Search

Background and Aims: Nocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Insulin degludec is associated with a lower risk of nocturnal hypoglycemia in T1D. As nocturnal hypoglycemia is often asymptomatic, we applied continuous glucose monitoring (CGM) to detect a more precise occurrence of nocturnal hypoglycemia in the HypoDeg trial, comparing insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia. Materials and Methods: In the HypoDeg trial, 149 people with T1D were included in an open-label randomized cross-over trial. Sixty-seven participants accepted optional participation in the predefined substudy of 4 × 6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events. Results: Treatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% confidence interval [CI]: 10%-54%; P

AimTo compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia.Materials and methodsThe HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia.ResultsThere were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of −4.3% (95% confidence interval [CI] −8.1 to −0.5; P ConclusionBased on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose. Aim: To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia. Materials and methods: The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia. Results: There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of −4.3% (95% confidence interval [CI] −8.1 to −0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]). Conclusion: Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.

OBJECTIVE We investigated the relationship between hs-CRP, a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS In patients with recent-onset T2D, we measured serum hs-CRP (n = 7,301) and C-peptide (n = 5,765) in the prospective Danish Centre for Strategic Research in Type 2 Diabetes cohort study. Patients with no prior CVE (n = 6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n = 7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for the interaction between hs-CRP and C-peptide. RESULTS During follow-up (median 4.8 years), high (>3 mg/L) versus low ( CONCLUSIONS The finding of high hs-CRP as a stronger prognostic biomarker of all-cause mortality than of CVEs may facilitate improved early detection and prevention of deadly diseases besides CVEs. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention.

Background Patient-reported Outcome (PRO) measures may be used as the basis for out-patient follow-up instead of fixed appointments. The patients attend follow-up from home by filling in questionnaires developed for that specific aim and patient group (telePRO). The questionnaires are handled in real time by a specific algorithm, which assigns an outcome color reflecting clinical need. The specific questionnaires and algorithms (named solutions) are constructed in a consensus process with clinicians. We aimed to describe AmbuFlex’ telePRO solutions and the algorithm outcomes and variation between patient groups, and to discuss possible applications and challenges. Methods TelePRO solutions with more than 100 processed questionnaires were included in the analysis. Data were retrieved together with data from national registers. Characteristics of patients, questionnaires and outcomes were tabulated for each solution. Graphs were constructed depicting the overall and within-patient distribution of algorithm outcomes for each solution. Results From 2011 to 2021, 29 specific telePRO solutions were implemented within 24 different ICD-10 groups. A total of 42,015 patients were referred and answered 171,268 questionnaires. An existing applicable instrument with cut-off values was available for four solutions, whereas items were selected or developed ad hoc for the other solutions. Mean age ranged from 10.7 (Pain in children) to 73.3 years (chronic kidney disease). Mortality among referred patients varied between 0 (obesity, asthma, endometriosis and pain in children) and 528 per 1000 patient years (Lung cancer). There was substantial variation in algorithm outcome across patient groups while different solutions within the same patient group varied little. Discussion TelePRO can be applied in diseases where PRO can reflect clinical status and needs. Questionnaires and algorithms should be adapted for the specific patient groups and clinical aims. When PRO is used as replacement for clinical contact, special carefulness should be observed with respect to patient safety.

Objective: We investigated the relationship between high-sensitivity C-reactive protein (hsCRP), a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D). Research Design and Methods: We measured serum hsCRP (n=7301) and C-peptide (n=5765) in patients with recent-onset T2D in the prospective Danish DD2 cohort study. Patients with no prior CVE (n=6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n=7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for interaction between hsCRP and C-peptide. Results: During follow-up (median=4.8 years), high (>3 mg/L) versus low ( Conclusions: The finding of high hsCRP as a stronger prognostic biomarker of all-cause mortality than of CVE may facilitate improved early detection and prevention of deadly diseases besides CVE. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention.

BACKGROUND: Successful diabetes management requires collaboration between patients and healthcare professionals and should be aligned with an individual's condition and resources. We developed a flexible, individualised, patient-reported outcome (PRO)-based telehealth intervention called "DiabetesFlex Care" in which patients completed an annual self-reported questionnaire from home, one required face-to-face appointment, and two optional outpatient consultations. In this study, we investigated patients' experiences using DiabetesFlex Care.METHODS: We conducted a qualitative, interpretive descriptive (ID) study based on semi-structured interviews with a purposeful sample of 36 patients with type 1 diabetes (T1D) who had used DiabetesFlex Care. Recorded audio data were transcribed and analysed inductively using the constant comparative method.RESULTS: DiabetesFlex Care changed participants' perspectives on living with diabetes. Patients became more involved in their own care and found that DiabetesFlex Care helped to make their conversations with healthcare professionals more relevant. Furthermore, participants appreciated the ability to both choose the format of their appointments (face-to-face vs. phone call) and cancel unnecessary appointments.CONCLUSION: DiabetesFlex Care was a flexible and inclusive health service that enabled patients to take more responsibility for their own diabetes management. The questionnaire-based approach in DiabetesFlex Care can help healthcare professionals systematically account for patients' perspectives and support user involvement and self-management. By extension, this approach can also help minimise healthcare-related disruptions in patients' lives. Further studies are needed to determine whether flexible PRO-based telehealth is an acceptable solution for all patients.

Aims/hypothesis Nocturnal hypoglycaemia remains a main limiting factor for achieving the recommended glycaemic target in type 1 diabetes (T1D). The long-acting insulin analogue degludec reduces the risk of nocturnal hypoglycaemia in patients with T1D at low risk of such events. This study investigates whether insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal and severe hypoglycaemia in patients prone to nocturnal severe hypoglycaemia. Methods Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last two years were included in a two-year prospective, randomised, open, multicentre, cross-over trial. A total of 149 patients were randomised 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period was one year long and consisted of three months of run-in or cross-over followed by nine months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat. Results Treatment with insulin degludec resulted in a 28% (95%CI: 9-43; p=0.02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95%CI: 16-53; p=0.002) RRR at level 2 (≤3.0 mmol/l), and a 35% (95%CI: 1-58; p=0.04) RRR in all-day severe hypoglycaemia compared to insulin glargine U100. Conclusions/interpretation Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec as compared with insulin glargine U100. This article is protected by copyright. All rights reserved.

Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. 13 individuals with type 2 diabetes were studied after four weeks treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with 11C-palmitate and 18F-FDG PET/CT. Oxygen consumption and myocardial external efficiency (MEE) were measured with 11C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using 15O-H2O PET/CT. Empagliflozin did not affect myocardial FFA uptake but reduced myocardial glucose uptake by 57% (p In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose towards other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition.

Critically ill patients have low circulating 25-hydroxyvitamin D (25OHD), vitamin D binding protein (DBP), and 1,25-dihydroxyvitamin D [1,25(OH)2D]. Low 25OHD is associated with poor outcomes, possibly explained by its effect on bone and immunity. In this prospective, randomized double-blind, placebo-controlled study, we investigated the feasibility of normalizing 25OHD in prolonged (>10 days) critically ill patients and the effects thereof on 1,25(OH)2D, bone metabolism, and innate immunity. Twenty-four patients were included and compared with 24 matched healthy subjects. Patients were randomized to either intravenous bolus of 200 μg 25OHD followed by daily infusion of 15 μg 25OHD for 10 days, or to placebo. Parameters of vitamin D, bone and mineral metabolism, and innate immune function were measured. As safety endpoints, ICU length of stay and mortality were registered. Infusion of 25OHD resulted in a sustained increase of serum 25OHD (from median baseline 9.2 –16.1 ng/ml at day 10), which, however, remained below normal levels. There was no increase in serum 1,25(OH)2D but a slight increase in serum 24,25(OH)2D. Mineral homeostasis, innate immunity and clinical safety endpoints were unaffected. Thus, intravenous 25OHD administration during critical illness increased serum 25OHD concentrations, though less than expected from data in healthy subjects, which suggests illness-induced alterations in 25OHD metabolism and/or increased 25OHD distribution volume. The increased serum 25OHD concentrations were not followed by a rise in 1,25(OH)2D nor were bone metabolism or innate immunity affected, which suggests that low 25OHD and 1,25OHD levels are part of the adaptive response to critical illness.

Aim: The objective of this study was to assess the impact of health care–initiated visits versus patient-controlled flexible visits on clinical and patient-reported outcomes in people with type 1 diabetes. Methods: The DiabetesFlex trial was a randomized controlled, pragmatic non-inferiority 15-month follow-up study comparing standard care (face-to-face visits every 4 months) with DiabetesFlex (patient-controlled flexible visits using patient-reported, outcome-based telehealth follow-up). Of 343 enrolled participants, 160 in each group completed the study. The primary outcome was mean change in HbA1c from baseline to 15-month follow-up. Secondary outcomes were blood pressure, lipid levels, frequency of visits, the World Health Organization score—five well-being-index (WHO-5), the Problem Areas In Diabetes (PAID) scale and experience of participation in own care (participation score). Results: The adjusted mean difference in HbA1c between standard care and DiabetesFlex was similar and below the predefined non-inferiority margin of 0.4% (−0.03% [95%CI: 0.15, 0.11]/−0.27 mmol/mol [−1.71, 1.16]). No intergroup mean changes in lipid or blood pressure were observed. Conversely, DiabetesFlex participants presented an increased mean WHO-5 index of 4.5 (1.3, 7.3), participation score of 1.1 (0.5, 2.0), and decreased PAID score of −4.8 (−7.1, −2.6) compared with standard care. During follow-up, DiabetesFlex participants actively changed 23% of face-to-face visits to telephone consultations, cancelled more visits (17% vs. 9%), and stayed away without cancellation less often (2% vs. 8%). Conclusion: Compared with standard care, flexible patient-controlled visits combined with patient-reported outcomes in participants with metabolic controlled type 1 diabetes and good psychological well-being further improved diabetes-related well-being and decreased face-to-face visits while maintaining safe diabetes management.

INTRODUCTION: Type 2 diabetes (T2D) is related to an increased fracture risk and low bone turnover. However, the mechanisms are not elucidated. In the present study we investigate the association between glycemic variability and bone turnover markers.METHODS: 100 participants with T2D and 100 age and gender matched controls were included in this cross-sectional study. All participants with T2D were equipped with a continuous glucose monitoring (CGM) sensor for 3 days (CGMS iPro Continuous Glucose Recorder; Medtronic MiniMed). The dawn glucose levels were defined as a morning period starting 1 h before breakfast ending 1 h post ingestion. On all participants serum (s)-C-terminal cross-linked telopeptide of type-I collagen (CTX), s-procollagen type 1 amino terminal propeptide (P1NP), and s-sclerostin were measured.RESULTS: Participants with T2D displayed significantly lower levels of the bone resorption marker s-CTX and the bone formation marker s-P1NP compared to controls. S-CTX was significantly negatively associated with the mean amplitude of glycemic excursions (MAGE) and the dawn glucose levels whereas s-P1NP only was significantly negatively associated with the dawn glucose levels while it was borderline significantly associated with MAGE (p=0.05). S-CTX and s-P1NP were significantly lower among the 50 % with the highest dawn glucose levels compared to the 50 % lowest dawn glucose levels also after adjustment for age, gender, glycated hemoglobin A1c (HbA1c), and body mass index (BMI).CONCLUSION: We observed that the amplitude of glycemic excursions and rise in dawn glucose was negatively associated with bone turnover markers. Future research is needed to determine whether reduction of the amplitude of glycemic excursions increase bone turnover markers.

Background Stroke is a serious complication in patients with type 2 diabetes (T2DM). Arterial stiffness may improve stroke prediction. We investigated the association between carotid-femoral pulse wave velocity [PWV] and the progression of cerebral white matter hyperintensities (WMH), a marker of stroke risk, in patients with T2DM and controls. Methods In a 5-year cohort study, data from 45 patients and 59 non-diabetic controls were available for analysis. At baseline, participants had a mean (± SD) age of 59 ± 10 years and patients had a median (range) diabetes duration of 1.8 (0.8–3.2) years. PWV was obtained by tonometry and WMH volume by an automated segmentation algorithm based on cerebral T2-FLAIR and T1 MRI (corrected by intracranial volume, cWMH). High PWV was defined above 8.94 m/s (corresponding to the reference of high PWV above 10 m/s using the standardized path length method). Results Patients with T2DM had a higher PWV than controls (8.8 ± 2.2 vs. 7.9 ± 1.4 m/s, p Conclusions PWV is associated with cWMH progression in patients with type 2 diabetes and non-diabetic controls. Our results indicate that arterial stiffness may be involved early in the pathophysiology leading to cerebrovascular diseases.

PURPOSE: Fibroblast growth factor (FGF) 21 is a circulating hormone with an important role in metabolic regulation. FGF21 production in humans responds positively to glucose consumption and we hypothesize that serum FGF21 concentration is associated to glycemic control.METHODS: We enrolled 31 patients with type 1 diabetes (T1D) based on their HbA1c (well-regulated (HbA1c 69 mmol/mol), (n = 13). Twelve patients (39%) were diagnosed with retinopathy. Twenty healthy individuals comparable for age and gender distribution were included as a reference group. Serum FGF21, intact FGF21, fibroblast activation protein (FAP), adiponectin, and C-Reactive Protein (CRP) were measured by immunoassays.RESULTS: No correlation between FGF21 concentration and HbA1c was found. Patients with T1D had lower levels of circulating FGF21 as compared with the reference group, but the difference was nonsignificant (p = 0.12). Dividing the patients according to retinopathy, we found that T1D patients with retinopathy had significantly lower FGF21 concentrations (10.0 ng/L) as compared with the healthy reference group (37.1 ng/L), (p = 0.02). We found significantly higher levels of the FGF21 cleaving enzyme, FAP, in patients with T1D (97.2 μg/L) as compared with the healthy control group (78.5 μg/L), (p = 0.006). Interestingly, serum FAP levels correlated significantly with circulating FGF21 levels in T1D patients, but this correlation was not found in the healthy controls.CONCLUSIONS: We found no association between circulating FGF21 levels and HbA1c. T1D patients with retinopathy had significantly lower FGF21 levels as compared with healthy individuals, but it remains unclear if the lower levels of FGF21 are pathogenically related to the development of microvascular complications. Of note, serum FAP levels were significantly higher in all T1D patients as compared with the healthy individuals.

Objectives: Coronary atherosclerosis in patients with type 2 diabetes mellitus may be promoted by regional fat distribution. We investigated the association between anthropometric measures of obesity, truncal fat mass, epicardial adipose tissue and coronary atherosclerosis in asymptomatic patients and matched controls. Methods: We examined 44 patients and 59 controls [mean (standard deviation) age 64.4 ± 9.9 vs 61.8 ± 9.7, male 50% vs 47%, diabetes duration mean (standard deviation) 7.7 ± 1.5] with coronary computed tomography angiography. Coronary plaques were quantified as total, calcified, non-calcified and low-density non-calcified plaque volumes (mm3). Regional fat distribution was assessed by dual-energy X-ray absorptiometry, body mass index (kg/m2), waist circumference (cm) and epicardial fat volume (mm3). Endothelial function and systemic inflammation were evaluated by peripheral arterial tonometry (log transformed Reactive Hyperemia Index) and C-reactive protein (mg/L). Results: Body mass index and waist circumference ( p 0.51), waist circumference ( p > 0.06) and epicardial adipose tissue ( p > 0.17) were not associated with coronary plaque volumes in adjusted analyses. Conclusion: Body mass index is associated with coronary plaque volumes in diabetic as well as non-diabetic individuals.

Key summary points Aim Confusion was more prevalent in frail than in non-frail older patients at hospital admission. Finding COVID-19 and accelerated functional decline were associated among frail older hospitalised patients when compared to non-frail. Message Ninety-day all-cause mortality was 70% among frail hospitalised patients with COVID-19 and 15% among non-frail., Purpose Older people are the most frequently hospital admitted patients with COVID-19. We aimed to describe the clinical presentation of COVID-19 among frail and nonfrail older hospitalised patients and to evaluate the potential association between frailty and clinical course, decision of treatment level with outcomes change in functional capacity and survival. Methods We performed a multi-center, retrospective cross-sectional cohort study examining data on clinical presentation and frailty-related domains for hospitalised people aged 75 + years with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test. Frailty was assessed at admission using record-based MPI (rMPI) and Clinical Frailty Scale (CFS). Decision on treatment level about invasive ventilation and cardiopulmonary resuscitation (CPR), change in CFS-score from admission to discharge, changed need of home care, and in-hospital, 30-day and 90-day mortality were registered. Results 100 patients (median age 82 years (IQR 78–86), 56% female) with COVID-19 were included. 54 patients were assessed moderately or severely frail (rMPI-score = 2 or 3) and compared to non-frail (rMPI-score = 1). At admission, frail patients presented more frequently with confusion. At discharge, functional decline measured by change in CFS and increased home care was more prevalent among frail than the non-frail. Decisions about no invasive ventilation or CPR were more prevalent among frail older patients with COVID-19 than non-frail. Ninety-day mortality was 70% among frail patients versus 15% in non-frail. Conclusion Frailty seems to be associated with confusion, more frequent decisions about treatment level, larger functional decline at discharge and a higher mortality rate among older patients with COVID-19.

AIMS: To investigate temporal trends in time to initiation of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide 1 analogues (cardioprotective glucose-lowering drugs [GLDs]) in patients with a new dual diagnosis of type 2 diabetes (T2DM) and cardiovascular disease (CVD).MATERIALS AND METHODS: In a cohort study, we identified patients with a new dual diagnosis of T2DM and CVD using linked healthcare data from nationwide registries on drug prescriptions and diagnosis codes. For each calendar year between 2012 and 2018, we examined time to initiation and cumulative user proportions (CUPs) for cardioprotective GLD use 1 and 2 years after the dual diagnosis.RESULTS: Among all individuals living in Denmark in the period 2012 to 2018, 41 733 patients with a new dual diagnosis of T2DM and CVD were identified (median [interquartile range] age 71 [64-79] years, 61% male, and 57% with CVD as the latest diagnosis). Incidence curve slopes and 1- and 2-year CUPs for cardioprotective GLDs increased during the study period (1-year CUP 4.0%, 95% confidence interval [CI] 3.6-4.5) in 2012 to 14.7, 95% CI 13.7-15.7, in 2018; 2-year CUP 5.5, 95% CI 5.0-6.1, in 2012 to 16.7, 95% CI 15.8-17.7, in 2017). T2DM patients with CVD as the second (latest) diagnosis had higher 1-year CUPs than CVD patients with T2DM as the latest diagnosis: 2012: 7.0 (95% CI 6.2-8.0) versus 1.4 (95% CI 1.0-1.8); 2018: 18.1 (95% CI 16.8-19.6) versus 10.0 (95% CI 8.8-11.3).CONCLUSIONS: In patients with T2DM and CVD, the incidence of cardioprotective GLD initiation increased between 2012 and 2018, however, within 2 years of dual diagnosis, it remained low.

H-ficolin recognizes patterns on microorganisms and stressed cells and can activate the lectin pathway of the complement system. We aimed to assess H-ficolin in relation to the progression of diabetic kidney disease (DKD), all-cause mortality, diabetes-related mortality, and cardiovascular events. Event rates per 10-unit H-ficolin-increase were compared in an observational follow-up of 2,410 individuals with type 1 diabetes from the FinnDiane Study. DKD progression occurred in 400 individuals. The unadjusted hazard ratio (HR) for progression was 1.29 (1.18–1.40) and 1.16 (1.05–1.29) after adjustment for diabetes duration, sex, HbA1c, systolic blood pressure, and smoking status. After adding triglycerides to the model, the HR decreased to 1.07 (0.97–1.18). In all, 486 individuals died, including 268 deaths of cardiovascular causes and 192 deaths of complications to diabetes. HRs for all-cause mortality and cardiovascular mortality were 1.13 (1.04–1.22) and 1.05 (0.93–1.17), respectively, in unadjusted analyses. These estimates lost statistical significance in adjusted models. However, the unadjusted HR for diabetes-related mortality was 1.19 (1.05–1.35) and 1.18 (1.02–1.37) with the most stringent adjustment level. Our results, therefore, indicate that H-ficolin predicts diabetes-related mortality, but neither all-cause mortality nor fatal/non-fatal cardiovascular events. Furthermore, H-ficolin is associated with DKD progression, however, not independently of the fully adjusted model.

To examine the predictive value of the Multidimensional Prognostic Index (MPI) on unplanned hospital readmission in geriatric patients. Frail patients have higher risk of unplanned readmission compared to non-frail. The aggregated MPI is superior to the prognostic value of every single domain in the tool according to the prediction of unplanned readmission. Targeting health care interventions requires valid measurements when predicting unplanned hospital readmission. The Multidimensional Prognostic Index (MPI) based on Comprehensive Geriatric Assessment (CGA) enables the prediction of mortality and length of stay (LOS) in older hospitalized patients. Our aim was to validate if the MPI as a frailty tool could predict unplanned hospital readmission in geriatric patients. This prognostic study was conducted in geriatric wards. The target population was 65 + -year-old patients hospitalized with acute illness. The MPI tool is derived from eight CGA domains by an interdisciplinary team: social aspects, number of drugs, activities of daily living (ADL), instrumental-ADL, cognitive status, severity of morbidity, risk of developing pressure sores, and nutritional status. Patients assessed were categorized into three groups: non-frail (MPI-1), moderate frail (MPI-2) or severe frail (MPI-3). Primary outcome was 30-day unplanned readmission and secondary LOS and 90-day mortality. In total 1467 patients were included from January 1, 2018, to October 1, 2019. Mean age was 84.2 years (± 7.4) and 59% were women. 15.7% were readmitted. Hazard ratio (HR) for readmission in the MPI-2 group (n = 635) was 2.57; 95% confidence interval (CI) 1.25–5.29 (p = 0.01), and 2.60; 95% CI 1.27–5.33 (p = 0.009) in the MPI-3 group (n = 711) compared to the MPI-1 group (n = 121). MPI was a predictor of LOS and mortality. Using the MPI tool to identify the frail and non-frail patients is applicable to predict unplanned hospital readmission in geriatric patients. The MPI is superior to the prognostic value of each single domain. MPI will be of great value to health professionals’ decision-making.

To examine the reproducibility and diagnostic accuracy of a comprehensive frailty assessment method based solely on the older medical inpatient’s electronic medical record. We found good reliability, high agreement, and considerable diagnostic accuracy when comparing the record-based method to the bedside method. The record-based MPI is highly desirable. It seems feasible, reproducible, accurate, and worth exploring in larger datasets and other settings. The comprehensive geriatric assessment (CGA) including frailty assessment is considered the gold standard of assessment in geriatric patients. The Multidimensional Prognostic Index (MPI) is a CGA-based bedside assessment tool. Older medical inpatients’ medical records comprehensively describe the MPI-featured components. Consequently, MPI-based frailty assessment may be accomplished retrospectively. We found no previous studies concerning record-based MPI. We studied the reproducibility and diagnostic accuracy of a record-based MPI. The study was designed as a fully crossed, prospective, and cross-sectional study. A total of 50 inpatients aged ≥ 75 years were included from two medical wards. Record-based MPI was assessed by two independent raters in patients who required personal assistance on a daily basis or had a Charlson Comorbidity Index (CCI) ≥ 1. In the same patients, a bedside MPI rating was performed. Inter-rater and inter-method reproducibility and diagnostic accuracy measures were calculated. Evaluating the inter-rater reproducibility; the mean difference was -0.02 points [95% confidence interval (CI) − 0.06 to 0.01, p = 0.20]. Intraclass correlation coefficient (ICC) was 0.71. Evaluating inter-method reproducibility; the mean difference was -0.02 (95% CI − 0.04 to 0.01, p = 0.18); ICC = 0.83. Sensitivity was 100% and specificity 80%. The areas under the receiver operating curves (ROC) was 0.92 (95% CI 0.75–1.00) and 0.77 (95% CI 0.52–1.00). The record-based MPI rating method has an acceptable inter-rater reliability, good inter-method reliability, and high agreement as compared to the bedside-rated MPI. The diagnostic accuracy seems considerable. The record-based MPI seems useful in retrospective frailty assessment among older medical inpatients.

AIMS: Adverse activation of the complement cascade in the innate immune system appears to be involved in development of vascular complications in diabetes. Dipeptidyl peptidase-4 (DPP-4) is a cell surface serine protease expressed in a variety of tissues. DPP-4 inhibitors are widely used in treatment of type 2 diabetes and appear to yield beneficial pleiotropic effects beyond their glucose-lowering action, e.g. renoprotective and anti-inflammatory properties, but the exact mechanisms remain unknown. We hypothesized that DPP-4 inhibitors block adverse complement activation by inhibiting complement-activating serine proteases.MATERIALS AND METHODS: We analyzed the effects of 7 different DPP-4 inhibitors on the lectin and classical pathway of the complement system in vitro by quantifying complement factor C4b deposition onto mannan or IgG coated surfaces, respectively. Furthermore, plasma concentrations of mannan-binding lectin (MBL), soluble membrane attack complex (sMAC), and C4b deposition were quantified in 71 patients with a recent acute coronary syndrome and glucose disturbances, randomly assigned to sitagliptin 100 mg (n=34) or placebo (n=37) for 12 weeks.RESULTS: All the 7 DPP-4 inhibitors tested in the study directly inhibited functional activity of the lectin pathway in a dose-dependent manner with varying potency in vitro. In vivo, MBL, sMAC, and C4b declined significantly during follow-up in both groups without significant effect of sitagliptin.CONCLUSIONS: We demonstrated an inhibitory effect of DPP-4 inhibitors on the lectin pathway in vitro. The clinical relevance of this effect of DPP-4 inhibitors remains to be fully elucidated. This article is protected by copyright. All rights reserved.

OBJECTIVE Mannose-binding lectin (MBL) is linked to risk of cardiovascular disease (CVD) in diabetes, but the nature of the association is unclear. We investigated the association between MBL and the risk of cardiovascular events (CVE) and all-cause mortality in type 2 diabetes. RESEARCH DESIGN AND METHODS In a cohort study of 7,588 patients with type 2 diabetes, we measured serum MBL in 7,305 patients and performed MBL expression genotyping in 3,043 patients. We grouped serum MBL and MBL expression genotypes into three categories: low, intermediate, and high. Outcomes were CVE (myocardial infarction, stroke, coronary revascularization, unstable angina, or cardiovascular death) and all-cause mortality. The association with outcomes was examined by spline and Cox regression analyses. RESULTS Serum MBL and CVE showed a U-shaped association. Compared with the intermediate serum MBL category, the adjusted hazard ratio (HR) for CVE was 1.82 (95% CI 1.34–2.46) for the low-MBL category and 1.48 (95% CI 1.14–1.92) for the high-MBL category. We found a similar U-shaped association for all-cause mortality, but with lower risk estimates. Compared with the intermediate MBL expression genotype, the adjusted HR for CVE was 1.40 (95% CI 0.87–2.25) for the low-expression genotype and 1.44 (95% CI 1.01–2.06) for the high-expression genotype. MBL expression genotype was not associated with all-cause mortality. CONCLUSIONS Both serum MBL and MBL expression genotype showed a U-shaped association with CVE risk in individuals with type 2 diabetes. Our findings suggest that serum MBL is a risk factor for CVD in this population.

Aim The DEPICT‐1 and ‐2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes who were receiving intensive insulin therapy. The DEPICT‐1 and ‐2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes. This post‐hoc study investigated the safety and efficacy of dapagliflozin in individuals with BMI ≥27 kg/m2 to assess if the benefit/risk ratio associated with dapagliflozin treatment can be further improved than that observed in the overall DEPICT population. Methods Changes in glycated haemoglobin (HbA1c) and body weight, percentage change in daily insulin dose and proportion of participants achieving HbA1c reduction ≥0.5% without severe hypoglycaemia were evaluated at weeks 24 and 52. Changes in mean interstitial glucose, mean amplitude of glycaemic excursions and time in target glycaemic range were evaluated at week 24. Safety was assessed until week 56. Results Week‐52 adjusted mean (SE) change from baseline for HbA1c was −0.26% (0.05) with dapagliflozin versus +0.08% (0.05) with placebo and for body weight was −2.74 kg (0.25) with dapagliflozin versus +0.81 kg (0.26) with placebo. Mean (SE) percentage change in daily insulin dose was −10.5% (1.23) with dapagliflozin versus −1.4% (1.36) with placebo. Time spent in target glycaemic range increased by 2.2 h/day versus placebo. Dapagliflozin was well tolerated, with fewer participants experiencing diabetic ketoacidosis (dapagliflozin, 1.7%; placebo, 1.0%) than dapagliflozin 5 mg receiving participants in the pooled DEPICT populations. Conclusions Compared with the pooled DEPICT population, the benefit/risk profile of adjunct dapagliflozin therapy was more favourable in individuals with type 1 diabetes with body mass index ≥27 kg/m2 because of the reduced risk of diabetic ketoacidosis in this population.

Introduction Hypoglycaemia is a common side effect of insulin therapy; low or high glycated haemoglobin (HbA1c) levels, history of hypoglycaemia or long diabetes duration are known modifiers of hypoglycaemia risk. In randomised clinical trials, lower rates of hypoglycaemia have been observed with the new-generation insulin analogue, long-acting insulin degludec, compared with other basal insulins. Methods The ReFLeCT study was a prospective observational study over 12 months. Patient-reported diary data on hypoglycaemia were collected from patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) who were switching from other basal insulins to insulin degludec (degludec) at their physician’s discretion in routine clinical care. Two secondary analyses were undertaken to investigate the change in number of hypoglycaemic events: a post hoc analysis using the updated American Diabetes Association (ADA) level 1, 2 and 3 hypoglycaemia definitions, and a pre-specified analysis using patient characteristics (baseline HbA1c, diabetes duration, and physician’s rationale for initiating degludec). Results Switching to degludec was associated with significantly fewer hypoglycaemic events for all definitions in T1D, and level 1 and 2 in T2D (too few level 3 events for statistical comparison). Moreover, patient characteristics did not influence the observed reduction in hypoglycaemia in T1D and T2D. Conclusion These results demonstrate that switching to degludec from other basal insulins was associated with reduced rates of hypoglycaemia, irrespective of the definition used or baseline patient characteristics. Trial Registration NCT02392117 Electronic Supplementary Material The online version of this article (10.1007/s13300-020-00875-1) contains supplementary material, which is available to authorized users., Plain Language Summary Low blood sugar levels (hypoglycaemia) are a common, and sometimes serious, side effect of treatment with insulin in people with diabetes. In the ReFleCT study, adults with type 1 (T1D) and type 2 diabetes (T2D) were asked to complete a diary for 12 months when their doctor changed their previous long-acting insulin treatment to insulin degludec (degludec). The key outcome of the study was whether the frequency of hypoglycaemia changed when a patient’s insulin treatment was switched. Here, we used the diary information from the ReFLeCT study to investigate whether the change in the rate of hypoglycaemia was related to the way hypoglycaemia was defined, or to patients’ characteristics at the time their insulin was switched. These characteristics included the length of time that patients had had diabetes, their blood sugar control, and their doctor’s reason for changing their medication. Our findings showed that the way hypoglycaemia was defined, and patients’ characteristics, did not generally influence the frequency of hypoglycaemia for patients with T1D or T2D. However, the most severe hypoglycaemia in patients with T2D occurred too infrequently to be assessed. Patients in all groups had less hypoglycaemia overall after switching compared with their previous treatment, suggesting that degludec may be a treatment option for a broad range of patients with diabetes. Electronic Supplementary Material The online version of this article (10.1007/s13300-020-00875-1) contains supplementary material, which is available to authorized users.

Background Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. Methods DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18–75 years and had inadequately controlled type 1 diabetes (HbA1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. Findings Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1c was 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA1c compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was −0·42% [95% CI −0·56 to −0·28; p

Uncontrolled activation of transforming growth factor beta (TGF-β) family members is hypothesized to participate in type 2 diabetes (T2D) dependent diabetic nephropathy (DN). We evaluated and compared downstream activation of the Smad2-signaling pathway in kidney samples from T2D patients to kidneys from the T2D model of leptin receptor deficient db/db mouse. Furthermore, expression of TGF-β family members was evaluated to elucidate molecular mechanisms in the mouse model. Kidney samples from patients with advanced stages of DN showed elevated pSmad2 staining whereas db/db mouse kidneys surprisingly showed a decrease in pSmad2 in the tubular compartment. Structurally, kidney tissue showed dilated tubules and expanded glomeruli, but no clear fibrotic pattern was found in the diabetic mice. Selective TGF-β family members were up-regulated at the mRNA level. Antagonists of bone morphogenetic protein (BMP) ligands, such as Gremlin1, USAG1 and Sclerostin, were strongly up-regulated suggesting a dampening effect on BMP pathways. Together, these results indicate a lack of translation from T2D patient kidneys to the db/db model with regards to Smad signaling pathway. It is plausible that a strong up-regulation of BMP antagonizing factors account for the lack of Smad1/5/8 activation, in spite of increased expression of several BMP members.

Mannan-binding lectin (MBL) has been reported to be involved in the pathophysiology of diabetic nephropathy. MBL is a pattern-recognition molecule of the innate immune system that initiates the lectin pathway of the complement system upon recognition of evolutionary conserved pathogen-associated molecular patterns or to altered self-tissue. Our group have previously shown direct effects of MBL on diabetes-induced kidney damage, and we hypothesized that MBL may cause autoactivation of the complement system via binding to neoepitopes induced by hyperglycemia. In the present study, we induced diabetes in MBL knockout mice and in wild type C57BL/6J mice by low-dose streptozotocin injection and measured blood glucose and urine albumin-to-creatinine ratio to monitor development of diabetes. After 24 weeks, fluorescently labelled recombinant MBL was injected intravenously in diabetic MBL knockout mice after which the distribution was investigated using in vivo fluorescence imaging. Mice were subjected to in vivo and ex vivo imaging 24 hours after injection. MBL was found to accumulate in the kidneys of diabetic mice as compared to healthy control mice (p<0.0001). These findings support the hypothesis of a significant role of MBL and the complement system in the pathophysiology of diabetic nephropathy.

Background: The role of transforming growth factor-β (TGF-β) has recently gained much attention in diabetic nephropathy and kidney fibrosis. In this study, we extend this to an assessment of transcriptional regulation of the entire TGF-β superfamily in kidneys from diabetic vs. healthy mice. In order to study the translation between mouse model and patients, we evaluated the signature of phosphorylated Sma- and Mad-related protein 2 (pSmad2), as molecular marker of TGF-β/activin activity, in the kidneys of streptozotocin (STZ)-treated mice compared to that of type 1 diabetes (T1D) patients. Methods: Patterns of pSmad2 were determined in kidneys from T1D patients with progressed diabetic nephropathy (DN), defined by hyperglycemia, microalbuminuria, and increased levels of serum creatinine. They were compared to changes seen in the STZ-induced DN mouse model. This was studied by immunohistochemistry (IHC) with an antibody specific for pSmad2. Diabetic mice were also characterized by pSmad1/5/8 (IHC), pSmad2/3 (flow cytometry), and TGF-β family members including bone morphogenetic protein (BMP)-like proteins (quantitative real-time polymerase chain reaction [qPCR]). Results: Renal tubules in DN patients and in STZ mice showed upregulation of pSmad2 concomitant with significantly enlarged distal tubule lumens (p < 0.0001). Renal-derived CD11b+ cells from STZ mice showed elevated pSmad2/3, while endothelial cells had reduced pSmad2/3 levels. No pSmad1/5/8 was observed in the tubule compartment of STZ-treated mice. On total kidney mRNA level, a signature favoring activation of the TGF-β/activin pathway and inhibition of the BMP pathway was demonstrated by qPCR. Conclusion: Although the pre-clinical DN model lacks the features of fibrosis present in human DN, both species show induction of a local milieu favoring pSmad2 signaling, which may be useful as a disease biomarker in pre-clinical models.

ReFLeCT was a multicenter, prospective, observational study designed to investigate the safety and effectiveness of switching to degludec from other basal insulins in patients with type 1 (T1D) or type 2 diabetes (T2D). ReFLeCT comprised a 4-week baseline period (pre-switch basal insulin) and 12-month follow-up period (degludec). The primary endpoint of overall hypoglycemia reported in patient diaries was reduced during follow-up vs. baseline in T1D and T2D without compromising glycemic control. As different hypoglycemia definitions can impact study outcomes, the previous (pre-specified) and updated (post hoc) American Diabetes Association (ADA) hypoglycemia definitions were analyzed and presented here (Figure). Definitions consisted of, documented asymptomatic and symptomatic, pseudo, probable symptomatic, and Level 1, 2 and 3 (severe) (Figure). Hypoglycemic events were analyzed using fully adjusted, negative binomial regression models. In T1D (n=556) and T2D (n=611), the estimated rate ratios across the previous and the updated ADA hypoglycemia definitions were significantly lower during the 12-month follow-up vs. baseline, except for asymptomatic hypoglycemia in T1D (Figure). Overall, switching to degludec from other basal insulins is associated with lower rates of hypoglycemia across a range of definitions. Disclosure H.W. de Valk: Advisory Panel; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. M. Feher: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. T.K. Hansen: None. J.H. Jendle: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Board Member; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Abbott, Dexcom, Inc., Medtronic, Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, Medtronic, Nordic Infucare, Novo Nordisk A/S, Sanofi. Á. Merchante: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Research & Development, Mundipharma International, Novo Nordisk A/S, Nutricia, Persan Pharma. Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S. M.M. Koefoed: Employee; Self; Novo Nordisk A/S. E. Parvaresh Rizi: Employee; Self; Nestlé, Novo Nordisk A/S. E. Zimmermann: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. G. Fadini: Consultant; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi. Funding Novo Nordisk A/S

Introduction: Diabetic retinopathy (DR) remains the leading cause of preventable vision loss in developed countries. Adverse activation of the complement system plays an essential role in development of complications in diabetes and has been demonstrated in eyes from patients with DR. We hypothesized that complement proteins of lectin pathway can predict severe DR, defined as proliferative DR and macular edema, in newly diagnosed type 1 diabetes. Methods: In this explorative study, incidence of severe DR was monitored in a cohort of newly diagnosed type 1 diabetes patients (n=270) with median follow-up time of 18 years (range 1-22 years). Baseline complement proteins MBL, M-ficolin, H-ficolin, MASP-1, MASP-2, MASP-3, MAp44, and MAp19 were quantified using immunoassays. A cox proportional hazards regression model was applied to test for difference between quantile groups and adjusted for age and HbA1c. Results: During follow-up, 28 patients developed severe DR. A tendency arose when testing association between MAp44 levels and severe DR in an unadjusted model (HR, 4th quartile vs. the remaining, 1.3; 95% CI 0.99, 1.6), p = 0.06), which became significant in the adjusted model (HR, 1.33; 95% CI 1.0, 1.7), p = 0.04), Fig. 1. Conclusion: MAp44 was significantly associated with development of severe DR, whereas other complement factors were not. Further analysis in a larger cohort is warranted. Disclosure C.B. Holt: None. I.T. Hoffmann-Petersen: None. J.A. østergaard: None. H.D. Parving: None. S. Thiel: None. P. Hovind: None. L. Tarnow: Stock/Shareholder; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk Foundation. P. Rossing: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novartis AG, Novo Nordisk A/S. T.K. Hansen: None. Funding Aarhus University; Foundation of Skibsredder Per Henriksen

ReFLeCT, a multicenter, prospective, observational study evaluated the safety and effectiveness of switching from other basal insulins to insulin degludec (degludec) in patients with type 1 (T1D) or type 2 diabetes (T2D) in routine clinical practice. ReFLeCT comprised a 4-week baseline period (pre-switch basal insulin) and 12-month follow-up period (degludec). The primary endpoint of overall hypoglycemia reported in patient diaries was reduced during the 12-month follow-up period vs. baseline, without compromising glycemic control. In pre-specified subgroup analyses of the primary endpoint, we assessed if the overall result was robust in different subgroups, characterized according to baseline A1C ( Disclosure H.W. de Valk: Advisory Panel; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. M. Feher: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. T.K. Hansen: None. J.H. Jendle: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Board Member; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Abbott, Dexcom, Inc., Medtronic, Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, Medtronic, Nordic Infucare, Novo Nordisk A/S, Sanofi. Á. Merchante: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Research & Development, Mundipharma International, Novo Nordisk A/S, Nutricia, Persan Pharma. Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S. M.M. Koefoed: Employee; Self; Novo Nordisk A/S. E. Parvaresh Rizi: Employee; Self; Nestlé, Novo Nordisk A/S. E. Zimmermann: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. G. Fadini: Consultant; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi. Funding Novo Nordisk A/S

BACKGROUND: Hypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes. The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia. The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial.METHODS/DESIGN: A Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms.DISCUSSION: In contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov : NCT02192450.