A Test in Context

Hemoglobin A_1c and Cardiovascular Disease

HbA_1c and CVD: Important Considerations for the Interpretation and Use of HbA_1c Assays

Hemoglobin A covalently bound to glucose (HbA_1c) is the most abundant form of glycated hemoglobin, and its levels are increased in the presence of persistent hyperglycemia. HbA_1c has lower biological variability than glucose, does not require fasting or timed collections, and provides a better reflection of longer-term glycemic exposure. However, a number of physiological and pathophysiological factors may influence HbA_1c levels, including race, conditions that affect erythrocyte age or lifespan, and conditions that affect hemoglobin production. In addition, the values of HbA_1c in children and adolescents and in gestational diabetes remain unclear. Contemporary HbA_1c assays have largely overcome early challenges, with advances in standardization underpinned by the ongoing NGSP program. Remaining measurement-related challenges include possible assay interference by hemoglobin variants (such as HbS, HbC, HbE, HbD, HbF) or by naturally occurring chemical modifications of hemoglobin (such as carbamyl Hb). When HbA_1c values are used for diabetes diagnosis, prognosis, and therapeutic monitoring, it is important to consider that, although therapeutic interventions that reduce HbA_1c also decrease the risk of diabetic microvascular complications, HbA_1c reduction per se is a poor predictor of a therapeutic regimen’s impact on macrovascular complications and survival. Use of personalized HbA_1c targets is emerging as essential for CVD prevention in diabetes. CVD = cardiovascular disease; HbA_1c = glycated hemoglobin A_1c; NGSP = National Glycohemoglobin Standardization Program.