Real-world performance of the MiniMed 780G advanced hybrid closed loop system in Latin America: Substantial improvement in glycaemic control with each technology iteration of the MiniMed automated insulin delivery system.

AIM: We studied real-world performance of MiniMed (MM) 780G system users from Argentina, Brazil, Colombia and Chile (geographical analysis), and the effect of each technology iteration of the MM system on glycaemic control (technology iteration analysis). MATERIALS AND METHODS: CareLink data from August 2020 to September 2022 were extracted. Endpoints included continuous glucose monitoring metrics. For the geographical analysis, aggregated endpoints for MM780G system users were calculated. For the technology iteration analysis, MM780G system user outcomes were compared with outcomes when the same individuals were still using the MM640G or MM670G system. RESULTS: On average, 1025 MM780G system users from the geographical analysis were followed for 136 (SD 135) days, spent 91.5 (14.3)% in advanced hybrid closed loop, showed a glucose management indicator (GMI) of 6.7 (0.3)%, a time in range between 70 and 180 mg/dl (TIR) of 76.5 (9.0)%, and a time below range 70 mg/dl (TBR) of 2.7 (2.1)%. The percentage of users reaching targets of GMI <7%, TIR >70% and TBR <4% was 80.8%, 78.1% and 80.1%, respectively. The technology iteration analysis on users transitioning from MM640G to MM780G system (N = 381) showed 0.4% decrease in GMI (7.1% to 6.7%, p < .0001), 10.7% increase in TIR (65.9% to 76.6%, p < .0001), while TBR remained. The percentage of insulin delivered automatically increased as well (47.5%-57.7%, p < .0001). Users transitioning from MM670G system (N = 78) showed a similar but less pronounced pattern. CONCLUSIONS: Real-world Latin American MM780G users on average showed good glucose control, achieving international targets. Glycaemic control increased with every technology iteration of the MM system, providing more automation each time.

Effect of Tight Glycemic Control on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing glucotoxicity. Previous studies have been hampered by an inability to achieve tight glycemic goals. Objective: To determine the effectiveness of intensive diabetes management to achieve near normalization of glucose levels on preservation of pancreatic beta cell function in youth with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This randomized, double-blind, clinical trial was conducted at 6 centers in the US (randomizations from July 20, 2020, to October 13, 2021; follow-up completed September 15, 2022) and included youths with newly diagnosed type 1 diabetes aged 7 to 17 years. Interventions: Random assignment to intensive diabetes management, which included use of an automated insulin delivery system (n = 61), or standard care, which included use of a continuous glucose monitor (n = 52), as part of a factorial design in which participants weighing 30 kg or more also were assigned to receive either oral verapamil or placebo. Main Outcomes and Measures: The primary outcome was mixed-meal tolerance test-stimulated C-peptide area under the curve (a measure of pancreatic beta cell function) 52 weeks from diagnosis. Results: Among 113 participants (mean [SD] age, 11.8 [2.8] years; 49 females [43%]; mean [SD] time from diagnosis to randomization, 24 [5] days), 108 (96%) completed the trial. The mean C-peptide area under the curve decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group, and from 0.60 to 0.50 pmol/mL in the standard care group (treatment group difference, -0.01 [95% CI, -0.11 to 0.10]; P = .89). The mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% in the intensive management group vs 64% in the standard care group (adjusted difference, 16% [95% CI, 10% to 22%]). One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group. Conclusions and Relevance: In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes. Objective: To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022. Interventions: Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care. Main Outcomes and Measures: The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes. Results: Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment. Conclusions and Relevance: In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

A Peek Under the Hood: Explaining the MiniMed™ 780G Algorithm with Meal Detection Technology.

The MiniMed™ 780G system (780G) received Conformité Européenne mark in June 2020 and was, recently, approved by the U.S. Food and Drug Administration (April 2023). Clinical trials and real-world analyses have demonstrated MiniMed™ 780G system safety and effectiveness and that glycemic outcomes (i.e., time in range) improve with recommended settings use. In this publication, we will explain the iterative development of the 780G algorithm and how this technology has simplified diabetes management.

TNF-α inhibitors for type 1 diabetes: exploring the path to a pivotal clinical trial.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing ß-cells in the pancreas. This destruction leads to chronic hyperglycemia, necessitating lifelong insulin therapy to manage blood glucose levels. Typically diagnosed in children and young adults, T1D can, however, occur at any age. Ongoing research aims to uncover the precise mechanisms underlying T1D and to develop potential interventions. These include efforts to modulate the immune system, regenerate ß-cells, and create advanced insulin delivery systems. Emerging therapies, such as closed-loop insulin pumps, stem cell-derived ß-cell replacement and disease-modifying therapies (DMTs), offer hope for improving the quality of life for individuals with T1D and potentially moving towards a cure. Currently, there are no disease-modifying therapies approved for stage 3 T1D. Preserving ß-cell function in stage 3 T1D is associated with better clinical outcomes, including lower HbA1c and decreased risk of hypoglycemia, neuropathy, and retinopathy. Tumor Necrosis Factor alpha (TNF-α) inhibitors have demonstrated efficacy at preserving ß-cell function by measurement of C-peptide in two clinical trials in people with stage 3 T1D. However, TNF-α inhibitors have yet to be evaluated in a pivotal trial for T1D. To address the promising clinical findings of TNF-α inhibitors in T1D, Breakthrough T1D convened a panel of key opinion leaders (KOLs) in the field. The workshop aimed to outline an optimal clinical path for moving TNF-α inhibitors to a pivotal clinical trial in T1D. Here, we summarize the evidence for the beneficial use of TNF-α inhibitors in T1D and considerations for strategies collectively identified to advance TNF-α inhibitors beyond phase 2 clinical studies for stage 3 T1D.

Glycemic Outcomes During Early Use of the MiniMed™ 780G Advanced Hybrid Closed-Loop System with Guardian™ 4 Sensor.

Background: Safety and significant improvement in overall glycated hemoglobin (A1C) and percentage of time spent in (TIR), below (TBR), and above (TAR) glucose range were demonstrated in the pivotal trial of adolescents and adults using the MiniMed™ advanced hybrid closed-loop (AHCL) system with the adjunctive, calibration-required Guardian™ Sensor 3. The present study evaluated early outcomes of continued access study (CAS) participants who transitioned from the pivotal trial investigational system to the approved MiniMed™ 780G system with the non-adjunctive, calibration-free Guardian™ 4 Sensor (MM780G+G4S). Study data were presented alongside those of real-world MM780G+G4S users from Europe, the Middle East, and Africa. Methods: The CAS participants (N = 109, aged 7-17 years and N = 67, aged >17 years) used the MM780G+G4S for 3 months and data of real-world MM780G+G4S system users (N = 10,204 aged ≤15 years and N = 26,099 aged >15 years) were uploaded from September 22, 2021 to December 02, 2022. At least 10 days of real-world continuous glucose monitoring (CGM) data were required for analyses. Glycemic metrics, delivered insulin and system use/interactions underwent descriptive analyses. Results: Time in AHCL and CGM use were >90% for all groups. AHCL exits averaged 0.1/day and there were few blood glucose measurements (BGMs) (0.8/day-1.0/day). Adults in both cohorts met most consensus recommendations for glycemic targets. Pediatric groups met recommendations for %TIR and %TBR, although not those for mean glucose variability and %TAR, possibly due to low use of recommended glucose target (100 mg/dL) and active insulin time (2 h) settings (28.4% in the CAS cohort and 9.4% in the real-world cohort). The CAS pediatric and adult A1C were 7.2% ± 0.7% and 6.8% ± 0.7%, respectively, and there were no serious adverse events. Conclusions: Early clinical use of the MM780G+G4S was safe and involved minimal BGMs and AHCL exits. Consistent with real-world pediatric and adult use, outcomes were associated with achievement of recommended glycemic targets. Clinical Trial Registration number: NCT03959423.

Safety and Glycemic Outcomes During the MiniMedTM Advanced Hybrid Closed-Loop System Pivotal Trial in Children and Adolescents with Type 1 Diabetes.

Background: During MiniMed™ advanced hybrid closed-loop (AHCL) use by adolescents and adults in the pivotal trial, glycated hemoglobin (A1C) was significantly reduced, time spent in range (TIR) was significantly increased, and there were no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). The present study investigated the same primary safety and effectiveness endpoints during AHCL use by a younger cohort with type 1 diabetes (T1D). Methods: An intention-to-treat population (N = 160, aged 7-17 years) with T1D was enrolled in a single-arm study at 13 investigational centers. There was a run-in period (∼25 days) using HCL or sensor-augmented pump with/without predictive low-glucose management, followed by a 3-month study period with AHCL activated at two glucose targets (GTs; 100 and 120 mg/dL) for ∼45 days each. The mean ± standard deviation values of A1C, TIR, mean sensor glucose (SG), coefficient of variation (CV) of SG, time at SG ranges, and insulin delivered between run-in and study were analyzed (Wilcoxon signed-rank test or t-test). Results: Compared with baseline, AHCL use was associated with reduced A1C from 7.9 ± 0.9% (N = 160) to 7.4 ± 0.7% (N = 136) (P < 0.001) and overall TIR increased from the run-in 59.4 ± 11.8% to 70.3 ± 6.5% by end of study (P < 0.001), without change in CV, time spent below range (TBR) <70 mg/dL, or TBR <54 mg/dL. Relative to longer active insulin time (AIT) settings (N = 52), an AIT of 2 h (N = 19) with the 100 mg/dL GT increased mean TIR to 73.4%, reduced TBR <70 mg/dL from 3.5% to 2.2%, and reduced time spent above range (TAR) >180 mg/dL from 28.7% to 24.4%. During AHCL use, there was no severe hypoglycemia or DKA. Conclusions: In children and adolescents with T1D, MiniMed AHCL system use was safe, A1C was lower, and TIR was increased. The lowest GT and shortest AIT were associated with the highest TIR and lowest TBR and TAR, all of which met consensus-recommended glycemic targets. ClinicalTrials.gov ID: NCT03959423.

An unusual presentation of primary adrenal insufficiency with new onset type 1 diabetes: case report and review of the literature.

OBJECTIVES: To describe an atypical presentation of primary adrenal insufficiency in conjunction with new onset type 1 diabetes. CASE PRESENTATION: Here, we describe a case of new-onset type 1 diabetes (T1D) presenting simultaneously with an unusual presentation of primary adrenal insufficiency in a previously healthy 16-year-old. He was admitted for a typical presentation of diabetic ketoacidosis, but with extreme hyponatremia. An extensive workup revealed a low aldosterone level, appropriate cortisol level, and positive 21-hydroxylase antibodies. While the phenomenon of multiple autoimmune conditions developing in the same patient is well-described, this particular case has several atypical aspects. Our patient's case highlights the danger of relying on random serum cortisol in the setting of acute illness to rule out adrenal insufficiency. CONCLUSIONS: Adrenal insufficiency can present as isolated hypoaldosteronism without hypocortisolemia and can manifest as severe hyponatremia in the context of diabetic ketoacidosis. Workup for an unusual presentation of T1D should include a 21-hydroxylase antibody, as well as thyroid and celiac disease studies.

Validation of a deep learning, value-based care model to predict mortality and comorbidities from chest radiographs in COVID-19.

We validate a deep learning model predicting comorbidities from frontal chest radiographs (CXRs) in patients with coronavirus disease 2019 (COVID-19) and compare the model's performance with hierarchical condition category (HCC) and mortality outcomes in COVID-19. The model was trained and tested on 14,121 ambulatory frontal CXRs from 2010 to 2019 at a single institution, modeling select comorbidities using the value-based Medicare Advantage HCC Risk Adjustment Model. Sex, age, HCC codes, and risk adjustment factor (RAF) score were used. The model was validated on frontal CXRs from 413 ambulatory patients with COVID-19 (internal cohort) and on initial frontal CXRs from 487 COVID-19 hospitalized patients (external cohort). The discriminatory ability of the model was assessed using receiver operating characteristic (ROC) curves compared to the HCC data from electronic health records, and predicted age and RAF score were compared using correlation coefficient and absolute mean error. The model predictions were used as covariables in logistic regression models to evaluate the prediction of mortality in the external cohort. Predicted comorbidities from frontal CXRs, including diabetes with chronic complications, obesity, congestive heart failure, arrhythmias, vascular disease, and chronic obstructive pulmonary disease, had a total area under ROC curve (AUC) of 0.85 (95% CI: 0.85-0.86). The ROC AUC of predicted mortality for the model was 0.84 (95% CI,0.79-0.88) for the combined cohorts. This model using only frontal CXRs predicted select comorbidities and RAF score in both internal ambulatory and external hospitalized COVID-19 cohorts and was discriminatory of mortality, supporting its potential use in clinical decision making.

MiniMedTM780G Insulin pump system with smartphone connectivity for the treatment of type 1 diabetes: overview of its safety and efficacy.

Introduction: Despite significant advances in diabetes care over the last three decades, the majority of people living with T1D are not meeting established metabolic goals. Automated insulin delivery can help achieve these metabolic goals (HbA1c and TIR).Areas covered: This review examines the new features and available data regarding safety and efficacy of the MiniMed™ 780 G, a second-generation advanced hybrid closed-loop system. Reported outcomes include time in, above and below range, HbA1c, diabetic ketoacidosis and severe hypoglycemia.Expert opinion: The initial pivotal trials of the MiniMed™ 780 G have demonstrated promising clinical and safety outcomes. Real-world data and longer-term studies are still needed. The success of AID devices moving forward hinges on their ease of use and ability to reduce and relieve the burden of living with T1D.

Single Islet Autoantibody at Diagnosis of Clinical Type 1 Diabetes is Associated With Older Age and Insulin Resistance.

CONTEXT: Multiple islet autoantibody positivity usually precedes clinical (stage 3) type 1 diabetes (T1D). OBJECTIVE: To test the hypothesis that individuals who develop stage 3 T1D with only a single autoantibody have unique metabolic differences. DESIGN: Cross-sectional analysis of participants in the T1D TrialNet study. SETTING: Autoantibody-positive relatives of individuals with stage 3 T1D. PARTICIPANTS: Autoantibody-positive relatives who developed stage 3 T1D (at median age 12.4 years, range = 1.4-58.6) and had autoantibody data close to clinical diagnosis (n = 786, 47.4% male, 79.9% non-Hispanic white). MAIN OUTCOME MEASURES: Logistic regression modeling was used to assess relationships between autoantibody status and demographic, clinical, and metabolic characteristics, adjusting for potential confounders and correcting for multiple comparisons. RESULTS: At diagnosis of stage 3 T1D, single autoantibody positivity, observed in 119 (15.1%) participants (72% GAD65, 13% microinsulin antibody assay, 11% insulinoma-associated antigen 2, 1% islet cell antibody, 3% autoantibodies to zinc transporter 8 [ZnT8]), was significantly associated with older age, higher C-peptide measures (fasting, area under the curve, 2-hour, and early response in oral glucose tolerance test), higher homeostatic model assessment of insulin resistance, and lower T1D Index60 (all P < 0.03). While with adjustment for age, 2-hour C-peptide remained statistically different, controlling for body mass index (BMI) attenuated the differences. Sex, race, ethnicity, human leukocyte antigen DR3-DQ2, and/or DR4-DQ8, BMI category, and glucose measures were not significantly associated with single autoantibody positivity. CONCLUSIONS: Compared with multiple autoantibody positivity, single autoantibody at diagnosis of stage 3 T1D was associated with older age and insulin resistance possibly mediated by elevated BMI, suggesting heterogeneous disease pathogenesis. These differences are potentially relevant for T1D prevention and treatment.

Fitness level and body composition are associated with inflammation in non-obese children.

Childhood obesity and poor fitness are associated with insulin resistance (IR), risk for coronary heart disease (CHD), and type 2 diabetes mellitus. Elevated markers of inflammation (e.g., C-reactive protein [CRP]) are independent predictors of CHD. Whether higher percent body fat and poor fitness in non-obese children are associated with evidence of inflammation and IR is unclear. We evaluated 75 children with non-obese body mass index (BMI) for age (<95th percentile), ages 11-14 years for fasting insulin, glucose, adiponectin, CRP, body composition, and maximum oxygen-consumption (VO2max). CRP correlated positively with body composition (BMI z-score, p = 0.00062; percent body fat, p = 0.00007; and total body fat in grams, p = 0.00006) and negatively with VO2max, p = 0.036. Using multivariate analysis, VO2max and percent body fat were both independent predictors of CRP. Fasting insulin and insulin resistance as assessed by QUICKI did not correlate with CRP, fitness, or fatness in these non-obese children. Adiponectin showed no significant correlations, and gender did not influence correlation analyses. We conclude that in non-obese children, low fitness and higher body fat are both associated with inflammation (i.e., higher levels of CRP). This observation strengthens the importance of promoting both fitness and healthy body composition in all children.

School-based exercise improves fitness, body composition, insulin sensitivity, and markers of inflammation in non-obese children.

BACKGROUND: Poor cardiovascular fitness (CVF) is a risk factor for obesity, as well as insulin resistance (IR), inflammation, and cardiovascular disease. We have previously shown that a school-based fitness curriculum can improve CVF, as well as IR and body composition in obese children. Whether such a program improves CVF, IR, and other health indicators in non-obese children is unresolved. AIM: To determine whether a school-based fitness program improves body composition, CVF, markers of inflammation (e.g. CRP, TNF-alpha, adiponectin), and insulin sensitivity in nonobese children. STUDY DESIGN: 35 non-obese middle school children with body mass index below the 95th percentile for age were enrolled in a 'fitness-oriented' gym class. Children underwent fasting evaluation of insulin, glucose, adiponectin, CRP, TNF-alpha, body composition by dual X-ray absorptiometry (DXA), and maximal VO2 treadmill testing at baseline (prior to the school year) and again at end of the school year. MAIN OUTCOME MEASURES: Testing for CVF (maximal VO2 treadmill testing), DXA, and fasting evaluation of insulin, glucose, adiponectin, CRP and TNF-alpha. RESULTS: Children demonstrated a decrease in BMI z-score (-0.14 +/- 0.33, p = 0.02), HOMA-IR (-0.15 +/- 0.35, p = 0.016), and TNF-alpha (-2.55 +/- 1.79 pg/ml, p < 0.001), and an increase in VO2(max) (+1.58 +/- 2.34 ml/kg/min, p < 0.001), adiponectin (+7,553 +/- 11,100 ng/ml, p < 0.001), and muscle mass (+2,282 +/- 1,882.73 g, p < 0.001) after nine months of study. CONCLUSIONS: The school-based fitness oriented curriculum resulted in improved body composition and insulin sensitivity, increased CVF, and decreased inflammation in non-obese children. Combined with prior studies, these data demonstrate that school-based fitness curricula can benefit both obese and non-obese children. Partnerships with schools to promote fitness should be part of a public health approach to improving children's health.

Effect of conjugated linoleic acid on body fat accretion in overweight or obese children.

BACKGROUND: Conjugated linoleic acid (CLA) is a supplemental dietary fatty acid that decreases fat mass accretion in young animals. OBJECTIVE: The aim of this study was to determine CLA's efficacy with regard to change in fat and body mass index (BMI; in kg/m(2)) in children. DESIGN: We conducted a 7 +/- 0.5-mo randomized, double-blind, placebo-controlled trial of CLA in 62 prepubertal children aged 6-10 y who were overweight or obese but otherwise healthy. The subjects were randomly assigned to receive 3 g/d of 80% CLA (50:50 cis-9,trans-11 and trans-10,cis-12 isomers) or placebo in chocolate milk. RESULTS: Fifty-three subjects completed the trial (n = 28 in the CLA group, n = 25 in the placebo group). CLA attenuated the increase in BMI (0.5 +/- 0.8) compared with placebo (1.1 +/- 1.1) (P = 0.05). The percentage change in body fat measured by dual-energy X-ray absorptiometry was smaller (P = 0.001) in the CLA group (-0.5 +/- 2.1%) than in the placebo group (1.3 +/- 1.8%). The change in abdominal body fat as a percentage of total body weight was smaller (P = 0.02) in the CLA group (-0.09 +/- 0.9%) than in the placebo group (0.43 +/- 0.6%). There were no significant changes in plasma glucose, insulin, or LDL cholesterol between groups. Plasma HDL cholesterol decreased significantly more (P = 0.05) in the CLA group (-5.1 +/- 7.3 mg/dL) than in the placebo group (-0.7 +/- 8 mg/dL). Bone mineral accretion was lower (P = 0.04) in the CLA group (0.05 +/- 0.03 kg) than in the placebo group (0.07 +/- 0.03 kg). Reported gastrointestinal symptoms did not differ significantly between groups. CONCLUSIONS: CLA supplementation for 7 +/- 0.5 mo decreased body fatness in 6-10-y-old children who were overweight or obese but did not improve plasma lipids or glucose and decreased HDL more than in the placebo group. Long-term investigation of the safety and efficacy of CLA supplementation in children is recommended.