The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults.

AIMS/HYPOTHESIS: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual's clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. METHODS: Data were collected from the large INNODIA cohort of individuals (aged 1.0-45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10-17 years; and ≥18 years. RESULTS: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0-382.0) pmol/l (AUC 749.3 [466.2-1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). CONCLUSIONS/INTERPRETATION: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline.

Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.

Towards the standardisation of adult person-reported outcome domains in diabetes research: A Consensus Statement development panel.

Diabetes is unique among chronic diseases because clinical outcomes are intimately tied to how the person living with diabetes reacts to and implements treatment recommendations. It is further characterised by widespread social stigma, judgement and paternalism. This physical, social and psychological burden collectively influences self-management behaviours. It is widely recognised that the individual's perspective about the impact of trying to manage the disease and the burden that self-management confers must be addressed to achieve optimal health outcomes. Standardised, rigorous assessment of mental and behavioural health status, in interaction with physical health outcomes is crucial to aid understanding of person-reported outcomes (PROs). Whilst tempting to conceptualise PROs as an issue of perceived quality of life (QoL), in fact health-related QoL is multi-dimensional and covers indicators of physical or functional health status, psychological and social well-being. This complexity is illuminated by the large number of person reported outcome measures (PROMs) that have been developed across multiple psychosocial domains. Often measures are used inappropriately or because they have been used in the scientific literature rather than based on methodological or outcome assessment rigour. Given the broad nature of psychosocial functioning/mental health, it is important to broadly define PROs that are evaluated in the context of therapeutic interventions, real-life and observational studies. This report summarises the central themes and lessons derived in the assessment and use of PROMs amongst adults with diabetes. Effective assessment of PROMs routinely in clinical research is crucial to understanding the true impact of any intervention. Selecting appropriate measures, relevant to the specific factors of PROs important in the research study will provide valuable data alongside physical health data.

An analysis of DPV and DIVE registry patients with chronic kidney disease according to the finerenone phase III clinical trial selection criteria.

BACKGROUND: The FIDELIO-DKD and FIGARO-DKD randomized clinical trials (RCTs) showed finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), reduced the risk of renal and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Using RCT inclusion and exclusion criteria, we analyzed the RCT coverage for patients with T2DM and CKD in routine clinical practice in Germany. METHODS: German patients from the DPV/DIVE registries who were ≥ 18 years, had T2DM and CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2 OR eGFR ≥ 60 mL/min/1.73m2 and albuminuria [≥ 30 mg/g]) were included. RCT inclusion and exclusion criteria were then applied, and the characteristics of the two populations compared. RESULTS: Overall, 65,168 patients with T2DM and CKD were identified from DPV/DIVE. Key findings were (1) Registry patients with CKD were older, less often male, and had a lower eGFR, but more were normoalbuminuric vs the RCTs. Cardiovascular disease burden was higher in the RCTs; diabetic neuropathy, lipid metabolism disorders, and peripheral arterial disease were more frequent in the registry. CKD-specific drugs (e.g., angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blocker [ARBs]) were used less often in clinical practice; (2) Due to the RCT's albuminuric G1/2 to G4 CKD focus, they did not cover 28,147 (43.2%) normoalbuminuric registry patients, 4,519 (6.9%) albuminuric patients with eGFR < 25, and 6,565 (10.1%) patients with microalbuminuria but normal GFR (≥ 90 ml/min); 3) As RCTs required baseline ACEi or ARB treatment, the number of comparable registry patients was reduced to 28,359. Of these, only 12,322 (43.5%) registry patients fulfilled all trial inclusion and exclusion criteria. Registry patients that would have been eligible for the RCTs were more often male, had higher eGFR values, higher rates of albuminuria, more received metformin, and more SGLT-2 inhibitors than patients that would not be eligible. CONCLUSIONS: Certain patient subgroups, especially non-albuminuric CKD-patients, were not included in the RCTs. Although recommended by guidelines, there was an undertreatment of CKD-patients with renin-angiotensin system (RAS) blockers. Further research into patients with normoalbuminuric CKD and a wider prescription of RAS blocking agents for CKD patients in clinical practice appears warranted.

Continuous glucose monitoring-based time-in-range using insulin glargine 300 units/ml versus insulin degludec 100 units/ml in type 1 diabetes: The head-to-head randomized controlled InRange trial.

AIM: To use continuous glucose monitoring (CGM)-based time-in-range (TIR) as a primary efficacy endpoint to compare the second-generation basal insulin (BI) analogues insulin glargine 300 U/ml (Gla-300) and insulin degludec 100 U/ml (IDeg-100) in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: InRange was a 12-week, multicentre, randomized, active-controlled, parallel-group, open-label study comparing glucose TIR and variability between Gla-300 and IDeg-100 using blinded 20-day CGM profiles. The inclusion criteria consisted of adults with T1D treated with multiple daily injections, using BI once daily and rapid-acting insulin analogues for at least 1 year, with an HbA1c of 7% or higher and of 10% or less at screening. RESULTS: Overall, 343 participants were randomized: 172 received Gla-300 and 171 IDeg-100. Non-inferiority (10% relative margin) of Gla-300 versus IDeg-100 was shown for the primary endpoint (percentage TIR ≥ 70 to ≤ 180 mg/dl): least squares (LS) mean (95% confidence interval) 52.74% (51.06%, 54.42%) for Gla-300 and 55.09% (53.34%, 56.84%) for IDeg-100; LS mean difference (non-inferiority): 3.16% (0.88%, 5.44%) (non-inferiority P = .0067). Non-inferiority was shown on glucose total coefficient of variation (main secondary endpoint): LS mean 39.91% (39.20%, 40.61%) and 41.22% (40.49%, 41.95%), respectively; LS mean difference (non-inferiority) -5.44% (-6.50%, -4.38%) (non-inferiority P < .0001). Superiority of Gla-300 over IDeg-100 was not shown on TIR. Occurrences of self-measured and CGM-derived hypoglycaemia were comparable between treatment groups. Safety profiles were consistent with known profiles, with no unexpected findings. CONCLUSIONS: Using clinically relevant CGM metrics, InRange shows that Gla-300 is non-inferior to IDeg-100 in people with T1D, with comparable hypoglycaemia and safety profiles.

Ultra rapid lispro showed greater reduction in postprandial glucose versus Humalog in children, adolescents and adults with type 1 diabetes mellitus.

AIM: This study compared the pharmacokinetics, glucodynamics and tolerability following single subcutaneous doses of ultra rapid lispro (URLi) versus Humalog in children (6-11 years), adolescents (12-17 years) and adults (18-64 years) with type 1 diabetes mellitus (T1D). MATERIALS AND METHODS: The study was a randomized, two-period, subject- and investigator-blind, crossover design in participants with T1D. Participants received a 0.2 U/kg bolus dose immediately before a liquid mixed meal tolerance test. Insulin lispro and glucose concentrations were measured. RESULTS: The study included 13 children, 14 adolescents and 15 adults. Consistently across the age groups, onset of appearance was 4-5 min faster, the early 50% tmax was reduced by 7-13 min, and exposure in the first 15 min was increased by 3.5-6.5-fold following URLi compared with Humalog (all p < .01). Exposure after 3 h was decreased by 37-58% (p = .02) and the duration was reduced by 56 min (p = .006) in children and 36 min (p = .022) in adolescents with URLi compared with Humalog. The maximum and overall exposure were similar between treatments. Postprandial glucose at 1 h was reduced by 42 mg/dl in children (p = .008), 19 mg/dl (p = .195) in adolescents and 34 mg/dl (p = .018) in adults following URLi versus Humalog. The glucose excursion during a 5-h test meal period was reduced by 16% in children and 9% in adolescents compared with Humalog. URLi was well tolerated in all age groups. CONCLUSIONS: URLi showed an accelerated insulin lispro absorption and greater postprandial glucose reduction compared with Humalog in children, adolescents and adults with T1D.

Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol in type 1 diabetes and type 2 diabetes: Lipid goal attainment in a large German-Austrian diabetes registry.

AIM: To assess the implementation of the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline recommendations for lipid-lowering therapies among more than 30 000 patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) in a German and Austrian registry from 2020 to 2022. MATERIALS AND METHODS: Registry data from 2020 and 2021 of 32 170 adult patients (8314 patients with T1D and 23 856 with T2D) were stratified according to the 2019 ESC/EAS risk categories, and guideline-based low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) goal attainment was analysed. RESULTS: In patients with T1D (median age 38.35 [20.51-57.13] years), overall statin use was 19.3%, ezetimibe use was 2.2% and the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors or fibrates was less than 1%. In patients with T2D (median age 68.76 [58.86-78.39] years), 45.7% received statins, 3.4% received ezetimibe, and fibrates and PCSK9 inhibitors were used by 1% and 0.1%, respectively. Among patients with T1D, 6.16% reached their risk-based recommended LDL-C goal of less than 55 mg/dL (very high risk), 10.97% of less than 70 mg/dL (high risk), and 69.50% of less than 100 mg/dL (moderate risk), respectively. In patients with T2D, 11.81% reached their risk-based goal of LDL-C less than 55 mg/dL, 16.25% of less than 70 mg/dL, and 51.33% of less than 100 mg/dL. Non-HDL-C goals were reached more often, with 15.3%, 25.52% and 91.61% in patients with T1D and 18.56%, 17.96% and 82.30% in patients with T2D for very high, high and moderate risk, respectively. CONCLUSION: Approximately 2 years after publication of the guidelines, LDL-C and non-HDL-C goal attainment was rarely achieved in patients with T1D and T2D with a high or very high cardiovascular risk.

Validation of a risk prediction model for early chronic kidney disease in patients with type 2 diabetes: Data from the German/Austrian Diabetes Prospective Follow-up registry.

AIM: To validate a recently proposed risk prediction model for chronic kidney disease (CKD) in type 2 diabetes (T2D). MATERIALS AND METHODS: Subjects from the German/Austrian Diabetes Prospective Follow-up (DPV) registry with T2D, normoalbuminuria, an estimated glomerular filtration rate of 60 ml/min/1.73m2 or higher and aged 39-75 years were included. Prognostic factors included age, body mass index (BMI), smoking status and HbA1c. Subjects were categorized into low, moderate, high and very high-risk groups. Outcome was CKD occurrence. RESULTS: Subjects (n = 10 922) had a mean age of 61 years, diabetes duration of 6 years, BMI of 31.7 kg/m2 , HbA1c of 6.9% (52 mmol/mol); 9.1% had diabetic retinopathy and 16.3% were smokers. After the follow-up (~59 months), 37.4% subjects developed CKD. The area under the curve (AUC; unadjusted base model) was 0.58 (95% CI 0.57-0.59). After adjustment for diabetes and follow-up duration, the AUC was 0.69 (95% CI 0.68-0.70), indicating improved discrimination. After follow-up, 15.0%, 20.1%, 27.7% and 40.2% patients in the low, moderate, high and very high-risk groups, respectively, had developed CKD. Increasing risk score correlated with increasing cumulative risk of incident CKD over a median of 4.5 years of follow-up (P < .0001). CONCLUSIONS: The predictive model achieved moderate discrimination but good calibration in a German/Austrian T2D population, suggesting that the model may be relevant for determining CKD risk.

Integrated safety and efficacy analysis of dasiglucagon for the treatment of severe hypoglycaemia in individuals with type 1 diabetes.

AIMS: To perform an integrated analysis of the safety and efficacy of dasiglucagon, a glucagon analogue available in a ready-to-use aqueous formulation, to treat severe hypoglycaemia (SH) in type 1 diabetes (T1D). MATERIALS AND METHODS: An integrated analysis of dasiglucagon safety was conducted on data from two placebo-controlled trials (placebo-controlled pool) and two placebo-controlled and four non-placebo-controlled trials (broad pool) in adults with T1D. An integrated analysis of dasiglucagon efficacy was conducted of pooled data and within demographic subgroups from the two placebo-controlled and two non-placebo-controlled trials in adults with T1D. RESULTS: Dasiglucagon had a similar safety and tolerability profile to that of reconstituted glucagon. In the placebo-controlled datasets, no serious adverse events (AEs), AEs leading to withdrawal from the trial, or deaths were reported. The most common causally related AEs were nausea (56.5%) and vomiting (24.6%). The broad pool safety analysis showed similar results. Dasiglucagon efficacy in time to plasma glucose recovery from insulin-induced SH was similar to that of reconstituted glucagon (median 10.0 and 12.0 minutes, respectively) and superior to placebo (median 40.0 minutes; P < 0.0001). The median recovery time was consistent across all placebo-controlled trial subgroups. CONCLUSIONS: Dasiglucagon was well tolerated and effective as a rapid rescue agent for insulin-induced SH in people with T1D.

Intermittent Use of Continuous Glucose Monitoring: A New Paradigm in Treatment of Type 2 Diabetes.

OBJECTIVES: To suggest how continuous glucose monitoring (CGM) may be used intermittently in individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: The use of CGM is largely in those with type 1 diabetes (T1D), in whom it makes sense to use CGM continuously as CGM provides a valuable tool to not only adjust their insulin doses but also to match it with their diet, physical activity, and other lifestyle modifications. In the case of T2D, however, especially for those not on insulin, the use of CGM may not be needed on a continuous basis. The use of CGM on an intermittent basis is rarely discussed in the literature. This article tries to provide clinical situations where CGM can be used intermittently. RESULTS: Intermittent use of CGM defined as the "use of CGM once in 2 or 3 months or a fixed frequency," and may be useful in several situations in those with T2D. We suggest the following indications for the intermittent use of CGM in T2D-newly diagnosed patients where treatment is being started, uncontrolled diabetes where treatment is being altered, starting intensive lifestyle modification, during infections, during preoperative control, in children and adolescents with T2D, as a motivational tool to improve behavioral modification, after metabolic surgery, and in patients on steroids, apart from other indications. CONCLUSION: Intermittent use of CGM in T2D can be useful in special situations and can also be cost saving particularly in resource-constrained regions of the world.

A comparison of two hybrid closed-loop systems in adolescents and young adults with type 1 diabetes (FLAIR): a multicentre, randomised, crossover trial.

BACKGROUND: Management of type 1 diabetes is challenging. We compared outcomes using a commercially available hybrid closed-loop system versus a new investigational system with features potentially useful for adolescents and young adults with type 1 diabetes. METHODS: In this multinational, randomised, crossover trial (Fuzzy Logic Automated Insulin Regulation [FLAIR]), individuals aged 14-29 years old, with a clinical diagnosis of type 1 diabetes with a duration of at least 1 year, using either an insulin pump or multiple daily insulin injections, and glycated haemoglobin (HbA1c) levels of 7·0-11·0% (53-97 mmol/mol) were recruited from seven academic-based endocrinology practices, four in the USA, and one each in Germany, Israel, and Slovenia. After a run-in period to teach participants how to use the study pump and continuous glucose monitor, participants were randomly assigned (1:1) using a computer-generated sequence, with a permuted block design (block sizes of two and four), stratified by baseline HbA1c and use of a personal MiniMed 670G system (Medtronic) at enrolment, to either use of a MiniMed 670G hybrid closed-loop system (670G) or the investigational advanced hybrid closed-loop system (Medtronic) for the first 12-week period, and then participants were crossed over with no washout period, to the other group for use for another 12 weeks. Masking was not possible due to the nature of the systems used. The coprimary outcomes, measured with continuous glucose monitoring, were proportion of time that glucose levels were above 180 mg/dL (>10·0 mmol/L) during 0600 h to 2359 h (ie, daytime), tested for superiority, and proportion of time that glucose levels were below 54 mg/dL (<3·0 mmol/L) calculated over a full 24-h period, tested for non-inferiority (non-inferiority margin 2%). Analysis was by intention to treat. Safety was assessed in all participants randomly assigned to treatment. This trial is registered with ClinicalTrials.gov, NCT03040414, and is now complete. FINDINGS: Between June 3 and Aug 22, 2019, 113 individuals were enrolled into the trial. Mean age was 19 years (SD 4) and 70 (62%) of 113 participants were female. Mean proportion of time with daytime glucose levels above 180 mg/dL (>10·0 mmol/L) was 42% (SD 13) at baseline, 37% (9) during use of the 670G system, and 34% (9) during use of the advanced hybrid closed-loop system (mean difference [advanced hybrid closed-loop system minus 670G system] -3·00% [95% CI -3·97 to -2·04]; p<0·0001). Mean 24-h proportion of time with glucose levels below 54 mg/dL (<3·0 mmol/L) was 0·46% (SD 0·42) at baseline, 0·50% (0·35) during use of the 670G system, and 0·46% (0·33) during use of the advanced hybrid closed-loop system (mean difference [advanced hybrid closed-loop system minus 670G system] -0·06% [95% CI -0·11 to -0·02]; p<0·0001 for non-inferiority). One severe hypoglycaemic event occurred in the advanced hybrid closed-loop system group, determined to be unrelated to study treatment, and none occurred in the 670G group. INTERPRETATION: Hyperglycaemia was reduced without increasing hypoglycaemia in adolescents and young adults with type 1 diabetes using the investigational advanced hybrid closed-loop system compared with the commercially available MiniMed 670G system. Testing an advanced hybrid closed-loop system in populations that are underserved due to socioeconomic factors and testing during pregnancy and in individuals with impaired awareness of hypoglycaemia would advance the effective use of this technology FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.

Universal screening for familial hypercholesterolemia in 2 populations.

PURPOSE: In Europe, >2 million individuals with familial hypercholesterolemia (FH) are currently undiagnosed. Effective screening strategies for FH diagnosis in childhood are urgently needed. We assessed the overall performances of 2 different FH screening programs in children: universal screening program with opt-out and opt-in type participation. METHODS: We analyzed the data from 2 independent populations based on >166,000 individuals screened for hypercholesterolemia. Genetic analyses of FH-related genes were finalized in 945 children and 99 parents. RESULTS: A total of 305 (32.3%) children were genotyped as positive or with a variant of uncertain significance in FH-related genes. For low-density lipoprotein cholesterol levels of 3.5 mmol L (135.3 mg/dL), the overall sensitivity and specificity for confirming FH were 90.5% and 55.3%, respectively. As part of child-parent screening, in >90% of the families, the parent with reported higher cholesterol levels was positive for the familial genetic variant. The cohort-based prevalence of FH from the opt-out universal screening program was estimated to be 1 in 431 individuals (95% CI = 1/391-1/472). CONCLUSION: Universal 3-step FH screening approach in children enabled detection of most children and their parents in every generation screened at reasonable costs. Opt-out screening strategy might be preferable over opt-in screening strategy.

The automated pancreas: A review of technologies and clinical practice.

Insulin pumps and glucose sensors are effective in improving diabetes therapy and reducing acute complications. The combination of both devices using an algorithm-driven interoperable controller makes automated insulin delivery (AID) systems possible. Many AID systems have been tested in clinical trials and have proven safety and effectiveness. However, currently, none of these systems are available for routine use in children younger than 6 years in Europe. For continued use, both users and prescribers must have sound knowledge of the features of the individual AID systems. Presently, all systems require various user interactions (e.g. meal announcements) because fully automated systems are not yet developed. Open-source systems are non-regulated variants to circumvent existing regulatory conditions. There are risks here for both users and prescribers. To evaluate AID therapy, the metric data of the glucose sensors, 'time in target range' and 'glucose management index', are novel recognized and suitable parameters allowing a consultation based on real glucose and insulin pump download data from the daily life of people with diabetes. Read out via cloud-based software or automatic download of such individual treatment data provides the ideal technical basis for shared decision-making through telemedicine, which must be further evaluated for general use.

In-home use of a hybrid closed loop achieves time-in-range targets in preschoolers and school children: Results from a randomized, controlled, crossover trial.

AIM: To obtain additional information on the incremental differences between using a sensor-augmented pump (SAP) without automated insulin delivery (AID), using it with predictive low-glucose management (PLGM) or as hybrid closed loop (HCL), in preschool and school children. METHODS: We conducted a monocentric, randomized, controlled, two-phase crossover study in 38 children aged 2-6 and 7-14 years. The primary endpoint was the percentage of time in range (TIR) of 70-180 mg/dl. Other continuous glucose sensor metrics, HbA1c, patient-related outcomes (DISABKIDS questionnaire, Fear of Hypoglycaemia Survey) and safety events were also assessed. Results from 2 weeks of SAP, 8 weeks of PLGM and 8 weeks of HCL were compared using a paired t-test or Wilcoxon signed-rank test. RESULTS: Overall, we found a high rate of TIR target (>70%) achievement with HCL in preschool (88%) and school children (50%), with average times in Auto Mode of 93% and 87%, respectively. Preschool children achieved a mean TIR of 73% ± 6% (+8% vs. SAP, +6% vs. PLGM) and school children 69% ± 8% (+15% vs. SAP and + 14% vs. PLGM). Overall, HbA1c improved from 7.4% ± 0.9% to 6.9% ± 0.5% (P = .0002). Diabetes burden and worries and fear of hypoglycaemia remained at low levels, without significant changes versus PLGM. No events of severe hypoglycaemia or diabetic ketoacidosis occurred. CONCLUSIONS: Preschool children profit from AID at least as much as those aged 7 years and older. To ensure safe use and prescribing modalities, regulatory approval is also required for young children.

Twenty years of the International Society for Pediatric and Adolescent Diabetes Science Schools programs: Assessment of their impact on the participants' personal careers and networking development.

OBJECTIVE: The following report describes the evaluation of the ISPAD Science School for Physicians (ISSP) and for Healthcare Professionals (ISSHP) in terms of their efficiency and success. METHODS: All past attendees from 2000-2019 ISSP and 2004-2019 ISSHP programs were invited to respond to an online survey to assess perceived outcomes of the programs on career development, scientific enhancement, scientific networking, and social opportunities. RESULTS: One-third of the past ISSP (129/428), and approximately 43% of the past ISSHP attendees (105/245) responded to the surveys. Most of ISSP attendees reported that the programs supported their career (82%) by helping to achieve a research position (59%), being engaged with diabetes care (68%) or research (63%) or starting a research fellowship (59%). Responders indicated that ISSP was effective in increasing interest in diabetes research (87%) and enhancing the number (66%) and quality (83%) of scientific productions, and promotion of international collaborations (86%). After the ISSP, 34% of responders received research grants. From the first round of the ISSHP survey (2004-2013), responders reported have improved knowledge (60%), gained more confidence in research (69%), undertaken a research project (63%), and achieved a higher academic degree (27%). From the second round (2014-2019), participants indicated that the program was valuable/useful in workplace (94%) through understanding (89%) and conducting (68%) research and establishing communication from other participants (64%) or from faculty (42%). After the ISSHP, 17% had received awards. CONCLUSIONS: From the participants' viewpoint, both programs were effective in improving engagement with diabetes research, supporting career opportunities, increasing scientific skills, and enhancing networking and research activities.

Efficacy and safety of adding sotagliflozin, a dual sodium-glucose co-transporter (SGLT)1 and SGLT2 inhibitor, to optimized insulin therapy in adults with type 1 diabetes and baseline body mass index ≥ 27 kg/m2.

Sotagliflozin, a dual sodium-glucose co-transporter (SGLT)1/SGLT2 inhibitor, is currently approved in Europe as an adjunct to optimal insulin therapy in adults with type 1 diabetes (T1D) and a body mass index (BMI) ≥ 27 kg/m2 . In this post hoc analysis, efficacy at 24 weeks and safety at 52 weeks from pooled phase 3 clinical trials were evaluated in patients with baseline BMI ≥ 27 kg/m2 . Sotagliflozin 200 mg and 400 mg added to insulin reduced glycated haemoglobin level and increased time in range assessed by continuous glucose monitoring versus placebo and also reduced body weight and systolic blood pressure. Differences in efficacy endpoints between sotagliflozin and placebo tended to be greater among patients with BMI ≥ 27 kg/m2 compared to those with baseline BMI < 27 kg/m2 . Consistent with published results for the entire population, fewer severe hypoglycaemia and documented hypoglycaemia ≤3.1 mmol/L events and a higher incidence of diabetic ketoacidosis occurred with sotagliflozin versus placebo in patients with BMI ≥ 27 kg/m2 . Sotagliflozin as an adjunct to optimized insulin therapy in overweight/obese patients with T1D addressed some unmet needs and may help achieve optimal glycaemic control, mitigating weight gain without increasing hypoglycaemia risk in this high-risk population.

Add-on therapy with dapagliflozin under full closed loop control improves time in range in adolescents and young adults with type 1 diabetes: The DAPADream study.

AIM: To investigate the effect of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on glucose levels overnight and during the following day after two unannounced meals under full closed loop (FCL) conditions. MATERIALS AND METHODS: For this single-centre, double-blind, randomized, placebo-controlled, cross-over trial, non-obese persons with type 1 diabetes (T1D) were studied twice (10 mg dapagliflozin bid vs. placebo) for 24 hours with two unannounced mixed meal tests 6 hours apart under FCL conditions. Primary outcome was sensor glucose time in range (TIR; 3.9-10 mmol/L). For safety evaluation, ß-hydroxybutyrate (BHB), glucagon, insulin and gastric inhibitory polypeptide were measured. RESULTS: Fifteen adolescents (aged 15.4 ± 1.6 years, diabetes duration 10.0 ± 3.4 years, HbA1c 8.4% ± 0.9% [67.7 ± 10.1 mmol/mol]) and 15 young adults (aged 18.7 ± 0.8 years; diabetes duration 12.5 ± 3.6 years; HbA1c 8.3% ± 0.9% [68.5 ± 11.2 mmol/mol]) completed the trial. TIR was significantly higher in the intervention group compared with placebo (68% ± 6% vs. 50% ± 13%; P < .001); nocturnal glucose was significantly lower with dapagliflozin (6.2 ± 0.7 vs. 7.3 ± 1.7 mmol/L; P = .003) without an increase in time at less than 3.9 mmol/L (3.3% ± 6.0% vs 3.1% ± 5.2%; P = .75). Urinary glucose excretion was increased 3-fold using dapagliflozin (149 ± 42 vs. 49 ± 23 g/24 hours) with a total insulin reduction of 22% (39.7 ± 12.7 vs. 30.6 ± 10.4 U; P = .004). No abnormal elevated BHB values were observed. CONCLUSIONS: In adolescents and adults with T1D, dapagliflozin significantly increased TIR on average by 259 minutes/day while reducing glycaemic variability during FCL control without any signs of hypoglycaemia or ketosis.

Dasiglucagon, a next-generation ready-to-use glucagon analog, for treatment of severe hypoglycemia in children and adolescents with type 1 diabetes: Results of a phase 3, randomized controlled trial.

BACKGROUND: Dasiglucagon, a next-generation, ready-to-use aqueous glucagon analog formulation, has been developed to treat severe hypoglycemia in individuals with diabetes. OBJECTIVE: The aim of this trial was to evaluate the safety and efficacy of dasiglucagon in pediatric individuals with type 1 diabetes (T1DM). Participants were children and adolescents (6-17 years) with T1DM. METHODS: In this randomized double-blind trial, 42 participants were randomly allocated (2:1:1) to a single subcutaneous (SC) injection of dasiglucagon (0.6 mg), placebo, or reconstituted glucagon (GlucaGen; dosed per label) during insulin-induced hypoglycemia. The primary endpoint was time to plasma glucose (PG) recovery (first PG increase ≥20 mg/dL after treatment initiation without rescue intravenous glucose). The primary comparison was dasiglucagon vs. placebo; glucagon acted as a reference. RESULTS: The median time (95% confidence interval) to PG recovery following SC injection was 10 min (8-12) for dasiglucagon vs. 30 min (20 to -) for placebo (P < .001); the median time for glucagon was 10 min (8-12), which did not include the time taken to reconstitute the lyophilized powder. PG recovery was achieved in all participants in the dasiglucagon and glucagon groups within 20 min of dosing compared to 2 out of 11 patients (18%) with placebo. The most frequent adverse events were nausea and vomiting, as expected with glucagon treatment. CONCLUSIONS: Consistent with adult phase 3 trials, dasiglucagon rapidly and effectively restored PG levels following insulin-induced hypoglycemia in children and adolescents with T1DM, with an overall safety profile similar to glucagon.

Guidelines adherence in the prevention and management of chronic kidney disease in patients with diabetes mellitus on the background of recent European recommendations - a registry-based analysis.

BACKGROUND: Recent European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) guidelines provide recommendations for detecting and treating chronic kidney disease (CKD) in diabetic patients. We compared clinical practice with guidelines to determine areas for improvement. METHODS: German database analysis of 675,628 patients with type 1 or type 2 diabetes, with 134,395 included in this analysis. Data were compared with ESC/EASD recommendations. RESULTS: This analysis included 17,649 and 116,747 patients with type 1 and type 2 diabetes, respectively. The analysis showed that 44.1 and 49.1 % patients with type 1 and type 2 diabetes, respectively, were annually screened for CKD. Despite anti-diabetic treatment, only 27.2 % patients with type 1 and 43.5 % patients with type 2 achieved a target HbA1c of < 7.0 %. Use of sodium-glucose transport protein 2 inhibitors (1.5 % type 1/8.7 % type 2 diabetes) and glucagon-like peptide-1 receptor agonists (0.6 % type 1/5.2 % type 2 diabetes) was limited. Hypertension was controlled according to guidelines in 41.1 and 67.7 % patients aged 18-65 years with type 1 and 2 diabetes, respectively, (62.4 vs. 68.4 % in patients > 65 years). Renin angiotensin aldosterone inhibitors were used in 24.0 and 40.9 % patients with type 1 diabetes (micro- vs. macroalbuminuria) and 39.9 and 47.7 %, respectively, in type 2 diabetes. CONCLUSIONS: Data indicate there is room for improvement in caring for diabetic patients with respect to renal disease diagnosis and treatment. While specific and potentially clinically justified reasons for non-compliance exist, the data may serve well for a critical appraisal of clinical practice decisions.

Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes.

BACKGROUND: In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes. METHODS: In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin. RESULTS: A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, -0.46 percentage points), weight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus dose of insulin (-2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively). CONCLUSIONS: Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035 .).