In this trial, high-risk nondiabetic relatives of patients with type 1 diabetes were randomly assigned to receive teplizumab (an anti-CD3 monoclonal antibody) or placebo and were followed for type 1 ...diabetes. Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants.
Following a diagnosis of type 1 diabetes (T1D), persisting C-peptide secretion leads to improved glycemic control and outcomes. Residual β-cell function is often assessed with serial mixed-meal ...tolerance tests, but these tests do not correlate well with clinical outcomes. Herein, we instead use β-cell glucose sensitivity (βGS) to assess changes in β-cell function, incorporating insulin secretion for a given serum glucose into the assessment of β-cell function. We evaluated changes in βGS in individuals enrolled in the placebo arm of 10 T1D trials performed at diabetes onset. We found that βGS showed a more rapid decline in children, as compared with adolescents and adults. Individuals in the top quartile of βGS baseline distribution had a slower rate in loss of glycemic control time over time. Notably, half of this group were children and adolescents. Finally, to identify predictors of glycemic control throughout follow-up, we ran multivariate Cox models and found that incorporating βGS significantly improved the overall model. Taken together, these data suggest that βGS may be of great utility in predicting those more likely to have a more robust clinical remission and may be of use in design of new-onset diabetes clinical trials and in evaluating response to therapies.
We undertook this study to better predict β-cell loss following type 1 diabetes diagnosis. We set out to answer whether β-cell glucose sensitivity (βGS) improves means to evaluate β-cell function postdiagnosis and whether βGS correlates with clinical outcomes. We found that βGS declines faster in children, subjects in the top baseline quartile of βGS exhibit slower β-cell decline (half are children), and incorporating βGS into multivariate Cox models for glycemic improves the model. The implications of our findings are that βGS predicts those likely to have robust clinical remissions and may help with clinical trials design.
Summary Background The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main ...antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes. Methods In this multicentre, double-blind, randomised controlled trial, patients aged 6–45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov , NCT00505375. Findings 112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6·1–112) higher at 2 years with abatacept (n=73, 0·378 nmol/L) than with placebo (n=30, 0·238 nmol/L; p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months' delay (95% CI 3·47–15·6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 22% patients on abatacept and 11 reactions in six 17% on placebo). There was no increase in infections (32 42% patients on abatacept vs 15 43% on placebo) or neutropenia (seven 9% vs five 14%). Interpretation Co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions. Funding US National Institutes of Health.
Type 1 diabetes (T1D) is an autoimmune disease that occurs in genetically susceptible individuals. Regulatory T cells (Tregs) have been shown to be defective in the autoimmune disease setting. Thus, ...efforts to repair or replace Tregs in T1D may reverse autoimmunity and protect the remaining insulin-producing β cells. On the basis of this premise, a robust technique has been developed to isolate and expand Tregs from patients with T1D. The expanded Tregs retained their T cell receptor diversity and demonstrated enhanced functional activity. We report on a phase 1 trial to assess safety of Treg adoptive immunotherapy in T1D. Fourteen adult subjects with T1D, in four dosing cohorts, received ex vivo-expanded autologous CD4(+)CD127(lo/-)CD25(+) polyclonal Tregs (0.05 × 10(8) to 26 × 10(8) cells). A subset of the adoptively transferred Tregs was long-lived, with up to 25% of the peak level remaining in the circulation at 1 year after transfer. Immune studies showed transient increases in Tregs in recipients and retained a broad Treg FOXP3(+)CD4(+)CD25(hi)CD127(lo) phenotype long-term. There were no infusion reactions or cell therapy-related high-grade adverse events. C-peptide levels persisted out to 2+ years after transfer in several individuals. These results support the development of a phase 2 trial to test efficacy of the Treg therapy.
We aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes in youth.
We studied 1,117 children in the TrialNet Pathway to Prevention cohort ...(autoantibody-positive relatives of patients with type 1 diabetes). Longitudinally accumulated BMI above the 85th age- and sex-adjusted percentile generated a cumulative excess BMI (ceBMI) index. Recursive partitioning and multivariate analyses yielded sex- and age-specific ceBMI thresholds for greatest type 1 diabetes risk.
Higher ceBMI conferred significantly greater risk of progressing to type 1 diabetes. The increased diabetes risk occurred at lower ceBMI values in children <12 years of age compared with older subjects and in females versus males.
Elevated BMI is associated with increased risk of diabetes progression in pediatric autoantibody-positive relatives, but the effect varies by sex and age.
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical ...phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.
Abstract Type 1 diabetes mellitus (T1DM) results from autoimmune destruction of insulin producing beta cells. Regulatory T cells (Tregs) have been shown to be defective in this setting. ...Immuno-therapies targeting T cells, and resetting the balance between T effectors and Tregs, have had some initial success in preserving beta cell function. With a goal to use Tregs themselves as a novel therapeutic, we developed a technique to isolate and expand Tregs from patients with T1DM. These ex vivo expanded CD4+ CD127lo/− CD25+ cells exhibit improved function and retain their T cell receptor diversity. These cells have subsequently been used in phase I clinical trials in patients with recent onset T1DM. The infusions were well tolerated, with no safety concerns. The studies are too small to assess efficacy definitively, although some individuals exhibit stable beta cell function over intervals as long as 2 years. These efforts set the stage for a larger phase II effort in new onset T1DM, and combination studies with other drugs, as well as efforts in other autoimmune diseases.
Objective:
Real-time continuous glucose monitoring (CGM) is effective for diabetes management in cases of type 1 diabetes and adults with type 2 diabetes (T2D) but has not been assessed in ...adolescents and young adults (AYAs) with T2D. The objective of this pilot interventional study was to assess the feasibility and acceptability of real-time CGM use in AYAs with T2D.
Methods:
Adolescents and young adults (13-21 years old) with T2D for six months or more and hemoglobin A1c (A1c) greater than 7%, on any Food and Drug Administration–approved treatment regimen, were included. After a blinded run-in period, participants were given access to a real-time CGM system for 12 weeks. The use and acceptability of the real-time CGM were evaluated by sensor usage, surveys, and focus group qualitative data.
Results:
Participants’ (n = 9) median age was 19.1 (interquartile range IQR 16.8-20.5) years, 78% were female, 100% were people of color, and 67% were publicly insured. Baseline A1c was 11.9% (standard deviation ±2.8%), with median diabetes duration of 2.5 (IQR 1.4-6) years, and 67% were using insulin. Seven participants completed the study and demonstrated statistically significant improvement in diabetes-related quality of life, with the mean Pediatric Quality of Life inventory (PedsQL) diabetes score increasing from 70 to 75 after using CGM (P = .026). Focus group results supported survey results that CGM use among AYAs with T2D is feasible, can improve quality of life, and has the potential to modify behavior.
Conclusion:
Real-time CGM is feasible and acceptable for AYAs with T2D and may improve the quality of life of patients with diabetes. Larger randomized controlled trials are needed to assess the effects on glycemic control and healthy lifestyle changes.
Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or ...older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown.
In this phase 3, randomized, placebo-controlled trial, we assessed β-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in β-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events.
Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval CI, 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome.
Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of β-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).
Trials of immune therapies in new-onset type 1 diabetes (T1D) have shown success, but not all subjects respond, and the duration of response is limited. Our aim was to determine whether two courses ...of teplizumab, an Fc receptor–nonbinding anti-CD3 monoclonal antibody, reduces the decline in C-peptide levels in patients with T1D 2 years after disease onset. We also set out to identify characteristics of responders. We treated 52 subjects with new-onset T1D with teplizumab for 2 weeks at diagnosis and after 1 year in an open-label, randomized, controlled trial. In the intent to treat analysis of the primary end point, patients treated with teplizumab had a reduced decline in C-peptide at 2 years (mean −0.28 nmol/L 95% CI −0.36 to −0.20) versus control (mean −0.46 nmol/L 95% CI −0.57 to −0.35;
P
= 0.002), a 75% improvement. The most common adverse events were rash, transient upper respiratory infections, headache, and nausea. In a post hoc analysis we characterized clinical responders and found that metabolic (HbA
1c
and insulin use) and immunologic features distinguished this group from those who did not respond to teplizumab. We conclude that teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D. Metabolic and immunologic features at baseline can identify a subgroup with robust responses to immune therapy.
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