The risk of progression to type 1 diabetes is highly variable in individuals with multiple autoantibodies following screening

Abstract

Aims/hypothesis: Young children who develop multiple autoantibodies (mAbs) are at very high risk for type 1 diabetes. We assessed whether a population with mAbs detected by screening is also at very high risk, and how risk varies according to age, type of autoantibodies and metabolic status.

Methods: Type 1 Diabetes TrialNet Pathway to Prevention participants with mAbs (n = 1815; age, 12.35 ± 9.39 years; range, 1-49 years) were analysed. Type 1 diabetes risk was assessed according to age, autoantibody type/number (insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], insulinoma-associated antigen-2 autoantibodies [IA-2A] or zinc transporter 8 autoantibodies [ZnT8A]) and Index60 (composite measure of fasting C-peptide, 60 min glucose and 60 min C-peptide). Cox regression and cumulative incidence curves were utilised in this cohort study.

Results: Age was inversely related to type 1 diabetes risk in those with mAbs (HR 0.97 [95% CI 0.96, 0.99]). Among participants with 2 autoantibodies, those with GADA had less risk (HR 0.35 [95% CI 0.22, 0.57]) and those with IA-2A had higher risk (HR 2.82 [95% CI 1.76, 4.51]) of type 1 diabetes. Those with IAA and GADA had only a 17% 5 year risk of type 1 diabetes. The risk was significantly lower for those with Index60 <1.0 (HR 0.23 [95% CI 0.19, 0.30]) vs those with Index60 values ≥1.0. Among the 12% (225/1815) ≥12.0 years of age with GADA positivity, IA-2A negativity and Index60 <1.0, the 5 year risk of type 1 diabetes was 8%.

Conclusions/interpretation: Type 1 diabetes risk varies substantially according to age, autoantibody type and metabolic status in individuals screened for mAbs. An appreciable proportion of older children and adults with mAbs appear to have a low risk of progressing to type 1 diabetes at 5 years. With this knowledge, clinical trials of type 1 diabetes prevention can better target those most likely to progress.

Keywords: Age; Autoantibodies; Index60; Metabolic; Type 1 diabetes.

Conflict of interest statement

Duality of interest The authors declare that there is no duality of interest associated with this manuscript.

Figures

Fig. 1

Cumulative incidence with 95% CI (shaded area) of type 1 diabetes in TrialNet PTP participants with (a) 2 autoantibodies (p = 0.0496, logrank test) or (b) >2 autoantibodies (p = 0.0008, logrank test). Red, <12 years of age; blue, ≥12 years of age

Fig. 2

Cumulative incidence with 95% CI (shaded area) of type 1 diabetes in participants with 2 autoantibodies, including either IA-2A without GADA (red) or GADA without IA-2A (blue) (p < 0.0001, logrank test)

Fig. 3

(a) Cumulative incidence with 95% CI (shaded area) of type 1 diabetes in participants with mAbs with Index60 ≥1.0 (red) or Index60 <1.0 (blue) (p < 0.0001, logrank test). (b, c) Cumulative incidence with 95% CI (shaded area) of type 1 diabetes in participants aged <12 years (red) and ≥12 years (blue) with Index60 values <1.0 (p = 0.0009, logrank test) (b) or ≥1.0 (p = 0.2555, logrank test) (c)

Fig. 4

Cumulative incidence with 95% CI (shaded area) of type 1 diabetes in the ‘highest’ risk group (p < 0.0001, logrank test)