Study of Ageing" (3398 men) aged 50-91years were followed until 2012/2013, after baseline assessment of depressive symptoms, social support, relational strain, and network size. Hazard ratios (HR) for incident diabetes were calculated using Cox proportional hazard models, adjusting for relevant confounders.Results: Age and sex adjusted HRs showed that social relations were associated with incident diabetes (Support: HR 0.98 95% CI 0.97; 0.99, Strain: HR 1.02 95% CI 1.01; 1.04, Networklimited: HR 1.19 95% CI 0.98; 1.44), however, when adjusted for age, sex, ethnicity, marital status, household wealth, health behaviour, and body mass index the associations were attenuated and were no longer statistically significant. Depressive symptoms were associated with higher diabetes risk. This effect was not modified by any of the social variables.Conclusions: People with stronger social relations are at lower risk of developing T2DM; however, this effect is largely explained by known diabetes risk factors. No evidence was found that stronger social relations reduce the association between depressive symptoms and incident T2DM. [ABSTRACT FROM AUTHOR]

A response by Solomon Tesfaye, Daniel R. Witte and John H. Fuller to several letters to the editor about their article "Vascular Risk Factors and Diabetic Neuropathy" in the January 27, 2005 issue is presented.

Background: Peripheral and central hemodynamic indices are modifiable by lifestyle and medical intervention. We aimed to determine the long-term effect of intensive multifactorial treatment on peripheral and central hemodynamic indices among people with screen-detected diabetes. Methods: Between 2001 and 2006, people with screen-detected type 2 diabetes were included in the Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION) trial (NCT00237549, ClinicalTrials.gov). In the Danish arm, participants were invited to a clinical examination in 2015–2016, 13 years after inclusion and 8 years after trial-end. Out of 586 eligible participants who attended the clinical examination, 411 had a valid examination of central and peripheral hemodynamic indices (242 received intensive treatment and 169 received routine care). Carotid-femoral pulse wave velocity (cfPWV), central blood pressure and augmentation index were assessed by applanation tonometry. We used mixed-effect models to examine the intervention effect adjusting for cluster randomization and heart rate. Results: Randomization to intensive treatment during the trial-period was associated with a 0.58 m/s lower cfPWV (95% CI − 1.09 to − 0.06) at follow-up. Adjustment for blood pressure attenuated the association. Differences between intervention groups for central augmentation index were − 1.25% (95% CI: − 3.28 to 0.78), central pulse pressure − 1.74 mmHg (95% CI − 4.79 to 1.31), central systolic blood pressure − 3.06 mmHg (− 7.08 to 0.96), and central diastolic blood pressure − 1.70 mmHg (− 3.74 to 0.34). Conclusions: Intensive multifactorial treatment of screen-detected type 2 diabetes has a sustained positive effect on aortic stiffness measured by cfPWV. Although all estimates pointed in favor of intensive treatment, we observed no clear beneficial effect on other hemodynamic indices. [ABSTRACT FROM AUTHOR]

Aims: We estimated and compared health‐related quality of life for individuals with normal glucose tolerance, prediabetes and diabetes. Methods: Participants in the ADDITION‐PRO study, Denmark, who attended a health assessment between 2009 and 2011, and who completed the 3‐level EuroQoL 5‐dimensions (EQ‐5D‐3L) questionnaire were included. For the present study, they were classified as normal glucose tolerance, prediabetes and diabetes (screen‐detected and known) using the 2019 American Diabetes Association criteria. Prediabetes was defined as impaired fasting glucose, impaired glucose tolerance or HbA1c between 5.7–6.4% (39–47 mmol/mol). EQ‐5D‐3L data were converted into utility scores using Danish and UK values, where '1' equals full health and '0' equals death. Regression models estimated the association between utility and the different glucose health states. Results: The mean EQ‐5D‐3L score in the sample population was 0.86 ± 0.17 (median 0.85, interquartile range 0.76 to 1) using UK values. Almost half of the sample (48%) reported full health with an EQ‐5D score of '1'. Individuals with known diabetes reported the lowest EQ‐5D‐3L utility scores (0.81 ± 0.20), followed by individuals with screen‐detected diabetes (0.85 ± 0.19), prediabetes (0.86 ± 0.17) and normal glucose tolerance (0.90 ± 0.15). The differences were statistically significant for normal glucose and known diabetes relative to prediabetes, after adjusting for sex, age, smoking, BMI and physical activity. These findings also held using Danish values albeit the differences were of smaller magnitude. Conclusions: Having prediabetes and diabetes was significantly associated with lower health‐related quality of life relative to normal glucose tolerance. Our estimates will be useful to inform the value of interventions to prevent diabetes or prediabetes. [ABSTRACT FROM AUTHOR]

• A latent class trajectory analysis of longitudinal HbA1c data in clinical practice. • We found four distinct HbA1c trajectories preceding diabetes treatment initiation. • The four trajectories varied in steepness of increase in HbA1c. • The 48 mmol/mol diagnostic threshold is exceeded 9–17 months before first treatment. • The high HbA1c values before first treatment initiation imply therapeutic inertia. To examine the longitudinal heterogeneity of HbA1c preceding the initiation of diabetes treatment in clinical practice. In this population-based study, we used HbA1c from routine laboratory and healthcare databases. Latent class trajectory analysis was used to classify individuals according to their longitudinal HbA1c patterns before first glucose-lowering drug prescription irrespective of type of diabetes. Among 21,556 individuals initiating diabetes treatment during 2017–2018, 20,733 (96 %) had HbA1c measured (median 4 measurements [IQR 2–7]) in the 5 years preceding treatment initiation. Four classes with distinct HbA1c trajectories were identified, with varying steepness of increase in HbA1c. The largest class (74 % of the individuals) had mean HbA1c above the 48 mmol/mol threshold 9 months before treatment initiation. Mean HbA1c was 52 mmol/mol (95 % CI 52–52) at treatment initiation. In the remaining three classes, mean HbA1c exceeded 48 mmol/mol almost 1.5 years before treatment initiation and reached 79 mmol/mol (95 % CI 78–80), 105 mmol/mol (95 % CI 104–106), and 137 mmol/mol (95 % CI 135–140) before treatment initiation. We identified four distinct longitudinal HbA1c patterns before initiation of diabetes treatment in clinical practice. All had mean HbA1c levels exceeding the diagnostic threshold many months before treatment initiation, indicating therapeutic inertia. [ABSTRACT FROM AUTHOR]

With an increased prevalence of concurrent morbidities during pregnancy, polypharmacy has become increasingly common in pregnant women. The risks associated with polypharmacy may exceed those of individual medication because of drug–drug interactions. This systematic review aims to evaluate the risk of congenital malformations in polymorbid pregnancies exposed to first‐trimester polypharmacy. PubMed, Embase and Scopus were searched to identify original human studies with first‐ trimester polypharmacy due to polymorbidity as the exposure and congenital malformations as the outcome. After screening of 4034 identified records, seven studies fulfilled the inclusion criteria. Four of the seven studies reported an increased risk of congenital malformations compared with unexposed or monotherapy, odds ratios ranging from 1.1 to >10.0. Particularly, short‐term anti‐infective treatment combined with other drugs and P‐glycoprotein substrates were associated with increased malformation risks. In conclusion, knowledge is limited on risks associated with first‐trimester polypharmacy due to polymorbidity with the underlying evidence of low quantity and quality. Therefore, an increased focus on pharmacovigilance to enable safe drug use in early pregnancy is needed. Large‐scale register‐based studies and better knowledge of placental biology are needed to support the clinical management of polymorbid pregnancies that require polypharmacy. [ABSTRACT FROM AUTHOR]

OBJECTIVE-The role of adiponectin in the natural history of diabetes is not well characterized. We set out to characterize prediagnosis trajectories of adiponectin in individuals who develop type 2 diabetes. RESEARCH DESIGN ANDMETHODS-In a case-cohort study (335 incident diabetes case and 2,474 noncase subjects) nested in the Whitehall II study, serum adiponectin was measured up to three times per participant (1991-1993, 1997-1999, and 2003-2004). Multilevel models adjusted for age and ethnicity were fitted to assess 13-year trajectories of log-transformed adiponectin preceding diabetes diagnosis or a randomly selected time point during follow-up (year0) based on 755/5,095 (case/noncase) person-examinations. RESULTS-Adiponectin levels were lower in diabetes case than in noncase subjects (median 7,141 [interquartile range 5,187-10,304] vs. 8,818 [6,535-12,369] ng/mL at baseline, P < 0.0001). Control subjects showed a modest decline in adiponectin throughout follow-up (0.3%per year, P<0.0001) at higher levels inwomen than inmen (difference at year0: 5,358ng/mL, P<0.0001). Female case and early-onset case (age at diagnosis<52 years) subjects had a steeper decline than control subjects (slope difference-1.1% per year, P = 0.001 in females, -1.6% per year in early-onset case subjects, P = 0.034). In men, adiponectin slopes for case and noncase subjects were parallel. The slope differences by diabetes onset were largely attenuated after adjustment for changes in obesity, whereas the sex-specific slope differences were independent of obesity. CONCLUSIONS-Lower adiponectin levels were observed already a decade before the diagnosis of diabetes. The marked sex difference in trajectories suggests that sex-specific mechanisms affect the association between adiponectin levels and diabetes development. [ABSTRACT FROM AUTHOR]

OBJECTIVE--There is limned evidence on how intensive multifactorial treatment (IT) improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. We examined the effects of early detection and IT of type 2 diabetes in primary care on the prevalence of diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) 6 years later in a pragmatic, cluster-randomized parallel group trial. RESEARCH DESIGN AND METHODS--A stepwise screening program in 190 general practices in Denmark was used to identify 1,533 people with type 2 diabetes. General practices were randomized to deliver either IT or routine care (RC) as recommended through national guidelines. Participants were followed for 6 years and measures of DPN and PAD were applied. RESULTS--We found no statistically significant effect of IT on the prevalence of DPN and PAD compared with RC. The prevalence of an ankle brachial index ≤0.9 was 9.1% (95% CI 6.0-12.2) in the RC arm and 7.3% (5.0-9.6) in the IT arm. In participants tested for vibration detection threshold and light touch sensation, the prevalence of a least one abnormal test was 34.8% (26.7-43.0) in the RC. arm and 30.1% (24.1-36.1) in the IT arm. CONCLUSIONS--In a population with screen-detected type 2 diabetes, we did not find that screening followed by IT led to a statistically significant difference in the prevalence of DPN and PAD 6 years after diagnosis. However, treatment levels were high in both groups. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To investigate the effect of psychosocial stress at work on risk of type 2 diabetes, adjusting for conventional risk factors, among a sample of British, white-collar, middle-aged men and women. RESEARCH DESIGN AND METHODS -- This was a prospective analysis (1991-2004) from the Whitehall II cohort study. The current sample consists of 5,895 Caucasian middle-aged civil servants free from diabetes at baseline. Type 2 diabetes was ascertained by an oral glucose tolerance test supplemented by self-reports at baseline and four consecutive waves of data collection including two screening phases. The job strain and iso-strain models were used to assess psychosocial work stress. RESULTS -- Iso-strain in the workplace was associated with a twofold higher risk of type 2 diabetes in age-adjusted analysis in women but not in men (hazard ratio 1.94 [95% CI 1.17-3.21). This effect remained robust to adjustment for socioeconomic position and outside work stressors and was only attenuated by 20% after adjustment for health behaviors, obesity, and other type 2 diabetes risk factors. CONCLUSIONS -- Psychosocial work stress was an independent predictor of type 2 diabetes among women after a 15-year follow-up. This association was not explained by potential confounding and mediating factors. More evidence from prospective studies using the same work stress models is needed to support the current findings and provide further information on sex differences. [ABSTRACT FROM AUTHOR]

Using a Mendelian randomization approach, Eric Brunner and colleagues show that the associations between serum C-reactive protein and insulin resistance, glycemia, and diabetes are likely to be noncausal. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS -- Baseline risk factors were measured in the EURODIAB Prospective Cohort Study with 2,787 type 1 diabetic patients (51% men and 49% women) recruited from 16 European countries. Mortality data were collected during a 7-year follow-up. RESULTS -- There was an annual mortality rate of 5 per 1,000 person-years in patients with type 1 diabetes (mean age at baseline 33 years, range 15-61 years); of the total 2,787 subjects, 102 died. The final multivariable model contained age at baseline (standardized hazard ratio 1.78 [95% CI 1.44-2.20]), A1C (1.18 [0.95-1.46]), waist-to-hip ratio (WHR) (1.32 [1.14-1.52]), pulse pressure (1.33 [1.13-1.58]), and non-HDL cholesterol (1.33 [1.12-1.60]) as risk factors for all-cause mortality. Macroalbuminuria (2.39 [1.19-4.78]) and peripheral (1.88 [1.06-3.35]) and autonomic neuropathy (2.40 [1.32-4.36]) were the most important risk markers for mortality. Similar risk factors were found for all-cause, non-cardiovascular disease (CVD), unknown-cause, and CVD mortality. CONCLUSIONS -- Important risk factors for the increased total and non-CVD mortality in type 1 diabetic patients are age, WHR, pulse pressure, and non-HDL cholesterol. Microvascular complications from macroalbuminuria and peripheral and autonomic neuropathy are strong risk markers for future mortality exceeding the effect of the traditional risk factors. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Glucose intolerance is a risk factor for coronary disease, but there is uncertainty about the shape of the dose-response relationship between glucose level and risk of coronary mortality. We examined the prospective relation of 2-h postload blood glucose (2hBG) with coronary and other major causes of mortality over 33 years. RESEARCH DESIGN AND METHODS -- A 50-g oral glucose tolerance test (OGTT) was performed at baseline (1967-1969) in 17,869 male civil servants aged 40-64 years. RESULTS -- There were 3,561 coronary deaths during 451,787 person-years of observation. All-cause, cardiovascular, and respiratory mortality were elevated among participants with glucose intolerance. The hazard of coronary mortality rose from 2hBG = 4.6 mmol/l (83 mg/dl [95% CI 4.2-5.3]). The dose-response relation was best fitted by a single slope above this level, with no evidence of nonlinearity, compared with Cox models using other threshold levels, and those containing log 2hBG terms. There was no evidence for a dose-response relationship below 2hBG = 4.6 mmol/l. Between this level and 11.1 mmol/l (200 mg/dl), the age-adjusted hazard ratio was 3.62 (95% CI 2.3-5.6). The graded relationship was attenuated by 45% after adjustment for baseline coronary heart disease (CHD), BMI, systolic blood pressure, blood cholesterol, smoking, physical activity, lung function, and employment grade. CONCLUSIONS -- A threshold model with linear slope best described the dose-response relationship between postload blood glucose and CHD mortality risk. [ABSTRACT FROM AUTHOR]

Background: People with type 1 diabetes often live for many years with different combinations of diabetes-related complications. We aimed to quantify how complication duration and total complication burden affect mortality, using data from national registers.Methods: This study included 33 396 individuals with type 1 diabetes, registered in the Swedish National Diabetes Register at any time between 2001 and 2012. Each individual was followed and classified according to their time-updated diabetes-related complication status. The main outcomes were all-cause mortality, cardiovascular (CV) mortality and non-CV mortality. Poisson models were used to estimate the rate of these outcomes as a function of the time-updated complication duration.Results: Overall, 1748 of the 33 396 individuals died during 198 872 person-years of follow-up. Overall, the time-updated all-cause mortality rate ratio (MRR) was 2.25 [95% confidence interval (CI): 1.99-2.54] for patients with diabetic kidney disease, 0.98 (0.82-1.18) for patients with retinopathy and 4.00 (3.56-4.50) for patients with cardiovascular disease relative to individuals without complications. The excess rate was highest in the first period after a diagnosis of CVD, with an 8-fold higher mortality rate, and stabilized after some 5 years. After diagnosis of diabetic kidney disease, we observed an increase in all-cause mortality with an MRR of around 2 compared with individuals without diabetic kidney disease, which stabilized after few years.Conclusions: In this cohort we show that duration of diabetes-related complications is an important determinant of mortality in type 1 diabetes, for example the MRR associated with CVD is highest in the first period after diagnosis of CVD. A stronger focus on time-updated information and thorough consideration of complication duration may improve risk stratification in routine clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Symptoms indicative of diabetic polyneuropathy (DPN) early in type 2 diabetes may act as a marker for cardiovascular disease (CVD) and death.Research Design and Methods: We linked data from two Danish type 2 diabetes cohorts, the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) and the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), to national health care registers. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was completed at diabetes diagnosis in ADDITION-Denmark and at a median of 4.6 years after diagnosis of diabetes in DD2. An MNSIq score ≥4 was considered as indicative of DPN. Using Poisson regressions, we computed incidence rate ratios (IRRs) of CVD and all-cause mortality comparing MNSIq scores ≥4 with scores <4. Analyses were adjusted for a range of established CVD risk factors.Results: In total, 1,445 (ADDITION-Denmark) and 5,028 (DD2) individuals were included in the study. Compared with MNSIq scores <4, MNSIq scores ≥4 were associated with higher incidence rate of CVD, with IRRs of 1.79 (95% CI 1.38-2.31) in ADDITION-Denmark, 1.57 (CI 1.27-1.94) in the DD2, and a combined IRR of 1.65 (CI 1.41-1.95) in a fixed-effect meta-analysis. MNSIq scores ≥4 did not associate with mortality; combined mortality rate ratio was 1.11 (CI 0.83-1.48).Conclusions: The MNSIq may be a tool to identify a subgroup within individuals with newly diagnosed type 2 diabetes with a high incidence rate of subsequent CVD. MNSIq scores ≥4, indicating DPN, were associated with a markedly higher incidence rate of CVD, beyond that conferred by established CVD risk factors. [ABSTRACT FROM AUTHOR]

Objective: The global rise in type 2 diabetes is associated with a concomitant increase in diabetic complications. Diabetic polyneuropathy is the most frequent type 2 diabetes complication and is associated with poor outcomes. The metabolic syndrome has emerged as a major risk factor for diabetic polyneuropathy; however, the metabolites associated with the metabolic syndrome that correlate with diabetic polyneuropathy are unknown. Methods: We conducted a global metabolomics analysis on plasma samples from a subcohort of participants from the Danish arm of Anglo‐Danish‐Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION‐Denmark) with and without diabetic polyneuropathy versus lean control participants. Results: Compared to lean controls, type 2 diabetes participants had significantly higher HbA1c (p = 0.0028), BMI (p = 0.0004), and waist circumference (p = 0.0001), but lower total cholesterol (p = 0.0001). Out of 991 total metabolites, we identified 15 plasma metabolites that differed in type 2 diabetes participants by diabetic polyneuropathy status, including metabolites belonging to energy, lipid, and xenobiotic pathways, among others. Additionally, these metabolites correlated with alterations in plasma lipid metabolites in type 2 diabetes participants based on neuropathy status. Further evaluating all plasma lipid metabolites identified a shift in abundance, chain length, and saturation of free fatty acids in type 2 diabetes participants. Importantly, the presence of diabetic polyneuropathy impacted the abundance of plasma complex lipids, including acylcarnitines and sphingolipids. Interpretation: Our explorative study suggests that diabetic polyneuropathy in type 2 diabetes is associated with novel alterations in plasma metabolites related to lipid metabolism. [ABSTRACT FROM AUTHOR]

Objective: Higher resting heart rate (rHR) and lower heart rate variability (HRV) are associated with increased risk of cardiovascular disease (CVD) and all-cause mortality in people with and without diabetes. It is unknown whether temporal changes in rHR and HRV may contribute to this risk. We investigated associations between 5-year changes in rHR and HRV and risk of future CVD and death, taking into account participants' baseline glycemic state.Research Design and Methods: In this prospective, population-based cohort study we investigated 4,611 CVD-free civil servants (mean [SD] age, 60 [5.9] years; 70% men). We measured rHR and/or six indices of HRV. Associations of 5-year change in 5-min rHR and HRV with fatal and nonfatal CVD and all-cause mortality or the composite of the two were assessed, with adjustments made for relevant confounders. Effect modification by glycemic state was tested.Results: At baseline, 63% of participants were normoglycemic, 29% had prediabetes, and 8% had diabetes. During a median (interquartile range) follow-up of 11.9 (11.4; 12.3) years, 298 participants (6.5%) experienced a CVD event and 279 (6.1%) died of non-CVD-related causes. We found no association between 5-year changes in rHR and HRV and future events. Only baseline rHR was associated with all-cause mortality. A 10 bpm-higher baseline HR level was associated with an 11.4% higher rate of all-cause mortality (95% CI 1.0-22.9%; P = 0.032). Glycemic state did not modify associations.Conclusions: Changes in rHR and HRV and possibly also baseline values of these measures are not associated with future CVD or death in people with or without dysglycemia. [ABSTRACT FROM AUTHOR]

In response to a study previously published in PLOS Biology, this Formal Comment thoroughly examines the concept of 'glucotypes' with regard to its generalisability, interpretability and relationship to more traditional measures used to describe data from continuous glucose monitoring. [ABSTRACT FROM AUTHOR]

Aims: Short‐term weight loss may lead to remission of type 2 diabetes but the effect of maintained weight loss on cardiovascular disease (CVD) is unknown. We quantified the associations between changes in weight 5 years following a diagnosis of diabetes, and incident CVD events and mortality up to 10 years after diagnosis. Materials and methods: Observational analysis of the ADDITION‐Europe trial of 2730 adults with screen‐detected type 2 diabetes from the UK, Denmark and the Netherlands. We defined weight change based on the maintenance at 5 years of weight loss achieved during the year after diabetes diagnosis, and as 5‐year overall change in weight. Incident CVD events (n = 229) and all‐cause mortality (n = 225) from 5 to 10 years follow‐up were ascertained from medical records. Results: Gaining >2% weight during the year after diabetes diagnosis was associated with higher hazard of all‐cause mortality versus maintaining weight [hazard ratio (95% confidence interval): 3.18 (1.30‐7.82)]. Losing ≥5% weight 1 year after diagnosis was also associated with mortality, whether or not weight loss was maintained at 5 years: 2.47 (0.99‐6.21) and 2.72 (1.17‐6.30), respectively. Losing ≥10% weight over 5 years was associated with mortality among those with body mass index <30 kg/m2 [4.62 (1.87‐11.42)]. Associations with CVD incidence were inconclusive. Conclusions: Both weight loss and weight gain after screen‐detected diabetes diagnosis were associated with higher mortality, but not CVD events, particularly among participants without obesity. The clinical implications of weight loss following a diagnosis of diabetes probably depend on its magnitude and timing, and may differ by body mass index status. Personalization of weight loss advice and support may be warranted. [ABSTRACT FROM AUTHOR]

Background: In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). Furthermore, we performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels. Methods: Plasma levels of glucagon were examined in samples obtained at three time points during an OGTT; 0, 30 and 120 min, in two separate cohorts with a total of up to 1899 individuals. Cross-sectional analyses were performed separately in the two cohorts and the results were combined in a meta-analysis. Results: A known type 2 diabetes variant in EYA2 was significantly associated with higher plasma glucagon level at 30 min during the OGTT (Beta 0.145, SE 0.038, P = 1.2 × 10–4) corresponding to a 7.4% increase in plasma glucagon level per effect allele. In the GWAS, we identified a marker in the MARCH1 locus, which was genome-wide significantly associated with reduced suppression of glucagon during the first 30 min of the OGTT (Beta − 0.210, SE 0.037, P = 1.9 × 10–8), equivalent to 8.2% less suppression per effect allele. Nine additional independent markers, not previously associated with type 2 diabetes, showed suggestive associations with reduced glucagon suppression during the first 30 min of the OGTT (P < 1.0 × 10–5). Conclusions: A type 2 diabetes risk variant in the EYA2 locus was associated with higher plasma glucagon levels at 30 min. Ten additional variants were suggestively associated with reduced glucagon suppression without conferring increased type 2 diabetes risk. [ABSTRACT FROM AUTHOR]

Background: There is a need to identify priority zones for cardiometabolic prevention. Disease mapping in countries with high heterogeneity in the geographic distribution of the population is challenging. Our goal was to map the cardiometabolic health and identify hotspots of disease using data from a national health survey. Methods: Using Chile as a case study, we applied a Bayesian hierarchical modelling. We performed a cross-sectional analysis of the 2009–2010 Chilean Health Survey. Outcomes were diabetes (all types), obesity, hypertension, and high LDL cholesterol. To estimate prevalence, we used individual and aggregated data by province. We identified hotspots defined as prevalence in provinces significantly greater than the national prevalence. Models were adjusted for age, sex, their interaction, and sampling weight. We imputed missing data. We applied a joint outcome modelling approach to capture the association between the four outcomes. Results: We analysed data from 4,780 participants (mean age (SD) 46 (19) years; 60% women). The national prevalence (percentage (95% credible intervals) for diabetes, obesity, hypertension and high LDL cholesterol were 10.9 (4.5, 19.2), 30.0 (17.7, 45.3), 36.4 (16.4, 57.6), and 13.7 (3.4, 32.2) respectively. Prevalence of diabetes was lower in the far south. Prevalence of obesity and hypertension increased from north to far south. Prevalence of high LDL cholesterol was higher in the north and south. A hotspot for diabetes was located in the centre. Hotspots for obesity were mainly situated in the south and far south, for hypertension in the centre, south and far south and for high LDL cholesterol in the far south. Conclusions: The distribution of cardiometabolic risk factors in Chile has a characteristic pattern with a general trend to a north-south gradient. Our approach is reproducible and demonstrates that the Bayesian approach enables the accurate identification of hotspots and mapping of disease, allowing the identification of areas for cardiometabolic prevention. [ABSTRACT FROM AUTHOR]

Background and aim: Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD. Methods: This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m2, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex. Results: A greater GLP-1 response was associated with lower central systolic and diastolic BP of − 1.17 mmHg (95% confidence interval (CI) − 2.07 to − 0.27 mmHg, P = 0.011) and − 0.74 mmHg (95% CI − 1.29 to − 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of − 1.27 mmHg (95% CI − 2.20 to − 0.33 mmHg, P = 0.008) and − 1.00 (95% CI − 1.56 to − 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: − 4.94 (95% CI − 8.56 to − 1.31) mmHg, central diastolic BP: − 3.05 (95% CI − 5.29 to − 0.80) mmHg, brachial systolic BP: − 5.18 (95% CI − 8.94 to − 1.42) mmHg, and brachial diastolic BP: − 2.96 (95% CI − 5.26 to − 0.67) mmHg). Conclusion: Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality. Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005 [ABSTRACT FROM AUTHOR]

Objective: Frailty is a dynamic state of vulnerability in the elderly. We examined whether individuals with overt diabetes or higher levels of HbA1c or fasting plasma glucose (FG) experience different frailty trajectories with aging.Research Design and Methods: Diabetes, HbA1c, and FG were assessed at baseline, and frailty status was evaluated with a 36-item frailty index every 2 years during a 10-year follow-up among participants from the English Longitudinal Study of Ageing (ELSA). Mixed-effects models with age as time scale were used to assess whether age trajectories of frailty differed as a function of diabetes, HbA1c, and FG.Results: Among 5,377 participants (median age [interquartile range] 70 [65, 77] years, 45% men), 35% were frail at baseline. In a model adjusted for sex, participants with baseline diabetes had an increased frailty index over aging compared with those without diabetes. Similar findings were observed with higher levels of HbA1c, while FG was not associated with frailty. In a model additionally adjusted for income, social class, smoking, alcohol, and hemoglobin, only diabetes was associated with an increased frailty index. Among nonfrail participants at baseline, both diabetes and HbA1c level were associated with a higher increased frailty index over time.Conclusions: People with diabetes or higher HbA1c levels at baseline had a higher frailty level throughout later life. Nonfrail participants with diabetes or higher HbA1c also experienced more rapid deterioration of frailty level with aging. This observation could reflect a role of diabetes complications in frailty trajectories or earlier shared determinants that contribute to diabetes and frailty risk in later life. [ABSTRACT FROM AUTHOR]

Objective: Autonomic nervous system dysfunction is associated with impaired glucose metabolism, but the temporality of this association remains unclear in individuals without diabetes. We investigated the association of autonomic function with 5-year changes in glucose metabolism in individuals without diabetes.Research Design and Methods: Analyses were based on 9,000 person-examinations for 3,631 participants without diabetes in the Whitehall II cohort. Measures of autonomic function included 5-min resting heart rate and six heart rate variability (HRV) indices. Associations between baseline autonomic function measures and 5-year changes in fasting and 2-h plasma glucose, serum insulin concentrations, insulin sensitivity (insulin sensitivity index [ISI0-120] and HOMA of insulin sensitivity), and β-cell function (HOMA of β-cell function) were estimated in models adjusting for age, sex, ethnicity, metabolic factors, and medication.Results: A 10-bpm higher resting heart rate was associated with 5-year changes in fasting and 2-h insulin and ISI0-120 of 3.3% change (95% CI 1.8; 4.8), P < 0.001; 3.3% change (1.3; 5.3), P = 0.001; and -1.4% change (-2.4; -0.3), P = 0.009, respectively. In models adjusted for age, sex, and ethnicity, higher baseline values of several HRV indices were associated with a 5-year decrease in fasting and 2-h insulin and ISI0-120. However, significance was lost by full adjustment. A majority of HRV indices exhibited a trend toward higher values being associated with lower insulin levels and higher insulin sensitivity.Conclusions: Higher resting heart rate in individuals without diabetes is associated with future unfavorable changes in insulin levels and insulin sensitivity. Associations may be mediated via autonomic function; however, results are inconclusive. Resting heart rate may be a risk marker for future pathophysiological changes in glucose metabolism. [ABSTRACT FROM AUTHOR]

[Display omitted] • A blood-based biomarker for DPN could support diagnosis and follow-up of DPN. • NfL levels were higher in +DPN than in -DPN individuals. • NfL's potential as a biomarker for the presence of DPN is however unlikely. • NfL was associated with worse peripheral nerve function in type 2 diabetes. • NfL's relation to nerve function indicates value of NfL in evaluation of DPN severity. To investigate the relationship between neurofilament light chain (NfL) and the presence and severity of diabetic polyneuropathy (DPN). We 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. 39 (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). S-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. [ABSTRACT FROM AUTHOR]

The article presents an analysis for Trends in HbA1c and LDL Cholesterol in Patients With Type 2 Diabetes Receiving First-Time Treatment in Northern Denmark, 2000–2017. Topics discussed include using laboratory and health care databases covering the entire population of Northern Denmark; generalizability of clinical trials to contemporary populations; and pretreatment HbA1c categories had increasingly large post treatment reductions.

Objective: Type 1 diabetes is a complex disease, and development of multiple complications over time can be analyzed only with advanced statistical methods. This study describes the development of microvascular complications and explores the effect of complication burden and important concurrent risk factors by applying a multistate model.Research Design and Methods: We used a clinical cohort at the Steno Diabetes Center Copenhagen to study the development of diabetic kidney disease, retinopathy, and neuropathy. We extracted information from electronic patient records and estimated incidence rates of complications by concurrent complication burden. We explored the extent to which concurrent complications modify the effect of selected risk factors on the development of microvascular complications.Results: We included 3,586 individuals. Incidence rate ratios in individuals with two previous complications were 3.2 (95% CI 2.3-4.5) for diabetic kidney disease, 2.1 (1.5-3.1) for retinopathy, and 1.7 (1.2-2.4) for neuropathy compared with individuals without complications. The models included diabetes duration; calendar time and age as timescales; and sex, HbA1c, lipid-lowering and antihypertensive treatment, systolic blood pressure, BMI, estimated glomerular filtration rate (eGFR), cardiovascular disease (CVD), LDL cholesterol, insulin dose (units/kg/day), and smoking status as covariates. Effects of HbA1c, diabetes duration, systolic blood pressure, BMI, eGFR, and LDL cholesterol where not modified by concurrent complication burden, whereas the effect of sex and CVD were.Conclusions: The risk of microvascular complications highly depends on the concurrent complication burden and risk factor profile in individuals with type 1 diabetes. The results emphasize attention to risk factors, regardless of existing number of complications, to prevent development of further microvascular complications. [ABSTRACT FROM AUTHOR]