Oral Insulin Delay of Stage 3 Type 1 Diabetes Revisited in HLA DR4-DQ8 Participants in the TrialNet Oral Insulin Prevention Trial (TN07)

Abstract

Objective: To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among patients with stage 1/2 who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2As).

Research and methods: Next-generation targeted sequencing technology was used to genotype eight HLA class II genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, and DPB1) in 546 participants in the TrialNet oral insulin preventative trial (TN07). Baseline levels of autoantibodies against insulin (IAA), GAD65 (GADA), and IA-2A were determined prior to treatment assignment. Available clinical and demographic covariables from TN07 were used in this post hoc analysis with the Cox regression model to quantify the preventive efficacy of oral insulin.

Results: Oral insulin reduced the frequency of T1D onset among participants with elevated IA-2A levels (HR 0.62; P = 0.012) but had no preventive effect among those with low IA-2A levels (HR 1.03; P = 0.91). High IA-2A levels were positively associated with the HLA DR4-DQ8 haplotype (OR 1.63; P = 6.37 × 10-6) and negatively associated with the HLA DR7-containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 extended haplotype (OR 0.49; P = 0.037). Among DR4-DQ8 carriers, oral insulin delayed the progression toward stage 3 T1D onset (HR 0.59; P = 0.027), especially if participants also had high IA-2A level (HR 0.50; P = 0.028).

Conclusions: These results suggest the presence of a T1D endotype characterized by HLA DR4-DQ8 and/or elevated IA-2A levels; for those patients with stage 1/2 disease with such an endotype, oral insulin delays the clinical T1D onset.

Graphical abstract

Figure 1

Distribution of baseline IA-2A levels, measured as maximum values over all measurements prior to the assignment of treatment and placebo. A: Distribution of original IA-2A values. B: Distribution of transformed IA-2A values by quadratic root. C: IA-2A distribution by primary, stratum 1, and strata 2 and 3. D: IA-2A distribution in the placebo and active arms. E: IA-2A distribution among male and female participants. F: IA-2A distribution among younger participants (<8 years old) and older participants (≥8 years old). Kruskal-Wallis (KW) tests are performed to compare differences of distributions with corresponding P values (KW P).

Figure 2

Incidence curves of the clinical onset of T1D in specific groups. A: Incidence among four groups from crossing (low, high) IA-2A levels with (placebo, active) arm, in which log-rank P values are unadjusted from intent-to-treat analysis. B: incidence among DR4 carriers in the placebo and active arms, in which both unadjusted and covariate-adjusted P values are listed.