This phase 3, treat-to-target study evaluated efficacy and safety of URLi vs. lispro in 716 pediatric patients (pts) with type 1 diabetes (T1D) . After 4-week lead-in to optimize basal insulin, pts ...were randomized to double-blind URLi (n=280) or lispro (n=298) injected 0-2 min prior to meals, or open-label URLi (n=138) injected up to 20 min after meals (URLi+20) . Pts remained on prestudy basal insulin (degludec, detemir, or glargine) . Primary endpoint was HbA1c change from baseline after 26 weeks.
Noninferiority was shown in HbA1c change with URLi vs. lispro: estimated treatment difference (ETD) -0.02% (95% CI -0.17, 0.13) and with URLi+20 vs. lispro: ETD -0.02% (95% CI -0.20, 0.17) . Postprandial glucose (PPG) measured by self-monitored blood glucose (SMBG) was lower with URLi vs. lispro 1 h after breakfast (p<0.001) and dinner (p=0.006) . URLi significantly reduced 1 h postmeal glucose daily mean vs. lispro (p=0.001) . Total daily insulin dose was similar between treatments.
There were no significant differences among treatments in rate or incidence of severe, nocturnal or documented hypoglycemia (<54 mg/dL) . With URLi vs. lispro, rate of postdose hypoglycemia (<54 mg/dL) was higher at ≤2 h (p=0.034) . Incidence of treatment-emergent adverse events was similar between groups. More pts reported an injection site reaction related event with URLi (7.9%) and URLi+20 (2.9%) vs. lispro (2.7%) . All injection site reactions were mild or moderate in severity. Two URLi patients discontinued the study due to injection site reactions.
In children and adolescents with T1D, URLi demonstrated similar overall glycemic control and greater PPG lowering with an acceptable safety and tolerability profile compared with lispro. URLi dosed at the start of meals or up to 20 min after the start of meals showed noninferiority for HbA1c change from baseline vs. lispro. URLi dosed at the beginning of meals showed lower PPG at 1 h after breakfast and dinner and lower 1 h postmeal glucose daily mean vs. lispro.
Disclosure
R. Wadwa: Advisory Panel; Dompé. Consultant; Beta Bionics, Inc. Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. Other Relationship; Tandem Diabetes Care, Inc. L.M. Laffel: Advisory Panel; Medtronic, Roche Diabetes Care. Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. D.R. Franco: Advisory Panel; Abbott Diabetes, Medtronic, Novo Nordisk, Sanofi. Research Support; Eli Lilly and Company. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Medtronic, Roche Diabetes Care, Sanofi. M.A. Dellva: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. R.K. Pollom: Employee; Eli Lilly and Company.
Funding
Eli Lilly and Company
Treatment of severe hypoglycemia outside of the hospital setting is limited to intramuscular glucagon requiring reconstitution prior to injection. The current study examined the safety and ...dose-response relationships of a needle-free intranasal glucagon preparation in youth aged 4 to <17 years.
A total of 48 youth with type 1 diabetes completed the study at seven clinical centers. Participants in the two youngest cohorts (4 to <8 and 8 to <12 years old) were randomly assigned to receive either 2 or 3 mg intranasal glucagon in two separate sessions or to receive a single, weight-based dose of intramuscular glucagon. Participants aged 12 to <17 years received 1 mg intramuscular glucagon in one session and 3 mg intranasal glucagon in the other session. Glucagon was given after glucose was lowered to <80 mg/dL (mean nadir ranged between 67 and 75 mg/dL).
All 24 intramuscular and 58 of the 59 intranasal doses produced a ≥25 mg/dL rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts.
Results of this phase 1, pharmacokinetic, and pharmacodynamic study support the potential efficacy of a needle-free glucagon nasal powder delivery system for treatment of hypoglycemia in youth with type 1 diabetes. Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to <17-year age range.
Continuous glucose monitors (CGM) display real-time glucose values enabling greater glycemic awareness with reduced management burden. Factory-calibrated CGM systems allow for glycemic assessment ...without the pain and inconvenience of fingerstick glucose testing. Advances in sensor chemistry and CGM algorithms have enabled factory-calibrated systems to have greater accuracy than previous generations of CGM technology. Despite these advances many patients and providers are hesitant about the idea of removing fingerstick testing from their diabetes care. In this commentary, we aim to review the clinical trials on factory-calibrated CGM systems, present the algorithms which facilitate factory-calibrated CGMs to improve accuracy, discuss clinical use of factory-calibrated CGMs, and finally present two cases demonstrating the dangers of utilizing exploits in commercial systems to prolong sensor life.
The objective of this study was to assess the safety and effectiveness of the first commercial configuration of a tubeless automated insulin delivery system, Omnipod
5, in children (6-13.9 years) and ...adults (14-70 years) with type 1 diabetes (T1D) in an outpatient setting.
This was a single-arm, multicenter, prospective clinical study. Data were collected over a 14-day standard therapy (ST) phase followed by a 14-day hybrid closed-loop (HCL) phase, where participants (
= 36) spent 72 h at each of three prespecified glucose targets (130, 140, and 150 mg/dL, 9 days total) then 5 days with free choice of glucose targets (110-150 mg/dL) using the Omnipod 5. Remote safety monitoring alerts were enabled during the HCL phase. Primary endpoints were difference in time in range (TIR) (70-180 mg/dL) between ST and HCL phases and proportion of participants reporting serious device-related adverse events.
Mean TIR was significantly higher among children in the free-choice period overall (64.9% ± 12.2%,
< 0.01) and when using a 110 mg/dL target (71.2% ± 10.2%,
< 0.01), a 130 mg/dL target (61.5% ± 7.7%,
< 0.01), and a 140 mg/dL target (64.8% ± 11.6%,
< 0.01), and among adults using a 130 mg/dL target (75.1% ± 11.6%,
< 0.05), compared to the ST phase (children: 51.0% ± 13.3% and adults: 65.6% ± 15.7%). There were no serious device-related adverse events reported during the HCL phase, nor were there episodes of severe hypoglycemia or diabetic ketoacidosis.
The Omnipod 5 System was safe and effective when used at glucose targets from 110 to 150 mg/dL for 14 days at home in children and adults with T1D.
Many youth with T1D and their parents do not achieve sufficient sleep duration or quality. While HCL use improves nocturnal glycemic control, it is unclear whether sleep duration and quality are ...impacted. The objective of this study was to measure sleep outcomes in children with T1D and parents after HCL initiation.
Youth with T1D starting the Tandem Control-IQ (CIQ) and a parent enrolled in an observational study. Actigraphy data (sleep duration, sleep efficiency, and wake after sleep onset (WASO)) and sleep surveys (Pittsburgh Sleep Quality Index (PSQI) , PROMIS Pediatric Sleep Disturbance and Sleep-Related Impairment) were collected at baseline and 3- and 6-months after CIQ initiation.
Thirty-nine youth (11.1±3.6 yrs (range 3-17) , T1D duration 2.5±3.0 yrs, 54% male) and parents (42.5±6.7 yrs, 18% male) participated. Parents significantly improved WASO at 3- and 6-months (p=0.0 and 0.007) and sleep quality at 3-months (p=0.011) . No significant changes in subjective or objective sleep outcomes for children occurred other than a decrease in PROMIS Sleep-Related Impairment parent proxy at 3 months (p=0.041) .
Youth with T1D and their parents experience insufficient sleep duration and poor sleep quality. Parent subjective sleep quality and WASO improved with CIQ use. Improving sleep quality is complex and further research is needed to identify causes of sleep disruptions and intervention methods.
Disclosure
E.C.Cobry: None. A.J.Karami: None. T.B.Vigers: None. L.Pyle: None. E.Jost: Other Relationship; Tandem Diabetes Care, Inc. L.J.Meltzer: None. R.Wadwa: Advisory Panel; Dompé, Consultant; Beta Bionics, Inc., Other Relationship; Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc.
Funding
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (K12DK094712)
TG concentrations across lipoprotein subclasses associate with diabetic kidney disease (DKD) in adults with T1D, but little is known about this relationship in youth with T1D. We evaluated ...cross-sectional relationships among TG concentrations across lipoprotein subclasses, intraglomerular hemodynamics, and renal oxygen availability (RO2) in youth with T1D. Glomerular filtration rate (GFR) , RO2, renal plasma flow (RPF) , afferent arteriolar resistance (RA) , efferent arteriolar resistance (RE) , intraglomerular pressure (PGLO) , and urine albumin-to-creatinine ratio (UACR) were assessed. Concentrations of lipid constituents from lipoprotein subclasses were quantified via targeted nuclear magnetic resonance spectroscopy (Nightingale Health Ltd., Helsinki, Finland) . Particle sizes for VLDL, LDL, intermediate-density lipoprotein, and HDL were measured. Fifty youth with T1D (age 16.0 ± 3.0 years, 50% female, HbA1c 8.7 ± 1.3%, T1D duration 5.7 ± 2.6 years) and 20 without T1D were included. VLDL-TG concentrations and small LDL-TG correlated with intraglomerular hemodynamic function parameters and RO2. To conclude, strong relationships were found among renal function markers and TG concentrations across lipoprotein subclasses in adolescents with T1D.
Disclosure
M.E.Pauley: None. K.L.Tommerdahl: None. C.Vinovskis: None. L.Pyle: None. R.Wadwa: Advisory Panel; Dompé, Consultant; Beta Bionics, Inc., Other Relationship; Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. R.G.Nelson: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company.
Funding
MEP supported by NIH (T32DK063687) ; KLT supported by NIH (K23 HL159292) , Children’s Hospital Colorado Research Institute Research Scholar Award, University of Colorado Diabetes Research Center (P30 DK116073) , Ludeman Family Center for Women’s Health Research at the University of Colorado, and Dept of Pediatrics, Section of Endocrinology at University of Colorado School of Medicine; PB supported by NIDDK (RDK129211, R21 DK129720, K23 DK116720, UC DK114886, and P30 DK116073) , JDRF (2-SRA-2019-845-S-B, 3-SRA-2017-424-M-B, 3-SRA-2022-1097-M-B) , Boettcher Foundation, American Heart Association (20IPA35260142) , Ludeman Family Center for Women’s Health Research at the University of Colorado, Department of Pediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine
Few studies have examined the relationship between diabetes-related family conflict and parent fear of hypoglycemia (FOH) in adolescents, thus the current research evaluated this connection. This ...study specifically examined three subdimensions of FOH which parents of children with diabetes may experience: maintaining blood glucoses higher than medical recommendations, worrying about and/or feeling helplessness about preventing low blood glucoses, and worrying about social consequences associated with low blood glucoses.
At the baseline visit of an RCT aimed at improving health outcomes of youth with elevated A1C (9-12% in the last year) , caregivers completed the Diabetes Family Conflict Scale and the Parent Hypoglycemia Fear Survey. N=1child-caregivers dyads (child age=14.7±1.9 years, T1D duration=6.5±3.4 years, A1C=9.9±1.6%; 53% female; 77% continuous glucose monitor; 82% insulin pump) .
In three separate regression models, no child demographic or T1D clinical characteristics other than A1C were associated with family conflict. After controlling for A1C, only Worry/Helplessness About Low Blood Glucose (b=0.182; p=0.025) and Worry About Negative Social Consequences (b=0.532; p=0.008) significantly predicted parent-reported family conflict; Maintain High Blood Glucose (b=0.082; p=0.73) was not significant.
This is the first study to demonstrate that caregivers’ worry about their adolescents having low blood glucoses is associated with diabetes-specific family conflict- a common adherence barrier for adolescents with T1D and their families. This finding supports screening caregivers for fear of hypoglycemia and incorporating into treatment when providing intervention for families with high levels of conflict. Important next steps include dyadic data analysis to understand how fear of hypoglycemia symptoms among child-caregiver dyads affect family conflict.
Disclosure
H.Manis: Other Relationship; Abbott Diabetes. H.K.O'donnell: None. G.T.Alonso: None. S.Majidi: None. J.K.Snell-bergeon: Stock/Shareholder; GlaxoSmithKline plc. R.Wadwa: Advisory Panel; Dompé, Consultant; Beta Bionics, Inc., Other Relationship; Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. K.A.Driscoll: None.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK113363)
Objective To test the hypothesis that cardiovascular disease (CVD) risk factors are similar in nondiabetic (non-DM) adolescents compared with those with type 1 diabetes (T1D) in the most ...insulin-sensitive (IS) tertile, and that CVD risk factors are more atherogenic with decreasing IS in adolescents with T1D. Study design IS for adolescents with T1D (n = 292; age = 15.4 ± 2.1 years; duration = 8.8 ± 3.0 years, hemoglobin A1c = 8.9% ± 1.6%) and non-DM controls (n = 89; age = 15.4 ± 2.1 years) was estimated using the model: loge IS = .64725 − 0.02032 (waist cm) − 0.09779 (hemoglobin A1c %) − 0.00235 (triglycerides mg/dL). CVD risk factors (blood pressure, fasting total and low- and high-density lipoprotein-cholesterol (HDL-c), high sensitivity C-reactive protein, and body mass index z score) were compared between all non-DM adolescents and those with T1D in the most IS tertile, and then examined for a linear trend by IS tertile in adolescents with T1D, adjusted for sex, race/ethnicity, and Tanner stage. Results Estimated IS was significantly lower in adolescents with T1D compared with those without (T1D = 7.8 ± 2.4, non-DM = 11.5 ± 2.9; P < .0001). CVD risk factors were similar for non-DM compared with the adolescents with T1D with the most IS, except for higher (HDL-c) and diastolic blood pressure in adolescents with T1D ( P < .05). Among adolescents with T1D, all CVD risk factors except for (HDL-c), were more atherogenic across decreasing IS tertiles in linear regression analysis ( P < .05). Conclusion Adolescents with T1D who are the most IS have similar CVD risk factors compared with non-DM adolescents. CVD risk factors are inversely associated with IS in adolescents with T1D. IS may be an important therapeutic target for reducing CVD risk factors in adolescents with T1D.
Treatment of severe hypoglycemia with loss of consciousness or seizure outside of the hospital setting is presently limited to intramuscular glucagon requiring reconstitution immediately prior to ...injection, a process prone to error or omission. A needle-free intranasal glucagon preparation was compared with intramuscular glucagon for treatment of insulin-induced hypoglycemia.
At eight clinical centers, a randomized crossover noninferiority trial was conducted involving 75 adults with type 1 diabetes (mean age, 33 ± 12 years; median diabetes duration, 18 years) to compare intranasal (3 mg) versus intramuscular (1 mg) glucagon for treatment of hypoglycemia induced by intravenous insulin. Success was defined as an increase in plasma glucose to ≥70 mg/dL or ≥20 mg/dL from the glucose nadir within 30 min after receiving glucagon.
Mean plasma glucose at time of glucagon administration was 48 ± 8 and 49 ± 8 mg/dL at the intranasal and intramuscular visits, respectively. Success criteria were met at all but one intranasal visit and at all intramuscular visits (98.7% vs. 100%; difference 1.3%, upper end of 1-sided 97.5% CI 4.0%). Mean time to success was 16 min for intranasal and 13 min for intramuscular (P < 0.001). Head/facial discomfort was reported during 25% of intranasal and 9% of intramuscular dosing visits; nausea (with or without vomiting) occurred with 35% and 38% of visits, respectively.
Intranasal glucagon was highly effective in treating insulin-induced hypoglycemia in adults with type 1 diabetes. Although the trial was conducted in a controlled setting, the results are applicable to real-world management of severe hypoglycemia, which occurs owing to excessive therapeutic insulin relative to the impaired or absent endogenous glucagon response.
Vitamin D deficiency is common and associated with increased cardiovascular disease (CVD) risk. Pulse wave velocity (PWV) is a marker of vascular stiffness associated with CVD. We hypothesized that ...Vitamin D (25 (OH) D) levels would be inversely associated with PWV in youth with and without type 1 diabetes (T1D).
Comparisons were made between adolescents with T1D (n = 211; age = 17.5 ± 2.3 years; diabetes duration = 10.9 ± 3.2 years; A1c = 9.1 ± 1.7%) and non-DM controls (n = 67; age = 16.9 ± 1.9 years). PWV was measured in the carotid-femoral segment (Sphygmocor Vx, AtCor Medical, Lisle, IL).
Vitamin D levels were similar in adolescents with T1D and controls (27.7 ± 0.7 v. 26.0 ± 1.3 ng/ml; p = 0.26). Vitamin D was significantly inversely associated with PWV after adjusting for age, sex, quarter of the year, and race-ethnicity in adolescents with T1D (beta = -0.01 ± 0.004, p = 0.02) but not in the non-DM adolescents (beta = -0.008 ± 0.008, p = 0.32). Vitamin D remained significantly associated with PWV after additionally adjusting for hs-CRP in adolescents with T1D (-0.01 ± 0.004, p = 0.01). After adjusting for BMI z-score, lipids, or blood pressure, the relationship of Vitamin D with PWV was not significant.
Vitamin D levels were inversely associated with PWV in adolescents with T1D, but not independently of BMI, lipids, or blood pressure. Our data contrast with other reports and suggest further research is indicated to determine if Vitamin D supplementation would be beneficial to lower CVD risk in adolescents with T1D with vitamin D insufficiency or deficiency.
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