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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.

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.

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.

ObjectivesPotentially inappropriate medications (PIMs) pose an increasing challenge in the ageing population. We aimed to assess the extent of PIMs and the prescriber-related variation in PIM prevalence.DesignNationwide register-based cohort study.SettingGeneral practice.ParticipantsThe 4.2 million adults listed with general practitioner (GP) clinics in Denmark (n=1906) in 2016.Main outcome measuresWe estimated the patients’ time with PIMs by using 29 register-operationalised STOPP criteria linking GP clinics and redeemed prescriptions. For each criterion and each GP clinic, we calculated ratios between the observed PIM time and that predicted by multivariate Poisson regressions on the patients. The observed variation was measured as the 90th/10th percentile ratios of these ratios. The extent of expectable random variation was assessed as the 90th/10th percentile ratios in randomly sampled GP populations (ie, the sampled variation). The GP-related excess variation was calculated as the ratio between the observed variation and sampled variation. The linear correlation between the observed/expected ratio for each of the criteria and the observed/expected ratio of total PIM time (for each clinic) was measured by Pearson’s rho.ResultsOverall, 294 542 individuals were exposed to 1 44 117 years of PIMs. The two most prevalent PIMs were long-term use (>3 months) of non-steroidal anti-inflammatory drugs (51 074 years of PIMs) or benzodiazepines (48 723 years of PIMs). These two criteria showed considerable excess variation of 2.33 and 3.05, respectively; for total PIMs, this figure was 1.65. For more than half of the criteria, we observed a positive correlation between the specific PIM and the sum of remaining PIMs.ConclusionsThis study documents considerable variations in the prescribing practice of GPs for certain PIMs. These findings highlight a need for exploring the causal explanations for such variations, which could be markers of suboptimal GP-prescribing strategies.

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 RESULTS In total, 1,445 (ADDITION-Denmark) and 5,028 (DD2) individuals were included in the study. Compared with MNSIq scores 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.

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.

Aims: We examined whether late evening food consumption was prospectively associated with the risk of developing prediabetes or diabetes in a large observational study of individuals with normoglycaemia. Methods: Participants were 2642 men and women with normoglycaemia (HbA1c 1c and risk of developing prediabetes or diabetes (HbA1c ≥ 39 mmol/mol; ≥ 5.7%). Potential heterogeneity in the association between TLEE and prediabetes or diabetes was examined using recursive partitioning modelling for time-to-event outcomes. Results: There was a tendency of an overall association of TLEE with change in HbA1c but with little effect size [β per 1-h increase in TLEE = 0.2 mmol/mol, 95% CI −0.0 to 0.3 (0.01%, −0.00 to 0.03); P = 0.055] and no association with the risk of developing prediabetes/diabetes (risk ratio per 1-h increase in TLEE = 1.03, 95% CI 0.94 to 1.13; P = 0.511). According to the recursive partitioning modelling, women with HbA1c ≤ 36 mmol/mol and TLEE after 21:00 had a 1.51 times (95% CI 1.16 to 1.93) higher 5-year risk of developing prediabetes or diabetes than those having their TLEE between 16:00 and 21:00 (35.4% vs. 23.5%; P = 0.003). Conclusions: There was no overall association of TLEE with the development of prediabetes or diabetes in the Whitehall II population. However, explorative analyses suggested that eating late in the evening was associated with increased risk of developing prediabetes/diabetes among women with good glycaemic control. Whether restricting late evening food consumption is effective and feasible for the prevention of Type 2 diabetes needs testing in randomized controlled trials.

BACKGROUND: Administrative patient registers are often used to estimate morbidity in epidemiological studies. The validity of register data is thus important. This study aims to assess the positive predictive value of myocardial infarction and stroke registered in the Danish National Patient Register, and to examine the association between cardiovascular risk factors and cardiovascular disease based on register data or validated diagnoses in a well-defined diabetes population.METHODS: We included 1533 individuals found with screen-detected type 2 diabetes in the ADDITION-Denmark study in 2001-2006. All individuals were followed for cardiovascular outcomes until the end of 2014. Hospital discharge codes for myocardial infarction and stroke were identified in the Danish National Patient Register. Hospital medical records and other clinically relevant information were collected and an independent adjudication committee evaluated all possible events. The positive predictive value for myocardial infarction and stroke were calculated as the proportion of cases recorded in the Danish National Patient Register confirmed by the adjudication committee.RESULTS: The positive predictive value was 75% (95% CI: 64;84) for MI and 70% (95% CI: 54;80) for stroke. The association between cardiovascular risk factors and incident cardiovascular disease did not depend on using register-based or verified diagnoses. However, a tendency was seen towards stronger associations when using verified diagnoses.CONCLUSIONS: Our results show that studies using only register-based diagnoses are likely to misclassify cardiovascular outcomes. Moreover, the results suggest that the magnitude of associations between cardiovascular risk factors and cardiovascular outcomes may be underestimated when using register-based diagnoses.

Fasting duration has been associated with lower fasting blood glucose levels, but higher 2-h post-load levels, and research has indicated an adverse effect of ‘weekend behavior’ on human metabolism. We investigated associations of fasting duration and weekday of examination with glucose, insulin, glucagon and incretin responses to an oral glucose tolerance test (OGTT). This cross-sectional study is based on data from the ADDITION-PRO study, where 2082 individuals attended a health examination including an OGTT. Linear regression analysis was applied to study the associations of overnight fasting duration and day of the week with glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses to an OGTT. We found that a 1 h longer fasting duration was associated with 1.7% (95% CI: 0.8,2.5) higher 2-h glucose levels, as well as a 3.0% (95% CI: 1.3,4.7) higher GIP and 2.3% (95% CI: 0.3,4.4) higher GLP-1 response. Fasting insulin levels were 20.6% (95% CI: 11.2,30.7) higher on Mondays compared to the other weekdays, with similar fasting glucose levels (1.7%, 95% CI: 0.0,3.4). In this study, longer overnight fasting duration was associated with a worsening of glucose tolerance and increased incretin response to oral glucose. We found higher fasting insulin levels on Mondays compared to the other days of the week, potentially indicating a worsened glucose regulation after the weekend.

IntroductionWe compared the degree of spousal concordance in a set of detailed pathophysiological markers and risk factors for type 2 diabetes to understand where in the causal cascade spousal similarities are most relevant.Research design and methodsThis is a cross-sectional analysis of couples who participated in The Maastricht Study (n=172). We used quantile regression models to assess spousal concordance in risk factors for type 2 diabetes, including four adiposity measures, two dimensions of physical activity, sedentary time and two diet indicators. We additionally assessed beta cell function and insulin sensitivity and glucose metabolism status with fasting and 2-hour plasma glucose and hemoglobin A1c.ResultsThe strongest spousal concordance (beta estimates) was observed for the Dutch Healthy Diet Index (DHDI) in men. A one-unit increase in wives’ DHDI was associated with a 0.53 (95% CI 0.22 to 0.67) unit difference in men’s DHDI. In women, the strongest concordance was for the time spent in high-intensity physical activity (HPA); thus, a one-unit increase in husbands’ time spent in HPA was associated with a 0.36 (95% CI 0.17 to 0.64) unit difference in women’s time spent in HPA. The weakest spousal concordance was observed in beta cell function indices.ConclusionsSpousal concordance was strongest in behavioral risk factors. Concordance weakened when moving downstream in the causal cascade leading to type 2 diabetes. Public health prevention strategies to mitigate diabetes risk may benefit from targeting spousal similarities in health-related behaviors and diabetes risk factors to design innovative and potentially more effective couple-based interventions.

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 –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.

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

The evolving evidence base for early diabetes detection and intensive treatment over the recent decades has likely led to a change in the profile of patients initiating type 2 diabetes treatment (1–3). Knowing in which direction the clinical profile of patients with diabetes is moving is important because treatment guidelines rely on the generalizability of clinical trials to contemporary populations (3). Many of these trials were conducted when both the diagnostic criteria and treatment targets were quite different than today (1–3). Population-based data investigating long-term trends in diabetes management and treatment targets are scarce. We aimed to examine 18-year changes in HbA1c and lipid testing and control among people initiating glucose-lowering drugs (GLDs) for type 2 diabetes. We performed one of the first population-based studies, using laboratory and health care databases covering the entire population of Northern Denmark (∼1.8 million people) (4). We identified people redeeming their first-ever GLD prescription at age ≥30 years. For all 94,175 GLD initiators 2000–2017, we examined pretreatment HbA1c and lipid levels and proportions of testing. For initiators 2000–2016, we assessed 12 months posttreatment lipid-lowering therapy and achievement of glycemic and LDL cholesterol targets. Mean HbA1c and LDL levels and reductions were plotted with 95% CIs. Median age at first GLD treatment fell from 64 years in 2000 to 61 in 2017; 56% of the study population were men. The proportion of patients with at least one HbA1c test within 12 months after GLD initiation increased from 53% (2000) to 95% (2016) (Fig. 1 A ). Concurrently, mean pretreatment HbA1c decreased from 9.2% (77 mmol/mol) (2000) to 7.9% (63 mmol/mol) (2017), with a nadir occurring in 2011 (7.3% [56 mmol/mol]). For mean posttreatment HbA1c, a smaller decline was seen from 7.1% …

Importance: Use of the sodium-glucose cotransporter 2 inhibitor empagliflozin has increased substantially since 2015. Little is known about characteristics of real-world patients who use empagliflozin or about empagliflozin's effectiveness in reducing glycated hemoglobin (HbA1c) levels in routine clinical care. Objectives: To characterize real-world initiators of empagliflozin, to examine the proportion of initiators who would have been eligible for participation in phase 3 randomized clinical trials (RCTs) of empagliflozin, and to assess changes in HbA1c levels after empagliflozin initiation. Design, Setting, and Participants: This cross-sectional study used linked population-based medical databases containing complete information on redeemed prescriptions, laboratory tests, and diagnoses for all residents in Northern Denmark. A total of 7034 residents of Denmark who filled a first-time empagliflozin prescription from January 2014 to December 2018 were included. Data analysis was performed in August 2019. Exposure: Empagliflozin initiation. Main Outcomes and Measures: Proportion of real-world users ineligible for RCT inclusion and absolute reduction in HbA1c level 6 months after empagliflozin initiation. Results: Of 7034 first-time empagliflozin initiators (median [interquartile range] age, 61.50 [53.30-69.38] years; 4475 [63.6%] men), 3878 (55.1%) would have been ineligible for phase 3 RCT participation; frequent reasons were concurrent use of specific glucose-lowering drugs (1955 initiators [27.8%]), baseline HbA1c level outside the eligibility range (1772 [25.2%]), or presence of comorbidities (1067 initiators [15.3%]). Initiation of empagliflozin was associated with a mean HbA1c reduction of -0.91% (95% CI, -0.94% to -0.87%) after 6 months, similar to phase 3 RCT results. Real-world empagliflozin initiators who would have been eligible for RCT participation experienced slightly lower mean HbA1c reductions (-0.78%; 95% CI, -0.82% to -0.74%) compared with patients who would have been ineligible (-1.01%; 95% CI, -1.07% to -0.95%). Ineligible initiators had higher median (interquartile range) baseline HbA1c values than eligible initiators (8.5% [7.4% to 10.1%] vs 8.2% [7.6% to 9.8%]). Conclusions and Relevance: In this cross-sectional study, more than half of empagliflozin initiators exhibited clinical characteristics that would have led to ineligibility for the RCTs leading to the drug's approval. While the findings suggest that the efficacy of empagliflozin in reducing HbA1c levels translates into real-world effectiveness, further studies should examine clinical outcome effectiveness and drug safety in routine clinical care.

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.

Aims: To determine the association between concurrent overall burden of disease, cardiovascular disease, cancer, self-rated health, HbA1c levels, and attendance at clinical follow-up of the Danish arm of the ADDITION-study. Methods: Logistic regression models were used to study factors proposed being associated with attendance in clinical follow-up. We used data from clinical examinations, questionnaires and national registers at a time-point near the follow-up examination. Results: A total of 1119 participants were eligible for the follow-up conducted a median of 12.8 years (IQR 11.6; 13.4) after type 2 diabetes diagnosis by screening. Concurrent high burden of disease was associated with lower attendance (OR 0.6 (95% CI: 0.4; 0.9) for high-versus no burden of disease). Concurrent cardiovascular disease and cancer showed no statistically significant association with attendance (OR 1.0 (95% CI: 0.7; 1.4)) and (OR 0.8 (95% CI: 0.6; 1.1) for (disease versus no disease). Similarly, self-rated health (OR 0.7 (95% CI: 0.5; 1.0) poor-versus good self-rated health) and HbA1c levels (OR 1.0 (95% CI: 0.9; 1.2 unit = 10 mmol/mol)) were not statistically significant associated with attendance. Conclusions: This study showed a lower attendance in clinical follow-up after nearly 13 years among individuals with concurrent high burden of disease. No associations were found between concurrent CVD, cancer, self-rated health and Hba1c levels and attendance.

AIM: To analyze the association of objective and subjective sleep measures with HbA1c and insulin sensitivity in the general population.METHODS: Using a cross-sectional design, data from 1028 participants in the ORISCAV-LUX-2 study from the general population in Luxembourg were analyzed. Objective sleep measures were assessed using accelerometers whereas subjective measures were assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Sleep measures were defined as predictors, while HbA1c and quantitative insulin sensitivity check index (QUICKI) scores were considered outcomes. Linear and spline regression models were fitted by progressively adjusting for demographic and lifestyle variables in the total sample population as well as by stratified analyses using gender, obesity status, depressive symptoms and diabetes status.RESULTS: In fully adjusted models, total and deep sleep durations were associated with lower HbA1c (mmol/mol) levels, whereas sleep coefficients of variation (%) and poor sleep efficiency, as measured by PSQI scores (units), were associated with higher HbA1c levels. In stratified models, such associations were observed mainly in men, and in subjects who had depressive symptoms, were overweight and no diabetes. In addition, total sleep, deep sleep, coefficients of variation and poor sleep efficiency as measured by PSQI revealed non-linear associations. Similarly, greater insulin sensitivity was associated with longer total sleep time and with PSQI-6 (use of sleep medication).CONCLUSION: Associations were more frequently observed between sleep characteristics and glycaemic control with the use of objective sleep measures. Also, such associations varied within subgroups of the population. Our results highlight the relevance of measuring sleep patterns as key factors in the prevention of diabetes.

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.

Rationale The hormone glucagon-like peptide-1 (GLP-1) decreases blood glucose and appetite. Greater physical activity (PA) is associated with lower incidence of type 2 diabetes. While acute exercise may increase glucose-induced response of GLP-1, it is unknown how habitual PA affects GLP-1 secretion. We hypothesised that habitual PA associates with greater glucose-induced GLP-1 responses in overweight individuals. Methods Cross-sectional analysis of habitual PA levels and GLP-1 concentrations in 1326 individuals (mean (s.d.) age 66 (7) years, BMI 27.1 (4.5) kg/m2) from the ADDITION-PRO cohort. Fasting and oral glucose-stimulated GLP-1 responses were measured using validated radioimmunoassay. PA was measured using 7-day combined accelerometry and heart rate monitoring. From this, energy expenditure (PAEE; kJ/kg/day) and fractions of time spent in activity intensities (h/day) were calculated. Cardiorespiratory fitness (CRF; mL O2/kg/min) was calculated using step tests. Age-, BMI- and insulin sensitivity-adjusted associations between PA and GLP-1, stratified by sex, were evaluated by linear regression analysis. Results In 703 men, fasting GLP-1 concentrations were 20% lower (95% CI: −33; −3%, P = 0.02) for every hour of moderate-intensity PA performed. Higher CRF and PAEE were associated with 1–2% lower fasting GLP-1 (P = 0.01). For every hour of moderate-intensity PA, the glucose-stimulated GLP-1 response was 16% greater at peak 30 min (1; 33%, P rAUC0-30 = 0.04) and 20% greater at full response (3; 40%, P rAUC0-120 = 0.02). No associations were found in women who performed PA 22 min/day vs 32 min/day for men. Conclusion Moderate-intensity PA is associated with lower fasting and greater glucose-induced GLP-1 responses in overweight men, possibly contributing to improved glucose and appetite regulation with increased habitual PA.

AIMS/HYPOTHESIS: In the UK, more than one million people have undiagnosed diabetes and an additional five million are at high risk of developing the disease. Given that early identification of these people is key for both primary and secondary prevention, new screening approaches are needed. Since spouses resemble each other in cardiometabolic risk factors related to type 2 diabetes, we aimed to investigate whether diabetes and cardiometabolic risk factors in one spouse can be used as an indicator of incident type 2 diabetes in the other spouse.METHODS: We analysed data from 3649 men and 3478 women from the English Longitudinal Study of Ageing with information on their own and their spouse's diabetes status and cardiometabolic risk factors. We modelled incidence rates and incidence rate ratios with Poisson regression, using spousal diabetes status or cardiometabolic risk factors (i.e. BMI, waist circumference, systolic and diastolic BP, HDL- and LDL-cholesterol and triacylglycerols) as exposures and type 2 diabetes incidence in the index individual as the outcome. Models were adjusted for two nested sets of covariates.RESULTS: Spousal BMI and waist circumference were associated with incident type 2 diabetes, but with different patterns for men and women. A man's risk of type 2 diabetes increased more steeply with his wife's obesity level, and the association remained statistically significant even after adjustment for the man's own obesity level. Having a wife with a 5 kg/m2 higher BMI (30 kg/m2 vs 25 kg/m2) was associated with a 21% (95% CI 11%, 33%) increased risk of type 2 diabetes. In contrast, the association between incident type 2 diabetes in a woman and her husband's BMI was attenuated after adjusting for the woman's own obesity level. Findings for waist circumference were similar to those for BMI. Regarding other risk factors, we found a statistically significant association only between the risk of type 2 diabetes in women and their husbands' triacylglycerol levels.CONCLUSIONS/INTERPRETATION: The main finding of this study is the sex-specific effect of spousal obesity on the risk of type 2 diabetes. Having an obese spouse increases an individual's risk of type 2 diabetes over and above the effect of the individual's own obesity level among men, but not among women. Our results suggest that a couples-focused approach may be beneficial for the early detection of type 2 diabetes and individuals at high risk of developing type 2 diabetes, especially in men, who are less likely than women to attend health checks.DATA AVAILABILITY: Data were accessed via the UK Data Service under the data-sharing agreement no. 91400 ( https://discover.ukdataservice.ac.uk/catalogue/?sn=5050&type=Data%20catalogue ).

Purpose Physical activity (PA) is important in the prevention of Type 2 diabetes, yet little is known about the role of specific dimensions of PA, including sedentary time in subgroups at risk for impaired glucose metabolism (IGM). We applied a data-driven decision tool to identify dimensions of PA associated with IGM across age, sex, and body mass index (BMI) groups. Methods This cross-sectional study included 1501 individuals (mean (SD) age, 65.6 (6.8) yr) at high risk for Type 2 diabetes from the ADDITION-PRO study. PA was measured by an individually calibrated combined accelerometer and heart rate monitor worn for 7 d. PA energy expenditure, time spent in different activity intensities, bout duration, and sedentary time were considered determinants of IGM together with age, sex, and BMI. Decision tree analysis was applied to identify subgroup-specific dimensions of PA associated with IGM. IGM was based on oral glucose tolerance test results and defined as a fasting plasma glucose level of ≥6.1 mmol·L-1 and/or a 2-h plasma glucose level of ≥7.8 mmol·L-1. Results Among overweight (BMI ≥25 kg·m-2) men, accumulating less than 30 min·d-1 of moderate-to-vigorous PA was associated with IGM, whereas among overweight women, sedentary time was associated with IGM. Among individuals older than 53 yr with normal weight (BMI -2), time spent in light PA was associated with IGM. None of the dimensions of PA were associated with IGM among individuals ≤53 yr of age with normal weight. Conclusions We identified subgroups in which different activity dimensions were associated with IGM. Methodology and results from this study may suggest a preliminary step toward the goal of tailoring and targeting PA interventions aimed at Type 2 diabetes prevention.

$\textbf{AIMS/HYPOTHESIS}$: South Asian individuals have reduced insulin sensitivity and increased risk of type 2 diabetes compared with white individuals. Temporal changes in glycaemic traits during middle age suggest that impaired insulin secretion is a particular feature of diabetes development among South Asians. We therefore aimed to examine ethnic differences in early changes in glucose metabolism prior to incident type 2 diabetes. $\textbf{METHODS}$: In a prospective British occupational cohort, subject to 5 yearly clinical examinations, we examined ethnic differences in trajectories of fasting plasma glucose (FPG), 2 h post-load plasma glucose (2hPG), fasting serum insulin (FSI), 2 h post-load serum insulin (2hSI), HOMA of insulin sensitivity (HOMA2-S) and secretion (HOMA2-B), and the Gutt insulin sensitivity index (ISI$_{0,120}$) among 120 South Asian and 867 white participants who developed diabetes during follow-up (1991-2013). We fitted cubic mixed-effects models to longitudinal data with adjustment for a wide range of covariates. $\textbf{RESULTS}$: Compared with white individuals, South Asians had a faster increase in FPG before diagnosis (slope difference 0.22 mmol/l per decade; 95% CI 0.02, 0.42; p = 0.03) and a higher FPG level at diagnosis (0.27 mmol/l; 95% CI 0.06, 0.48; p = 0.01). They also had higher FSI and 2hSI levels before and at diabetes diagnosis. South Asians had a faster decline and lower HOMA2-S (log e -transformed) at diagnosis compared with white individuals (0.33; 95% CI 0.21, 0.46; p

AIMS/HYPOTHESIS: We assessed whether the risk of developing type 2 diabetes and the age of onset varied with the age at diabetes diagnosis of affected family members.METHODS: We performed a national register-based open cohort study of individuals living in Denmark between 1995 and 2012. The population under study consisted of all individuals aged 30 years or older without diagnosed diabetes at the start date of the cohort (1 January 1995) and who had information about their parents' identity. Individuals who turned 30 years of age during the observation period and had available parental identity information were also added to the cohort from that date (open cohort design). These criteria restricted the study population mostly to people born between 1960 and 1982. Multivariable Poisson regression models adjusted for current age and highest educational attainment were used to estimate incidence rate ratios (IRRs) of type 2 diabetes.RESULTS: We followed 2,000,552 individuals for a median of 14 years (24,034,059 person-years) and observed 76,633 new cases of type 2 diabetes. Compared with individuals of the same age and sex who did not have a parent or full sibling with diabetes, the highest risk of developing type 2 diabetes was observed in individuals with family members diagnosed at an early age. The IRR was progressively lower with a higher age at diabetes diagnosis in family members: 3.9 vs 1.4 for those with a parental age at diagnosis of 50 or 80 years, respectively; and 3.3 vs 2.0 for those with a full sibling's age at diagnosis of 30 or 60 years, respectively.CONCLUSIONS/INTERPRETATION: People with a family member diagnosed with diabetes at an earlier age are more likely to develop diabetes and also to develop it at an earlier age than those with a family member diagnosed in later life. This finding highlights the importance of expanding our understanding of the interplay between genetic diabetes determinants and the social, behavioural and environmental diabetes determinants that track in families across generations. Accurate registration of age at diagnosis should form an integral part of recording a diabetes family history, as it provides easily obtainable and highly relevant detail that may improve identification of individuals at increased risk of younger onset of type 2 diabetes. In particular, these individuals may benefit from closer risk factor assessment and follow-up, as well as prevention strategies that may involve the family.

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.

Aims/hypothesis Reversion from prediabetes to normoglycaemia is accompanied by an improvement in cardiovascular risk factors, but it is unclear whether this translates into a reduction in risk of cardiovascular disease (CVD) events or death. Hence, we studied the probability of reversion from prediabetes to normoglycaemia and the associated risk of future CVD and death using data from the Whitehall II observational cohort study. Methods Three glycaemic criteria for prediabetes (fasting plasma glucose [FPG] 5.6–6.9 mmol/l, 2 h plasma glucose [2hPG] 7.8–11.0 mmol/l, and HbA1c 39–47 mmol/mol [5.7–6.4%]) were assessed in 2002–2004 and 2007–2009 for 5193 participants free of known diabetes at enrolment. Among participants with prediabetes in the first examination, we calculated the probability of reversion to normoglycaemia by re-examination according to each glycaemic criterion. Poisson regression analysis was used to estimate and compare incidence rates of a composite endpoint of a CVD event or death in participants with prediabetes who did vs did not revert to normoglycaemia. Analyses were adjusted for age, sex, ethnicity and previous CVD. Results Based on the FPG criterion, 820 participants had prediabetes and 365 (45%) of them had reverted to normoglycaemia in 5 years. The corresponding numbers were 324 and 120 (37%) for the 2hPG criterion and 1709 and 297 (17%) for the HbA1c criterion. During a median follow-up of 6.7 (interquartile range 6.3–7.2) years, 668 events of non-fatal CVD or death occurred among the 5193 participants. Reverting from 2hPG-defined prediabetes to normoglycaemia vs remaining prediabetic or progressing to diabetes was associated with a halving in event rate (12.7 vs 29.1 per 1000 person-years, p = 0.020). No association with event rate was observed for reverting from FPG-defined (18.6 vs 18.2 per 1000 person-years, p = 0.910) or HbA1c-defined prediabetes to normoglycaemia (24.5 vs 22.9 per 1000 person-years, p = 0.962). Conclusions/interpretation Most people with HbA1c-defined prediabetes remained prediabetic or progressed to diabetes during 5 years of follow-up. In contrast, reversion to normoglycaemia was frequent among people with FPG- or 2hPG-defined prediabetes. Only reversion from 2hPG-defined prediabetes to normoglycaemia was associated with a reduction in future risk of CVD and death. Electronic supplementary material The online version of this article (10.1007/s00125-019-4895-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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

Background: We assessed the effect of parental and sibling age at diabetes diagnosis on index individuals’ risk of developing diabetes. Methods: We carried out a register-based closed cohort analysis of 869,489 initially diabetes-free index individuals living in Denmark between 1995 and 2012. We assessed the effect of parents’ and full siblings’ age at diabetes diagnosis on the incidence of diabetes in the index individual, beyond the general effect of a positive family history. We calculated incidence rate ratios (IRR) in sex-stratified Poisson regression models. Results: A total of 58,339 index individuals developed diabetes during 14 million person-years of follow-up. Diabetes risk was highest when parents had a diabetes diagnosis at a younger age. Men and women with a mother diagnosed with diabetes at age 50 had an IRR of 3.62 (95% CI: 2.86 to 4.57) and 5.03 (95% CI: 3.90 to 6.49) respectively compared to people of the same age and sex without a mother with diabetes. At a maternal diagnosis age of 70, the IRRs were 1.56 (95% CI: 1.46 to 1.57) and 1.67 (95% CI: 1.53 to 1.82) for men and women respectively. Conclusions: Diabetes early detection strategies might consider that younger parental age at diabetes diagnosis may reflect more severe forms of diabetes, conferring a higher risk of developing the disease. Disclosure J. Silverman Retana: Other Relationship; Self; Danish Diabetes Academy, Steno Diabetes Center Aarhus. A. Hulman: None. J. NIelsen: None. B. Carstensen: Consultant; Self; Leo Pharma. Speaker's Bureau; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. R.K. Simmons: None. L. Bjerg: None. L. Johnston: None. D.R. Witte: None. Funding Danish Diabetes Academy (to J.O.S.R.); Novo Nordisk Foundation; Steno Diabetes Center Aarhus

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

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.

Intermediate time points during the oral glucose tolerance test (OGTT) have received more attention recently (1), with some researchers even suggesting to use 1-h glucose when screening for prediabetes (2). We demonstrated that characterization of glucose response patterns from OGTTs with five time points provides useful insights into the heterogeneity of type 2 diabetes development (3). Although such analyses are feasible in small pathophysiological investigations, they are not common in large epidemiological studies where the number of glucose measurements during an OGTT is often limited. Therefore, we aimed to study how well different combinations of fewer than five time points during an OGTT approximate glucose response patterns based on five time points. We analyzed data from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study, which we previously used to develop a glucose pattern classification model (3). The Tubingen Family Study (TUEF) cohort was used for external validation (4). Both studies included five-point OGTTs with glucose measurements at 0, 30, 60, 90, and 120 min. We excluded participants with self-reported diabetes or screen-detected diabetes (fasting plasma glucose ≥7.0 mmol/L or 2-h postload plasma glucose ≥11.1 mmol/L), participants taking glucose-lowering medication, and those with missing measurements at any of the five time points. We previously identified four glucose …

OBJECTIVES: The aim of this study is to explore the contribution of genetically driven cardiometabolic risk factors for development of carotid arterial thickening in patients with type 2 diabetes.METHODS: In total, 12 genetic risk scores for blood pressure, blood lipids and glycaemic traits were constructed. The genetic risk scores were tested for association with carotid intima-media thickness and plaques in patients with type 2 diabetes ( n = 401) and in non-diabetic individuals ( n = 648) and for association with glucose levels in two population-based cohorts ( n = 1328 and n = 6161).RESULTS: In patients with type 2 diabetes, the genetic risk scores for pulse pressure were positively associated with plaque formation ( β = 0.036 ± 0.01 standard deviation/allele, p = 0.003). The genetic risk score for diastolic blood pressure was negatively associated with carotid intima-media thickness ( β = -0.037 ± 0.01 standard deviation/allele, p = 0.005), although not significant after correction for multiple testing ( p CONCLUSION: Genetic loci for pulse pressure are associated with plaque formation among patients with type 2 diabetes, suggesting an underlying genetic contribution to arterial stiffening and atherosclerosis.

Aims: The glycolysis-derived metabolite methylglyoxal has been linked to clinical microvascular complications, including diabetic nephropathy. We aimed to further investigate the hypothesis that methylglyoxal is involved in decline in renal function by assessing the associations between measures of renal function during a 6-year follow-up in 1481 people with screen-detected Type 2 diabetes, as part of the Danish arm of the ADDITION-Europe trial (ADDITION-DK). Methods: Biobank serum samples collected at ADDITION-DK baseline (2001–2006) and follow-up (2009–2010) were used in the current analysis of methylglyoxal. We assessed cross-sectional baseline and longitudinal associations between methylglyoxal and urinary albumin-to-creatinine ratio (ACR) or estimated GFR (eGFR), and between methylglyoxal and categories of albuminuria or reduced eGFR. Results: Baseline methylglyoxal was positively associated with ACR at baseline (12% higher ACR per doubling in methylglyoxal levels), and change in methylglyoxal during 6 years of follow-up was inversely associated with change in eGFR (–1.6 ml/min/1.73 m2 per doubling in methylglyoxal change), in models adjusted for age, sex, HbA1c, systolic blood pressure, anti-hypertensive treatment, LDL-cholesterol, lipid-lowering treatment, C-reactive protein and smoking. Conclusions: In a population of people with screen-detected Type 2 diabetes, we observed associations between methylglyoxal and markers of renal function: 6-year change in methylglyoxal was inversely associated with 6-year change in eGFR. Also, methylglyoxal at baseline was positively associated with ACR at baseline. Our study lends further support to a role for methylglyoxal in the pathogenesis of diabetic nephropathy. © 2016 Diabetes UK Aims: The glycolysis-derived metabolite methylglyoxal has been linked to clinical microvascular complications, including diabetic nephropathy. We aimed to further investigate the hypothesis that methylglyoxal is involved in decline in renal function by assessing the associations between measures of renal function during a 6-year follow-up in 1481 people with screen-detected Type 2 diabetes, as part of the Danish arm of the ADDITION-Europe trial (ADDITION-DK). Methods: Biobank serum samples collected at ADDITION-DK baseline (2001–2006) and follow-up (2009–2010) were used in the current analysis of methylglyoxal. We assessed cross-sectional baseline and longitudinal associations between methylglyoxal and urinary albumin-to-creatinine ratio (ACR) or estimated GFR (eGFR), and between methylglyoxal and categories of albuminuria or reduced eGFR. Results: Baseline methylglyoxal was positively associated with ACR at baseline (12% higher ACR per doubling in methylglyoxal levels), and change in methylglyoxal during 6 years of follow-up was inversely associated with change in eGFR (–1.6 ml/min/1.73 m 2 per doubling in methylglyoxal change), in models adjusted for age, sex, HbA 1c, systolic blood pressure, anti-hypertensive treatment, LDL-cholesterol, lipid-lowering treatment, C-reactive protein and smoking. Conclusions: In a population of people with screen-detected Type 2 diabetes, we observed associations between methylglyoxal and markers of renal function: 6-year change in methylglyoxal was inversely associated with 6-year change in eGFR. Also, methylglyoxal at baseline was positively associated with ACR at baseline. Our study lends further support to a role for methylglyoxal in the pathogenesis of diabetic nephropathy.

Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test with measurements of circulating glucose, insulin, and glucagon concentrations at 0, 30 and 120 min. Early glucagon suppression was defined as suppression in the period from 0 to 30 min, and late glucagon suppression as 30 to 120 min after glucose intake. Insulin sensitivity was estimated by the validated insulin sensitivity index. Individuals with screen-detected diabetes had 30% higher fasting glucagon levels and diminished early glucagon suppression, but greater late glucagon suppression when compared with individuals with normal glucose tolerance (P ≤ 0.014). Higher insulin resistance was associated with higher fasting glucagon levels, less early glucagon suppression, and greater late glucagon suppression (P < 0.001). The relationship between insulin sensitivity and fasting glucagon concentrations was nonlinear (P < 0.001). In conclusion, increased fasting glucagon levels and delayed glucagon suppression, together with increased circulating insulin levels, develop in parallel with insulin resistance. Therefore, glucose maintenance during insulin resistance may depend not only on hyperinsulinemia but also on the ability to suppress glucagon early after glucose intake.

BackgroundThere is no long-term evidence on the effectiveness of training for motivational interviewing in diabetes treatment.AimWithin a trial of intensive treatment of people with screen-detected diabetes, which included training in motivational interviewing for GPs, the study examined the effect of the intervention on incident cardiovascular disease (CVD) and all-cause mortality.Design & settingIn the ADDITION-Denmark trial, 181 general practices were cluster randomised in a 2:1:1 ratio to: (i) to screening plus routine care of individuals with screen-detected diabetes (control group); (ii) screening plus training and support in intensive multifactorial treatment of individuals with screen-detected diabetes (intensive treatment group); or (iii) screening plus training and support in intensive multifactorial treatment and motivational interviewing for individuals with screen-detected diabetes (intensive treatment plus motivational interviewing group). The study took place from 2001–2009.MethodAfter around 8 years follow-up, rates of first fatal and non-fatal CVD events and all-cause mortality were compared between screen-detected individuals in the three treatment groups.ResultsCompared with the routine care group, the risk of CVD was similar in the intensive treatment group (hazard ratio [HR] 1.11, 95% confidence interval [CI] = 0.82 to 1.50) and the intensive treatment plus motivational interviewing group (HR 1.26, 95% CI = 0.96 to 1.64). The incidence of death was similar in all three treatment groups.ConclusionTraining of GPs in intensive multifactorial treatment, with or without motivational interviewing, was not associated with a reduction in mortality or CVD among those with screen-detected diabetes.

OBJECTIVE Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1–associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

Background Ambiguity exists in relation to the role of physical activity (PA) for cardiovascular disease (CVD) risk reduction. We examined the interplay between PA dimensions and more conventional CVD risk factors to assess which PA dimensions were associated with the first CVD event and whether subgroup differences exist. Methods A total of 1449 individuals [median age 65.8 (IQR: 61.2, 70.7) years] with low to high risk of type 2 diabetes and free from CVD from the Danish ADDITION-PRO study were included for survival analysis. PA was measured by individually calibrated heart rate and movement sensing for 7 consecutive days. The associations of different PA dimensions (PA energy expenditure, time spent in light-, moderate- and vigorous intensity PA), sedentary time and other conventional CVD risk factors with the first CVD event were examined by tree-structured survival analysis. Baseline information was linked to data on the first CVD event (ischemic heart disease, ischemic stroke, heart failure, atrial flutter/fibrillation and atherosclerotic disease) and mortality obtained from Danish registers. Results During a median follow-up time of 5.5 (IQR: 5.1–6.1) years, a total of 201 individuals (13.9%) developed CVD. Overall CVD incidence rate was 2.6/100 person-years. PA energy expenditure above 43 kJ/kg/day was associated with lower rates of CVD events among participants ≤ 70 years and with HbA1c ≤ 5.7% (39 mmol/mol), systolic blood pressure ≤ 156 mmHg and albumin creatinine ratio ≤ 70 (incidence rates 0.0–0.8/100 person-years). Conclusions Any type of PA resulting in increased PA energy expenditure may over time be the best prevention strategy to uphold reduced risk of CVD. Electronic supplementary material The online version of this article (10.1186/s12933-018-0769-x) contains supplementary material, which is available to authorized users.

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.

AIMS: To examine whether the development of obesity with age was different for individuals with and without a spouse with diabetes.METHODS: We analysed data from the English Longitudinal Study of Ageing [n= 7123, median (interquartile range) age 59 (53-67) years, 51% men], which included four clinical examination waves between 1998 and 2012. The main exposure was having a spouse with diabetes. Outcomes of interest were BMI and waist circumference. We fitted quadratic age-related trajectories using mixed-effect models stratified by sex and adjusted for education, smoking and the corresponding interaction terms between age and spousal diabetes status.RESULTS: The baseline spousal diabetes prevalence was 4.4%. Men with a wife with diabetes experienced a steeper increase in BMI (1.6 kg/m2 ) between ages 50 to 65 years than men with a wife without diabetes (0.9 kg/m2 ). Women with a husband with diabetes had a similarly shaped BMI trajectory to women with a husband without diabetes, but their average BMI levels were higher between ages 55 and 65 years. Waist circumference trajectories showed a similar shape by spousal diabetes status for men and women, although individuals with a spouse with diabetes had higher waist circumference values throughout follow-up.CONCLUSIONS: We found a positive association between spousal diabetes status and obesity development, which differed by sex among middle-aged individuals. Evidence from couple-based interventions is needed to test whether the latter could improve the current individual-focused public health strategies for obesity prevention.

AIMS/HYPOTHESIS: The role of burden and duration of multiple microvascular complications on mortality rate has not been explored in detail in type 1 diabetes. Taking complication burden and time-updated duration into account we aimed to quantify mortality rate in individuals with and without microvascular complications.METHODS: This observational clinical cohort included 3828 individuals with type 1 diabetes attending the Steno Diabetes Center Copenhagen in 2001-2013. We used information on mortality and detailed clinical measures of microvascular complications from electronic patient records. Poisson models were used to model mortality rates according to complication burden.RESULTS: During 26,665 person-years of follow-up, 503 deaths occurred. Compared with individuals without microvascular complications, the mortality rate ratio was 2.20 (95% CI 1.79, 2.69) for individuals with diabetic kidney disease, 1.72 (95% CI 1.39, 2.12) for individuals with neuropathy and 1.02 (95% CI 0.77, 1.37) for individuals with retinopathy, all adjusted for calendar time (year/month/day), age, duration of diabetes, sex, HbA1c, LDL-cholesterol, BMI, smoking status, systolic blood pressure, use of antihypertensive and lipid-lowering medication, and cardiovascular disease status. In individuals with two complications or more, the risk of mortality did not exceed the combined risk from each individual complication. Mortality rate ratios increased immediately after diagnosis of neuropathy and diabetic kidney disease. Mortality rate ratios were independent of the duration of neuropathy and retinopathy, while the mortality rate associated with diabetic kidney disease reached a stable level after approximately 3 years.CONCLUSIONS/INTERPRETATION: Neuropathy and diabetic kidney disease are strong and independent risk markers of mortality in type 1 diabetes, whereas no evidence of higher mortality rate was found for retinopathy. We found no indication that the mortality risk with multiple complications exceeds the risk conferred by each complication separately. The duration spent with microvascular complications had only a marginal effect on mortality.

Tidligere studier af type 2-diabetes viser, at op mod hver anden eller tredje person med diabetes udvikler polyneuropati i løbet af de første 10 år. Polyneuropati kan ikke behandles og forbindes med både højere sygelighed og dødelighed. Dette studie viser en langt mindre udvikling af diabetisk polyneuropati end set i tidligere studier af type 2-diabetes: kun 10% af deltagerne udviklede polyneuropati i løbet af 13 års opfølgning. Studiet bygger på data for 1256 personer med screeningsopdaget type 2 diabetes, som blev fulgt i almen praksis. Risikoen for at udvikle polyneuropati var større for de personer, der ved diagnosetidspunktet var overvægtige (ud fra vægt, BMI og taljemål), havde lavere værdier af HDL-cholesterol og højere værdier af methylglyoxal (en markør for dicarbonyl stress). Studiet viser, at tidlig opsporing og behandling af diabetes formentlig har en positiv effekt på udviklingen af polyneuropati. Desuden indikerer studiet, at der bør være ekstra fokus på optimal behandling af overvægtige personer med diabetes for yderligere at reducere risikoen for at udvikle polyneuropati. 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 markerofdicarbonyl stress, are identifiedasrisk factors for the developmentofDPN.

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.

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.

The authors have discovered a coding error in the statistical analysis syntax file used for the mixed-effect model analyses in this paper. The error has led to differences (first decimal) in the estimates for the main results.

Aims/hypothesis: In addition to blood glucose concentrations measured in the fasting state and 2 h after an OGTT, intermediate measures during an OGTT may provide additional information regarding a person’s risk of future diabetes and cardiovascular disease (CVD). First, we aimed to characterise heterogeneity of glycaemic patterns based on three time points during an OGTT. Second, we compared the incidences of diabetes and CVD and all-cause mortality rates among those with different patterns. Methods: Our cohort study included 5861 participants without diabetes at baseline from the Danish Inter99 study. At baseline, all participants underwent an OGTT with measurements of plasma glucose levels at 0, 30 and 120 min. Latent class mixed-effects models were fitted to identify distinct patterns of glycaemic response during the OGTT. Information regarding incident diabetes, CVD and all-cause mortality rates during a median follow-up time of 11, 12 and 13 years, respectively, was extracted from national registers. Cox proportional hazard models with adjustment for several cardiometabolic risk factors were used to compare the risk of diabetes, CVD and all-cause mortality among individuals in the different latent classes. Results: Four distinct glucose patterns during the OGTT were identified. One pattern was characterised by high 30 min but low 2 h glucose values. Participants with this pattern had an increased risk of developing diabetes compared with participants with lower 30 min and 2 h glucose levels (HR 4.1 [95% CI 2.2, 7.6]) and participants with higher 2 h but lower 30 min glucose levels (HR 1.5 [95% CI 1.0, 2.2]). Furthermore, the all-cause mortality rate differed between the groups with significantly higher rates in the two groups with elevated 30 min glucose. Only small non-significant differences in risk of future CVD were observed across latent classes after confounder adjustment. Conclusions/interpretation: Elevated 30 min glucose is associated with increased risk of diabetes and all-cause mortality rate independent of fasting and 2 h glucose levels. Therefore, subgroups at high risk may not be revealed when considering only fasting and 2 h glucose levels during an OGTT.

AIMS: To examine the prevalence of micro- and macrovascular complications and their associated clinical characteristics at time of type 2 diabetes (T2D) diagnosis.METHODS: We examined the prevalence of complications and associated clinical characteristics among 6958 newly diagnosed T2D patients enrolled in the prospective Danish Center for Strategic Research in T2D cohort during 2010-2016. We calculated age- and gender-adjusted prevalence ratios (aPRs) of complications using log-binomial and Poisson regression.RESULTS: In total, 35% (n=2456) T2D patients had diabetic complications around diagnosis; 12% (n=828) had microvascular complications, 17% (n=1186) macrovascular complications, and 6% (n=442) had both. HbA1c levels of ≥7% were associated with microvascular complications [HbA1c 7%-8%; aPR: 1.35, 95% confidence interval (CI): 1.12-1.62] but not macrovascular complications [aPR: 0.91, 95% CI: 0.76-1.08]. High C-peptide≥800pmol/L was associated with macrovascular [aPR 1.34, 95% CI: 1.00-1.80] but not microvascular [aPR 0.97, 95% CI: 0.71-1.33] complications. Macrovascular complications were associated with male sex, age>50years, obesity, hypertriglyceridemia, low HDL cholesterol, smoking, elevated CRP levels, and anti-hypertensive therapy. Microvascular complications were associated with high blood pressure, hypertriglyceridemia, and absence of lipid-lowering therapy.CONCLUSIONS: One-third of patients with T2D had diabetes complications around time of diagnosis. Our findings suggest different pathophysiological mechanisms behind micro- and macrovascular complications.

Background Frail elderly people experience elevated mortality. However, no consensus exists on the definition of frailty, and many frailty scores have been developed. The main aim of this study was to compare the association between 35 frailty scores and incident cardiovascular disease (CVD), incident cancer, and all-cause mortality. Also, we aimed to assess whether frailty scores added predictive value to basic and adjusted models for these outcomes. Methods and findings Through a structured literature search, we identified 35 frailty scores that could be calculated at wave 2 of the English Longitudinal Study of Ageing (ELSA), an observational cohort study. We analysed data from 5,294 participants, 44.9% men, aged 60 years and over. We studied the association between each of the scores and the incidence of CVD, cancer, and all-cause mortality during a 7-year follow-up using Cox proportional hazard models at progressive levels of adjustment. We also examined the added predictive performance of each score on top of basic models using Harrell’s C statistic. Using age of the participant as a timescale, in sex-adjusted models, hazard ratios (HRs) (95% confidence intervals) for all-cause mortality ranged from 2.4 (95% CI: 1.7–3.3) to 26.2 (95% CI: 15.4–44.5). In further adjusted models including smoking status and alcohol consumption, HR ranged from 2.3 (95% CI: 1.6–3.1) to 20.2 (95% CI: 11.8–34.5). In fully adjusted models including lifestyle and comorbidity, HR ranged from 0.9 (95% CI: 0.5–1.7) to 8.4 (95% CI: 4.9–14.4). HRs for CVD and cancer incidence in sex-adjusted models ranged from 1.2 (95% CI: 0.5–3.2) to 16.5 (95% CI: 7.8–35.0) and from 0.7 (95% CI: 0.4–1.2) to 2.4 (95% CI: 1.0–5.7), respectively. In sex- and age-adjusted models, all frailty scores showed significant added predictive performance for all-cause mortality, increasing the C statistic by up to 3%. None of the scores significantly improved basic prediction models for CVD or cancer. A source of bias could be the differences in mortality follow-up time compared to CVD/cancer, because the existence of informative censoring cannot be excluded. Conclusion There is high variability in the strength of the association between frailty scores and 7-year all-cause mortality, incident CVD, and cancer. With regard to all-cause mortality, some scores give a modest improvement to the predictive ability. Our results show that certain scores clearly outperform others with regard to three important health outcomes in later life. Finally, we think that despite their limitations, the use of frailty scores to identify the elderly population at risk is still a useful measure, and the choice of a frailty score should balance feasibility with performance., Using data from the English Longitudinal Study of Ageing, Gloria Aguayo and colleagues compare the association between 35 frailty scores and cardiovascular events, cancer, and total mortality., Author summary Why was this study done? Frailty has been associated with poor outcomes in the elderly, and the need for valid instruments for its assessment is generally recognised. Many frailty scores have been developed based on different theoretical concepts; however, none of them can be considered the gold standard. The predictive capacity of frailty scores has mainly been studied for mortality, and evidence on their ability to predict other important outcomes in the elderly population, such as cardiovascular or cancer events, is limited (cardiovascular) or nonexistent (cancer) at the present time. What did the researchers do and find? We performed secondary analyses of the most comprehensive list of frailty scores in 5,294 participants of the English Longitudinal Study of Ageing, and we demonstrated that all frailty scores were associated with future mortality and that some of them were also associated with later cardiovascular events. However, no relationship with cancer was observed. In addition, the results of this study showed that multidimensional frailty scores may have a stronger and more stable association with mortality and incidence of cardiovascular events. Beside the results evidenced that despite significant associations of frailty scores with mortality, the added discriminative ability of frailty scores to chronological age may be limited. What do these findings mean? The comparative evaluation of the strength of associations between different frailty scores and major health outcomes in older adults provides a solid evidence base for researchers, clinicians, and health professionals working with elderly populations to choose the most appropriate instrument for their needs. Furthermore, the findings highlight the vast heterogeneity in composition and performance of existing frailty scores.

AIMS: Insulin treatment in type 1 diabetes encompasses multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII). Both population-based studies and comparative studies regarding CSII use are sparse. The aim of the current study was to describe the prevalence and distribution of CSII use among adults with type 1 diabetes in the Central Denmark Region and to compare metabolic control in CSII-treated patients to those treated with MDI.METHODS: A database was constructed using the Danish Adult Diabetes Registry in 2014/2015 in combination with an audit of the patients' medical records.RESULTS: 3909 adults with type 1 diabetes patients were included. The proportion of patients treated with CSII differed significantly between the 8 regional hospitals from 12.0 % to 31.1 %. CSII users had a significantly lower HbA1c compared to MDI treated patients (7.6 % (60 mmol/mol) versus 8.0 % (64 mmol/mol)) in unadjusted analyses. After adjustment for clinically relevant characteristics the difference between CSII and MDI-treated patients was attenuated, but remained statistically significant.CONCLUSION: The distribution of CSII differed markedly between hospitals and CSII users had better glycemic control, even after adjustment for sex, age, BMI, diabetes duration, smoking, use of lipid-lowering and blood pressure-lowering medication.

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.

Background Biomarkers of inflammation and adiponectin are associated with cardiovascular autonomic neuropathy (CAN) in cross-sectional studies, but prospective data are scarce. This study aimed to assess the associations of biomarkers of subclinical inflammation and adiponectin with subsequent changes in heart rate (HR) and heart rate variability (HRV) in non-diabetic and diabetic individuals. Methods Data are based on up to 25,050 person-examinations for 8469 study participants of the Whitehall II cohort study. Measures of CAN included HR and several HRV indices. Associations between baseline serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra) and adiponectin and 5-year changes in HR and six HRV indices were estimated using mixed-effects models adjusting for age, sex, ethnicity, body mass index (BMI), metabolic covariates and medication. A modifying effect of diabetes was tested. Results Higher levels of IL-1Ra were associated with higher increases in HR. Additional associations with measures of HRV were observed for hsCRP, IL-6 and IL-1Ra, but these associations were explained by BMI and other confounders. Associations between adiponectin, HR and HRV differed depending on diabetes status. Higher adiponectin levels were associated with more pronounced decreases in HR and increases in three measures of HRV reflecting both sympathetic and vagal activity, but these findings were limited to individuals with type 2 diabetes. Conclusions Higher IL-1Ra levels appeared as novel risk marker for increases in HR. Higher adiponectin levels were associated with a more favourable development of cardiovascular autonomic function in individuals with type 2 diabetes independently of multiple confounders. Electronic supplementary material The online version of this article (10.1186/s12933-017-0634-3) contains supplementary material, which is available to authorized users.