Abstract
Introduction
Although the articles selected for the article are studies conducted in all stages of type 1 diabetes (T1D) (stages 1 through 3), it is becoming more evident that preventing T1D autoimmunity or halting the further progression remains key to finding a cure for T1D. This article has discussed the first stage 1 study looking into the use of oral insulin as an antigen‐based therapy to prevent autoimmunity. Though the study did not reach its primary outcome, it provided findings that highlight the heterogeneity of the disease process, and that future T1D clinical trials and treatment may need to be stratified and individualized respectively.
Additionally, regardless of the stage of the disease process, trials looking into combined immunomodulatory agents may prove to be more beneficial compared to single agent immune modulators.
Key Articles Reviewed for the Article
Sims EK, Bundy BN, Stier K, Serti E, Lim N, Long A, Geyer SM, Moran A, Greenbaum C, Evans‐Molina C, Herold KC, Type 1 Diabetes TrialNet Study Group
von Herrath M, Bain SC, Bode B, Clausen JO, Coppieters K, Gaysina L, Gumprecht J, Hansen TK, Mathieu C, Morales C, Mosenzon O, Segel S, Tsoukas G, Pieber TR, on behalf of the Anti‐IL‐21–liraglutide Study Group investigators and contributors
Assfalg R, Knoop J, Hoffman KL, Pfirrmann M, Zapardiel‐Gonzalo JM, Hofelich A, Eugster A, Weigelt M, Matzke C, Reinhardt J, Fuchs Y, Bunk M, Weiss A, Hippich M, Halfter K, Hauck SM, Hasford J, Petrosino JF, Achenbach P, Bonifacio E, Ziegler AG
Balzano‐Nogueira L, Ramirez R, Zamkovaya, Dailey J, Ardissone AN, Chamala S, Serrano‐Quílez J, Rubio T, Haller MJ, Concannon P, Atkinson MA, Schatz DA, Triplett EW, Conesa A
Jacobsen LM, Bundy BN, Greco MN, Schatz DA, Atkinson MA, Brusko TM, Mathews CE, Herold KC, Gitelman SE, Krischer JP, Haller MJ
Lin A, Mack JA, Bruggeman B, Jacobsen LM, Posgai AL, Wasserfall CH, Brusko TM, Atkinson MA, Gitelman SE, Gottlieb PA, Gurka MJ, Mathews CE, Schatz DA, Haller MJ
Teplizumab Improves and Stabilizes Beta Cell Function in Antibody‐Positive High‐Risk Individuals
Sims EK1, Bundy BN3, Stier K4, Serti E5, Lim N5, Long A6, Geyer SM7, Moran A8, Greenbaum C6, Evans‐Molina C1,2, Herold KC4, Type 1 Diabetes TrialNet Study Group
1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN; 2Department of Medicine, Indiana University School of Medicine, Indianapolis, IN; 3Department of Epidemiology, and Pediatrics University of South Florida, Tampa, FL; 4Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT; 5Immune Tolerance Network, Bethesda, MD; 6Benaroya Research Institute, Seattle WA; 7Mayo Clinic, Rochester, MN; 8Department of Pediatrics, University of Minnesota, Minneapolis, MN
Background
In a previous phase 2, randomized study, the authors demonstrated that teplizumab (an Fc receptor–nonbinding anti‐CD3 monoclonal antibody) administered to patients with stage 2 type 1 diabetes (dysglycemic but not with type 1 diabetes) daily for 14 days delayed the diagnosis of type 1 diabetes (T1D) by almost 24 months (median time), and also reduced the rate of progression to diagnosis (35.9% to 14.9% per year). In this study, the authors analyzed metabolic and immune responses before, during, and after conclusion of the trial.
Methods
Data were obtained from the TrialNet Pathway to Prevention study (TN01), TN10 anti‐CD3 prevention trial, and the TrialNet Long Term Investigational Follow‐up study for metabolic follow‐up (July 2011 to March 2020). Patients were ≥ 8 years at randomization, had a relative with T1D, positive titers for 2/ more islet autoantibodies, and dysglycemia. After receiving intravenous teplizumab or saline for 14 days, OGTTs were performed 3‐ and 6‐months post-infusion and every 6 months thereafter. Random screening glucose concentrations were carried out every 3 months, and an oral glucose tolerance test (OGTT) was performed if the random glucose concentration was >200 mg/dL (11.1 mM). T1D was diagnosed using American Diabetes Association criteria after two sequentially confirmed OGTT. OGTT data from islet autoantibody–negative relatives through TrialNet testing were also analyzed, and matched to study participants by sex and age. Peripheral blood mononuclear cells collected from all participants and cryopreserved were assessed for immunological markers.
Results
Participants were followed for a median duration of 923 days. The median time to diabetes diagnosis was 59.6 months for the teplizumab group vs 27.1 months for the placebo group (HR=0.457, P=0.01). After 5 years, 18% of the teplizumab‐treated participants versus 6% of the placebo‐treated participants remained diabetes free. C‐peptide AUC increased significantly from baseline in the teplizumab‐treated participants at 6 months after enrollment, while there was continued decline in the placebo group (P=0.04 vs P>0.5). Insulin secretion in the first and second hour of the OGTT increased in the teplizumab group (P=0.007, 0.03) vs placebo (P=0.38). There was a significant association between the frequency (P=0.014) and the absolute number (P=0.02) of partially exhausted memory KLRG1+ TIGIT+ CD8+ T cells and the change in C‐peptide. These cells also showed reduced secretion of IFNγ and TNFα.
Conclusion
A 14‐day course of teplizumab in those at risk for type 1 diabetes enhanced β cell function, improved insulin secretion quantitatively and qualitatively, and delayed progression to type 1 diabetes in those at risk for almost 5 years.
Comment
In those at risk for type 1 diabetes, delay in the onset of diabetes is the primary goal in the absence of true prevention; in those with onset of the disease, preserved β cell function is sought. Teplizumab is the first agent shown to delay the onset of the disease (albeit not in all at‐risk subjects), and preserve β cell function in some at‐risk subjects for several years later. Whether administering repeat doses of the drug or combining it with other agents like antithymocyte globulin (ATG) will have even better efficacy should be investigated. Further understanding of both the mechanism leading to disease and beneficial action of the drugs is crucial.
Anti‐Interleukin‐21 Antibody and Liraglutide for the Preservation of β ‐Cell Function in Adults with Recent‐Onset Type 1 Diabetes: A Randomised, Double‐Blind, Placebo‐Controlled, Phase 2 Trial
von Herrath M1, Bain SC2, Bode B3,4, Clausen JO1, Coppieters K5, Gaysina L6, Gumprecht J7, Hansen TK8, Mathieu C9, Morales C10, Mosenzon O11, Segel S12, Tsoukas G13, Pieber TR14, on behalf of the Anti‐IL‐21–liraglutide Study Group investigators and contributors
1Novo Nordisk A/S, Søborg, Denmark; 2Swansea University Medical School, Swansea, UK; 3Atlanta Diabetes Associates, Atlanta, GA; 4Emory University School of Medicine, Atlanta, GA; 5Novo Nordisk A/S, Måløv, Denmark; 6Kazan Federal University, Kazan, Russia; 7Medical University of Silesia, Katowice, Poland; 8Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; 9Clinical and Experimental Endocrinology, UZ Gasthuisberg, University of Leuven, Leuven, Belgium; 10Endocrinology and Nutrition Department, Virgen Macarena Hospital, Seville, Spain; 11Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Centre, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; 12Novo Nordisk A/S, Aalborg, Denmark; 13Department of Medicine, McGill University, Montreal, QC, Canada; 14Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
Background
Interleukin‐21 (IL‐21) has been implicated in the pathogenesis of type 1 diabetes in mice and human studies. Thus, the authors investigated the effects of the administration of IL‐21 antibodies in combination with liraglutide, a GLP‐1 agonist. GLP‐1 agonists have been proposed to reduce β cell stress and apoptosis and protect against cytokine‐mediated inhibitory effects on glucose stimulated insulin release. An IL‐21 antibody/GLP‐1 agonist combination showed promising results in a mouse model of type 1 diabetes.
Methods
This was a randomized, placebo‐controlled, double‐blind, phase 2 trial conducted in participants aged 18–45 years diagnosed with type 1 diabetes within 20 weeks of screening. Eligible participants (N=308) were randomly assigned (1:1:1:1) to anti‐IL‐21 plus liraglutide, anti‐IL‐21, liraglutide, or placebo, all as an adjunct to insulin. Stratification was done based on baseline stimulated peak C‐peptide concentration (mixed‐meal tolerance test/MMTT). The primary outcome was the change in area under the concentration‐time curve (AUC) of MMTT‐stimulated (over 4 hours) C‐peptide concentration at week 54 (end of treatment) relative to baseline. After treatment cessation, participants were followed up for an additional 26 weeks off‐treatment.
Results
The combination treatment group had a smaller decrease in MMTT‐stimulated C‐peptide from baseline to week 54 (ratio to baseline 0.90, 10% decrease) compared to placebo (0.61, 39% decrease). However, anti‐IL‐21 or liraglutide as sole agents did not have a significant difference compared to placebo. There was no significant difference in HbA1c decrease between the groups. Changes in immune cell subsets across groups were transient and mild (<10% change over time). Gastrointestinal disorders were the most common side effects (and likely due to liraglutide).
Conclusion
A combination of anti‐IL‐21 and liraglutide preserves β‐cell function in recently diagnosed type 1 diabetes, and without major adverse effects. Efficacy and safety should be further evaluated in a phase 3 trial program.
Comment
Combination therapy, not surprisingly, with anti‐IL‐21 and liraglutide preserved β‐cell function better than individual agents alone. Whether liraglutide could be even more effective when used with other agents including teplizumab and ATG needs to be explored.
Oral Insulin Immunotherapy in Children at Risk for Type 1 Diabetes in a Randomised Controlled Trial
Assfalg R1,2,3, Knoop J1, Hoffman KL4, Pfirrmann M5, Zapardiel‐Gonzalo JM1, Hofelich A2, Eugster A6,7, Weigelt M6, Matzke C1, Reinhardt J6, Fuchs Y6, Bunk M1, Weiss A1, Hippich M1, Halfter K5, Hauck SM8, Hasford J5, Petrosino JF4, Achenbach P1,2,3, Bonifacio E3,6,7,9, Ziegler AG1,2,3
1Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich‐Neuherberg, Germany; 2Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany; 3German Center for Diabetes Research (DZD), Munich, Germany; 4Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX; 5Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig‐Maximilians‐University Munich, Munich, Germany; 6Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany; 7Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, Dresden, Germany; 8Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich‐Neuherberg, Germany; 9 Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Munich‐Neuherberg, Germany
Background
Insulin autoantibodies often appear early in life in children with a high genetic risk for type 1 diabetes in the first year of life with a peak incidence at 9 to 12 months of age. In a pilot study, the authors previously demonstrated that daily oral administration of insulin to young children with a genetic risk of type 1 diabetes was safe (no hyper or hypoglycemia), and was associated in some individuals with the induction of low‐affinity antibodies against insulin and insulin‐responsive regulatory CD4+ T cells. In this study (Pre‐POInT), the authors hypothesized that administration of oral insulin (antigen‐specific) early in life might prevent the induction of islet autoimmunity and progression to clinical disease.
Methods
This phase I/II randomized, controlled trial was conducted in children aged 6 months to 2.99 years (N=44) with a first‐degree relative with type 1 diabetes, and positive for HLA DR4‐DQ8‐containing genotype. All were insulin autoantibody–negative (IAA), GAD (GADA), insulinoma‐associated antigen 2 (IA‐2A) and zinc transporter‐8 (ZnT8) autoantibody negative. Children were randomized 1:1 to daily oral insulin (7.5 mg for 3 months, followed by 22.5 mg for 3 months with dose escalation to 67.5 mg for 6 months) or placebo for 12 months. Children reached study end point and stopped treatment if they developed persistent islet autoantibodies (GADA, IA‐2A, or ZnT8A) or clinical diabetes. The primary immune efficacy outcome was an increase in serum IgG antibodies to insulin or salivary IgA antibodies to insulin, or serum IAA or a CD4+ T cell response to insulin.
Results
Although there were no significant adverse effects of oral insulin, immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate significant immune effect (P=0.54). However, in exploratory analyses, antibody responses to insulin were more frequent in insulin‐treated (72.7%) as compared to placebo‐treated children (18.2%; P=0.03) in those with type 1 diabetes‐susceptible INS genotype (n=22).
Conclusion
Oral insulin immunotherapy in young, genetically at‐risk children is safe, but is not associated with a specified beneficial immune response outcome. Antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin‐responsive T cells.
Comment
Although the study did not demonstrate the primary outcome of immune efficacy with oral insulin, it provided evidence of an interaction between an immune response to treatment, and the INS gene. Whether oral insulin alone or as part of a cocktail may be used in some patients as part of a personalized medicine approach remains to be determined.
Integrative Analyses of TEDDY Omics Data Reveal Lipid Metabolism Abnormalities, Increased Intracellular ROS and Heightened Inflammation Prior to Autoimmunity for Type 1 Diabetes
Balzano‐Nogueira L1, Ramirez R1, Zamkovaya T1, Dailey J1, Ardissone AN1, Chamala S2, Serrano‐Quílez J3, Rubio T4, Haller MJ5, Concannon P2,6, Atkinson MA5, Schatz DA5, Triplett EW1, Conesa A1,6
1Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, FL; 2Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL; 3Gene Expression and RNA Metabolism Laboratory, Instituto de Biomedicina de Valencia (CSIC), Valencia, Spain; 4Laboratory of Neurobiology, Prince Felipe Research Center, Valencia, Spain; 5Department of Pediatrics, University of Florida Diabetes Institute, Gainesville, FL; 6University of Florida Genetics Institute, Gainesville, FL
Background
The start of pancreatic β‐cell death, as well as the interplay between genetic risk, physiological biomarkers, and environmental triggers in type 1 diabetes (T1D) is poorly understood. Many mechanistic studies such as genome wide association, transcriptomics, metabolomics, proteomics, and microbiome analyses have led to the discovery of features that reflect islet autoimmunity, such as overexpression of interleukin‐1 family members, which are involved in immunocyte chemotaxis and immune receptor activity. Metabolomic studies have suggested that a stress signature impacting levels of phospholipids, methionine, glutamate, and energy metabolites are present before seroconversion. The authors of the TEDDY (The Environmental Determinants of Diabetes in the Young) study have employed a multi‐omics approach to assess the TEDDY cohort, and evaluated the relationship between disease state of subjects and their biomolecular profiles across time.
Methods
The participants were selected from the TEDDY study group and were positive for HLA‐DR‐DQ genotype (high risk of developing T1D). Participants were followed for the development of (islet antibodies) or type 1 diabetes (every 3 months from birth to age 48 months, and every 3 or 6 months thereafter). Blood samples were collected at each visit and gene expression, metabolomics, and dietary biomarker profiling were carried out later. Patients were followed either until development of T1D (30% of enrolled individuals) or to the age of 15 (control individuals). IA cases were defined by confirmed autoantibody positivity to either insulin (IAA), GAD, or IA‐2 in two consecutive visits.
Results
There are abnormalities in lipid metabolism, decreased nutrient absorption, and intracellular ROS accumulation in children as early as 1 year before seroconversion. Additionally, there is extracellular matrix remodeling, inflammation, cytotoxicity, angiogenesis, and increased activity of antigen‐presenting cells, which may contribute to β cell destruction.
Conclusion
Abnormalities in lipid metabolism, accumulation of ROS, and many components of inflammation are seen prior to seroconversion.
Comment
This study revealed that altered metabolism of lipids, increased formation of ROS, and decreased nutrient uptake are some of the changes already seen in the first year of life, before the actual detection of autoantibodies in children at risk for type 1 diabetes. The authors have commented that it opens a window of opportunity for therapeutic intervention. The question remains as to which agent(s) will provide the most benefit in preventing the trigger of islet autoimmunity.
Comparing Beta Cell Preservation Across Clinical Trials in Recent‐Onset Type 1 Diabetes
Jacobsen LM1, Bundy BN2, Greco MN1, Schatz DA1, Atkinson MA3, Brusko TM3, Mathews CE3, Herold KC4, Gitelman SE5, Krischer JP2, Haller MJ1
1Division of Pediatric Endocrinology, University of Florida, Gainesville, FL; 2Health Informatics Institute, University of South Florida, Tampa, FL; 3Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL; 4Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT; 5Diabetes Center, University of California San Francisco, San Francisco, CA
Background
Although several immunotherapies have demonstrated endogenous insulin preservation in recent‐onset type 1 diabetes (T1D), analytical comparisons of efficacy across T1D intervention trials have been limited. The authors of this study have attempted to compare C‐peptide preservation across the most successful T1D immunotherapy trials utilizing a model‐based adjustment approach.
Methods
Seven interventions were chosen for comparison and included the Type 1 Diabetes TrialNet‐sponsored (1) rituximab, (2) abatacept, (3) low‐dose antithymocyte globulin (ATG), and (4) low‐dose ATG/granulocyte‐colony–stimulating factor (G‐CSF) trials, and the Immune Tolerance Network (ITN)‐sponsored (5) teplizumab, (6) alefacept, and (7) high‐dose ATG trials. All trials included children and adults, were placebo‐controlled, blinded, and had 2:1 randomization within 100 days of diagnosis except for the open label teplizumab trial and the 1:1:1 randomized low‐dose ATG, ATG/G‐CSF, and placebo trial. An analysis of covariance (ANCOVA) model was fitted to 1‐year (and separately 2‐year) C‐peptide AUC means from the 2‐h MMTT from all six studies.
Results
Treatment effects (percentage change relative to control) for years 1 and 2, respectively, and ordered from lowest to highest for year 1, were high‐dose ATG (9% and 16%), rituximab (18% and 15%), alefacept (18% and 36%), abatacept (22% and 37%), low‐dose ATG/G‐CSF (30% and 49%), teplizumab (48% and 63%), and low‐dose ATG (55% and 103%)
Conclusion
Low‐dose ATG and teplizumab show the greatest impact on C‐peptide preservation among recent new‐onset T1D studies; these should be further explored as core immunotherapies in the T1D prevention setting.
Comment
Given that there are short‐term and long‐term benefits of preservation of C‐peptide, such as reduction of severe hypoglycemia and decreased complication risk, respectively, it is important to identify which therapeutic agents demonstrate the greatest potential for benefit. Other considerations such as the timing of administration, duration of therapy, cost, and side effect profile should also be considered.
Low‐Dose ATG/GCSF in Established Type 1 Diabetes: A Five‐Year Follow‐Up Report
Lin A1, Mack JA2, Bruggeman B3, Jacobsen LM3, Posgai AL1, Wasserfall CH1, Brusko TM1,3, Atkinson MA1,3, Gitelman SE4, Gottlieb PA5, Gurka MJ2, Mathews CE1, Schatz DA3, Haller MJ3
1Department of Pathology, Immunology, and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL; 2Department of Health Outcomes and Biomedical Informatics, University of Florida, Gainesville, FL; 3Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL; 4Division of Endocrinology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA; 5Division of Endocrinology, Department of Pediatrics and Medicine, University of Colorado, Denver, CO
Background
Past studies have shown the efficacy and safety of low‐dose antithymocyte globulin (ATG) combined with granulocyte colony stimulating factor (GCSF) in both established cases as well as new‐onset patients. This report sought to determine the outcome of ATG‐plus GCSF intervention in a subset of those with established disease followed for 5 years. Furthermore, the authors sought to determine whether short‐term biomarkers such as peripheral blood gene expression and T‐cell depletion shortly after treatment could predict long‐term outcomes.
Methods
The participants (N=25) were aged 12–45 years with type 1 diabetes, and enrolled 4 months to 2 years after diagnosis. Follow‐up data for 15 participants (out of the 25) were collected at 30, 36, 42, 48, 54, and 60 months. Participants were randomly assigned 2:1 to receive intravenous low‐dose ATG (2.5 mg/kg total dose over 2 days) and subcutaneous pegylated GCSF (6 mg every 2 weeks for six doses) or placebo. Five received placebo, and 10 received ATG/GCSF. HbA1c, C‐peptide (2‐h or 4‐h mixed‐meal test (MMTT) were performed together with detailed immunological analyses. These included flow cytometry and gene expression analyses. The primary end point was area under the curve (AUC) C‐peptide during a 2‐h mixed‐meal tolerance test.
Results
At year 5, treatment group had no significant differences from placebo group (P=0.9059). Two subgroups, responders (N=9) and nonresponders (N=6), were identified based on a predicted delta AUC C‐peptide effect size at 1 year. The participants in the responder group had a nearly unchanged A1c over 5 years. Interestingly, responders had higher HbA1c at enrollment when compared with nonresponders and placebo (7.3 versus 6.1 and 6.0%). Albeit small numbers, 50% of ATG/GCSF treated individuals had a peak C‐peptide >0.2 pmol/mL at the 5‐year time point, compared to only 20% of placebo‐treated subjects. Responders also had a smaller change in AUC C‐peptide than nonresponders, though the difference was not significant. Low‐dose ATG/GCSF was not associated with significant changes in gene expression in whole PBMCs at 2, 4, or 12 weeks post-treatment as compared with baseline for any of the 64 T‐cell or granulocytic genes assayed.
Conclusion
No long‐term safety effects were noted. However, only a small number of patients were followed for 5 years. In this small sample of only 15 participants, statistical significance was highly unlikely. We would not have expected changes in AUC C‐peptide, HbA1c, and insulin use between ATG/GCSF and placebo recipients.
Comment
Although no statistical significances overall were noted in this study, responders and nonresponders were identified in this study. An ongoing European study (INNODIA) is currently looking into different doses of ATG vs placebo in new onset type 1 diabetes (clinical trial reg. no. NCT04509791, ClinicalTrials.gov). Additionally, new data have emerged showing that low‐dose ATG is more beneficial compared to other immunomodulatory agents and equivalent to teplizumab, but with a lower cost.
Footnotes
Author Disclosure Statement
No competing financial interests exist.