Risk of Progression to Clinical Type 1 Diabetes in Older Adolescents Positive for Islet Autoantibodies

Objective: Evaluate progression to type 1 diabetes (T1D) among adolescents with persistent islet autoimmunity. Background: Few studies have continued to follow adolescents with islet autoimmunity through to young adulthood. With the emergence of treatments to delay clinical diabetes and general population screening, there is need to accurately predict and communicate risk for progression to T1D in autoantibody positive persons. Methods: Included in this analysis were 203 participants of prospective studies (DAISY, TEDDY Graduates, ASK) who were persistently positive for islet autoantibodies and free of diabetes between 13-15 y of age. Of those, 51% were female, 52% non-Hispanic white, and 32% had a first-degree T1D relative. Autoantibodies to insulin, GAD, IA-2, and ZnT8 were measured using standard radio-binding assays. Results: During the median 3.0 y (IQR 1.2-5.2) follow-up, 14.8% (n=30) of the participants progressed to T1D. The 5-year risk of progression to clinical diabetes was 33.1% (95%CI 20.0-51.7%) among adolescents with multiple autoantibodies vs 7.8% (95%CI 3.9-15.2%) in those with a single persistent autoantibody. Independent predictors of progression to diabetes included: multiple autoantibodies (HR=3.2, 95%CI 1.4-7.5, p=0.008) and higher baseline HbA1c (HR=1.7 per 0.5%, 95%CI 1.2-2.2. p=001). A receiver operating characteristic based on autoantibody status and HbA1c (AUC 0.78) did not improve significantly with addition of sex, ethnicity, and family history of T1D (AUC 0.81). Conclusion: One third of adolescents with multiple islet autoantibodies progress to clinical diabetes within 5 years, with baseline HbA1c being highly predictive of progression. Disclosure K.Waugh: None. C.Geno rasmussen: None. F.Dong: None. P.D.Gesualdo: None. B.I.Frohnert: Advisory Panel; Provention Bio, Inc. M.Rewers: Research Support; Provention Bio, Juvenile Diabetes Research Foundation (JDRF), Hemsley Charitable Trust, Dexcom, Inc., Janssen Research & Development, LLC. Funding National Institutes of Health (5R01DK032493-36); JDRF (2-SRA-2022-1270-S-B)