TOPLINE:

High-dose oral insulin (up to 67.5 mg/d) administered to children with stage 1 type 1 diabetes (T1D) for 12 months did not delay progression to dysglycemia or clinical diabetes compared with placebo, nor did it produce significant changes in immune responses to insulin.

METHODOLOGY:

• Oral administration of an antigen can induce immunologic tolerance. In childhood T1D, insulin is a key autoantigen; therefore, researchers wanted to test if high-dose oral insulin could prevent or modulate autoimmune response.
• They conducted a phase 2 clinical trial involving 220 children aged 2-12 years with stage 1 T1D (112 girls; median age, 4.8 years) to test the efficacy of high-dose oral insulin; stage 1 disease was defined as seropositivity for more than one autoantibody to insulin, glutamic acid decarboxylase, islet antigen‑2, or zinc transporter-8, and normoglycemia.
• Participants received either oral insulin (7.5 mg/d for 3 months, followed by 67.5 mg/d for 9 months; n = 110) or placebo (n = 110) daily for 12 months, with follow-up continuing for at least 24 months after treatment.
• Co-primary outcomes were progression to dysglycemia or clinical diabetes and an increased immune response to insulin within 12 months of treatment; the latter was assessed in the first 90 participants.
• The analysis included measurement of serum antibodies to insulin, salivary immunoglobulin A antibodies to insulin, CD4+ T-cell responses to insulin, and flow cytometry of lymphocyte and monocyte subsets.

TAKEAWAY:

• After a median follow-up of 3.6 years, dysglycemia or clinical diabetes developed in 87 participants: 46 in the oral insulin group and 41 in the placebo group (hazard ratio, 1.07; P = .74); the annualized rate of progression was 10.9% in the insulin group and 10.0% in the placebo group, with a 5-year progression rate of 40% in both groups.
• A statistically significant interaction was observed between oral insulin treatment and the INS rs689 genotype for progression to clinical diabetes (P = .03).
• An immune response to insulin occurred in 11 of 44 (25%) participants in the oral insulin group and 13 of 42 (31%) participants in the placebo group (P = .63).
• Blood glucose concentrations did not fall below 50 mg/dL in either group even when the dose was increased.

IN PRACTICE:

“Our results do not support the use of 12-month treatment with high-dose oral insulin for delaying disease progression in children with stage 1 T1D,” the authors wrote.

SOURCE:

The study was led by Anette-Gabriele Ziegler of the German Research Center for Environmental Health, Neuherberg, Germany. It was published online in Diabetes Care.

LIMITATIONS:

The study was limited by its short treatment duration of 12 months. The dropout rate of 18.6% exceeded the predicted rate of 13%, and the rate of progression to the co-primary outcome was lower than anticipated. Additionally, the overall power of the study to detect differences in progression rates between treatment groups was less than 80%.

DISCLOSURES:

The study was supported by the Leona M. and Harry B. Helmsley Charitable Trust. Some authors disclosed serving on advisory boards for Sanofi and Novo Nordisk, receiving support for Sanofi-sponsored lectures, and obtaining travel and accommodation support to attend international conferences. Eli Lilly provided recombinant human insulin crystals.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.