Background and Aims

Residual beta cell function is crucial for prevention of complications. Most immune interventions have failed with minimal efficacy and/or unacceptable risks. GAD-alum (Diamyd^®) in combination with Vitamin D has shown promising results in Type 1 diabetes (T1D) patients carrying HLA DR3-DQ2.

We aimed to further explore the efficacy of intralymphatic GAD-alum (Diamyd^®) therapy combined with vitamin D on blood glucose recorded by continuous glucose monitoring (CGM) in individuals with recent-onset T1D carrying HLA DR3-DQ2.

Methods

DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12–24 years with GAD65 antibodies and fasting C-peptide >0.12 nmol/L, which randomized patients to either three intralymphatic injections of 4 μg GAD-alum and oral vitamin D, or placebo. 14-day CGM recording at Month 0, 6 and 15 were obtained. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values.

Results

We included 98 patients with CGM recordings of sufficient quality (27 Diamyd-treated and 15 placebo-treated DR3-DQ2-positive patients) with a median (mean) recording length of 14 (13) days. In DR3-DQ2-positive patients, % time in range (3.9-10 mmol/L; 70-180 mg/dL) declined less between baseline and Month 15 in Diamyd-treated compared to placebo-treated patients (-5.1% and -16.7%, respectively, P =.0075), with reduced time (P=.0036) and number of excursions (P=.0072) above 13.9 mmol/L (250 mg/dL), and better glucose management indicator (GMI, P=.0025). GMI correlated strongly with HbA1c after 6 months.

Conclusions

Intralymphatic GAD-alum (Diamyd®) improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

Background and Aims

An indirect treatment comparison (ITC) evaluated the efficacy and safety differences between 2 ready-to-use severe hypoglycemia rescue treatments, nasal glucagon (NG, Eli Lilly and Company) and liquid stable glucagon rescue pen (GRP, Xeris Pharmaceuticals), in adults with type 1 or type 2 diabetes.

Methods

Systematic literature reviews identified 3 randomized clinical trials assessing the efficacy and safety of NG versus reconstituted injectable glucagon (IG), and 3 trials of GRP versus IG. No head-to-head trials of NG versus GRP were identified. The Bayesian fixed-effect network meta-analysis was used to perform the ITC. Endpoints included the proportion of participants achieving treatment success (defined as increase in blood glucose to ≥70mg/dL or an increase of ≥20mg/dL from nadir blood glucose within 30mins), maximum blood glucose, and treatment-emergent adverse events (TEAE). Participants with a nadir blood glucose value of ≤54mg/dL were analyzed.

Results

A similar proportion of GRP (98.9%[279/282]) and NG participants (99.4%[155/156]) achieved treatment success (Wald method p=0.63). The mean max blood glucose values were 220mg/dL for GRP and 168mg/dL for NG, with a significant treatment difference between GRP and NG, while adjusting IG as a comparator (17.32mg/dL, 95% credible interval: [3.94, 30.97]). Proportions of participants experiencing ≥1 TEAE were 48.8% for GRP and 38.5% for NG (odds ratio: 1.31[0.67, 2.31]). Subgroup analyses showed consistent results.

Conclusions

NG and GRP had comparable efficacy in reversing insulin-induced hypoglycemia in adults with diabetes. NG had a mean max blood glucose below 180mg/dL, which may have implications on the re-establishment of euglycemia after severe hypoglycemia rescue.

Background and Aims

C-peptide (CP) is a useful measure in type 1 diabetes (T1D) to assess interventions to preserve beta cell function, risk progression in pre-clinical T1D and diabetes etiology. Venous sampling is limited due to practical considerations, including invasive sampling, limited access to phlebotomy, shielding patients, and remote consultations. We assessed plasma CP collected from a transdermal capillary blood (TCB) device as a practical alternative.

Methods

71 children and adults with T1D (median age 14.8y(IQR 9.1-17.7), diabetes duration 4.0y(1.5-7.7)) and 20 controls (age 42.2y(IQR:38.0-52.1) had a concomitant venous and TCB sample collected for measurement of plasma CP. Acceptability was assessed by age-appropriate questionnaires.

Results

Venous plasma CP was assessed across a wide range of values (median=45.5pmol/L, IQR(<3.3, 626), range (<3pmol/L, 2792). Median TCB plasma volume was 50uL(IQR 40, 50). TCB plasma CP was highly correlated to venous plasma CP (correlation coefficient=0.996). TCB CP had 100% sensitivity and 98% specificity to detect venous CP >200pmol/L.

Children and adults with T1D self-reported higher pain scores for venous compared to TCB sampling (<16y: 2/10 venous vs 1.1/10 TCB, 0=no pain, 10=very painful); >16y: 2.9/7 vs 1.2/7, 1=no pain, 7=very painful). T1D participants preferred TCB over venous sampling (63% (44/70) vs 7% (5/70)); 30% (21/70) were undecided.

Conclusions

Transdermal collection for C-peptide is a highly sensitive and specific method for detecting endogenous insulin production and is a preferred method in children, young people and adults with type 1 diabetes compared to venous sampling. TCB may be a practical alternative to venous sampling for C-peptide, avoiding the need to access a healthcare professional for traditional venepuncture.

Background and Aims

The DFRQ is a widely-used measure of parent involvement in diabetes management, created >30 years ago. With increased use of diabetes technologies, it is timely to update the DFRQ regarding CGM use. We evaluated the psychometric properties of an updated DFRQ.

Methods

Youth with T1D participating in a CGM study and their parents completed the DFRQ survey with four additional CGM-specific items (i.e., responding to CGM alerts/alarms). Higher scores indicate more parent involvement. Item-to-total correlations and Cronbach’s α assessed internal consistency; correlations determined concurrent and predictive validity.

Results

Participants (N=119, 49% female) were (mean±SD) aged 13.2±2.7yrs, with T1D for 6.6±3.5yrs.

The revised survey had 14 items after removal of items with little variability, low item-to-total correlation, or outdated features.

Cronbach’s α for the updated DFRQ was 0.88 for youth and 0.93 for parents. Youth and parent DFRQ scores were highly correlated (r=0.81, p<0.0001). Youth and parent scores were inversely correlated with youth age (r=-0.76, r=-0.81, respectively, both p<0.0001) and T1D duration (r=-0.23, p=0.01; r=-0.33, p=0.0004).

Higher youth and parent scores were also correlated with higher parent reports of youth diabetes treatment adherence (r=0.43, r=0.49, respectively, both p<0.0001).

For youth aged <13yrs, higher parent DFRQ scores were positively associated with youth CGM percent time-in-range (TIR) (70-180mg/dL) 3 months later (r=0.36, p=0.02).

Conclusions

The updated DFRQ youth and parent surveys demonstrated strong psychometric properties and predictive validity for percent TIR for youth aged <13yrs. These surveys can help assess family responsibility-sharing for CGM use in clinical and research settings.

Background and Aims

Initiating onto an injectable diabetes treatment can be met with resistance, concerns, and misconceptions by end users (2009, Rubin et al., 2014, Brod et al.). Without addressing these issues, patients may reject or discontinue their treatment (Atvur, 2021).

Methods

We performed thematic analysis of qualitative and quantitative research regarding the lived experiences of people on injectable therapies for T2 diabetes. We synthesized findings relating to end user concerns, desires, and expectations in order to form a list of “jobs-to-be-done” for a successful solution (2016, Chistensen et al.)

Results

This analysis uncovered >70 jobs-to-be-done, constraints, and outcome expectations people initiating on injectable therapy may experience. These findings were organized into 5 UX criteria which can be used for improving system design decisions for T2 treatment solutions.

Conclusions

The resulting 5 UX criteria can be used to inform foundational design and systems development activities towards a more user-centred T2 treatment solution.

Background and Aims

DME is a serious, vision-threatening complication of diabetic retinopathy. Intravitreal anti-VEGF therapy is the standard of care for DME; however, optimal vision outcomes often require frequent injections that are burdensome for patients, caregivers, and health care systems. Dual inhibition of VEGF-A and angiopoietin-2 may promote vascular stability and durable efficacy beyond anti-VEGF therapies. YOSEMITE (NCT03622580) and RHINE (NCT03622593) evaluated dual VEGF-A/angiopoietin-2 inhibition with faricimab, the first bispecific antibody designed for intraocular use.

Methods

Patients with DME were randomized 1:1:1 to faricimab every 8 weeks (Q8W), faricimab per personalized treatment interval (PTI), or aflibercept Q8W. Dosing intervals in the PTI arms were adjusted (Q4W up to Q16W) based on prespecified vision and anatomic criteria. The primary endpoint was mean best-corrected visual acuity change at 1 year, averaged over weeks 48, 52, and 56. Other efficacy and safety endpoints were assessed Q4W through week 100.

Results

In total, 1891 patients were enrolled in YOSEMITE (N = 940) and RHINE (N = 951). Both trials met their primary endpoint: mean 1-year vision gains with faricimab Q8W or PTI were noninferior to aflibercept Q8W. Anatomic outcomes (including change in central subfield thickness, absence of DME, and absence of intraretinal fluid over time) consistently favored faricimab over aflibercept. At week 52, > 50% and > 70% of the faricimab PTI arms achieved Q16W and ≥ Q12W dosing, respectively. Faricimab was well tolerated, with no new safety signals identified.

Conclusions

At 1 year, faricimab Q8W or PTI offered durable vision gains and anatomic improvements with up to Q16W dosing.

Background and Aims

Hypoglycemia is life-threatening and can lead to serious physical and psychological sequelae resulting in fear of hypoglycemia (FOH). FOH can impact diabetes self-management, glycemic control and reduce quality of life. The aim of this study was to determine the impact of a cognitive-behavioral therapy intervention (Fear Reduction Efficacy Evaluation [FREE]) compared to a diabetes education attention control on the primary outcome of FOH and secondary outcomes of self-management, glycemic control and variability.

Methods

This clinical trial of 51 young adults (18-35 years) with T1D > 1 year who experienced FOH were randomized to 8 weeks of either the FREE program or a diabetes education attention control group. Real-time continuous glucose monitors (CGM) were worn by all participants. Measures of FOH, A1C, CGM-derived glucose parameters and diabetes self-management were obtained at: baseline (week 0) and post-program (weeks 8 and 12).

Results

FOH was reduced and self-management improved at the end of the FREE program compared to the attention control. FREE was associated with an improvement in glycemic parameters: time-in-range (TIR; +6.4% vs. -0.7% p = .011) and reduced time in hyperglycemia (-5.4% vs. +0.6%, p = .028) respectively, compared to the attention control group. FREE had direct and indirect effects on self-management behavior and TIR.

Conclusions

A cognitive behavioral therapy-based intervention demonstrated promise in reducing FOH and improving glucose indices by improving self-management behavior.

Background and Aims

Acetone in exhaled breath has the potential to be a biomarker for non-invasive monitoring of the progress of diabetes. From this point of view, an acetone bio-sniffer (gas-phase biosensor) for the assessment of acetone in exhaled breath for early diagnosis of diabetes mellitus was developed and applied to the breath acetone analysis.

Methods

NADH-dependent secondary alcohol dehydrogenase (S-ADH) can reduce acetone to be isopropanol with the oxidation of NADH to NAD+. Therefore, the decreasing of NADH fluorescence intensity with the S-ADH reaction can be utilized to determinate acetone concentration. The acetone bio-sniffer was composed of an NADH fluorescence measurement unit, a flow-cell attached to the optical fiber probe, and an enzyme-immobilized membrane. When bio-sniffer contacted the gaseous acetone, the change of fluorescence intensity caused by S-ADH would be detected by the photo detector.

Results

This acetone bio-sniffer showed high sensitivity to acetone vapor. The dynamic range of the sensor was from 20 to 5300 ppb acetone. Then, we applied the bio-sniffer to measure breath acetone concentration. The mean concentration of breath acetone in all healthy subjects was 750.0 ppb. However, the mean exhaled acetone in diabetic patients was 1207.7 ppb, which was much higher than that in healthy subjects and showed a significant difference.

Conclusions

The breath acetone level for diabetic patients was higher than that of healthy subjects. This finding is worthwhile in the study of breath biomarkers for diabetes mellitus diagnosis. This bio-sniffer provides a new kind of analytical tool for the non-invasive early diagnosis of diabetes mellitus in the near future.

Background and Aims

Despite documented benefits of Continuous Glucose Monitors and insulin pumps in managing type 1 diabetes, inequities in the use of devices persist with lower use among Non-Hispanic Blacks and Hispanic patients compared to Non-Hispanic White patients. We aimed to examine the role of insurance mediated provider implicit bias in recommending diabetes technology

Methods

One hundred and nine adult and pediatric diabetes providers across seven US endocrinology centers completed an implicit bias assessment using a revised D-PIB tool. Providers were randomized and assigned case vignettes with different insurance statuses and patient names to proxy racial identity. Bias was tagged as providers recommending more technology for patients with private insurance or ranking insurance as one of the top 3 factors considered in recommending diabetes technology. Analysis was done using descriptive statistics and multivariate logistic regression.

Results

Implicit bias against public insurance was common (n=66, 61%). When compared to those who had a bias, providers who did not have bias had fewer practice years (5.3±5.3 years vs 9.3±9 years, p=0.006). The difference in mean age between the group with bias (42.2±11 years) versus the group without bias (38.3±9.3 years) trended towards significance, p=0.05. The provider's sex, race/ethnicity, personal diagnosis of T1D, roles, workplace characteristics, or perception of bias did not differ in the groups

Conclusions

Insurance mediated implicit bias was observed in our cohort. Addressing implicit bias will involve an approach rooted in racial justice, economic equity, and equitable access to health care and education. Public insurers need to increase equitable coverage to reduce inequities

Background and Aims

Basal insulin Fc (BIF; LY3209590) is a novel, once-weekly, long-acting IgG Fc-fusion protein assessed for the treatment of diabetes mellitus. A 32-week study evaluating the safety and efficacy of BIF vs degludec in persons with type 2 diabetes mellitus (T2DM) previously treated with a basal insulin showed HbA1c non-inferiority of BIF vs degludec with significantly fewer hypoglycemic events (≤70 mg/dL). Here we present continuous glucose monitoring (CGM) data derived by Dexcom G6, allowing a more detailed assessment of glycemic control of BIF vs degludec.

Methods

The study included 2 dosing algorithms for BIF with different fasting glucose (FG) targets: ≤140 mg/dL (BIF-A1) and ≤120 mg/dL (BIF-A2). Degludec was titrated to FG ≤100 mg/dL. Subjects were randomized to 1 of the 3 arms.

Results

Subject (N=399) mean age was 60.2 yrs and baseline HbA1c was 8.1%. For the entire 32 weeks, the percent of 24 hrs in range, hyperglycemia and hypoglycemia was similar for the 3 arms (Figure). At Week 32, total duration of hypoglycemia was similar across 7 days post-injection for BIF-A1 and A2, showing that duration of hypoglycemia is independent of day post-injection.

Conclusions

CGM data confirm that BIF showed similar glycemic control vs degludec despite higher FG targets and numerically lower time in hypoglycemia. The flat pharmacokinetic profile enables near peakless insulin concentrations without an increase in hypoglycemia risk at highest exposure.