New therapies towards a better glycemic control in youths with type 1 diabetes.

Type 1 diabetes (T1D) is the most frequent form of diabetes in pediatric age, affecting more than 1.5 million people younger than age 20 years worldwide. Early and intensive control of diabetes provides continued protection against both microvascular and macrovascular complications, enhances growth, and ensures normal pubertal development. In the absence of definitive reversal therapy for this disease, achieving and maintaining the recommended glycemic targets is crucial. In the last 30 years, enormous progress has been made using technology to better treat T1D. In spite of this progress, the majority of children, adolescents and young adults do not reach the recommended targets for glycemic control and assume a considerable burden each day. The development of promising new therapeutic advances, such as more physiologic insulin analogues, pioneering diabetes technology including continuous glucose monitoring and closed loop systems as well as new adjuvant drugs, anticipate a new paradigm in T1D management over the next few years. This review presents insights into current management of T1D in youths.

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.

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.

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.

Three-variate trajectories of metabolic control, body mass index, and insulin dose: Heterogeneous response to initiation of pump therapy in youth with type 1 diabetes.

OBJECTIVE: Continuous subcutaneous insulin infusion (CSII) in youths with type 1 diabetes (T1D) is often associated with lower HbA1c, lower total daily insulin dose (TDD), and lower body mass index (BMI) compared with multiple daily injections (MDI). Individual responses to CSII are diverse. The aim was to identify unique three-variate patterns of HbA1c, BMI standard deviation score (SDS), and TDD after switching to CSII. METHODS: Five thousand one hundred and thirty-three youths (≤20 years; 48% boys; median age at pump start 12.5 years) with T1D duration ≥3 years at CSII initiation were selected from the multicenter DPV registry. We applied group-based multitrajectory modeling to identify groups of individuals following similar trajectories. Measurements were aggregated quarterly during a 3-year follow-up period. Trajectory variables were changes of HbA1c, BMI-SDS, and TDD from baseline (delta = quarterly aggregated values at each time point [i] minus the respective baseline value). RESULTS: Four groups of diverging Delta-HbA1c, Delta-BMI-SDS, and Delta-TDD patterns were identified. All showed improvements in HbA1c during the first 3 months. Group 1 (12%) was characterized by modest HbA1c increase thereafter, TDD reduction, and stable BMI-SDS. In Group 2 (39%), increasing HbA1c, decreasing BMI-SDS, and stable TDD were found. By contrast, sustainably improved HbA1c, increasing BMI-SDS, and stable TDD were observed in Group 3 (32%). Group 4 (17%) was characterized by increasing levels for HbA1c, BMI-SDS, and TDD. Between-group differences in baseline HbA1c, BMI-SDS, TDD as well as in sex ratio, age at diabetes onset and at pump start were observed. CONCLUSIONS: Definite trajectories of glycemic control, BMI, and TDD over 3 years after CSII initiation were identified in youths with T1D allowing a more personalized treatment recommendation.

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.

Pediatric diabetes and skin disease (PeDiSkin): A cross-sectional study in 369 children, adolescents and young adults with type 1 diabetes.

BACKGROUND: The spectrum of skin disorders in children with type 1 diabetes (T1D) and their impact on affected persons are still incompletely understood. This study assessed the prevalence of skin diseases, cutaneous complications associated with T1D treatment and skin-related quality of life (QoL) in young T1D persons. METHODS: Participation in this interdisciplinary, single-center, cross-sectional, observational study was offered to all persons with T1D ≤20 years. Participants were characterized by a detailed medical history, routine laboratory workup, thorough clinical examinations and an established QoL questionnaire. RESULTS: Three hundred and sixty-nine persons were recruited (55% male; age 12.3 ± 4.4 years; HbA1c 7.4 ± 1.0%; mean ± SD). Continuous subcutaneous insulin infusion (CSII) was used by 72.4%, multiple daily injections (MDI) by 27.6% and continuous glucose monitoring (CGM) by 76%. Skin affections occurred in 91.8% of the study population. Device-associated lesions were most prevalent, including lipohypertrophy in 42.2% of MDI and 46.8% of CGM users and contact eczema associated with CSII or CGM in 14.2% and 18.3%, respectively. Diabetes-associated skin disorders and skin infections were rare or absent. Skin-related QoL impairment was low or absent in 95% of patients. CONCLUSIONS: Skin diseases have a high prevalence and a broad spectrum in young persons with T1D. Eczematous reactions to CSII and CGM devices represent the most frequent skin complications. This highlights the need for regular skin checkups as an integral part of pediatric diabetes consultations and interdisciplinary cooperation for classification and treatment options.

The association between anti-insulin aspart antibodies and the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in children and adolescents with type 1 diabetes.

BACKGROUND: Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) ensuring ultrafast absorption and effect. AIM: To compare the pharmacokinetics between faster aspart and IAsp, based on free or total IAsp measurement, and investigate the association between anti-IAsp antibodies and faster aspart and IAsp pharmacological properties in children and adolescents with type 1 diabetes (T1D). METHODS: In a randomized, two-period crossover trial, 12 children, 16 adolescents, and 15 adults (6-11, 12-17, and 18-64 years) received 0.2 U/kg double-blindsingle-dose subcutaneous faster aspart or IAsp followed by a standardized liquid meal test. RESULTS: Across age groups, the pharmacokinetic profile was left-shifted including greater early exposure for faster aspart vs IAsp irrespective of free or total IAsp assay. Onset of appearance occurred 2.4 to 5.0 minutes (free) or 1.8 to 3.0 minutes (total) earlier for faster aspart vs IAsp (P < .05). Treatment ratios (faster aspart/IAsp) for 0 to 30 minutes IAsp exposure were 1.60 to 2.11 and 1.62 to 1.96, respectively (children, free: P = .062; otherwise P < .05). The ratio of free/total IAsp for overall exposure (AUCIAsp,0-t ) was negatively associated with anti-IAsp antibody level across age. Pooling with a previous similar trial showed no clear association between anti-IAsp antibodies and meal test 1- or 2-hour postprandial glucose increment independent of age and insulin treatment (R2 ≤ .070; P ≥ .17). CONCLUSIONS: In children and adolescents with T1D, faster aspart provides ultrafast pharmacokinetics irrespective of free or total IAsp assay. Elevated anti-IAsp antibodies are associated with higher total IAsp concentration, but do not impact faster aspart and IAsp glucose-lowering effect.

Lipoatrophy in children, adolescents and adults with insulin pump treatment: Is there a beneficial effect of insulin glulisine?

AIM: To investigate whether zinc-free insulin is an effective treatment option for lipoatrophy. METHODS: Controlled, randomized, open-label parallel study in young people with type 1 diabetes, pump treatment and lipoatrophy at injection sites. Participants underwent dermatological examination and evaluation of affected areas using ultrasound and magnetic resonance imaging (MRI). After randomization, half of themswitched to insulin glulisine (intervention group) for 6 months. The control group continued their treatment with zinc-containing insulin and switched to insulin glulisine 6 months later. Both groups were followed-up until month 12. Primary endpoint was the increase of the relative thickness of the subcutaneous fat layer of the most atrophic site at 6 months as documented by MRI. RESULTS: Fourteen participants were included into the study. While relative thickness of subcutaneous fat tissue was comparable between intervention (-60% [-98.8 - -17.6], n = 7) and control group (-50% [-72.7 - -1.0], P = .511; median (range), n = 7)at baseline, it improved in the intervention (-14.3% [-85.7-83.3] vs -31.3% (-66.7-0), P = .031), but not in the control group (P = .125) after 6 months. At 12 months, relative fat thickness (P = .003), number (P = .015) and size of most atrophic sites (P = .001) were improved in the intervention group. Number (P = .018) and size of most atrophic sites (P = .008) were also reduced in the control group between 6 and 12 months. CONCLUSIONS: Although the present pilot study is based on a small sample, the data give first hint that the use of the zinc-free insulin glulisine may be beneficial in people with diabetes, pump and lipoatrophy.

Blood pressure measurement methodology and technology in the SWEET diabetes centers: An international SWEET database survey.

INTRODUCTION: The accuracy of blood pressure (BP) measurement is a prerequisite for the reliable diagnosis and management of hypertension. OBJECTIVES: This survey evaluated the use of office and out-of-office BP measurements and the antihypertensive pharmacological treatment in expert pediatric diabetes centers. METHODS: A questionnaire was distributed in 78 reference pediatric diabetes centers of the SWEET international consortium. The methodology, devices, indications, and interpretation of office BP measurements (OBPM), 24-hour ambulatory BP monitoring (ABPM) and home BP monitoring (HBPM), and the preference for antihypertensive drug treatment was assessed. A grading score was developed to evaluate centers for overall BP measurement performance. RESULTS: Fifty-two centers responded. The average score for OBPM methodology was 72.5%, for technology 77.5% and the overall center score was 74.75%.The majority of the centers used appropriate methodology and technology, however, there was heterogeneity among them. Manual auscultatory or automated devices specifically validated for children were used by 26/52 centers. ABPM was recommended by 35/52 centers (27/35 had health insurance coverage) and HBPM by 18/52 centers. The BP measurement methodology and devices used for ABPM and HBPM were frequently inadequate. Angiotensin converting enzyme inhibitors were the most frequently prescribed drugs for treating hypertension. CONCLUSIONS: The majority of SWEET pediatric diabetes centers use adequate methodology and devices for BP measurement. ABPM is recommended by two thirds of the centers, whereas HBPM is less widely used. Further improvement in the quality of office and out-of-office BP measurements and harmonization among centers is necessary according to current guidelines.

Beyond type 2 diabetes: sodium glucose co-transporter-inhibition in type 1 diabetes.

Use of sodium glucose cotransporter (SGLT) inhibitors are a well-established therapeutic option in type 2 diabetes (T2D) with a variety of proven therapeutic benefits. They have become a pillar of current treatment guidelines. In type 1 diabetes (T1D), initial exploratory studies have shown benefits in glycemic control, weight control, and cardiovascular risk parameters, leading to trials aiming for regulatory submission with several agents. Results from four 1-year trials, which included a total of 3052 patients, are now available, demonstrating promising findings that target the unmet needs of patients with T1D with a novel insulin-independent adjunct therapy. However, these positive effects must be balanced against the risks associated with this class of drugs. Specifically, current T1D studies have shown an increased risk of diabetic ketoacidosis (DKA), which, in some cases, presented with only slightly elevated glucose levels. While this complication may be clinically manageable once detected, the metabolic shift towards ketogenesis associated with this class of agents mandates appropriate patient selection. Currently, there are no validated tools for DKA risk assessment. Although the experience gained in studies and off-label use provides some indication for appropriate patient selection, this would have to be evaluated closely in the event that these drugs would receive regulatory approval. Risk mitigation includes training in ketone measurement (preferably as blood ß-hydroxybutyrate testing), teaching the concept of euglycemic DKA, and providing a clear treatment algorithm to avoid progression of ketosis to full-blown DKA. Because similar unmet needs also exist in pediatric population studies, risk mitigation in youth should be initiated as well to allow an evidence-based, risk-benefit assessment in this vulnerable population.

DREAM5: An open-label, randomized, cross-over study to evaluate the safety and efficacy of day and night closed-loop control by comparing the MD-Logic automated insulin delivery system to sensor augmented pump therapy in patients with type 1 diabetes at home.

AIMS: Previous DREAM studies demonstrated the safety and efficacy of the CE marked MD-Logic closed-loop system (DreaMed GlucoSitter) in different settings for overnight glycaemic control. The present study aimed to evaluate the system for day and night use for 60 hours during the weekend at home compared to sensor-augmented pump (SAP) therapy in participants with type 1 diabetes. METHODS: This was a prospective, multicentre, crossover, controlled study (clinicaltrials.gov NCT01238406). All participants were connected in randomized order for one weekend to SAP therapy or the MD-Logic System. In the intervention arm only, the amount of carbohydrate was entered into the bolus calculator; the rest of insulin delivery was automated and wireless via a tablet computer. The primary endpoint was percentage of glucose values between 70 and 180 mg/dL. RESULTS: The ITT population comprised 48 (19 males, 29 females) adolescents and adults experienced in sensor use: (median, [IQR]): age, 16.1years [13.2-18.5]; diabetes duration, 9.4 years [5.0-12.7]; pump use, 5.4 years [3.1-9.4]; HbA1c, 7.6% [7.0-8.1]. A significant increase in the percentage of time within target range (70-180 mg/dL) (66.6% vs 59.9%, P = 0.002) was observed with the closed-loop system vs control weekends with unchanged percentage of time below 70 mg/dL (2.3% vs 1.5%, P = 0.369). Mean weekend glucose level per participant was significantly lower (153 [142-175] vs 164 [150-186] mg/dL, P = 0.003). No safety signals were observed. CONCLUSIONS: The MD-Logic system was safe and associated with better glycaemic control than SAP therapy for day and night use. The absence of remote monitoring did not lead to safety signals in adapting basal rates nor in administration of automated bolus corrections.

Comparison of pharmacokinetics and the exposure-response relationship of dapagliflozin between adolescent/young adult and adult patients with type 1 diabetes mellitus.

AIMS: To quantitatively compare pharmacokinetics (PK) and the exposure-response (ER) relationship of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, between adolescents/young adults and adults with type 1 diabetes mellitus (T1DM). METHODS: Data from 2 clinical studies for dapagliflozin were analysed using a non-linear mixed-effects approach. The PK and the relationship between dapagliflozin exposure and response (24-hour urinary glucose excretion) were characterized. PK was evaluated using a 2-compartment model with first-order absorption while the exposure response-relationship was analysed using a sigmoidal maximal-effect model. The 24-hour median blood glucose, estimated glomerular filtration rate (eGFR), sex, age and body weight were evaluated as covariates. RESULTS: A 2-compartment model with first order absorption provided a reasonable fit to the dapagliflozin PK data. Body weight was found to be a significant covariate on dapagliflozin exposure. The ER relationship was best described by a sigmoidal maximal effect model with 24-hour median blood glucose and eGFR as significant covariates on maximal effect. In accordance with the observed data, model-predicted urinary glucose excretion response following 10 mg dapagliflozin dose was higher in the study in adolescents/young adults (138.0 g/24 h) compared to adults (70.5 g/24 h) with T1DM. This is linked to higher eGFR and 24-hour median blood glucose in this trial. CONCLUSIONS: Dapagliflozin PK and ER relationship were similar in the 2 analysed studies after accounting for covariate effects. These results suggest that no dose adjustment is required for adolescent patients with T1DM.

Adjusting insulin doses in patients with type 1 diabetes who use insulin pump and continuous glucose monitoring: Variations among countries and physicians.

AIMS: To evaluate physicians' adjustments of insulin pump settings based on continuous glucose monitoring (CGM) for patients with type 1 diabetes and to compare these to automated insulin dose adjustments. METHODS: A total of 26 physicians from 16 centres in Europe, Israel and South America participated in the study. All were asked to adjust insulin dosing based on insulin pump, CGM and glucometer downloads of 15 patients (mean age 16.2 ± 4.3 years, six female, mean glycated haemoglobin 8.3 ± 0.9% [66.8 ± 7.3 mmol/mol]) gathered over a 3-week period. Recommendations were compared for the relative changes in the basal, carbohydrate to insulin ratio (CR) and correction factor (CF) plans among physicians and among centres and also between the physicians and an automated algorithm, the Advisor Pro (DreaMed Diabetes Ltd, Petah Tikva, Israel). Study endpoints were the percentage of comparison points for which there was full agreement on the trend of insulin dose adjustments (same trend), partial agreement (increase/decrease vs no change) and full disagreement (opposite trend). RESULTS: The percentages for full agreement between physicians on the trend of insulin adjustments of the basal, CR and CF plans were 41 ± 9%, 45 ± 11% and 45.5 ± 13%, and for complete disagreement they were 12 ± 7%, 9.5 ± 7% and 10 ± 8%, respectively. Significantly similar results were found between the physicians and the automated algorithm. The algorithm magnitude of insulin dose change was at least equal to or less than that proposed by the physicians. CONCLUSIONS: Physicians provide different insulin dose recommendations based on the same datasets. The automated advice of the Advisor Pro did not differ significantly from the advice given by the physicians in the direction or magnitude of the insulin dosing.

Outcomes of using flash glucose monitoring technology by children and young people with type 1 diabetes in a single arm study.

BACKGROUND AND OBJECTIVE: Outcomes of using flash glucose monitoring have been reported in adults. This trial evaluated use in children and teenagers with type 1 diabetes. METHODS: Prospective, single arm, non-inferiority multicenter study to demonstrate equivalence of time in range (TIR [70-180 mg/dL]) by comparing 14-day masked sensor wear (baseline) with self-monitored blood glucose (SMBG) testing to the final 14-days of 8-week open-label system use for diabetes self-management including insulin dosing. RESULTS: A total of 76 children and teenagers (46.1% male; age 10.3 ± 4.0 years, type 1 diabetes duration 5.4 ± 3.7 years; mean ± SD) from 10 sites participated. TIR improved significantly by 0.9 ± 2.8 h/d (P = 0.005) vs SMBG baseline. Time in hyperglycemia (>180 mg/dL) reduced by -1.2 ± 3.3 h/d (P = 0.004). HbA1c reduced by -0.4% (-4.4 mmol/mol), from 7.9 ± 1.0% (62.9 ± 11.2 mmol/mol) baseline to 7.5 ± 0.9% (58.5 ± 9.8 mmol/mol) study end (P < 0.0001) with reductions across all age-subgroups (4-6, 7-12 and 13-17 years). Time in hypoglycemia (<70 mg/dL) was unaffected. Throughout the treatment phase system utilization was 91% ± 9; sensor scanning was 12.9 ± 5.7/d with SMBG dropping to 1.6 ± 1.9 from 7.7 ± 2.5/d. Diabetes Treatment Satisfaction Questionnaire "Total Treatment Satisfaction" score improved for parents (P < 0.0001) and teenagers (P < 0.0001). No adverse events (n = 121) were associated with sensor accuracy, 42 participants experienced sensor insertion signs and symptoms. Three participants experienced three mild device-related (sensor wear) symptoms, resolving quickly (without treatment [n = 2], non-prescription antihistamines [n = 1]). CONCLUSIONS: Children with diabetes improved glycemic control safely and effectively with short-term flash glucose monitoring compared to use of SMBG in a single arm study.

Long-term study of tubeless insulin pump therapy compared to multiple daily injections in youth with type 1 diabetes: Data from the German/Austrian DPV registry.

OBJECTIVE: To examine glycemic control in youth with type 1 diabetes (T1D) who switched from multiple daily injections (MDI) to a tubeless insulin pump (Omnipod Insulin Management System, Insulet Corporation, Billerica, Massachusetts) compared to patients who continued MDI therapy over a 3-year time period. RESEARCH DESIGN AND METHODS: This retrospective analysis of the German/Austrian Diabetes Patienten Verlaufsdokumentation registry included data from 263 centers and 2529 patients <20 years (n = 660 tubeless insulin pump; n = 1869 MDI) who initiated treatment on a tubeless insulin pump as of January 1, 2013 and had 1 year of data preswitch from MDI and 3 years of data postswitch to a tubeless pump. Outcomes included the change in glycated hemoglobin (HbA1c), insulin dose, and body mass index (BMI) SD score (SDS). RESULTS: Youth with T1D who switched from MDI therapy to a tubeless insulin pump showed better glycemic control at 1 year compared to patients who continued MDI treatment, adjusted mean ± SE: 7.5% ± 0.03% (58 mmol/mol) vs 7.7% ± 0.02% (61 mmol/mol); P < .001, with no between-group difference at 2 and 3 years. Total daily insulin dose was lower (P < .001) in the tubeless insulin pump group, 0.80 ± 0.01, 0.81 ± 0.01, and 0.85 ± 0.01 U/kg, vs the MDI group, 0.89 ± 0.01, 0.94 ± 0.01, and 0.97 ± 0.01 U/kg, at 1, 2, and 3 years, respectively (all P < .001). BMI SDS increased in both groups and was not different over time. CONCLUSIONS: Treatment with a tubeless insulin pump in youth with T1D was associated with improvements in glycemic control compared to MDI after 1 year and appears to be an effective alternative to MDI.

Closed-loop glucose control in young people with type 1 diabetes during and after unannounced physical activity: a randomised controlled crossover trial.

AIMS/HYPOTHESIS: Hypoglycaemia during and after exercise remains a challenge. The present study evaluated the safety and efficacy of closed-loop insulin delivery during unannounced (to the closed-loop algorithm) afternoon physical activity and during the following night in young people with type 1 diabetes. METHODS: A randomised, two-arm, open-label, in-hospital, crossover clinical trial was performed at a single site in Slovenia. The order was randomly determined using an automated web-based programme with randomly permuted blocks of four. Allocation assignment was not masked. Children and adolescents with type 1 diabetes who were experienced insulin pump users were eligible for the trial. During four separate in-hospital visits, the participants performed two unannounced exercise protocols: moderate intensity (55% of [Formula: see text]) and moderate intensity with integrated high-intensity sprints (55/80% of [Formula: see text]), using the same study device either for closed-loop or open-loop insulin delivery. We investigated glycaemic control during the exercise period and the following night. The closed-loop insulin delivery was applied from 15:00 h on the day of the exercise to 13:00 h on the following day. RESULTS: Between 20 January and 16 June 2016, 20 eligible participants (9 female, mean age 14.2 ± 2.0 years, HbA1c 7.7 ± 0.6% [60.0 ± 6.6 mmol/mol]) were included in the trial and performed all trial-mandated activities. The median proportion of time spent in hypoglycaemia below 3.3 mmol/l was 0.00% for both treatment modalities (p = 0.7910). Use of the closed-loop insulin delivery system increased the proportion of time spent within the target glucose range of 3.9-10 mmol/l when compared with open-loop delivery: 84.1% (interquartile range 70.0-85.5) vs 68.7% (59.0-77.7), respectively (p = 0.0057), over the entire study period. This was achieved with significantly less insulin delivered via the closed-loop (p = 0.0123). CONCLUSIONS/INTERPRETATION: Closed-loop insulin delivery was safe both during and after unannounced exercise protocols in the in-hospital environment, maintaining glucose values mostly within the target range without an increased risk of hypoglycaemia. TRIAL REGISTRATION: Clinicaltrials.gov NCT02657083 FUNDING: University Medical Centre Ljubljana, Slovenian National Research Agency, and ISPAD Research Fellowship.

Liraglutide in an Adolescent Population with Obesity: A Randomized, Double-Blind, Placebo-Controlled 5-Week Trial to Assess Safety, Tolerability, and Pharmacokinetics of Liraglutide in Adolescents Aged 12-17 Years.

OBJECTIVES: To investigate the safety, tolerability, and pharmacokinetics of liraglutide in adolescents with obesity. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled trial. Twenty-one subjects, aged 12-17 years and Tanner stage 2-5, with obesity (body mass index [BMI] corresponding to both a BMI ≥95th percentile for age and sex and to a BMI of ≥30 kg/m2 for adults; additionally, BMI was ≤45 kg/m2) were randomized (2:1) to receive 5 weeks of treatment with liraglutide (0.6 mg with weekly dose increase to a maximum of 3.0 mg for the last week) (n = 14) or placebo (n = 7). The primary endpoint was number of treatment-emergent adverse events (TEAEs). Secondary endpoints included safety measures, and pharmacokinetic and pharmacodynamic endpoints. RESULTS: All participants receiving liraglutide, and 4 receiving placebo (57.1%), had at least 1 TEAE. The most common TEAEs were gastrointestinal disorders. No severe TEAEs, TEAE-related withdrawals, or deaths occurred. Twelve hypoglycemic episodes occurred in 8 participants receiving liraglutide and 2 in 1 participant receiving placebo. No severe hypoglycemic episodes were reported. Liraglutide exposure in terms of trough concentration increased with dose, although dose proportionality was confounded by unexpectedly low trough concentration values at the 2.4 mg dose. Exposure in terms of model-derived area under the plasma concentration time curve from 0 to 24 hours after dose in steady state was similar to that in adults with obesity. CONCLUSIONS: Liraglutide had a similar safety and tolerability profile compared with adults when administered to adolescents with obesity, with no unexpected safety/tolerability issues. Results suggest that the dosing regimen approved for weight management in adults may be appropriate for use in adolescents. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01789086.