Time Below Range as a Digital Biomarker

Time below range is the percentage of time a person's glucose falls beneath the target range. Consensus splits it into two levels: level one hypoglycaemia below 70 mg/dL, or 3.9 mmol/L, and clinically significant level two hypoglycaemia below 54 mg/dL, or 3.0 mmol/L. The recommended targets are demanding, with less than four percent of time below 70 and less than one percent below 54 for most adults with diabetes. Time below range is the safety counterpart to time in range, and the two must be read together, because almost any intervention can improve time in range if it is allowed to push glucose downward. Continuous glucose monitoring transformed this measure, because it detects the asymptomatic and nocturnal lows that fingerstick testing and patient recall almost entirely miss.

The same continuous glucose monitor and analysis window used for time in range produce time below range, by computing the proportion of readings falling under each threshold across a recommended fourteen day period with at least seventy percent data capture. Because level two hypoglycaemia is rare in most participants, the estimate is far more sensitive to data gaps than time in range is, and a single missing night can meaningfully change the figure. Consensus also distinguishes the percentage of time from the number and duration of discrete hypoglycaemic events, since fifteen minutes below threshold on ten occasions is clinically different from one prolonged episode. Sensors are validated against laboratory reference glucose, and manufacturers report accuracy separately for the hypoglycaemic range because performance there differs from the mid range.

Time below range is a standard safety endpoint across diabetes trials and a primary efficacy endpoint in studies specifically targeting hypoglycaemia, including trials of closed-loop systems, newer insulin analogues and hypoglycaemia awareness interventions. In the public DiMe endpoint library it is the second most frequently registered digital measure after time in range, and it is registered as a primary endpoint in a substantial share of those trials. Nocturnal time below range is often analysed separately, because overnight lows are both the most dangerous and the least likely to be noticed. Trials routinely pair the measure with the Hypoglycemia Fear Survey, since fear of hypoglycaemia drives defensive behaviour that raises glucose and worsens time in range, making the objective and subjective measures directly interpretable against each other.

Sensor accuracy is generally at its weakest in the hypoglycaemic range, which is precisely where this measure operates, so small absolute errors translate into large proportional ones. Because the quantity being measured is small, the estimate is unstable with incomplete data capture and should not be reported without stating the capture rate. Interstitial lag means rapid falls are detected late, so brief lows can be missed or misdated. Thresholds also differ by population, with different targets in pregnancy and in older adults, and time below range says nothing about whether an episode was symptomatic, which is a separate and clinically important dimension.

• Battelino T, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the International Consensus on Time in Range. Diabetes Care. 2019. pubmed.ncbi.nlm.nih.gov
• Danne T, et al. International consensus on use of continuous glucose monitoring. Diabetes Care. 2017. pubmed.ncbi.nlm.nih.gov
• International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2017. pubmed.ncbi.nlm.nih.gov
• American Diabetes Association. Diabetes technology: standards of care in diabetes 2024. Diabetes Care. 2024. pubmed.ncbi.nlm.nih.gov