Insulin Dose-Adjusted Hemoglobin A1c Has Suboptimal Performance for Identifying C-Peptide-Defined Partial Remission: The SEARCH for Diabetes in Youth Study.

Abstract

Objective: Insulin dose-adjusted hemoglobin A1c (IDAA1c = HbA1c [%] + [4 × total daily dose in units/kg/day]) ≤9 is widely used to define partial remission in pediatric type 1 diabetes and as an eligibility criterion or outcome in disease-modifying therapy trials. However, it has not been validated in U.S. youth. Because higher BMI increases insulin resistance and insulin requirements, we hypothesized that IDAA1c would perform suboptimally in participants with overweight or obesity.

Research design and methods: We analyzed data from 422 SEARCH for Diabetes in Youth study participants with mixed-meal tolerance test (MMTT)-stimulated C-peptide within 12 months of diagnosis. Partial remission was defined using MMTT-stimulated area under the curve (AUC) mean C-peptide. Participant characteristics were compared by BMI category (<85th percentile [normal or underweight] and ≥85th percentile [overweight or obese]) using Wilcoxon rank sum and Fisher exact tests. Sensitivity, specificity, and receiver operating characteristic (ROC) AUC of IDAA1c ≤9 for identifying partial remission were evaluated.

Results: Participants with normal or underweight versus participants with overweight or obesity had lower IDAA1c (8.95 vs. 9.28, P = 0.043) despite lower stimulated C-peptide (1.25 vs. 1.88 ng/mL, P < 0.001). Overall, IDAA1c ≤9 had 61% sensitivity and 79% specificity for predicting C-peptide ≥0.91 ng/mL with an ROC AUC of 0.77. Among participants with overweight or obesity, sensitivity was 45% and specificity 81%. A Youden index-derived cutoff of IDAA1c ≤11.6 improved sensitivity to 93%, with specificity of 54% in participants with overweight or obesity.

Conclusions: IDAA1c ≤9 demonstrated suboptimal accuracy as a screening test for partial remission, especially underestimating β-cell function in youth with overweight or obesity. BMI-specific cutoffs improved sensitivity but reduced specificity.