Different trials showed a better preservation of residual pancreatic β‐cell function in T1D patients supplemented with different forms of vitamin D (cholecalciferol, alfacalcidiol or calcitriol), as proven by the significantly higher level of fasting C‐peptide and/or lower needed daily insulin dose observed in supplemented groups [37, 39]. However, there are also studies that indicate no significant role for vitamin D in the treatment of T1D. The IMDIAB XI trial was an open‐label randomized trial designed to determine whether supplementation with the active form of vitamin D (calcitriol) at diagnosis of T1D could improve parameters of glycemic control [40]. The secretion of C‐peptide as an index of residual pancreatic β‐cell function was the primary end point, with HbA1c and insulin requirement as secondary end points. The aim of this study was to investigate whether supplementation with the active form of vitamin D (calcitriol) in subjects with recent‐onset T1D, protects residual pancreatic β‐cell function and improves glycemic control (HbA1c and insulin requirement). In this open‐label randomized trial, 70 subjects with recent‐onset T1D, mean age 13.6 ± 7.6 years, were randomized to calcitriol (0.25 microg on alternate days) or nicotinamide (25 mg/kg daily) and were followed up for 1 year. Intensive insulin therapy was implemented with three daily injections of regular insulin + NPH insulin at bedtime. No significant differences were observed between calcitriol and nicotinamide groups in respect of baseline/stimulated C‐peptide or HbA1c 1 year after diagnosis, but the insulin dose at 3 and 6 months was significantly reduced in the calcitriol group. In conclusion, at the dosage used, calcitriol had a modest effect on residual pancreatic β‐cell function and only temporarily reduced the insulin dose [40]. These results were confirmed later by the same group (IMDIAB XIII Trial), who found no effect of calcitriol in protecting β‐cell function in subjects with recent‐onset T1D and high C‐peptide at diagnosis followed‐up for 2 years [41]. Currently, a pilot study (POSEIDON) is investigating the safety and efficacy of a regimen that combines Omega‐3 fatty acids and cholecalciferol in subjects at T1D onset (NCT03406897). Thus, omega‐3 fatty acids have effects on several immunotypes and are known to increase T‐reg cell differentiation. The recruitment is still open.
Immune Intervention Therapies at Diagnosis of T1D
Other strategies for prevention of β‐cells damage with immune intervention at onset of the disease are based on immunotolerance (monoclonal antibodies, antigen‐based treatments, pro‐inflammatory cytokine‐based treatments) (Figure 2.3, Tables 2.2 and 2.3).
In the last decades, experience obtained with the use of the antiCD3 monoclonal antibody in two studies (one in the USA and the other in Europe) has revitalized the interest in these types of intervention [42, 43]. The drug, a modified form of anti‐CD3 antibody that minimizes first‐dose side effects, was studied by comparing 12 subjects aged 7 to 30 who were treated with the antibody to an equal number of patients in a control group who did not receive the drug. One year after treatment with anti‐CD3, the treated patients produced more insulin and needed less insulin therapy than the untreated patients. Those who received the antibody treatment also had better HbA1c levels. The anti‐CD3 was designed to act on the immune system's T‐cells in a more specific manner than previous attempts at immune intervention in early diabetes.
Most recently, a phase 2, randomized, placebo‐controlled, double‐blind trial showed that a single 14‐day course of teplizumab (an Fc receptor–nonbinding anti‐CD3 monoclonal antibody) significantly slowed progression to clinical T1D in high‐risk, nondiabetic relatives of patients with diabetes who had at least two autoantibodies. At the conclusion of the trial, the percentage of diabetes‐free persons in the teplizumab group (57%) was double that in the placebo group (28%). Median delay in the diagnosis of diabetes was 2 years. However, the cohort was relatively small, and the estimated power limited. Furthermore, authors did not assess the potential development of antibodies to teplizumab, which would be a concern [44].
In the DEFEND‐1 and DEFEND‐2 phase III trials, anti‐CD3 antibody Otelixizumab revealed a narrow therapeutic window. At a low dose, there was no preservation of β‐mass [45]. This was indeed observed at 18 months, but with significant adverse effects. Otelixizumab is a chimeric monoclonal antibody that targets the CD3/T‐cell receptor, which is genetically modified by removing the glycosylation site in the Fc domain, thus affecting binding of complement or Fc receptors. This reduces secondary reactions due to cytokine release. Otelixizumab downregulates pathogenic T‐cells and upregulates T‐reg cells, thus halting the autoimmune process in T1D.
Only one trial has focused on β‐cell function in T1D after treatment with Rituximab, which produces B cell depletion [46]. Although T1D is a T‐cell mediated autoimmune disorder, B lymphocytes play a pathogenetic role by acting as antigen‐presenting cells (APC) and modulating the islet environment. In recent‐onset T1D subjects, administration of Rituximab reduced HbA1c levels and exogenous insulin demand due to the preservation of C‐peptide levels over 1 year. Interestingly, after 2 years' follow‐up, Rituximab delayed the decrease in C‐peptide levels but did not influence insulin dose, suggesting B cell deletion is not sufficient to restore β‐cell tolerance.
FIG 2.3 T1D clinical research over the past 10 year. Atkinson MA, Roep BO, Posgai A et al. The challenge of modulating β‐cell autoimmunity in type 1 diabetes. Lancet Diabetes Endocrinol 2019;7(1):52–64.
TABLE 2.2 Current TrialNet studies. (Source: www.trialnet.net)
| Study | Status | Description |
|---|---|---|
| Teplizumab Prevention Study | Completed | This study tested the drug teplizumab to see if it could delay or prevent progression of early stage T1D (stage 2) and prevent clinical diagnosis (stage 3). |
| Oral Insulin Prevention Study | Completed | This study tested the drug oral insulin to see if it can delay or prevent T1D (stage 1) from progressing to stage 2 and ultimately prevent clinical diagnosis (stage 3). |
| Hydroxychloroquine (HCQ) | Currently Enrolling | This study tests the drug hydroxychloroquine (HCQ) to see if it can delay or prevent early stage T1D (stage 1) from progressing to abnormal glucose tolerance (stage 2) and ultimately prevent clinical diagnosis (stage 3). |
| ATG/GCSF New Onset Study | Completed | This study was designed to build on prior findings of a pilot study suggesting thymoglobulin (ATG) combined with pegylated granulocyte colony stimulating factor (GCSF) preserved insulin production for more than 1 year after treatment in people who had type 1 diabetes for 4 months to 2 years. |
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Abatacept Prevention
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