Diabetes-related risk factors and survival among individuals with type 2 diabetes and breast, lung, colorectal, or prostate cancer.

Premature death in diabetes is increasingly caused by cancer. The objectives were to estimate the excess mortality when individuals with type 2 diabetes(T2D) were diagnosed with cancer, and to examine the impact of modifiable diabetes-related risk factors. This longitudinal nationwide cohort study included individuals with T2D registered in the Swedish National Diabetes Register between 1998-2019. Poisson models were used to estimate mortality as a function of time-updated risk-factors, adjusted for sex, age, diabetes duration, marital status, country of birth, BMI, blood pressure, lipids, albuminuria, smoking, and physical activity. We included 690,539 individuals with T2D and during 4,787,326 person-years of follow-up 179,627 individuals died. Overall, the all-cause mortality rate ratio was 3.75 [95%confidence interval(CI):3.69-3.81] for individuals with T2D and cancer compared to those remaining free of cancer. The most marked risk factors associated to mortality among individuals with T2D and cancer were low physical activity, 1.59 (1.57-1.61) and smoking, 2.15 (2.08-2.22), whereas HbA1c, lipids, hypertension, and BMI had no/weak associations with survival. In a future with more patients with comorbid T2D and cancer diagnoses, these results suggest that smoking and physical activity might be the two most salient modifiable risk factors for mortality in people with type 2 diabetes and cancer.

Use of medication in pregnancy on the rise: Study on 1.4 million Danish pregnancies from 1998 to 2018.

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

Association of general health and lifestyle factors with the salivary microbiota - Lessons learned from the ADDITION-PRO cohort.

Introduction: Previous research indicates that the salivary microbiota may be a biomarker of oral as well as systemic disease. However, clarifying the potential bias from general health status and lifestyle-associated factors is a prerequisite of using the salivary microbiota for screening. Materials & Methods: ADDDITION-PRO is a nationwide Danish cohort, nested within the Danish arm of the Anglo-Danish-Dutch Study of Intensive treatment in People with Screen-Detected Diabetes in Primary Care. Saliva samples from n=746 individuals from the ADDITION-PRO cohort were characterized using 16s rRNA sequencing. Alpha- and beta diversity as well as relative abundance of genera was examined in relation to general health and lifestyle-associated variables. Permutational multivariate analysis of variance (PERMANOVA) was performed on individual variables and all variables together. Classification models were created using sparse partial-least squares discriminant analysis (sPLSDA) for variables that showed statistically significant differences based on PERMANOVA analysis (p < 0.05). Results: Glycemic status, hemoglobin-A1c (HbA1c) level, sex, smoking and weekly alcohol intake were found to be significantly associated with salivary microbial composition (individual variables PERMANOVA, p < 0.05). Collectively, these variables were associated with approximately 5.8% of the observed differences in the composition of the salivary microbiota. Smoking status was associated with 3.3% of observed difference, and smoking could be detected with good accuracy based on salivary microbial composition (AUC 0.95, correct classification rate 79.6%). Conclusions: Glycemic status, HbA1c level, sex, smoking and weekly alcohol intake were significantly associated with the composition of the salivary microbiota. Despite smoking only being associated with 3.3% of the difference in overall salivary microbial composition, it was possible to create a model for detection of smoking status with a high correct classification rate. However, the lack of information on the oral health status of participants serves as a limitation in the present study. Further studies in other cohorts are needed to validate the external validity of these findings.

Health-related quality of life for normal glycaemia, prediabetes and type 2 diabetes mellitus: Cross-sectional analysis of the ADDITION-PRO study.

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

Polypharmacy in polymorbid pregnancies and the risk of congenital malformations-A systematic review.

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.

Diabetic Polyneuropathy Early in Type 2 Diabetes Is Associated With Higher Incidence Rate of Cardiovascular Disease: Results From Two Danish Cohort Studies.

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

Role of fasting duration and weekday in incretin and glucose regulation.

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.

Factors associated with attendance at clinical follow-up of a cohort with screen-detected type 2 diabetes: ADDITION-Denmark.

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=10mmol/mol)) were not statistically significant associated with attendance. CONCLUSIONS: This study showed a lower attendance in clinical follow-up after nearly 13years among individuals with concurrent high burden of disease. No associations were found between concurrent CVD, cancer, self-rated health and Hba1c levels and attendance.

Long-term effects of intensive multifactorial therapy in individuals with screen-detected type 2 diabetes in primary care: 10-year follow-up of the ADDITION-Europe cluster-randomised trial.

BACKGROUND: The multicentre, international ADDITION-Europe study investigated the effect of promoting intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes over 5 years. Here we report the results of a post-hoc 10-year follow-up analysis of ADDITION-Europe to establish whether differences in treatment and cardiovascular risk factors have been maintained and to assess effects on cardiovascular outcomes. METHODS: As previously described, general practices from four centres (Denmark, Cambridge [UK], Leicester [UK], and the Netherlands) were randomly assigned by computer-generated list to provide screening followed by routine care of diabetes, or screening followed by intensive multifactorial treatment. Population-based stepwise screening programmes among people aged 40-69 years (50-69 years in the Netherlands), between April, 2001, and December, 2006, identified patients with type 2 diabetes. Allocation was concealed from patients. Following the 5-year follow-up, no attempts were made to maintain differences in treatment between study groups. In this report, we did a post-hoc analysis of cardiovascular and renal outcomes over 10 years following randomisation, including a 5 years post-intervention follow-up. As in the original trial, the primary endpoint was a composite of first cardiovascular event, including cardiovascular mortality, cardiovascular morbidity (non-fatal myocardial infarction and non-fatal stroke), revascularisation, and non-traumatic amputation, up to Dec 31, 2014. Analyses were based on the intention-to-treat principle. ADDITION-Europe is registered with ClinicalTrials.gov, NCT00237549. FINDINGS: 343 general practices were randomly assigned to routine diabetes care (n=176) or intensive multifactorial treatment (n=167). 317 of these general practices (157 in the routine care group, 161 in the intensive treatment group) included eligible patients between April, 2001, and December, 2006. Of the 3233 individuals with screen-detected diabetes, 3057 agreed to participate (1379 in the routine care group, 1678 in the intensive treatment group), but at the 10-year follow-up 14 were lost to follow-up and 12 withdrew, leaving 3031 to enter 10-year follow-up analysis. Mean duration of follow-up was 9·61 years (SD 2·99). Sustained reductions over 10 years following diagnosis were apparent for bodyweight, HbA1c, blood pressure, and cholesterol in both study groups, but between-group differences identified at 1 and 5 years were attenuated at the 10-year follow-up. By 10 years, 443 participants had a first cardiovascular event and 465 died. There was no significant difference between groups in the incidence of the primary composite outcome (16·1 per 1000 person-years in the routine care group vs 14·3 per 1000 person-years in the intensive treatment group; hazard ratio [HR] 0·87, 95% CI 0·73-1·04; p=0·14) or all-cause mortality (15·6 vs 14·3 per 1000 person-years; HR 0·90, 0·76-1·07). INTERPRETATION: Sustained reductions in glycaemia and related cardiovascular risk factors over 10 years among people with screen-detected diabetes managed in primary care are achievable. The differences in prescribed treatment and cardiovascular risk factors in the 5 years following diagnosis were not maintained at 10 years, and the difference in cardiovascular events and mortality remained non-significant. FUNDING: National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Novo Nordisk, Novo Nordisk Foundation, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, UK National Health Service, Merck, Julius Center for Health Sciences and Primary Care, UK Department of Health, and Nuts-OHRA.

Prospective Study of Neuropathic Symptoms Preceding Clinically Diagnosed Diabetic Polyneuropathy: ADDITION-Denmark.

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.

Prospective Association Among Diabetes Diagnosis, HbA1c, Glycemia, and Frailty Trajectories in an Elderly Population.

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.

Validity of Danish register diagnoses of myocardial infarction and stroke against experts in people with screen-detected diabetes.

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.

Effect of duration and burden of microvascular complications on mortality rate in type 1 diabetes: an observational clinical cohort study.

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.

Development of Microvascular Complications and Effect of Concurrent Risk Factors in Type 1 Diabetes: A Multistate Model From an Observational Clinical Cohort Study.

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.

Risk-Factor Trajectories Preceding Diabetic Polyneuropathy: ADDITION-Denmark.

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.

Prevalence and geographical distribution of insulin pump therapy in the Central Denmark Region and its association with metabolic parameters.

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.

Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses.

BACKGROUND: Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused by a dysfunctional Kv11.1 voltage-gated potassium channel. Based on these findings in patients with rare variants in hERG, we hypothesized that common variants in hERG may also lead to alterations in glucose homeostasis. Subsequently, we aimed to evaluate the effect of two common gain-of-function variants in hERG (rs36210421 and rs1805123) on QT interval and plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon during an oral glucose tolerance test (OGTT). We used two population-based cohorts for evaluation of the effect of common variants in hERG on QT-interval and circulation levels of incretins, insulin and glucagon. The Danish population-based Inter99 cohort (n = 5895) was used to assess the effect of common variants on QT-interval. The Danish ADDITION-PRO cohort was used (n = 1329) to study genetic associations with levels of GLP-1, GIP, insulin and glucagon during an OGTT. RESULTS: Carriers of either the minor A-allele of rs36210421 or the minor G-allele of rs1805123 had ~ 2 ms shorter QT interval per risk allele (p = 0.025 and p = 1.9 × 10- 7). Additionally, both variants were associated with alterations in pancreatic and gut hormone release among carriers. The minor A- allele of rs36210421 was associated with increased GLP-1 and decreased GIP response to oral glucose stimulation, whereas the minor G-allele of rs1805123 is associated with decreased fasting plasma insulin and glucagon release. A genetic risk score combining the two gene variants revealed reductions in glucose-stimulated GIP, as well as suppressed glucagon response to increased glucose levels during an OGTT. CONCLUSIONS: Two common missense polymorphisms of the Kv11.1 voltage-gated hERG potassium channel are associated with alterations in circulating levels of GIP and glucagon, suggesting that hERG potassium channels play a role in fasting and glucose-stimulated release of GIP and glucagon. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT00289237 ). Trial retrospectively registered at February 9, 2006. Studies were approved by the Ethical Committee of the Central Denmark Region (journal no. 20080229) and by the Copenhagen County Ethical Committee (KA 98155).

Risk Factors for Incident Diabetic Polyneuropathy in a Cohort With Screen-Detected Type 2 Diabetes Followed for 13 Years: ADDITION-Denmark.

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

Comparative analysis of the association between 35 frailty scores and cardiovascular events, cancer, and total mortality in an elderly general population in England: An observational study.

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.

Prevalence of micro- and macrovascular diabetes complications at time of type 2 diabetes diagnosis and associated clinical characteristics: A cross-sectional baseline study of 6958 patients in the Danish DD2 cohort.

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.