The Effect of Insulin Degludec Versus Insulin Glargine U100 on Glucose Metrics Recorded During Continuous Glucose Monitoring in People With Type 1 Diabetes and Recurrent Nocturnal Severe Hypoglycemia.

AIM: Comparing continuous glucose monitoring (CGM)-recorded metrics during treatment with insulin degludec (IDeg) versus insulin glargine U100 (IGlar-100) in people with type 1 diabetes (T1D) and recurrent nocturnal severe hypoglycemia. MATERIALS AND METHODS: This is a multicenter, two-year, randomized, crossover trial, including 149 adults with T1D and minimum one episode of nocturnal severe hypoglycemia within the last two years. Participants were randomized 1:1 to treatment with IDeg or IGlar-100 and given the option of six days of blinded CGM twice during each treatment. CGM traces were reviewed for the percentage of time-within-target glucose range (TIR), time-below-range (TBR), time-above-range (TAR), and coefficient of variation (CV). RESULTS: Seventy-four participants were included in the analysis. Differences between treatments were greatest during the night (23:00-06:59). Treatment with IGlar-100 resulted in 54.0% vs 49.0% with IDeg TIR (70-180 mg/dL) (estimated treatment difference [ETD]: -4.6%, 95% confidence interval [CI]: -9.1, -0.0, P = .049). TBR was lower with IDeg at level 1 (54-69 mg/dL) (ETD: -1.7% [95% CI: -2.9, -0.5], P < .05) and level 2 (<54 mg/dL) (ETD: -1.3% [95% CI: -2.1, -0.5], P = .001). TAR was higher with IDeg compared with IGlar-100 at level 1 (181-250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.3], P < .05) and level 2 (> 250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.2], P < .05). The mean CV was lower with IDeg than that with IGlar-100 (ETD: -3.4% [95% CI: -5.6, -1.2], P < .05). CONCLUSION: For people with T1D suffering from recurrent nocturnal severe hypoglycemia, treatment with IDeg, compared with IGlar-100, results in a lower TBR and CV during the night at the expense of more TAR.

ChatGPT- versus human-generated answers to frequently asked questions about diabetes: A Turing test-inspired survey among employees of a Danish diabetes center.

Large language models have received enormous attention recently with some studies demonstrating their potential clinical value, despite not being trained specifically for this domain. We aimed to investigate whether ChatGPT, a language model optimized for dialogue, can answer frequently asked questions about diabetes. We conducted a closed e-survey among employees of a large Danish diabetes center. The study design was inspired by the Turing test and non-inferiority trials. Our survey included ten questions with two answers each. One of these was written by a human expert, while the other was generated by ChatGPT. Participants had the task to identify the ChatGPT-generated answer. Data was analyzed at the question-level using logistic regression with robust variance estimation with clustering at participant level. In secondary analyses, we investigated the effect of participant characteristics on the outcome. A 55% non-inferiority margin was pre-defined based on precision simulations and had been published as part of the study protocol before data collection began. Among 311 invited individuals, 183 participated in the survey (59% response rate). 64% had heard of ChatGPT before, and 19% had tried it. Overall, participants could identify ChatGPT-generated answers 59.5% (95% CI: 57.0, 62.0) of the time, which was outside of the non-inferiority zone. Among participant characteristics, previous ChatGPT use had the strongest association with the outcome (odds ratio: 1.52 (1.16, 2.00), p = 0.003). Previous users answered 67.4% (61.7, 72.7) of the questions correctly, versus non-users' 57.6% (54.9, 60.3). Participants could distinguish between ChatGPT-generated and human-written answers somewhat better than flipping a fair coin, which was against our initial hypothesis. Rigorously planned studies are needed to elucidate the risks and benefits of integrating such technologies in routine clinical practice.

Effects of DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors and sulphonylureas on mortality, cardiovascular and renal outcomes in type 2 diabetes: A network meta-analyses-driven approach.

AIMS: The aim of our meta-analyses was to compare the effects of glucose-lowering drugs on mortality, cardiovascular and renal endpoints for a range of type 2 diabetes (T2D) subgroups defined by their specific cardiovascular risk profile. METHODS: Meta-analyses comparing drugs within the classes of GLP-1RAs and SGLT-2 inhibitors were performed and compared to sulphonylureas and DPP-4 inhibitors with available cardiovascular outcome trials. The comparison between the different classes of glucose-lowering drugs included analyses of T2D populations with low risk and high risk for cardiovascular disease including populations with established cardiovascular disease and/or kidney disease. Outcomes included mortality, major cardiovascular adverse events (MACE), hospitalisation for heart failure (HHF) and a composite renal endpoint as applied in the underlying clinical trials. RESULTS: SGLT-2 inhibitors and GLP-1RAs showed beneficial effects on mortality and MACE compared to the classes of DPP-4 inhibitors and sulphonylureas. SGLT-2 inhibitors were shown to be the most effective treatment in terms of HHF and kidney disease. Metformin was used as background therapy for the vast majority of participants in all included studies. Overall, the absolute effects of SGLT-2 inhibitors and GLP-1RAs on these important outcomes were evident for patients with established or at high risk for cardiovascular disease but limited for the low-risk subgroup. CONCLUSIONS: The findings from our analyses substantiate the relevance of treatment with SGLT-2 inhibitors or GLP-1RAs as an add-on to metformin in patients with T2D and a high risk for cardiovascular disease, and furthermore, support the recommendation for SGLT-2 inhibitor treatment in patients with T2D and heart failure or established kidney disease.

CRP, C-Peptide, and Risk of First-Time Cardiovascular Events and Mortality in Early Type 2 Diabetes: A Danish Cohort Study.

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 (<1 mg/L) hs-CRP was associated with increased CVE risk (aHR 1.45 [95% CI 1.07-1.96]) and with even greater risk of all-cause mortality (2.47 [1.88-3.25]). Compared with patients with low hs-CRP (≤3 mg/L) and low C-peptide (<1,470 pmol/L), those with high levels of both biomarkers had the highest CVE (1.61 [1.10-2.34]) and all-cause mortality risk (2.36 [1.73-3.21]). Among patients with high C-peptide, risk of CVEs did not differ by low or high hs-CRP, whereas risk of all-cause mortality did. 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.

Flexible patient-reported outcome-based telehealth follow-up for type 1 diabetes: A qualitative study.

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.

Effect of insulin degludec versus insulin glargine U100 on nocturnal glycaemia assessed by plasma glucose profiles in people with type 1 diabetes prone to nocturnal severe hypoglycaemia.

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.

Patient-reported outcome (PRO) measurements in chronic and malignant diseases: ten years' experience with PRO-algorithm-based patient-clinician interaction (telePRO) in AmbuFlex.

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.

Test-retest reliability and measurement error of the WHO-5 Well-being Index and the Problem Areas in Diabetes questionnaire (PAID) used in telehealth among patients with type 1 diabetes.

BACKGROUND: Patient-reported outcome (PRO) measures may be used in telehealth for the clinical assessment of mental health and diabetes distress, which are important aspects in diabetes care, but valid and reliable instruments on these topics are necessary. We aimed to evaluate the test-retest reliability and measurement error of the Danish versions of the WHO-Five Well-being Index (WHO-5) and Problem Areas in Diabetes (PAID) questionnaires used in a PRO-based telehealth intervention among patients with type 1 diabetes. A further aim was to evaluate the test-retest reliability of single items concerning patients' symptom burden and general health status. METHODS: Outpatients with type 1 diabetes from the Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark, were enrolled from April 2019 to June 2020. Patients aged ≥ 18 who had type 1 diabetes for > 1 year, internet access, and the ability to understand, read, and write Danish were included. Intraclass correlation coefficients (ICC) and weighted Kappa values were used to assess test-retest reliability, and measurement error was assessed by estimating the minimal detectable change (MDC). RESULTS: A total of 146/255 (57%) patients completed the web questionnaire twice. The median response time between the two-time points was five days. The ICC of the WHO-5 scale was 0.87 (95% CI 0.82-0.90), and MDC was 18.56 points (95% CI 16.65-20.99). The ICC of the PAID scale was 0.89 (95% CI 0.84-0.92), and MDC was 11.86 points (95% CI 10.46-13.70). Overall, test-retest reliability of single symptoms and general health status items was substantial. CONCLUSIONS: The WHO-5 and PAID questionnaires, and single symptoms and general health status items showed substantial test-retest reliability among patients with type 1 diabetes. Measurement error of the PAID questionnaire was considered acceptable; however, a larger measurement error of the WHO-5 questionnaire was observed. Further research is recommended to explore these findings.

Randomized controlled study to evaluate the impact of flexible patient-controlled visits in people with type 1 diabetes: The DiabetesFlex Trial.

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.

Hypoglycemia event prediction from CGM using ensemble learning.

This work sought to explore the potential of using standalone continuous glucose monitor (CGM) data for the prediction of hypoglycemia utilizing a large cohort of type 1 diabetes patients during free-living. We trained and tested an algorithm for the prediction of hypoglycemia within 40 minutes on 3.7 million CGM measurements from 225 patients using ensemble learning. The algorithm was also validated using 11.5 million synthetic CGM data. The results yielded a receiver operating characteristic area under the curve (ROC AUC) of 0.988 and a precision-recall area under the curve (PR AUC) of 0.767. In an event-based analysis for predicting hypoglycemic events, the algorithm had a sensitivity of 90%, a lead-time of 17.5 minutes and a false-positive rate of 38%. In conclusion, this work demonstrates the potential of using ensemble learning to predict hypoglycemia, using only CGM data. This could help alarm patients of a future hypoglycemic event so countermeasures can be initiated.

Glucose variability and low bone turnover in people with type 2 diabetes.

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.

The pattern-recognition molecule H-ficolin in relation to diabetic kidney disease, mortality, and cardiovascular events in type 1 diabetes.

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.

Anti-interleukin-21 antibody and liraglutide for the preservation of ß-cell function in adults with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Type 1 diabetes is characterised by progressive loss of functional ß-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve ß-cell function) could enable ß-cell survival with a reduced risk of complications compared with traditional immunomodulation. METHODS: This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual ß-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155. FINDINGS: Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA1c (a key secondary outcome) at week 54 was greater with all active treatments (-0·50 percentage points) than with placebo (-0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (<10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema). INTERPRETATION: The combination of anti-IL-21 and liraglutide could preserve ß-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme. FUNDING: Novo Nordisk.

Mannose-binding lectin and risk of infections in type 2 diabetes: A Danish cohort study.

AIMS: In individuals at increased risk of infections, e.g., patients with type 2 diabetes, low MBL may have detrimental effects. We used the Mendelian randomization principle to examine whether genetically low MBL is a risk factor for developing infections in patients with type 2 diabetes. METHODS: Serum MBL (n = 7305) and MBL genotype (n = 3043) were determined in a nationwide cohort of patients with new type 2 diabetes and up to 8 years follow-up for hospital-treated infections and community-based antimicrobial prescriptions. The associations were examined in spline and Cox regression analyses. RESULTS: 1140 patients (16%) were hospitalized with an infection and 5077 patients (70%) redeemed an antimicrobial prescription. For low (≤100 µg/L) versus intermediate (101-1000 µg/L) serum MBL concentration, the adjusted hazard ratios (aHRs) were 1.13(95% confidence interval, 0.96-1.33) for any hospital-treated infections and 1.19(1.01-1.41) for bacterial infections. Low MBL expression genotype was not associated with risk of any hospital-treated infections except for diarrheal diseases (aHR 2.23[1.04-4.80]). Low MBL expression genotype, but not low serum MBL, was associated with increased risk for antimicrobial prescriptions (aHR 1.18[1.04-2.34] and antibacterial prescriptions 1.20[1.05-1.36]). CONCLUSIONS: Low MBL is a weak causal risk factor for developing infections in patients with type 2 diabetes.

Benefit/risk profile of dapagliflozin 5 mg in the DEPICT-1 and -2 trials in individuals with type 1 diabetes and body mass index ≥27 kg/m2.

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.

Switching to Degludec is Associated with Reduced Hypoglycaemia, Irrespective of Definition Used or Patient Characteristics: Secondary Analysis of the ReFLeCT Prospective, Observational Study.

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.

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.

Mannose-Binding Lectin and Risk of Cardiovascular Events and Mortality in Type 2 Diabetes: A Danish Cohort Study.

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.

Complement Receptor 2 Based Immunoassay Measuring Activation of the Complement System at C3-Level in Plasma Samples From Mice and Humans.

We aimed at establishing a sensitive and robust assay for estimation of systemic complement activation at complement component C3 level in mouse and human plasma samples. In order to capture the activation products iC3b and C3dg in a specific and physiological relevant manner we utilized a construct consisting of the iC3b/C3dg-binding site of human complement receptor 2 (CR2) attached to an Fc-part of mouse IgG. This construct binds C3dg and iC3b from both mice and humans. We purified the CR2-IgG construct from mouse B myeloma cell line supernatants, J558L-CR2-IgG, by protein G affinity chromatography. The CR2-IgG construct was used for capturing C3 fragments in microtiter wells and an anti-mouse or an anti-human-C3 antibody was used for detection of bound C3 fragments. Initially we tested the specificity of the assays with the use of purified C3 fragments. Further, with the use of the CR2-based assay, we measured an up to three-fold higher signal in activated mouse serum as compared to non-activated mouse serum, whereas activated serum from a C3 knock-out mouse gave no signal. We tested in vivo generated samples from a mouse experiment; complement activation was induced by injecting cobra venom factor or heat aggregated IgG into C57bl6 mice, followed by withdrawal of EDTA blood samples at different time points and measurement of iC3b/C3dg. We observed a clear time-dependent distinction in signals between samples with expected high and low complement activation. Furthermore, with the use of the assay for human C3 fragments, we observed that patients with systemic lupus erythematosus (SLE) (n = 144) had significantly higher iC3b/C3dg levels as compared to healthy individuals (n = 144) (p < 0.0001). We present two functional immunoassays, that are able to measure systemic levels of the C3-activation products iC3b and C3dg in mice and humans. To our knowledge, these are the first assays for complement activation that use a physiological relevant capture construct such as CR2. These assays will be a relevant tool when investigating mouse models and human diseases involving the complement system.

Switching to Degludec From Other Basal Insulins Is Associated With Reduced Hypoglycemia Rates: A Prospective Study.

CONTEXT: Observational studies of insulin degludec (degludec) with hypoglycemia events prospectively recorded are lacking. OBJECTIVE: To evaluate the safety and effectiveness of degludec in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) switching from other basal insulins in routine care. DESIGN: Results From Real-World Clinical Treatment With Tresiba® was a multinational, multicenter, prospective, observational, single-arm study comprising a 4-week baseline period (preswitch basal insulin) and 12-month follow-up (degludec). SETTING: Routine clinical practice. PATIENTS OR OTHER PARTICIPANTS: Insulin-treated patients (≥18 years) with T1D (n = 556) or T2D (n = 611) with treatment plans to initiate degludec. INTERVENTIONS: Switching to degludec from other basal insulins. MAIN OUTCOME MEASURE: Change from baseline in number of overall hypoglycemic events recorded in patient diaries. RESULTS: In T1D, the 12-month follow-up/baseline rate ratios (95% CI) of overall [0.80 (0.74 to 0.88)], nonsevere [0.83 (0.76 to 0.91)], severe [0.28 (0.14 to 0.56)], and nocturnal [0.61 (0.50 to 0.73)] hypoglycemia suggested significantly lower hypoglycemia rates with degludec (all Ps < 0.001). At 12 months, HbA1c, fasting plasma glucose (FPG), and basal insulin dosage decreased significantly. Body weight increased, and treatment satisfaction improved significantly. In T2D, the hypoglycemia rate ratios were overall [0.46 (0.38 to 0.56)], nonsevere [0.53 (0.44 to 0.64)], and nocturnal [0.35 (0.20 to 0.62)] (all Ps < 0.001; too few events for analysis of severe hypoglycemia). At 12 months, HbA1c and FPG decreased significantly. Body weight and insulin dosages remained unchanged, and treatment satisfaction was significantly improved. CONCLUSIONS: In a routine clinical care setting, switching to degludec from other basal insulins was associated with significantly lower rates of hypoglycemia, improved glycemic control, and treatment satisfaction in patients with T1D or T2D.

The effect of insulin degludec on risk of symptomatic nocturnal hypoglycaemia in adults with type 1 diabetes and high risk of nocturnal severe hypoglycaemia (the HypoDeg trial): study rationale and design.

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.