A frequentist design for basket trials using adaptive lasso.

A basket trial aims to expedite the drug development process by evaluating a new therapy in multiple populations within the same clinical trial. Each population, referred to as a "basket", can be defined by disease type, biomarkers, or other patient characteristics. The objective of a basket trial is to identify the subset of baskets for which the new therapy shows promise. The conventional approach would be to analyze each of the baskets independently. Alternatively, several Bayesian dynamic borrowing methods have been proposed that share data across baskets when responses appear similar. These methods can achieve higher power than independent testing in exchange for a risk of some inflation in the type 1 error rate. In this paper we propose a frequentist approach to dynamic borrowing for basket trials using adaptive lasso. Through simulation studies we demonstrate adaptive lasso can achieve similar power and type 1 error to the existing Bayesian methods. The proposed approach has the benefit of being easier to implement and faster than existing methods. In addition, the adaptive lasso approach is very flexible: it can be extended to basket trials with any number of treatment arms and any type of endpoint.

A Randomized Trial of Closed-Loop Control in Children with Type 1 Diabetes.

BACKGROUND: A closed-loop system of insulin delivery (also called an artificial pancreas) may improve glycemic outcomes in children with type 1 diabetes. METHODS: In a 16-week, multicenter, randomized, open-label, parallel-group trial, we assigned, in a 3:1 ratio, children 6 to 13 years of age who had type 1 diabetes to receive treatment with the use of either a closed-loop system of insulin delivery (closed-loop group) or a sensor-augmented insulin pump (control group). The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring. RESULTS: A total of 101 children underwent randomization (78 to the closed-loop group and 23 to the control group); the glycated hemoglobin levels at baseline ranged from 5.7 to 10.1%. The mean (±SD) percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter increased from 53±17% at baseline to 67±10% (the mean over 16 weeks of treatment) in the closed-loop group and from 51±16% to 55±13% in the control group (mean adjusted difference, 11 percentage points [equivalent to 2.6 hours per day]; 95% confidence interval, 7 to 14; P<0.001). In both groups, the median percentage of time that the glucose level was below 70 mg per deciliter was low (1.6% in the closed-loop group and 1.8% in the control group). In the closed-loop group, the median percentage of time that the system was in the closed-loop mode was 93% (interquartile range, 91 to 95). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either group. CONCLUSIONS: In this 16-week trial involving children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with the use of a closed-loop system than with the use of a sensor-augmented insulin pump. (Funded by Tandem Diabetes Care and the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number, NCT03844789.).

Twelve-month psychosocial outcomes of continuous glucose monitoring with behavioural support in parents of young children with type 1 diabetes.

AIM: Managing type 1 diabetes in young children can cause significant stress for parents. Continuous glucose monitoring (CGM) may reduce parental burden. The Strategies to Enhance CGM Use in Early Childhood (SENCE) trial randomized parents of children (ages 2 to <8 years) with type 1 diabetes to CGM with family behavioural intervention (CGM + FBI), CGM alone (Standard-CGM) or blood glucose monitoring for 26 weeks before receiving CGM + FBI (BGM-Crossover). This report assesses changes in psychosocial outcomes for all groups over 52 weeks. METHODS: CGM + FBI (n = 45), Standard-CGM (n = 42) and BGM-Crossover (n = 44) participants completed psychosocial assessments at baseline, 26 weeks and 52 weeks. Repeated measures linear regression models evaluated change within and between treatment groups. RESULTS: The BGM-Crossover group reported improved diabetes burden (Δ -6.9, 95% CI [-11.3, -2.6], p = 0.003), fear of hypoglycaemia (Δ -6.4, CI [-10.1, -2.6], p = 0.002) and technology satisfaction (Δ 7.3, CI [2.4, 12.2], p = 0.005) from 26 to 52 weeks, similar to published findings in the CGM + FBI group over the first 26 weeks. The Standard-CGM group reported increased technology satisfaction (Δ 7.3, CI [0.6, 14.0], p = 0.027) from baseline to 52 weeks. The CGM + FBI group reported less diabetes burden and fear of hypoglycaemia from baseline to 52 weeks, but changes were not statistically significant. Scores from 26 to 52 weeks did not deteriorate. CONCLUSIONS: Parents demonstrated psychosocial benefits following FBI that appeared to maintain without additional intervention. CGM-focused education with behavioural support likely helps parents of young children with type 1 diabetes reduce burden and worry in the short- and long-term.

Fully order restricted multi-arm multi-stage clinical trial design.

We consider a multi-arm trial with two or more active treatments plus a control where it is reasonable to assume an order for the treatment effects of the active arms compared to control. For example, the arms could be a high dose and low dose of a new drug and a placebo. The objective of the trial is to compare each active arm to control while maintaining strong control of the type 1 error rate. We show that when the study is powered to identify all promising treatments, a design that uses the order of the treatment effects to calculate the test statistic and to set the order of testing requires a smaller sample size than a design where each active arm is tested against the control arm independently. Under the considered settings, the sample size for a single-stage trial and a two-stage trial was reduced by at least 20%.

Lived experience of CamAPS FX closed loop system in youth with type 1 diabetes and their parents.

AIM: To examine changes in the lived experience of type 1 diabetes after use of hybrid closed loop (CL), including the CamAPS FX CL system. MATERIALS AND METHODS: The primary study was conducted as an open-label, single-period, randomized, parallel design contrasting CL versus insulin pump (with or without continuous glucose monitoring). Participants were asked to complete patient-reported outcomes before starting CL and 3 and 6 months later. Surveys assessed diabetes distress, hypoglycaemia concerns and quality of life. Qualitative focus group data were collected at the completion of the study. RESULTS: In this sample of 98 youth (age range 6-18, mean age 12.7 ± 2.8 years) and their parents, CL use was not associated with psychosocial benefits overall. However, the subgroup (n = 12) using the CamAPS FX system showed modest improvements in quality of life and parent distress, reinforced by both survey (p < .05) and focus group responses. There were no negative effects of CL use reported by study participants. CONCLUSIONS: Closed loop use via the CamAPS FX system was associated with modest improvements in aspects of the lived experience of managing type 1 diabetes in youth and their families. Further refinements of the system may optimize the user experience.

Development and delivery of a brief family behavioral intervention to support continuous glucose monitor use in young children with type 1 diabetes.

BACKGROUND: Despite potential glycemic benefits of continuous glucose monitor (CGM) use in young children with type 1 diabetes, psychosocial and behavioral challenges may interfere with sustained use. We developed a 5-session family behavioral intervention (FBI) to support CGM use. OBJECTIVE: We report on the multi-step development of the FBI, training interventionists, implementation in a 14-site clinical trial, and participant satisfaction. METHODS: A multidisciplinary team created the FBI based on mixed-methods (i.e., survey data, qualitative research) preliminary work with parents of young children. Investigators trained non-physician staff to deliver the 5 sessions per an intervention manual. Trial participants received the FBI either during the first (FBI group, n = 50) or second 6-months (Crossover group, n = 44) of the 1-year trial. Investigators listened to session recordings to rate intervention fidelity, and participants rated satisfaction with the FBI. RESULTS: The complete 5-session FBI was delivered to 89% of participants, in-person (73%) or by telephone (23%). Sessions lasted 23 min on average, and fidelity was high across sessions. Over 80% of participants rated very high satisfaction with all aspects of the FBI and offered few recommendations for improvement. CONCLUSIONS: Having been developed based on experiences and input of families of young children with type 1 diabetes, the FBI represented a novel behavioral approach to enhance sustained CGM use during a challenging developmental period. Evidence of strong feasibility and acceptability supports its potential for implementation in research and clinical care. As diabetes technologies evolve, the FBI may continue to be refined to address parents' most relevant concerns.

Effect of Continuous Glucose Monitoring on Glycemic Control in Adolescents and Young Adults With Type 1 Diabetes: A Randomized Clinical Trial.

Importance: Adolescents and young adults with type 1 diabetes exhibit the worst glycemic control among individuals with type 1 diabetes across the lifespan. Although continuous glucose monitoring (CGM) has been shown to improve glycemic control in adults, its benefit in adolescents and young adults has not been demonstrated. Objective: To determine the effect of CGM on glycemic control in adolescents and young adults with type 1 diabetes. Design, Setting, and Participants: Randomized clinical trial conducted between January 2018 and May 2019 at 14 endocrinology practices in the US including 153 individuals aged 14 to 24 years with type 1 diabetes and screening hemoglobin A1c (HbA1c) of 7.5% to 10.9%. Interventions: Participants were randomized 1:1 to undergo CGM (CGM group; n = 74) or usual care using a blood glucose meter for glucose monitoring (blood glucose monitoring [BGM] group; n = 79). Main Outcomes and Measures: The primary outcome was change in HbA1c from baseline to 26 weeks. There were 20 secondary outcomes, including additional HbA1c outcomes, CGM glucose metrics, and patient-reported outcomes with adjustment for multiple comparisons to control for the false discovery rate. Results: Among the 153 participants (mean [SD] age, 17 [3] years; 76 [50%] were female; mean [SD] diabetes duration, 9 [5] years), 142 (93%) completed the study. In the CGM group, 68% of participants used CGM at least 5 days per week in month 6. Mean HbA1c was 8.9% at baseline and 8.5% at 26 weeks in the CGM group and 8.9% at both baseline and 26 weeks in the BGM group (adjusted between-group difference, -0.37% [95% CI, -0.66% to -0.08%]; P = .01). Of 20 prespecified secondary outcomes, there were statistically significant differences in 3 of 7 binary HbA1c outcomes, 8 of 9 CGM metrics, and 1 of 4 patient-reported outcomes. The most commonly reported adverse events in the CGM and BGM groups were severe hypoglycemia (3 participants with an event in the CGM group and 2 in the BGM group), hyperglycemia/ketosis (1 participant with an event in CGM group and 4 in the BGM group), and diabetic ketoacidosis (3 participants with an event in the CGM group and 1 in the BGM group). Conclusions and Relevance: Among adolescents and young adults with type 1 diabetes, continuous glucose monitoring compared with standard blood glucose monitoring resulted in a small but statistically significant improvement in glycemic control over 26 weeks. Further research is needed to understand the clinical importance of the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT03263494.

Effect of Continuous Glucose Monitoring on Hypoglycemia in Older Adults With Type 1 Diabetes: A Randomized Clinical Trial.

Importance: Continuous glucose monitoring (CGM) provides real-time assessment of glucose levels and may be beneficial in reducing hypoglycemia in older adults with type 1 diabetes. Objective: To determine whether CGM is effective in reducing hypoglycemia compared with standard blood glucose monitoring (BGM) in older adults with type 1 diabetes. Design, Setting, and Participants: Randomized clinical trial conducted at 22 endocrinology practices in the United States among 203 adults at least 60 years of age with type 1 diabetes. Interventions: Participants were randomly assigned in a 1:1 ratio to use CGM (n = 103) or standard BGM (n = 100). Main Outcomes and Measures: The primary outcome was CGM-measured percentage of time that sensor glucose values were less than 70 mg/dL during 6 months of follow-up. There were 31 prespecified secondary outcomes, including additional CGM metrics for hypoglycemia, hyperglycemia, and glucose control; hemoglobin A1c (HbA1c); and cognition and patient-reported outcomes, with adjustment for multiple comparisons to control for false-discovery rate. Results: Of the 203 participants (median age, 68 [interquartile range {IQR}, 65-71] years; median type 1 diabetes duration, 36 [IQR, 25-48] years; 52% female; 53% insulin pump use; mean HbA1c, 7.5% [SD, 0.9%]), 83% used CGM at least 6 days per week during month 6. Median time with glucose levels less than 70 mg/dL was 5.1% (73 minutes per day) at baseline and 2.7% (39 minutes per day) during follow-up in the CGM group vs 4.7% (68 minutes per day) and 4.9% (70 minutes per day), respectively, in the standard BGM group (adjusted treatment difference, -1.9% (-27 minutes per day); 95% CI, -2.8% to -1.1% [-40 to -16 minutes per day]; P <.001). Of the 31 prespecified secondary end points, there were statistically significant differences for all 9 CGM metrics, 6 of 7 HbA1c outcomes, and none of the 15 cognitive and patient-reported outcomes. Mean HbA1c decreased in the CGM group compared with the standard BGM group (adjusted group difference, -0.3%; 95% CI, -0.4% to -0.1%; P <.001). The most commonly reported adverse events using CGM and standard BGM, respectively, were severe hypoglycemia (1 and 10), fractures (5 and 1), falls (4 and 3), and emergency department visits (6 and 8). Conclusions and Relevance: Among adults aged 60 years or older with type 1 diabetes, continuous glucose monitoring compared with standard blood glucose monitoring resulted in a small but statistically significant improvement in hypoglycemia over 6 months. Further research is needed to understand the long-term clinical benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT03240432.

CHEIROARTHROPATHY: A COMMON DISORDER IN PATIENTS IN THE T1D EXCHANGE.

OBJECTIVE: Diabetic cheiroarthropathy is a long-term complication of diabetes that causes significant morbidity and can impair functional abilities. It has not been well studied in individuals with type 1 diabetes (T1D). The T1D Exchange registry provided an opportunity to assess the frequency of cheiroarthropathy and related characteristics. METHODS: An internet-based survey was sent to 6,199 registry participants ≥18 years old, with 1,911 (31%) responding (62% female, 90% non-Hispanic White, mean age 40 years, median diabetes duration 20 years, mean glycated hemoglobin [HbA1c] 7.7% [61 mmol/mol]). RESULTS: A total of 586 (31%) adults reported a diagnosis of ≥1 upper extremity disorder: 293 (15%) reported frozen shoulder, 293 (15%) trigger finger, 261 (14%) carpal tunnel, and 92 (5%) Dupuytren contracture, with 281 (15%) reporting ≥2 disorders. Those with upper extremity joint disorders were more likely older ( P<.001) and had longer duration of diabetes ( P<.001) than those without. HbA1c levels at the time of survey completion were 7.6% in participants with cheiroarthropathy versus 7.8% (62 mmol/mol) in participants without cheiroarthropathy. CONCLUSION: Cheiroarthropathy is common in adults with T1D. Additional research is needed to understand the pathogenesis and risk factors for this disorder. Standards of care for early recognition and treatment of diabetic cheiroarthropathy are also needed, particularly for adults with long-term diabetes. Improved awareness of cheiroarthropathy signs and symptoms of is needed so that patients can be identified and seek treatment before the condition causes disability. ABBREVIATIONS: BMI = body mass index; CGM = continuous glucose monitor; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; HbA1C = glycated hemoglobin; T1D = type 1 diabetes; T2D = type 2 diabetes.

Use of the Community-Derived Open-Source Automated Insulin Delivery Loop System in Type 2 Diabetes.

Background: No published data are available on the use of the community-derived open-source Loop hybrid closed-loop controller ("Loop") by individuals with type 2 diabetes (T2D). Methods: Through social media postings, we invited individuals with T2D currently using the Loop system to join an observational study. Thirteen responded of whom seven were eligible for the study, were using the Loop algorithm, and provided data. Results: Mean (±standard deviation) age was 61 ± 13 years, and mean body mass index was 31 ± 5 kg/m2. All but one participant were using noninsulin glucose-lowering medications. Self-reported mean hemoglobin A1c decreased from 7.3% ± 1.1% before starting Loop to 6.0% ± 0.5% on Loop. Time in range 70-180 mg/dL increased from 84% to 93%. The amount of time in hypoglycemia was extremely low before and with Loop (time <54 mg/dL was 0.04% ± 0.06% vs. 0.09% ± 0.07%, respectively). No severe hypoglycemia or diabetic ketoacidosis events were reported while using Loop. Conclusion: These data, though limited, suggest that the Loop system is likely to be effective when used by individuals with T2D and should be evaluated in large-scale studies. Clinical Trial Registration numbers: NCT05951569.

The Association of High and Low Glycation With Incident Diabetic Retinopathy in Adults With Type 1 Diabetes.

BACKGROUND: We investigated the risk of incident diabetic retinopathy (DR) among high glycator compared to low glycator patients based on the hemoglobin glycation index (HGI). Visit-to-visit variations in HGI also were assessed. METHODS: Glycated hemoglobin (HbA1c) and continuous glucose monitoring data were collected up to 7 years prior to the date of eye examination defining incident DR or no retinopathy (control). Hemoglobin glycation index was calculated as difference in measured HbA1c and an estimated A1c from sensor glucose (eA1c) to define high (HbA1c - eA1c >0%) or low (HbA1c - eA1c <0%) glycator. Stable glycators were defined as ≥75% of visits with same HGI category. Logistic regression was used to assess the association between glycation category and incident DR. RESULTS: Of 119 adults with type 1 diabetes (T1D), 49 (41%) were stable low glycator (HbA1c - eA1c <0%), 36 (30%) were stable high glycator (HbA1c - eA1c >0%), and 34 (29%) were unstable glycator. Using alternate criteria to define high vs low glycator (consistent difference in HbA1c - eA1c of > 0.4% or <0.4%, respectively), 53% of the adults were characterized as unstable glycator. Compared to low glycators, high glycators did not have a significantly higher risk for incident DR over time when adjusted for age, T1D duration and continuous glucose monitoring (CGM) sensor type (odds ratio [OR] = 1.31, 95% confidence interval [CI] = 0.48-3.62, P = .15). CONCLUSIONS: The risk of diabetic retinopathy was not found to differ significantly comparing high glycators to low glycators in adults with T1D. Moreover, HbA1c - eA1c relationship was not stable in nearly 30% to 50% adults with T1D, suggesting that discordance in HbA1c and eA1c are mostly related either HbA1c measurements or estimation of A1c from sensor glucose rather than physiological reasons.

Time in Range Is Associated with Incident Diabetic Retinopathy in Adults with Type 1 Diabetes: A Longitudinal Study.

Abstract Objective: To evaluate the association between continuous glucose monitoring (CGM)-based time in various ranges and the subsequent development of diabetic retinopathy (incident DR) in adults with type 1 diabetes. Methods: Between June 2018 and March 2022, adults with type 1 diabetes with incident DR or no retinopathy (control) were identified. CGM data were collected retrospectively for up to 7 years before the date of eye examination defining incident DR or control. Associations between incident DR and CGM metrics were evaluated using logistic regression models. Results: This analysis included 71 adults with incident DR (mean age 27 years, 52% females, and mean diabetes duration 15 years) and 92 adults without DR (mean age 38 years, 48% females, and mean diabetes duration 20 years). Adjusting for age, diabetes duration, and CGM type, each 0.5% increase in glycated hemoglobin (HbA1c), 10 mg/dL increase in mean glucose, 5% decrease in time in target range 70-180 mg/dL (TIR), 5% decrease in time in tight target range 70-140 mg/dL (TITR), and 5% increase in time above 180 mg/dL (TAR) were associated with 24%, 22%, 18%, 28%, and 20% increase in odds of incident DR, respectively. Spearman correlations of TIR, TITR, TAR, and mean glucose with each other were all ≥0.97. Conclusion: Similar to HbA1c, TIR, TITR, TAR, and mean glucose were associated with increased risk for incident DR in adults with type 1 diabetes. These CGM metrics are highly correlated indicating that they provide similar information on glycemic control and diabetic retinopathy risk.

Risk factors associated with cognitive performance and cognitive impairment in older adults with type 1 diabetes: Data from the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) study.

BACKGROUND: Adults with type 1 diabetes (T1D) are considered at increased risk for cognitive impairment and accelerated brain aging. However, longitudinal data on cognitive impairment and dementia in this population are scarce. OBJECTIVE: To identify risk factors associated with cognitive performance and cognitive impairment in a longitudinal sample of older adults with T1D. METHODS: We analyzed data collected as part of the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) Study, in which 22 endocrinology practices participated. Randomized participants with T1D ≥60 years of age who completed at least one cognitive assessment were included in this study (n = 203). Cognitive impairment was classified using published recommendations. RESULTS: Older age, male sex, non-private health insurance, worse daily functioning, diagnosis of neuropathy, and longer duration of diabetes were associated with worse cognitive performance, but not cognitive impairment. 49 % and 39 % of the sample met criteria for cognitive impairment at baseline and 52 weeks respectively. Of the participants that had data at both time points, 10 % were normal at baseline and impaired at 52 weeks and 22 % of participants (44 % of those classified with cognitive impairment at baseline) reverted to normal over 52 weeks. CONCLUSION: This study indicated that several demographic and clinical characteristics are associated with worse cognitive performance in older adults with T1D, but there were no associations between these characteristics and cognitive impairment defined by NIH Toolbox cognitive impairment criteria. Caution is warranted when assessing cognition in older adults with T1D, as a large percentage of those identified as having cognitive impairment at baseline reverted to normal after 52 weeks. There is need for future studies on the interrelationship of cognition and aging to better understand the effects of T1D on cognitive health, to improve clinical monitoring and help mitigate the risk of dementia in this population.

Cost-Effectiveness of Closed-Loop Automated Insulin Delivery Using the Cambridge Hybrid Algorithm in Children and Adolescents with Type 1 Diabetes: Results from a Multicenter 6-Month Randomized Trial.

BACKGROUND/OBJECTIVE: The main objective of this study is to evaluate the incremental cost-effectiveness (ICER) of the Cambridge hybrid closed-loop automated insulin delivery (AID) algorithm versus usual care for children and adolescents with type 1 diabetes (T1D). METHODS: This multicenter, binational, parallel-controlled trial randomized 133 insulin pump using participants aged 6 to 18 years to either AID (n = 65) or usual care (n = 68) for 6 months. Both within-trial and lifetime cost-effectiveness were analyzed. Analysis focused on the treatment subgroup (n = 21) who received the much more reliable CamAPS FX hardware iteration and their contemporaneous control group (n = 24). Lifetime complications and costs were simulated via an updated Sheffield T1D policy model. RESULTS: Within-trial, both groups had indistinguishable and statistically unchanged health-related quality of life, and statistically similar hypoglycemia, severe hypoglycemia, and diabetic ketoacidosis (DKA) event rates. Total health care utilization was higher in the treatment group. Both the overall treatment group and CamAPS FX subgroup exhibited improved HbA1C (-0.32%, 95% CI: -0.59 to -0.04; P = .02, and -1.05%, 95% CI: -1.43 to -0.67; P < .001, respectively). Modeling projected increased expected lifespan of 5.36 years and discounted quality-adjusted life years (QALYs) of 1.16 (U.K. tariffs) and 1.52 (U.S. tariffs) in the CamAPS FX subgroup. Estimated ICERs for the subgroup were £19 324/QALY (United Kingdom) and -$3917/QALY (United States). For subgroup patients already using continuous glucose monitors (CGM), ICERs were £10 096/QALY (United Kingdom) and -$33 616/QALY (United States). Probabilistic sensitivity analysis generated mean ICERs of £19 342/QALY (95% CI: £15 903/QALY to £22 929/QALY) (United Kingdom) and -$28 283/QALY (95% CI: -$59 607/QALY to $1858/QALY) (United States). CONCLUSIONS: For children and adolescents with T1D on insulin pump therapy, AID using the Cambridge algorithm appears cost-effective below a £20 000/QALY threshold (United Kingdom) and cost saving (United States).

Descemet Membrane Endothelial Keratoplasty: 10-Year Cell Loss and Failure Rate Compared With Descemet Stripping Endothelial Keratoplasty and Penetrating Keratoplasty.

PURPOSE: The aim of this study was to assess long-term endothelial cell loss (ECL) and graft failure with Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping endothelial keratoplasty (DSEK) versus penetrating keratoplasty (PK) performed for the same indications (primarily Fuchs dystrophy and pseudophakic corneal edema) in the Cornea Donor Study. METHODS: This retrospective study included consecutive primary DMEK (529 recipients, 739 eyes) and DSEK cases (585 recipients, 748 eyes) with 1 or more endothelial cell density (ECD) measurements at 6 months to 16 years. Main outcomes were ECD, longitudinal ECL, and graft failure. RESULTS: Between 6 months and 8 years the ECD declined linearly by approximately 118 cells/mm2/yr after DMEK and 112 cells/mm2/yr after DSEK. Beyond 8 years postoperatively the rate of decline slowed substantially. Selective dropout from graft failure did not significantly affect the ECD trend. At 10 years, median ECL (interquartile range) was 63% (45, 73) with DMEK, 68% (48, 78) with DSEK, and 76% (70, 82) with PK (P = 0.01 DMEK vs. DSEK, P <0.001 DMEK vs. PK, and P < 0.001 DSEK vs. PK). The proportion of surviving grafts with 10-year ECD <500 cells/mm2 was 1.4% with DMEK, 7.3% with DSEK, and 23.9% with PK. The cumulative risk of graft failure between 6 months and 10 years was 5% with DMEK, 11% with DSEK, and 19% with PK (P < 0.001). CONCLUSIONS: Compared with PK and DSEK, DMEK had significantly lower ECL and significantly lower risk of secondary graft failure through 10 years.

A Meta-Analysis of Randomized Trial Outcomes for the t:slim X2 Insulin Pump with Control-IQ Technology in Youth and Adults from Age 2 to 72.

Objective: To evaluate the effect of hybrid-closed loop Control-IQ technology (Control-IQ) in randomized controlled trials (RCTs) in subgroups based on baseline characteristics such as race/ethnicity, socioeconomic status (SES), prestudy insulin delivery modality (pump or multiple daily injections), and baseline glycemic control. Methods: Data were pooled and analyzed from 3 RCTs comparing Control-IQ to a Control group using continuous glucose monitoring in 369 participants with type 1 diabetes (T1D) from age 2 to 72 years old. Results: Time in range 70-180 mg/dL (TIR) in the Control-IQ group (n = 256) increased from 57% ± 17% at baseline to 70% ± 11% during follow-up, and in the Control group (n = 113) was 56% ± 15% and 57% ± 14%, respectively (adjusted treatment group difference = 11.5%, 95% confidence interval +9.7% to +13.2%, P < 0.001), an increase of 2.8 h/day on average. Significant reductions in mean glucose, hyperglycemia metrics, hypoglycemic metrics, and HbA1c were also observed. A statistically similar beneficial treatment effect on time in range 70-180 mg/dL was observed across the full age range irrespective of race-ethnicity, household income, prestudy continuous glucose monitor use, or prestudy insulin delivery method. Participants with the highest baseline HbA1c levels showed the greatest improvements in TIR and HbA1c. Conclusion: This pooled analysis of Control-IQ RCTs demonstrates the beneficial effect of Control-IQ in T1D across a broad spectrum of participant characteristics, including racial-ethnic minority, lower SES, lack of prestudy insulin pump experience, and high HbA1c levels. The greatest benefit was observed in participants with the worst baseline glycemic control in whom the auto-bolus feature of the Control-IQ algorithm appears to have substantial impact. Since no subgroups were identified that did not benefit from Control-IQ, hybrid-closed loop technology should be strongly considered for all youth and adults with T1D. Clinical Trials Registry: clinicaltrials.gov; NCT03563313, NCT03844789, and NCT04796779.

Long-term Continuous Glucose Monitor Use in Very Young Children With Type 1 Diabetes: One-Year Results From the SENCE Study.

OBJECTIVES: Achieving optimal glycemic outcomes in young children with type 1 diabetes (T1D) is challenging. This study examined the durability of continuous glucose monitoring (CGM) coupled with a family behavioral intervention (FBI) to improve glycemia. STUDY DESIGN: This one-year study included an initial 26-week randomized controlled trial of CGM with FBI (CGM+FBI) and CGM alone (Standard-CGM) compared with blood glucose monitoring (BGM), followed by a 26-week extension phase wherein the BGM Group received the CGM+FBI (BGM-Crossover) and both original CGM groups continued this technology. RESULTS: Time in range (70-180 mg/dL) did not improve with CGM use (CGM+FBI: baseline 37%, 52 weeks 41%; Standard-CGM: baseline 41%, 52 weeks 44%; BGM-Crossover: 26 weeks 38%, 52 weeks 40%). All three groups sustained decreases in hypoglycemia (<70 mg/dL) with CGM use (CGM+FBI: baseline 3.4%, 52 weeks 2.0%; Standard-CGM: baseline 4.1%, 52 weeks 2.1%; BGM-Crossover: 26 weeks 4.5%, 52 weeks 1.7%, P-values <.001). Hemoglobin A1c was unchanged with CGM use (CGM+FBI: baseline 8.3%, 52 weeks 8.2%; Standard-CGM: baseline 8.2%, 52 weeks 8.0%; BGM-Crossover: 26 weeks 8.1%, 52 weeks 8.3%). Sensor use remained high (52-week study visit: CGM+FBI 91%, Standard-CGM 92%, BGM-Crossover 88%). CONCLUSION: Over 12 months young children with T1D using newer CGM technology sustained reductions in hypoglycemia and, in contrast to prior studies, persistently wore CGM. However, pervasive hyperglycemia remained unmitigated. This indicates an urgent need for further advances in diabetes technology, behavioral support, and diabetes management educational approaches to optimize glycemia in young children.

Insulin Pump Infusion Set Failures Associated with Prolonged Hyperglycemia: Frequency and Relationship to Age and Type of Infusion Set During 22,741 Infusion Set Wears.

Background: Although insulin pump infusion set failures are common, studies assessing the failure rate are limited. Methods: Data were analyzed from two clinical trials, in which 263 participants aged 6-72 years used 22,741 infusion sets. The frequency of removal due to prolonged hyperglycemia (continuous glucose monitor measuring >300 mg/dL immediately before removal and >250 mg/dL continuously for at least 2 h before removal with at least 90 min >300 mg/dL out of the prior 120 min) was determined. Differences in failure rates among age groups and infusion set types were evaluated. Results: Among 22,741 infusion sets, 748 (3.3%) were removed before 72 h in association with prolonged hyperglycemia. The percentage replaced within 48 h and within 24 h with prolonged hyperglycemia were 1.8% and 1.0%, respectively. Mean duration of continuous time >250 mg/dL before removal was 5.1 ± 3.7 h. Using a less restrictive definition of failure related to hyperglycemia, 1688 (7.4%) sets were removed before 72 h with a glucose level >300 mg/dL at the time of removal. The frequency of insulin set failure with prolonged hyperglycemia was lower in adults ≥18 years old (1.9%) than in those 14-17 years old (5.8%, P < 0.001) or 6-13 years old (4.4%, P = 0.002). The 90° Teflon sets had the highest frequency of prolonged hyperglycemia failure within 72 h (4.0%) compared with the angled Teflon set frequency (1.3%, P = 0.01) or the steel set frequency (1.9%, P = 0.006). Conclusions: Based on the data from these 22,741 infusion sets, infusion set changes associated with prolonged hyperglycemia occur on average about four times a year, with the frequency being higher in youth than adults. The frequency also appears to be higher with straight Teflon sets compared with angled Teflon sets and steel sets. Clinical Trials Registration Number: NCT03563313.

Continuous Glucose Monitoring Profiles in Healthy, Nondiabetic Young Children.

Context: Continuous glucose monitoring (CGM) is increasingly being used both for day-to-day management in patients with diabetes and in clinical research. While data on glycemic profiles of healthy, nondiabetic individuals exist, data on nondiabetic very young children are lacking. Objective: This work aimed to establish reference sensor glucose ranges in healthy, nondiabetic young children, using a current-generation CGM sensor. Methods: This prospective observational study took place in an institutional practice with healthy, nondiabetic children aged 1 to 6 years with normal body mass index. A blinded Dexcom G6 Pro CGM was worn for approximately 10 days by each participant. Main outcome measures included CGM metrics of mean glucose, hyperglycemia, hypoglycemia, and glycemic variability. Results: Thirty-nine participants were included in the analyses. Mean average glucose was 103 mg/dL (5.7 mmol/L). Median percentage time between 70 and 140 mg/dL (3.9-7.8 mmol/L) was 96% (interquartile range, 92%-97%), mean within-individual coefficient of variation was 17 ±â€…3%, median time spent with glucose levels greater than 140 mg/dL was 3.4% (49 min/day), and median time less than 70 mg/dL (3.9 mmol/L) was 0.4% (6 min/day). Conclusion: Collecting normative sensor glucose data and describing glycemic measures for young children fill an important informational gap and will be useful as a benchmark for future clinical studies.

The Insulin-Only Bionic Pancreas Pivotal Trial Extension Study: A Multi-Center Single-Arm Evaluation of the Insulin-Only Configuration of the Bionic Pancreas in Adults and Youth with Type 1 Diabetes.

Objective: To evaluate a transition from standard-of-care (SC) management of type 1 diabetes (any insulin delivery method including hybrid closed-loop systems plus real-time continuous glucose monitoring [CGM]) to use of the insulin-only configuration of the iLet® bionic pancreas (BP) in 90 adults and children (age 6-71 years). Research Design and Methods: After the SC group completed the randomized controlled trial (RCT) portion of the Insulin-Only BP Pivotal Trial, 90 of the 107 participants participated in a 13-week study using the BP. The key outcomes were change from baseline in HbA1c and CGM metrics after 13 weeks on the BP. Results: Using the BP, mean HbA1c decreased from 7.7% ± 1.0% (61 ± 10.9 mmol/mol) at baseline to 7.1% ± 0.6% (54 ± 6.6 mmol/mol) at 13 weeks (mean change -0.55% ± 0.72% [-6 ± 7.9 mmol/mol], P < 0.001), time in range 70-180 mg/dL increased by 12.0% ± 12.5% (from 53% ± 17% to 65% ± 9%, P < 0.001), and mean glucose decreased by -18 ± 23 mg/dL (from 182 ± 32 to 164 ± 15 mg/dL, P < 0.001). The higher the baseline HbA1c level, the greater the change in HbA1c. Results were similar in the adult (N = 42) and pediatric (N = 48) cohorts. Time <70 mg/dL decreased from baseline over the 13 weeks by -0.50% ± 1.86% (P = 0.02), and time <54 mg/dL was similar (change from baseline -0.08% ± 0.59%, P = 0.24). Two severe hypoglycemia events (in same participant) and one diabetic ketoacidosis event occurred. Conclusions: Glycemic control improved after adult and pediatric participants in the SC arm in the Insulin-Only BP Pivotal Trial transitioned to use of the BP. Improvement using the BP was of similar magnitude to that observed during the RCT. ClinicalTrials.gov number, NCT04200313.