Within-subject variation of HbA1c: A systematic review and meta-analysis

Background: Glycosylated haemoglobin (HbA1c) measurement is used to diagnose and to guide treatment of diabetes mellitus. Within-subject variability in measured HbA1c affects its clinical utility and interpretation, but no comprehensive systematic review has described within-subject variability. Methods: A systematic review and meta-analysis was performed of within-subject variability of HbA1c. Multiple databases were searched from inception to November 2022 for follow-up studies of any design in adults or children, with repeated measures of HbA1c or glycosylated haemoglobin. Title and abstract screening was performed in duplicate, full text screening and data extraction by one reviewer and verified by a second. Risk of bias of included papers was assessed using a modified consensus-based standards for the selection of health measurement Instruments (COSMIN) tool. Intraclass correlation coefficient (ICC) results were pooled with a meta-analysis and coefficient of variation (CV) results were described by median and range. Results: Of 2675 studies identified, 111 met the inclusion criteria. Twenty-five studies reported variability data in healthy patients, 19 in patients with type 1 diabetes and 59 in patients with type 2 diabetes. Median within-subject coefficient of variation (CV) was 0.070 (IQR 0.034 to .09). For healthy subjects the median CV for HbA1c % was 0.017 (IQR 0.013 to 0.022), for patients with type 1 diabetes 0.084 (IQR 0.067 to 0.89) and for type 2 diabetes 0.083 (IQR 0.06 to 0.10). CV increased with mean population HbA1c. Limitations: Assessment of variability was not the main aim of many of the included studies and some relevant papers may have been missed. Many included papers had few participants or few repeated measurements. Conclusions: Within-subject variability of HbA1c is higher for patients with than without diabetes and increases with mean population HbA1c. This may confound observed relationships between HbA1c variability and health outcomes. Because of its importance in clinical decision-making there is a need for better estimates and understanding of factors associated with of HbA1c variability.