Impact of Hemoglobin Glycation Gap in the Diagnosis and the Management of Diabetes: Case Reports

Glycated hemoglobin (HbA1c) is the cornerstone for the diagnosis and the monitoring of diabetes, yet inter-individual variation in HbA1c glycation can produce marked discordance between HbA1c and true glycemic exposure, described as the “glycation gap” (GGap) or “hemoglobin glycation index”. Individuals with a low or negative GGap (“low glycators”) may have spuriously low HbA1c despite sustained hyperglycemia, leading to potential underdiagnosis and undertreatment if HbA1c is used in isolation. This study describes two adult males with persistently elevated capillary and plasma glucose values, abnormal continuous glucose monitoring (CGM) metrics, and high fructosamine, in whom serial HbA1c values remained low when compared with glucose values despite exclusion of hemoglobinopathies, anemia, or drug-induced assay interference. These case reports reinforce that low-glycator phenotypes are clinically relevant and underscore the need to integrate CGM, self-monitoring of blood glucose, fructosamine, and, when appropriate, oral glucose tolerance testing alongside HbA1c to avoid misclassification of glycemic status and to individualize treatment targets.