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.

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.

Guideline-level monitoring, biomarker levels and pharmacological treatment in migrants and native Danes with type 2 diabetes: Population-wide analyses.

The prevalence of type 2 diabetes (T2D) is higher in migrants compared to native populations in many countries, but the evidence on disparities in T2D care in migrants is inconsistent. Therefore, this study aimed to examine this in Denmark. In a cross-sectional, register-based study on 254,097 individuals with T2D, 11 indicators of guideline-level care were analysed: a) monitoring: hemoglobin-A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), screening for diabetic nephropathy, retinopathy, and foot disease, b) biomarker control: HbA1c and LDL-C levels, and c) pharmacological treatment: glucose-lowering drugs (GLD), lipid-lowering drugs, angiotensin-converting enzyme-inhibitors/angiotensin receptor blockers, and antiplatelet therapy. Migrants were grouped by countries of origin: Middle East, Europe, Turkey, Former Yugoslavia, Pakistan, Sri Lanka, Somalia, Vietnam. In all migrant groups except the Europe-group, T2D was more prevalent than in native Danes (crude relative risk (RR) from 0.62 [0.61-0.64] (Europe) to 3.98 [3.82-4.14] (Sri Lanka)). In eight indicators, non-fulfillment was common (>25% among native Danes). Apart from monitoring in the Sri Lanka-group, migrants were at similar or higher risk of non-fulfillment than native Danes across all indicators of monitoring and biomarker control (RR from 0.64 [0.51-0.80] (HbA1c monitoring, Sri Lanka) to 1.78 [1.67-1.90] (LDL-C control, Somalia)), while no overall pattern was observed for pharmacological treatment (RR from 0.61 [0.46-0.80] (GLD, Sri Lanka) to 1.67 [1.34-2.09] (GLD, Somalia)). Care was poorest in migrants from Somalia, who had increased risk in all eleven indicators, and the highest risk in nine. Adjusted risks were elevated in some migrant groups, particularly in indicators of biomarker control (fully-adjusted RR from 0.84 [0.75-0.94] (LDL-C levels, Vietnam) to 1.44 [1.35-1.54] (LDL-C levels, Somalia)). In most migrant groups, T2D was more prevalent, and monitoring and biomarker control was inferior compared to native Danes. Migrants from Somalia received the poorest care overall, and had exceedingly high lipid levels.

Glucose-lowering drug use in migrants and native Danes with type 2 diabetes: Disparities in combination therapy and drug types.

AIM: To examine disparities in glucose-lowering drug (GLD) usage between migrants and native Danes with type 2 diabetes (T2D). MATERIALS AND METHODS: In a nationwide, register-based cross-sectional study of 253 364 individuals with prevalent T2D on December 31, 2018, we examined user prevalence during 2019 of (i) GLD combination therapies and (ii) individual GLD types. Migrants were grouped by origin (Middle East, Europe, Turkey, Former Yugoslavia, Pakistan, Sri Lanka, Somalia, Vietnam), and relative risk (RR) versus native Danes was computed using robust Poisson regression to adjust for clinical and socioeconomic characteristics. RESULTS: In 2019, 34.7% of native Danes received combination therapy, and prevalence was lower in most migrant groups (RR from 0.78, 95% confidence interval CI 0.71-0.85 [Somalia group] to 1.00, 95% CI 0.97-1.04 [former Yugoslavia group]). Among native Danes, the most widely used oral GLD was metformin (used by 62.1%), followed by dipeptidyl peptidase-4 inhibitors (13.3%), sodium-glucose cotransporter-2 inhibitors (11.9%) and sulphonylureas (5.2%), and user prevalence was higher in most migrant groups (RR for use of any oral GLD: 0.99, 95% CI 0.97-1.01 [Europe group] to 1.09, 95% CI 1.06-1.11 [Sri Lanka group]). Furthermore, 18.7% of native Danes used insulins and 13.3% used glucagon-like peptide-1 receptor agonists (GLP-1RAs), but use was less prevalent in migrants (RR for insulins: 0.66, 95% CI 0.62-0.71 [Sri Lanka group] to 0.94, 95% CI 0.89-0.99 [Europe group]; RR for GLP-1RAs: 0.29, 95% CI 0.22-0.39 [Somalia group] to 0.95, 95% CI 0.89-1.01 [Europe group]). CONCLUSIONS: Disparities in GLD types and combination therapy were evident between migrants and native Danes. Migrants were more likely to use oral GLDs and less likely to use injection-based GLDs, particularly GLP-1RAs, which may contribute to complication risk and mortality among this group.

Validation of Register-Based Diabetes Classifiers in Danish Data.

Purpose: To validate two register-based algorithms classifying type 1 (T1D) and type 2 diabetes (T2D) in a general population using Danish register data. Patients and Methods: After linking data on prescription drug usage, hospital diagnoses, laboratory results and diabetes-specific healthcare services from nationwide healthcare registers, diabetes type was defined for all individuals in Central Denmark Region age 18-74 years on 31 December 2018 according to two distinct register-based classifiers: 1) a novel register-based diabetes classifier incorporating diagnostic hemoglobin-A1C measurements, the Open-Source Diabetes Classifier (OSDC), and 2) an existing Danish diabetes classifier, the Register for Selected Chronic Diseases (RSCD). These classifications were validated against self-reported data from the Health in Central Denmark survey - overall and stratified by age at onset of diabetes. The source-code of both classifiers was made available in the open-source R package osdc. Results: A total of 2633 (9.0%) of 29,391 respondents reported having any type of diabetes, divided across 410 (1.4%) self-reported cases of T1D and 2223 (7.6%) cases of T2D. Among all self-reported diabetes cases, 2421 (91.9%) were classified as diabetes cases by both classifiers. In T1D, sensitivity of OSDC-classification was 0.773 [95% CI 0.730-0.813] (RSCD: 0.700 [0.653-0.744]) and positive predictive value (PPV) 0.943 [0.913-0.966] (RSCD: 0.944 [0.912-0.967]). In T2D, sensitivity of OSDC-classification was 0.944 [0.933-0.953] (RSCD: 0.905 [0.892-0.917]) and PPV 0.875 [0.861-0.888] (RSCD: 0.898 [0.884-0.910]). In age at onset-stratified analyses of both classifiers, sensitivity and PPV were low in individuals with T1D onset after age 40 and T2D onset before age 40. Conclusion: Both register-based classifiers identified valid populations of T1D and T2D in a general population, but sensitivity was substantially higher in OSDC compared to RSCD. Register-classified diabetes type in cases with atypical age at onset of diabetes should be interpreted with caution. The validated, open-source classifiers provide robust and transparent tools for researchers.

Autonomic dysfunction is associated with the development of arterial stiffness: the Whitehall II cohort.

This study aims to examine the association between baseline level and change of autonomic nervous function with subsequent development of arterial stiffness. Autonomic nervous function was assessed in 4901 participants of the Whitehall II occupational cohort by heart rate variability (HRV) indices and resting heart rate (rHR) three times between 1997 and 2009, while arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) measured twice between 2007 and 2013. First, individual HRV/rHR levels and annual changes were estimated. Then, we modelled the development of PWV by HRV/rHR using linear mixed effect models. First, we adjusted for sex and ethnicity (model 1), and then for socioeconomic and lifestyle factors, various clinical measurements, and medications (model 2). A decrease in HRV and unchanged rHR was associated with subsequent higher levels of PWV, but the effect of a change in HRV was less pronounced at higher ages. A typical individual aged 65 years with a SDNN level of 30 ms and a 2% annual decrease in SDNN had 1.32 (0.95; 1.69) higher PWV compared to one with the same age and SDNN level but with a 1% annual decrease in SDNN. Further adjustment had no major effect on the results. People who experience a steeper decline in autonomic nervous function have higher levels of arterial stiffness. The association was stronger in younger people.

The impact of diabetes on cancer detection during the prevalence round of a national screening program for colorectal cancer.

AIMS: Diabetes is associated with a higher risk of colorectal cancer (CRC) and inferior survival after CRC. Screening may enable the early detection of CRC. We aimed to assess the impact of diabetes on cancer detection and disease stage during the prevalence round of a national CRC screening program. METHODS: We performed a register-based cohort study based on the randomized procedure for inviting Danish residents aged 50-74 years to the prevalence round of national CRC screening program in 2014-2017. By comparing the random half of the population who had been invited by 1 May 2016 with the not yet invited half, the effect of screening was assessed by the detection of CRC and disease stage among individuals with and without diabetes. Further, the impact of diabetes on the screening participation rate was calculated. RESULTS: By randomisation, 504,673 individuals had been invited to the CRC screening by 1 May 2016, and 549,359 individuals had not yet been invited. The diabetes prevalence was 10% in both groups. When comparing those not yet invited to those invited, the effect of screening on the number of detected cancers per 100,000 individuals was higher in those with diabetes (from 207 to 494 cancers) than in those without diabetes (from 147 to 364 cancers), and screening resulted in overall higher proportions of stage I cancer. Among those invited to screening, the participation rate was 9.1% lower (95% CI: 8.7%-9.5%) in individuals with versus without diabetes. CONCLUSIONS: Despite a lower participation rate, the effect of CRC screening was higher in individuals with diabetes.

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.

Gender disparities in time-to-initiation of cardioprotective glucose-lowering drugs in patients with type 2 diabetes and cardiovascular disease: a Danish nationwide cohort study.

BACKGROUND: We aimed to examine the impact of gender and specific type of cardiovascular disease (CVD) diagnosis (ischemic heart disease [IHD], heart failure, peripheral artery disease [PAD] or stroke) on time-to-initiation of either a sodium glucose cotransporter 2 inhibitor or glucagon-like peptide 1 analogue (collectively termed cardioprotective GLD) after a dual diagnosis of type 2 diabetes (T2DM) and CVD. METHODS: In a nationwide cohort study, we identified patients with a new dual diagnosis of T2DM and CVD (January 1, 2012 and December 31, 2018). Cumulative user proportion (CUP) were assessed. Poisson models were used to estimate the initiation rate of cardioprotective GLDs. The final analyses were adjusted for potential confounders. RESULTS: In total, we included 70,538 patients with new-onset T2DM and CVD (38% female, mean age 70 ± 12 years at inclusion). During 183,256 person-years, 6,276 patients redeemed a prescription of a cardioprotective GLD. One-year CUPs of cardioprotective GLDs were lower in women than men. Initiation rates of GLDs were lower in women (female-to-male initiation-rate-ratio crude: 0.76, 95% CI 0.72-0.81); adjusted 0.92, 95% CI 0.87-0.97). In CVD-stratified analysis, the adjusted initiation rate ratio was lower in female patients with IHD and heart failure (IHD: 0.91 [95% CI 0.85-0.98], heart failure: 0.85 [95% CI 0.73-1.00], PAD: 0.92 [95% CI 0.78-1.09], and stroke: 1.06 [95% CI 0.93-1.20]). CONCLUSIONS: Among patients with a new dual diagnosis of T2DM and CVD, female gender is associated with lower initiation rates of cardioprotective GLDs, especially if the patient has IHD or heart failure.

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.

Cohort profile: Health in Central Denmark (HICD) cohort - a register-based questionnaire survey on diabetes and related complications in the Central Denmark Region.

PURPOSE: The Health in Central Denmark (HICD) cohort is a newly established cohort built on extensive questionnaire data linked with laboratory data and Danish national health and administrative registries. The aim is to establish an extensive resource for (1) gaining knowledge on patient-related topics and experiences that are not measured objectively at clinical health examinations and (2) long-term follow-up studies of inequality in diabetes and diabetes-related complications. PARTICIPANTS: A total of 1.3 million inhabitants reside in the Central Denmark Region. Using register data and a prespecified diabetes classification algorithm, we identified 45 507 persons aged 18-75 years with prevalent diabetes on 31 December 2018 and a group without diabetes of equal size matched by sex, age and municipality. A 90-item questionnaire was distributed to eligible members of this cohort on 18 November 2020 (estimated time required for completion: 15-20 min). FINDINGS TO DATE: We invited 90 854 persons to take part in the survey, of whom 51 854 answered the questionnaire (57.1%). Among these respondents, 2,832 persons had type 1 diabetes (55.9%), 21,140 persons had type 2 diabetes (53.2%), while 27,892 persons were part of the matched group without diabetes (60.4%). In addition to questionnaire data, the cohort is linked to nationwide registries that provide extensive data on hospital diagnoses and procedures, medication use and socioeconomic status decades before enrolment while laboratory registries has provided repeated measures of biochemical markers, for example, lipids, albuminuria and glycated haemoglobin up to 10 years before enrolment. FUTURE PLANS: The HICD will serve as an extensive resource for studies on patient-related information and inequality in type 1 diabetes and type 2 diabetes. Follow-up is planned to continue for at least 10 years and detailed follow-up questionnaires, including new topics, are planned to be distributed during this period, while registry data are planned to be updated every second year.

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.

Duration of diabetes-related complications and mortality in type 1 diabetes: a national cohort study.

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

Effect of familial diabetes status and age at diagnosis on type 2 diabetes risk: a nation-wide register-based study from Denmark.

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

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.

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.