Changes in type 2 diabetes incidence and mortality associated with introduction of HbA1c as diagnostic option: A Danish 24-year population-based study.

BACKGROUND: In 2011, the World Health Organization began recommending glycated haemoglobin (HbA1c) as a measure for diagnosing type 2 diabetes (T2D). This initiative may have changed basic T2D epidemiology. Consequently, we examined time changes in T2D incidence and mortality during 1995-2018. METHODS: In this population-based cohort study, we included 415,553 individuals with incident T2D. We calculated annual age-standardized incidence rates of T2D. We examined HbA1c testing and used Poisson-regression to investigate all-cause mortality among the T2D patients and a matched comparison cohort from the general population over successive 3-year periods. FINDINGS: From 1995 to the 2012 introduction of HbA1c testing as a diagnostic option in Denmark, the annual standardized incidence rate (SIR) of T2D doubled, from 193 to 396 per 100,000 persons (4.1% increase annually). From 2012 onwards, the T2D incidence declined by 36%, reaching 253 per 100,000 persons in 2018 (5.7% decrease annually). This was driven by fewer patients starting treatment with an HbA1c measurement of <6·5% or without prior HbA1c testing. Mortality per 1,000 person-years following a T2D diagnosis decreased by 44% between 1995-1997 and 2010-2012, from 69 deaths to 38 deaths (adjusted mortality rate ratio: 0·55 (95% CI: 0·54-0·56)). After the low level during 2010-2012, mortality increased again by 27% to 48 per 1,000 person-years (95% CI: 46-50) by 2016-2018. INTERPRETATION: Our findings suggest that introducing HbA1c as a diagnostic option may have changed basic T2D epidemiology by leaving patients undiagnosed, that previously would have been diagnosed and treated. FUNDING: Aarhus University funded the study and had no further involvement.

Abdominal visceral and subcutaneous adipose tissue and associations with cardiometabolic risk in Inuit, Africans and Europeans: a cross-sectional study.

OBJECTIVES: Abdominal fat has been identified as a risk marker of cardiometabolic disease independent of overall adiposity. However, it is not clear whether there are ethnic disparities in this risk. We investigated the associations of visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) with cardiometabolic risk factors in three ethnic diverse populations of Inuit, Africans and Europeans. DESIGN: Cross-sectional pooled study. SETTING: Greenland, Kenya and Denmark. METHODS: A total of 5113 participants (2933 Inuit, 1397 Africans and 783 Europeans) from three studies in Greenland, Kenya and Denmark were included. Measurements included abdominal fat distribution assessed by ultrasound, oral glucose tolerance test, hepatic insulin resistance, blood pressure and lipids. The associations were analysed using multiple linear regressions. RESULTS: Across ethnic group and gender, an increase in VAT of 1 SD was associated with higher levels of hepatic insulin resistance (ranging from 14% to 28%), triglycerides (8% to 16%) and lower high-density lipoprotein cholesterol (HDL-C, -1.0 to -0.05 mmol/L) independent of body mass index. VAT showed positive associations with most of the other cardiometabolic risk factors in Inuit and Europeans, but not in Africans. In contrast, SAT was mainly associated with the outcomes in Inuit and Africans. Of notice was that higher SAT was associated with higher HDL-C in African men (0.11 mmol/L, 95% CI: 0.03 to 0.18) and with lower HDL-C in Inuit (-0.07 mmol/L, 95% CI: -0.12 to -0.02), but not in European men (-0.02 mmol/L, 95% CI: -0.09 to 0.05). Generally weaker associations were observed for women. Furthermore, the absolute levels of several of the cardiometabolic outcomes differed between the ethnic groups. CONCLUSIONS: VAT and SAT were associated with several of the cardiometabolic risk factors beyond overall adiposity. Some of these associations were specific to ethnicity, suggesting that ethnicity plays a role in the pathway from abdominal fat to selected cardiometabolic risk factors.

Predictive value of spirometry in early detection of lung disease in adults: a cohort study.

BACKGROUND: Spirometry is essential to identify cases with obstructive lung diseases (OLDs) in primary care. However, knowledge about the long-term prognostic outcome among younger individuals is sparse. AIM: To describe the predictive value of spirometry among individuals in the age groups 30-49 years and 45-64 years. DESIGN & SETTING: A population-based cohort study supplied with data from Danish national registries. METHOD: Spirometry was performed in 905 adults aged 30-49 years in 1991 and in 1277 adults aged 45-64 years in 2006. The participants were categorised into three groups: forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <70, 70-75, and >75. They were followed throughout 2017 using Danish national registries. Lung disease was defined as fulfilling at least one of the following: two prescriptions for respiratory medicine were redeemed within a year; one lung-related contact to the hospital; or lung-related death. RESULTS: In the 1991 cohort, 21% developed lung diseases and in the 2006 cohort 17% developed lung diseases throughout 2017. The probability of developing lung disease if FEV1/FVC 70-75 was 35% (95% confidence interval [CI] = 25% to 44%) in the 1991 cohort and 23% (95% CI = 17% to 28%) in the 2006 cohort. The positive predicted value (PPV) was higher for both cohorts when focusing on smoking history and self-reported respiratory symptoms. CONCLUSION: The initial spirometry has a high predictive value to identify cases of future lung diseases. In addition, the group with FEV1/FVC 70-75 had a high risk of developing lung diseases later in life, suggesting this group would be a meaningful target of special interest.

Alanine Aminotransferase and 20-Year Risk of Major Chronic Diseases and Death in a Healthy Cohort Aged 30 to 49 Years.

PURPOSE: Alanine aminotransferase is the most frequently used marker of liver cell injury. We examined the association between alanine aminotransferase levels and long-term absolute risks of morbidity and mortality in healthy Danish people aged 30-49 years. PATIENTS AND METHODS: We divided 671 healthy participants from the Ebeltoft Health Promotion Project into four categories based on their baseline alanine aminotransferase values: low (≤10U/l), medium-low (men: 11-34U/l, women: 11-22U/l), medium-high (men: 35-69U/l, women: 23-44U/l) and high (men: ≥70U/l, women: ≥45U/l), and followed them through Danish healthcare registries for up to 20 years. We examined mortality and absolute risks of liver disease, overall cancer, ischemic heart disease, and diabetes. RESULTS: The risk of any cancer was highest for participants with "low alanine aminotransferase" or "high alanine aminotransferase" (20-year risk: 17.2% [95% confidence interval (CI): 6.3-32.7%] and 18.2% [95% CI: 5.7-36.3%], respectively). The risk of diabetes was highest for participants with "medium-high alanine aminotransferase" or "high alanine aminotransferase" (20-year risk: 12.1% [95% CI: 7.3-18.3%] and 9.1% [95% CI: 1.6-25.1%], respectively). Participants with "high alanine aminotransferase" had the highest 20-year risk of liver disease (20-year risk: 13.6% [95% CI: 3.4-30.9%], while it was 1.0% or less in the other groups). The chance of being alive after 20 years without having been diagnosed with liver disease, cancer, ischemic heart disease, or diabetes was lowest in the "high alanine aminotransferase" group (50% [95% CI: 28-68%]) and 72-79% in the other groups. CONCLUSION: Our findings suggest that persons with high or abnormally low alanine aminotransferase measurements are at increased long-term risk of several chronic diseases.

Lung function in adults and future burden of obstructive lung diseases in a long-term follow-up.

Spirometry is recommended in symptomatic smokers to identify obstructive lung diseases. However, it is unknown whether there are certain characteristics that can be used to identify the individual risk of developing obstructive lung diseases. The aim of this study was to examine the association between lung function in adults and burden of lung diseases throughout 27 years of follow-up. We performed a cohort study among individuals aged 30-49 years at baseline (1991). Spirometry measurements were divided into three groups: (1) FEV1/FVC < 70, (2) FEV1/FVC: 70-75, (3) FEV1/FVC > 75 (reference). Using negative binominal regression, the burden of lung diseases was measured by contacts to general practice, hospitalisations, redeemed respiratory medicine and socioeconomic parameters between 1991 and 2017. A total of 905 citizens were included; mean age of 40.3 years, 47.5% were males and 51.2% were smokers at baseline. The group with an FEV1/FVC: 70-75 received more respiratory medicine (IRR = 3.37 (95% CI: 2.69-4.23)), had lower income (IRR = 0.96 (95% CI: 0.93-0.98)), and had more contacts to general practice (IRR = 1.14 (95% CI: 1.07-1.21)) and hospitals for lung diseases (IRR = 2.39 (95% CI: 1.96-5.85)) compared to the reference group. We found an association between lung function and the future burden of lung diseases throughout 27 years of follow-up. In particular, adults with an FEV1/FVC: 70-75 need extra attention in the case finding.

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.

The effect of training GPs in motivational interviewing on incident cardiovascular disease and mortality in people with screen-detected diabetes. Results from the ADDITION-Denmark randomised trial.

BACKGROUND: There is no long-term evidence on the effectiveness of training for motivational interviewing in diabetes treatment. AIM: Within 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 & SETTING: In 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. METHOD: After 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. RESULTS: Compared 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. CONCLUSION: Training 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.

Habitual physical activity is associated with lower fasting and greater glucose-induced GLP-1 response in men.

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.

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.

A Randomised Trial Examining Cardiovascular Morbidity and All-Cause Mortality 24 years Following General Health Checks: the Ebeltoft Health Promotion Project (EHPP).

INTRODUCTION: Global prevalence of risk factors for cardiovascular disease (CVD) and all-cause mortality is increasing. Treatments are available but can only be implemented if individuals at risk are identified. General health checks have been suggested to facilitate this process. OBJECTIVES: To examine the long-term effect of population-based general health checks on CVD and all-cause mortality. DESIGN AND SETTING: The Ebeltoft Health Promotion Project (EHPP) is a parallel randomised controlled trial in a Danish primary care setting. PARTICIPANTS: The EHPP enrolled individuals registered in the Civil Registration System as (1) inhabitants of Ebeltoft municipality, (2) registered with a general practitioner (GP) participating in the study and (3) aged 30-49 on 1 January 1991. A total of 3464 individuals were randomised as invitees (n=2000) or non-invitees (n=1464). Of the invitees, 493 declined. As an external control group, we included 1 511 498 Danes living outside the municipality of Ebeltoft. INTERVENTIONS: Invitees were offered a general health check and, if test-results were abnormal, recommended a 15-45 min consultation with their GP. Non-invitees in Ebeltoft received a questionnaire at baseline and were offered a general health check at year 5. The external control group, that is, the remaining Danish population, received routine care only. OUTCOME MEASURES: HRs for CVD and all-cause mortality. RESULTS: Every individual randomised was analysed. When comparing invitees to non-invitees within the municipality of Ebeltoft, we found no significant effect of general health checks on CVD (HR=1.11 (0.88; 1.41)) or all-cause mortality (HR=0.93 (0.75; 1.16)). When comparing invitees to the remaining Danish population, we found similar results for CVD (adjusted HR=0.99 (0.86; 1.13)) and all-cause mortality (adjusted HR=0.96 (0.85; 1.09)). CONCLUSION: We found no effect of general health checks offered to the general population on CVD or all-cause mortality. TRIAL REGISTRATION NUMBER: NCT00145782; 2015-57-0002; 62908, 187.

Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures.

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.

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.

Impact of Geriatrician-Performed Comprehensive Geriatric Care on Medication Use and Cognitive Function in Older Adults Referred to a Non-Hospital-Based Rehabilitation Unit.

BACKGROUND AND PURPOSE: Eighty-eight percent of older adults referred to Danish non-hospital-based rehabilitation units used ≥5 regular drugs per day at the beginning of rehabilitation. The aim of the study was to explore whether geriatrician-performed comprehensive geriatric care had an impact on medication use and cognitive function in older adults after a 90-day follow-up. METHODS: There were 368 individuals aged ≥65 years recruited from 2 Danish non-hospital-based rehabilitation units and randomized to geriatric care (the intervention group) or usual care (the control group). The medication adjustment was the key element of the geriatric intervention. The control group received standard rehabilitation with general practitioners as back-up. The outcomes were prevalence of hyperpolypharmacy (≥10 regular medications prescribed concurrently), the change in medication profile, and cognitive function measured using the Mini-Mental State Examination. RESULTS: In the intervention group, fewer persons were exposed to hyperpolypharmacy (odds ratio 0.5; 95% confidence interval, 0.3-0.9) compared with the control group after 90 days. The prevalence of use of proton pump inhibitors, loop diuretics, or antiasthmatic inhalers was lower, while the prevalence of cholecalciferol use was higher in the intervention group compared with the control group. The prevalence of other drug use and cognitive function between groups were not different. CONCLUSIONS: Geriatrician-performed comprehensive geriatric care may reduce the prevalence of hyperpolypharmacy and optimize the medication profile in older adults referred to a non-hospital-based rehabilitation. No impact on cognitive function was found.

Risk Factors for the Presence and Progression of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: ADDITION-Denmark.

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.

The role of physical activity in the development of first cardiovascular disease event: a tree-structured survival analysis of the Danish ADDITION-PRO cohort.

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.

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.

Effect of screening for type 2 diabetes on healthcare costs: a register-based study among 139,075 individuals diagnosed with diabetes in Denmark between 2001 and 2009.

AIMS/HYPOTHESIS: Trials have not demonstrated benefits to the population of screening for type 2 diabetes. However, there may be cost savings for those found to have diabetes. We therefore aimed to compare healthcare costs among individuals with incident type 2 diabetes in a screened group with those in an unscreened group. METHODS: In this register-based, non-randomised controlled trial, eligible individuals were men and women aged 40-69 years without known diabetes who were registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes risk-score questionnaire. Individuals with a moderate-to-high risk were invited to visit their family doctor for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other practices in Denmark constituted the retrospectively constructed no-screening (control) group. In this post hoc analysis, we identified individuals from the screening and no-screening groups who were diagnosed with diabetes between 2001 and 2009 (n = 139,075). Using national registry data, we quantified the cost of healthcare services in these two groups between 2001 and 2012. From a healthcare sector perspective, we estimated the potential healthcare cost savings for individuals with diabetes that were attributable to the screening programme. RESULTS: In the screening group, 27,177 of 153,107 individuals (18% of those sent a risk-score questionnaire) attended for screening, 1533 of whom were diagnosed with diabetes. Between 2001 and 2009, 13,992 people were newly diagnosed with diabetes in the screening group (including those diagnosed by screening) and 125,083 in the no-screening group. Healthcare costs were significantly lower in the screening group compared with the no-screening group (difference in mean total annual healthcare costs -€889 per individual with incident diabetes; 95% CI -€1196, -€581). The screening programme was associated with a cost saving per person with incident diabetes over a 5-year period of €2688 (95% CI €1421, €3995). CONCLUSIONS/INTERPRETATION: Healthcare costs were lower among individuals with incident type 2 diabetes in the screened group compared with the unscreened group. The relatively modest cost of screening per person discovered to have developed diabetes was offset within 2 years by savings in the healthcare system.

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.