Assessing Time Below Range as a Predictor of Severe Hypoglycemia: Insights From Six Clinical Trials

OBJECTIVE: To evaluate whether baseline continuous glucose monitoring (CGM)-derived time below range (TBR) metrics-TBR level 1 (TBR1) (<70 mg/dL) and TBR level 2 (TBR2) (<54 mg/dL)-predicts severe hypoglycemia (SH) during follow-up of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: Baseline CGM TBR levels and their association with SH adverse events during six clinical trials were analyzed using Wilcoxon rank sum tests and Spearman correlations. Analyses were stratified by sex, race, and age group. Sensitivity, specificity, and false-positive rates (FPRs) were calculated for thresholds (1-5%), and receiver operating characteristic (ROC) analysis assessed discrimination. RESULTS: Participants (n = 1,433; median age 4-43 years; 50-62% female sex; 83-96% White race) had a baseline median TBR2 range of 0.1% to 0.7% and TBR1 from 1.2% to 4.1% across the six clinical trials. Those who developed SH had slightly higher baseline TBR2 (0.41% vs. 0.32%; P = 0.022) and TBR1 (2.58% vs. 2.23%; P = 0.044). Predictive accuracy was limited: sensitivity of TBR2 fell from 48.9% at a 1% cutoff to 18.2% at 5% (specificity 75.9-95.0%), and TBR1 sensitivity declined from 81.8% to 44.3% (specificity 29.6-77.7%), with modest discrimination by ROC analysis (area under the curve = 0.62 [95% CI 0.55-0.69] for TBR2; and 0.65 [95% CI 0.58-0.71] for TBR1). CONCLUSIONS: Baseline TBR1 and TBR2 had limited predictive value for SH. No threshold achieved strong discrimination, a finding that supports the need to integrate additional clinical factors for SH risk stratification.