Navigating the discordance: a comprehensive review of HbA1c-glycemia mismatch in clinical practice

Glycated hemoglobin (HbA1c) is a cornerstone of diabetes diagnosis and management. For most individuals, HbA1c remains reliable; however clinically significant discordance between HbA1c levels and actual blood glucose values occurs in defined subpopulations with specific confounding conditions (e.g., anemia, hemoglobinopathies, chronic kidney disease). This narrative review synthesizes current evidence on the multifactorial etiology and clinical consequences of HbA1c-glycemia mismatch. We highlight biological variability, hematological conditions, systemic diseases, and analytical factors that contribute to this discrepancy. The review emphasizes that recognizing these limitations is crucial to avoid clinical misjudgment, such as inappropriate treatment escalation or dangerous therapeutic inertia. We advocate for a systematic diagnostic approach when discordance is suspected, including evaluation for confounders and alternative biomarkers such as fructosamine, and critically, the integration of continuous glucose monitoring (CGM). When CGM is utilized, a comprehensive assessment of glycemic control should incorporate the full panel of consensus metrics- Time-in-Range (TIR), Time-Below-Range (TBR), Glycemic Variability (GV), and the Glucose Management Indicator (GMI). However, CGM systems have their own limitations, including inter-sensor variability and differences between device models, which must be considered when interpreting discordance. This review aims to equip clinicians with the knowledge to navigate HbA1c discordance, promoting personalized, safe, and equitable diabetes care.