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.

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.

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.

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.

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.

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.

The formation of quiescent glomerular endothelial cell monolayer in vitro is strongly dependent on the choice of extracellular matrix coating.

BACKGROUND AND AIMS: Nephropathy involves pathophysiological changes to the glomerulus. The primary glomerular endothelial cells (GEnCs) have emerged as an important tool for studying glomerulosclerotic mechanisms and in the screening process for drug-candidates. The success of the studies is dependent on the quality of the cell model. Therefore, we set out to establish an easy, reproducible model of the quiescent endothelial monolayer with the use of commercially available extracellular matrices (ECMs). METHODS: Primary hGEnCs were seeded on various ECMs. Cell adhesion was monitored by an impedance sensing system. The localization of junctional proteins was assessed by immunofluorescence and the barrier function by passage of fluorescent dextrans and magnitude of VEGF response. RESULTS: All ECM matrices except recombinant human laminin 111 (rhLN111) supported comparable cell proliferation. Culturing hGEnCs on rhLN521, rhLN511 or fibronectin resulted in a physiologically relevant barrier to 70kDa dextrans which was 82% tighter than that formed on collagen type IV. Furthermore, only hGEnCs cultured on rhLN521 or rhLN511 showed plasma-membrane localized zonula occludens-1 and vascular endothelial cadherin indicative of proper tight and adherens junctions (AJ). CONCLUSION: We recommend culturing hGEnCs on the mature glomerular basement membrane laminin - rhLN521 - which, as the only commercially available ECM, promotes all of the characteristics of the quiescent hGEnC monolayer: cobblestone morphology, well-defined AJs and physiological perm-selectivity.

Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes.

Increasing evidence links mannan-binding lectin (MBL) to late vascular complications of diabetes. MBL is a complement-activating pattern recognition molecule of the innate immune system that can mediate an inflammation response through activation of the lectin pathway. In two recent animal studies, we have shown that autoreactivity of MBL is increased in the kidney in diabetic nephropathy. We hypothesize that long-term exposure to uncontrolled high blood glucose in diabetes may mediate formation of neoepitopes in several tissues and that MBL is able to recognize these structures and thus activate the lectin pathway. To test this hypothesis, we induced diabetes by injection of low-dose streptozotocin in MBL double-knockout (MBL/DKO) mice. Development of diabetes was followed by measurements of blood glucose and urine albumin-to-creatinine ratio. Fluorophore-labelled recombinant MBL was injected intravenously in diabetic and nondiabetic mice followed by ex vivo imaging of several organs. We observed that MBL accumulated in the heart, liver, brain, lung, pancreas, and intestines of diabetic mice. We furthermore detected increased systemic complement activation after administration of MBL, thus indicating MBL-mediated systemic complement activation in these animals. These new findings indicate a global role of MBL during late diabetes-mediated vascular complications in various tissues.

Disparate phospho-Smad2 levels in advanced type 2 diabetes patients with diabetic nephropathy and early experimental db/db mouse model.

Uncontrolled activation of transforming growth factor beta (TGF-ß) 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-ß 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-ß 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.

Ficolin B in Diabetic Kidney Disease in a Mouse Model of Type 1 Diabetes.

BACKGROUND: The innate immune system may have adverse effects in diabetes and cardiovascular disease. The complement system seems to play a key role through erroneous complement activation via hyperglycaemia-induced neoepitopes. Recently mannan-binding lectin (MBL) was shown to worsen diabetic kidney changes. We hypothesize that mouse ficolin B exerts detrimental effects in the diabetic kidney as seen for MBL. METHODS: We induced diabetes with streptozotocin in female wild-type mice and ficolin B knockout mice and included two similar nondiabetic groups. Renal hypertrophy and excretion of urinary albumin and creatinine were quantified to assess diabetic kidney damage. RESULTS: In the wild-type groups, the kidney weighed 24% more in the diabetic mice compared to the controls. The diabetes-induced increase in kidney weight was 29% in the ficolin B knockout mice, that is, equal to wild-type animals (two-way ANOVA, P = 0.60). In the wild-type mice the albumin-to-creatinine ratio (ACR) was 32.5 mg/g higher in the diabetic mice compared to the controls. The difference was 62.5 mg/g in the ficolin B knockout mice, but this was not significantly different from the wild-type animals (two-way ANOVA, P = 0.21). CONCLUSIONS: In conclusion, the diabetes-induced effects on kidney weight and ACR were not modified by the presence or absence of ficolin B.

Heart rate variability in neurorehabilitation patients with severe acquired brain injury.

INTRODUCTION: Acquired brain injury (ABI) cause neural deficits. In addition to motor and cognitive deficits, the autonomic nervous system may be affected. This has been shown for neurorehabilitation patients with traumatic brain injury (TBI) by means of reduced heart rate variability (HRV). It was hypothesized that patient groups with other ABI aetiology (mainly stroke, subarachnoid haemorrhage and anoxia) would also present reduced HRV. METHODS: Patients consecutively admitted and severely ABI injured were considered for HRV measurements. HRV was extracted as a mean of four 5-minute ECG recordings at 6 pm, 10 pm, 2 am and 6 am the following day (scheduled resting periods). One 5-minute HRV recording from a sex- and age-matched group of healthy volunteers constituted control data. Standard deviation of normal-to-normal intervals (SDNN) and low frequency (LF) were primary HRV variables. RESULTS: Of 71 admitted patients, HRV was extracted from 49 patients. Patient SDNN and LF were reduced compared to controls (SDNN: 13 ms (CI = [10.8; 15.3]) vs 40.3 ms (CI = [36.6; 44.2]), p < 0.0001; LF: 29.4 ms² (CI = [19.8; 43.7]) vs 518 ms² (CI = [419; 639]), p < 0.0001). HRV appeared identical across ABI aetiology. CONCLUSION: It was found that HRV was considerably reduced in an heterogenic ABI patient group admitted for neurorehabilitation.

Plasma levels of the arterial wall protein fibulin-1 are associated with carotid-femoral pulse wave velocity: a cross-sectional study.

BACKGROUND: The arterial system in diabetic patients is characterized by generalized non-atherosclerotic alterations in the vascular extracellular matrix causing increased arterial stiffness compared with subjects without diabetes. The underlying pathophysiology remains elusive. The elastin-associated extracellular matrix protein, fibulin-1, was recently found in higher concentrations in the arterial wall and in plasma in patients with long duration type 2 diabetes. Furthermore, plasma fibulin-1 independently predicted total mortality and was associated with pulse pressure, an indirect measure of arterial stiffness. Whether plasma fibulin-1 is associated with arterial stiffness at earlier phases of type 2 diabetes has not been determined. METHODS: In this cross-sectional study, we examined 90 patients with recently diagnosed type 2 diabetes (< 5 years) and 90 gender- and age-matched controls. Plasma fibulin-1 was measured immunochemically. Arterial stiffness was assessed by carotid-femoral Pulse Wave Velocity (PWV). Differences in means were assessed by t-tests. Associations were assessed by multivariate regression analyses. RESULTS: Plasma fibulin-1 levels were lower in the diabetic group compared with the control group, 93 ± 28 vs 106 ± 30 µg/mL, p = 0.005. In unadjusted analysis of the total study sample, plasma fibulin-1 was not associated with PWV, p = 0.46. However, with adjustment for the confounders age, gender, mean blood pressure, heart rate, body mass index, diabetes and glomerular filtration rate, a 10 µg/mL increase in plasma fibulin was associated with 0.09 ± 0.04 m/s increase in PWV, p < 0.05. In subgroup analysis, plasma fibulin-1 was associated with PWV in the diabetes group, (0.16 ± 0.07 m/s increase in PWV per 10 µg/mL increase in plasma fibulin-1, p<0.05), but not controls, ß = 0.021 ± 0.057 m/s per 10 µg/mL, p = 0.70. The association remained significant in the diabetes group after adjustment for covariates, p < 0.05. CONCLUSIONS: Plasma fibulin-1 is independently associated with PWV. Yet, as the plasma level of fibulin-1 was lower in patients with recently diagnosed type 2 diabetes than in healthy controls, plasma fibulin-1 levels are not a simple marker of the degree of arterial stiffening. Further studies are needed to determine the exact role of fibulin-1 in arterial stiffness and cardiovascular risk in patients with type 2 diabetes.

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.

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.

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.

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.

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.

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.

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.