Use of electronic patient data overview with alerts in primary care increases prescribing of lipid-lowering medications in patients with type 2 diabetes.

AIMS/HYPOTHESIS: We aimed to assess whether general practices (GPs) using an electronic disease management program (DMP) with population overviews, including alerts when patients failed to receive guideline-recommended prescription medications, increased prescriptions of lipid-lowering drugs for patients with type 2 diabetes with no history of lipid-lowering treatment. METHODS: This observational study included 165 GPs that reached a high level of use of the DMP in 2012 and a control group of 135 GPs who reached a high level of use in 2013 and, hence, who were less exposed to the DMP throughout 2012. A binary measure for having been prescribed and filled lipid-lowering drugs at any time within a 12-month exposure period was derived for all patients with type 2 diabetes who did not receive a prescription for lipid-lowering drugs in the baseline year prior to the study period (i.e. 2011). Results were derived using ORs from multivariate logistic regression analyses. Subgroup stratification based on age, sex, diabetes duration, deprivation status and Charlson Comorbidity Index (CCI) score was conducted and assessed. Placebo tests were carried out to assess bias from selection to treatment. RESULTS: Patients who did not receive a prescription of lipid-lowering drugs in the year prior to being listed with GPs that used the DMP had statistically significant greater odds of receiving a prescription of lipid-lowering medications when compared with individuals who attended control GPs (OR 1.23 [95% CI 1.09, 1.38]). When the analysis period was shifted back by 2 years, no significant differences in lipid-lowering drug prescription between the two groups were found to occur, which indicates that these results were not driven by selection bias. Subgroup analyses showed that the increase in lipid-lowering drug prescriptions was primarily driven by changes among male participants (OR 1.32 [95% CI 1.12, 1.54]), patients aged 60-70 years (OR 1.40 [95% CI 1.13, 1.74]), patients with a diabetes duration of ≤5 years (OR 1.33 [95% CI 1.13, 1.56]), non-deprived patients (OR 1.25 [95% CI 1.08, 1.45]) and patients without comorbidities (CCI score = 0; OR 1.27 [95% CI 1.11, 1.45]). CONCLUSIONS/INTERPRETATION: Access to population overviews using a DMP with alerts of clinical performance measures with regard to adhering to guideline-recommended prescription of medications can increase GP prescriptions of lipid-lowering drugs.

Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management.

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes.

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.

The utility of a point-of-care sural nerve conduction device for detection of diabetic polyneuropathy: A cross-sectional study.

INTRODUCTION: Rapid and accessible methods for diagnosing diabetic polyneuropathy (DPN) have been developed, but not validated, in large cohorts of people with diabetes. METHODS: The performance of a point-of-care device (POCD) was studied in 168 patients with type 2 diabetes, estimating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) compared with conventional sural nerve conduction studies (NCS). RESULTS: A POCD amplitude limit of 6 µV increased the sensitivity (96%) and NPV (98%), but decreased the specificity (71%) and PPV (54%) compared with the 4-µV limit, which had values of 78%, 92%, 89%, and 71%, respectively. POCD on both legs showed better performance than on 1 leg. POCD amplitudes and conduction velocities correlated significantly with conventional sural NCS, but POCD values were underestimated compared with NCS. DISCUSSION: The POCD may be used as a suitable screening tool for detection of DPN. Patients with abnormal and borderline results should undergo conventional NCS. Muscle Nerve 59:187-193, 2019.

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.

The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy.

Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so-called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings.

Association of self-perceived body image with body mass index and type 2 diabetes-The ADDITION-PRO study.

OBJECTIVE: Weight loss is important for prevention of type 2 diabetes and an accurate self-perceived body image can promote weight reduction. We evaluated the association of self-perceived body image with body mass index (BMI) and type 2 diabetes. METHODS: Data from the Danish ADDITION-PRO cohort study (2009-2011) were used. A total of 2082 men and women attended a health examination including assessment of BMI, waist circumference, the Stunkard scale of self-perceived obesity and an oral glucose tolerance test for assessment of diabetes risk. RESULTS: Mean (SD) age was 66.2 (6.9) years and 24% were obese (BMI ≥30kg/m(2)). However, only 7% of obese men and 11% of obese women perceived themselves as obese. Among obese women, for a given level of BMI and waist circumference, one unit higher self-perceived body image was associated with 52% (95% CI: 14-73) lower risk of having type 2 diabetes and 45% (95% CI: 12-65) lower risk of having pre-diabetes. Overweight, but not obese, men had a 35% (95% CI: 36-56) lower risk of type 2 diabetes per unit increase in body image. CONCLUSIONS: Obese individuals seem to underestimate their body shape. However, having a realistic body image (higher self-perceived obesity) is independently associated with lower diabetes risk. Self-perceived body image might serve as a valuable tool for type 2 diabetes risk assessment.

Prevalence of sexual desire and satisfaction among patients with screen-detected diabetes and impact of intensive multifactorial treatment: results from the ADDITION-Denmark study.

OBJECTIVE: Sexual problems are common in people with diabetes. It is unknown whether early detection of diabetes and subsequent intensive multifactorial treatment (IT) are associated with sexual health. We report the prevalence of low sexual desire and low sexual satisfaction among people with screen-detected diabetes and compare the impact of intensive multifactorial treatment with the impact of routine care (RC) on these measures. DESIGN: A cross-sectional analysis of the ADDITION-Denmark trial cohort six years post-diagnosis. SETTING: 190 general practices around Denmark. SUBJECTS: A total of 968 patients with screen-detected type 2 diabetes. MAIN OUTCOME MEASURES: Low sexual desire and low sexual satisfaction. RESULTS: Mean (standard deviation, SD) age was 64.9 (6.9) years. The prevalence of low sexual desire was 53% (RC) and 54% (IT) among women, and 24% (RC) and 25% (IT) among men. The prevalence of low sexual satisfaction was 23% (RC) and 18% (IT) among women, and 27% (RC) and 37% (IT) among men. Among men, the prevalence of low sexual satisfaction was significantly higher in the IT group than in the RC group, p = 0.01. CONCLUSION: Low sexual desire and low satisfaction are frequent among men and women with screen-detected diabetes, and IT may negatively impact men's sexual satisfaction.

Bidirectional Associations Between Mental Health Disorders and Chronic Diabetic Complications in Individuals With Type 1 or Type 2 Diabetes.

OBJECTIVE: To determine bidirectional associations between the timing of chronic diabetes complications (CDCs) and mental health disorders (MHDs) in individuals with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: We used a nationally representative health care claims database to identify matched individuals with type 1 or 2 diabetes or without diabetes using a propensity score quasirandomization technique stratified by age (0-19, 20-39, 40-59, and 60+ years). CDCs and MHDs were identified using ICD-9/10 codes. We fit Cox proportional hazards models with time-varying diagnoses of CDCs or MHDs to investigate their association with the hazard of developing MHDs or CDCs, respectively. RESULTS: From 2001 to 2018, a total of 553,552 individuals were included (44,735 with type 1 diabetes, 152,187 with type 2 diabetes, and 356,630 without diabetes). We found that having a CDC increased the hazard of developing an MHD (hazard ratio [HR] 1.9-2.9; P < 0.05, with higher HRs in older age strata), and having an MHD increased the hazard of developing a CDC (HR 1.4-2.5; P < 0.05, with the highest HR in age stratum 0-19 years). In those age <60 years, individuals with type 1 diabetes were more likely to have CDCs, whereas individuals with type 2 diabetes were more likely to have MHDs. However, the relationship between CDCs and MHDs in either direction was not affected by diabetes type (P > 0.05 for interaction effects). CONCLUSIONS: We found a consistent bidirectional association between CDCs and MHDs across the life span, highlighting the important relationship between CDCs and MHDs. Prevention and treatment of either comorbidity may help reduce the risk of developing the other.

Longitudinal Change in Serum Neurofilament Light Chain in Type 2 Diabetes and Early Diabetic Polyneuropathy: ADDITION-Denmark.

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

The STC2-PAPP-A-IGFBP4-IGF1 axis and its associations to mortality and CVD in T2D.

Objective: Physiologically, pregnancy-associated plasma protein-A (PAPP-A) serves to liberate bound IGF1 by enzymatic cleavage of IGF-binding proteins (IGFBPs), IGFBP4 in particular. Clinically, PAPP-A has been linked to cardiovascular disease (CVD). Stanniocalcin-2 (STC2) is a natural inhibitor of PAPP-A enzymatic activity, but its association with CVD is unsettled. Therefore, we examined associations between the STC2-PAPP-A-IGFBP4-IGF1 axis and all-cause mortality and CVD in patients with type 2 diabetes (T2D). Design: We followed 1284 participants with T2D from the ADDITION trial for 5 years. Methods: Circulating concentrations of STC2, PAPP-A, total and intact IGFBP4 and IGF1 and -2 were measured at inclusion. End-points were all-cause mortality and a composite CVD event: death from CVD, myocardial infarction, stroke, revascularisation or amputation. Survival analysis was performed by Cox proportional hazards model. Results: During follow-up, 179 subjects presented with an event. After multivariable adjustment, higher levels of STC2, PAPP-A, as well as intact and total IGFBP4, were associated with all-cause mortality; STC2: hazard ratio (HR) = 1.84 (1.09-3.12) (95% CI); P = 0.023, PAPP-A: HR = 2.81 (1.98-3.98); P < 0.001, intact IGFBP4: HR = 1.43 (1.11-1.85); P = 0.006 and total IGFBP4: HR = 3.06 (1.91-4.91); P < 0.001. Higher PAPP-A levels were also associated with CVD events: HR = 1.74 (1.16-2.62); P = 0.008, whereas lower IGF1 levels were associated with all-cause mortality: HR = 0.51 (0.34-0.76); P = 0.001. Conclusions: This study supports that PAPP-A promotes CVD and increases mortality. However, STC2 is also associated with mortality. Given that STC2 inhibits the enzymatic effects of PAPP-A, we speculate that STC2 either serves to counteract harmful PAPP-A actions or possesses effects independently of the PAPP-A-IGF1 axis. Significance statement: PAPP-A has pro-atherosclerotic effects and exerts these most likely through IGF1. IGF1 is regulated by the STC2-PAPP-A-IGFBP4-IGF1 axis, where STC2, an irreversible inhibitor of PAPP-A, has been shown to reduce the development of atherosclerotic lesions in mice. We examined the association of this axis to mortality and CVD in T2D. We demonstrated an association between PAPP-A and CVD. All components of the STC2-PAPP-A-IGFBP4-IGF1 axis were associated with mortality and it is novel that STC2 was associated with mortality in T2D. Our study supports that inhibition of PAPP-A may be a new approach to reducing mortality and CVD. Whether modification of STC2 could serve as potential intervention warrants further investigation.

Serum neurofilament light chain - A potential biomarker for polyneuropathy in type 2 diabetes?

AIMS: To investigate the relationship between neurofilament light chain (NfL) and the presence and severity of diabetic polyneuropathy (DPN). METHODS: We performed cross-sectional analysis of data from 178 participants of the ADDITION-Denmark cohort of people with screen-detected type 2 diabetes and 32 healthy controls. Biobank serum samples were analyzed for NfL using single-molecule array. DPN was defined by Toronto criteria for confirmed DPN. Original and axonal nerve conduction study (NCS) sum z-scores were used as indicators of the severity of DPN and peripheral nerve damage. RESULTS: 39 (21.9%) participants had DPN. Serum NfL (s-NfL) was significantly higher in participants with DPN (18.8 ng/L [IQR 14.4; 27.9]) than in participants without DPN (15.4 ng/L [IQR 11.7; 20.1]). There were no unadjusted s-NfL differences between controls (17.6 ng/L [IQR 12.7; 19.8]) and participants with or without DPN. Higher original and axonal NCS sum z-scores were associated with 10% higher s-NfL (10.2 and 12.1% [95% CI's 4.0; 16.8 and 6.6; 17.9] per 1 SD). The AUC of s-NfL for DPN was 0.63 (95% CI 0.52; 0.73). CONCLUSIONS: S-NfL is unlikely to be a reliable biomarker for the presence of DPN. S-NfL is however associated tothe severity of the nerve damage underlying DPN.

Long-term effects of intensive multifactorial treatment on aortic stiffness and central hemodynamics after 13 years with screen-detected type 2 diabetes: the ADDITION-Denmark trial.

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

Improving frequency of urinary albumin testing in type 2 diabetes in primary care - An analysis of cross-sectional studies in Denmark.

BACKGROUND: To ensure high quality standards in chronic care of type 2 diabetes, it is paramount to ensure regular measurement of clinical risk factors. For prevention of diabetic kidney disease, testing for albuminuria and kidney function is vital. The majority of individuals with type 2 diabetes in Denmark are treated in general practice, and given the recent development of kidney-protective treatments, a renewed focus on renal risk factors is important. OBJECTIVE: To assess the frequency of albuminuria and kidney function testing in general practice in Denmark and describe developments over the last decade. The proportion of patients with the recommended annual measurements of albuminuria and kidney function was the primary variable. METHODS: We used data from subjects with type 2 diabetes in three cross-sectional general practice studies from 2009 to 2017. RESULTS: Data from 5592 individuals were available. Almost all subjects (96-99%) in the studies had annual measurement of kidney function performed. During the combined observation period there was a clear increase in the proportion of subjects that had albuminuria measured, from 57.2% to 68.0% to 82.8%. CONCLUSION: The regular assessment of renal risk factors in individuals with type 2 diabetes attending primary care in Denmark has seemingly improved over the last decade. This provides the required base for renal risk assessment and appropriate therapy selection.

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.

Plasma lipid metabolites associate with diabetic polyneuropathy in a cohort with type 2 diabetes.

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.

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.

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.

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.

Optos wide-field imaging versus conventional camera imaging in Danish patients with type 2 diabetes.

PURPOSE: Diabetic retinopathy (DR) screening methods are costly, requiring specialized personnel and patient mydriasis. The Optos apparatus can be operated by nonspecialists and provides ultra-wide-field imaging, with 200° views of the retina in a single image. We compared DR grading obtained from Optos imaging with DR grading from conventional Topcon imaging. METHODS: We conducted a cross-sectional study of 101 persons with diabetes who participated in the Addition-DK 10-year follow-up study. Retina fundus photos using both Optos and Topcon imaging were taken for both eyes. All photos were graded by specialist ophthalmologic nurses, using a modified version of the 'Proposed International Clinical DR severity scale'. We constructed frequency tables and assessed levels of agreement between Optos and Topcon gradings using weighted Kappa statistics, separately for peripheral and macular grading. We tested if the agreements between the two cameras were significantly different using a stratified Wilcoxon test. RESULTS: Significantly, more lesions in the periphery were identified by Optos compared with Topcon (p < 0.01), resulting in a fair Kappa agreement of 0.21. We saw no significant differences in the grading of the macula region (p = 0.97) between the two cameras. Although only 7% of the macula image gradings differed between the cameras, the Kappa agreement of macula grading was only moderate (Kappa = 0.52). CONCLUSION: The inter-camera agreement was acceptable for macula image grading, but only fair for peripheral grading, with Optos identifying more microvascular changes in the periphery. The clinical significance and impact on screening modality and frequency remain to be explored.