BMI Normalization Is Associated With Lower Risk of Progression to Type 1 Diabetes, Primarily in Youth

OBJECTIVE: Elevated BMI is associated with increased risk of progression to stage 3 type 1 diabetes (T1D). We tested whether normalization of BMI is associated with lower stage 3 risk among autoantibody-positive individuals with overweight or obesity. RESEARCH DESIGN AND METHODS: We studied 833 autoantibody-positive participants in the TrialNet Pathway to Prevention study with overweight or obesity at baseline. Cumulative incidence of stage 3 T1D was evaluated using Cox proportional hazards models. Reported P values were adjusted for baseline age, BMI z score, and T1D stage, unless otherwise noted. RESULTS: During follow-up, BMI normalized in 26.8% of participants and was associated with a lower risk of progression to stage 3 T1D (hazard ratio 0.516, P < 0.001) over a median follow-up time of 4.1 years. This association was primarily observed in youth (n = 421, hazard ratio 0.497, P = 0.001), including boys <12 years old (n = 140, P < 0.001) and girls ≥12 years old (n = 73, P = 0.043), but not in adults (n = 412, P = 0.130). BMI normalization was also associated with a lower risk of transition from stage 1 to stage 2 and from stage 2 to stage 3, but not clearly from stage 0 to stage 1 (P = 0.010, P = 0.003, and P = 0.051, respectively, adjusted for baseline age and BMI z score). In exploratory models, adjustment for insulin sensitivity/resistance indices or oral disposition index weakened the association between BMI normalization and lower progression risk, whereas adjustment for insulin secretion, glycemia-adjusted C-peptide, or progression-risk indices generally strengthened it. CONCLUSIONS: Among autoantibody-positive individuals with overweight or obesity, BMI normalization was associated with a 48.4% lower risk of clinical T1D, primarily in youth.