Background: Sickle cell anemia (SCA) is an autosomal recessive blood disorder resulting from a point mutation in the beta-globin gene, which causes the synthesis of aberrant hemoglobin S (HbS). The accuracy of hemoglobin A1c as a glycemic biomarker, is impaired by chronic hemolysis and reduced red blood cell (RBC), posing a diagnostic issue for people with both sickle cell anemia and diabetes mellites (DM)
Objectives: This study examines the molecular pathophysiology of sickle cell anemia (SCA), the biochemistry involved in hemoglobin A1c (HbA1c) measurement, and the mechanisms by which hemoglobin S (HbS) interferes with HbA1c assays, both physiologically and analytically. It also reviews clinical methods for addressing these challenges. 
Methods: A comprehensive literature review was conducted across Scopus, PubMed/MEDLINE, , and Web of Science for identifying peer-reviewed articles published between 1990 and 2025. The investigation employed the subsequent MeSH terms: sickle cell anemia, HbA1c, hemoglobin variations, glycated hemoglobin,  glycated albumin, diabetes mellitus, and fructosamine.
Results: Polymerization of hemoglobin S (HbS) results in vaso-occlusion, persistent hemolysis, and organ destruction. The decreased lifespan of red blood cells in sickle cell anemia (17–29 days against the normal 90–120 days) results in a consistent underestimate of HbA1c levels. Analytical interference varies according to the testing technique employed. Ion-exchange high-performance liquid chromatography (IE-HPLC), immunoassay, boronate affinity chromatography, and capillary electrophoresis exhibit distinct interference patterns with HbS and increased fetal hemoglobin (HbF). Additional biomarkers, such as fructosamine and glycated albumin (GA), offer insights into shorter glycemic periods; yet each has distinct limits. Recent evidence suggests that continuous glucose monitoring (CGM) offers the most precise real-time glycemic evaluation in this demographic.
Conclusion: Clinicians should recognize the limitations of HbA1c in patients with sickle cell anemia and use tailored glycemic monitoring. For patients with SCA and diabetes, combine NGSP-certified HbA1c with alternative biomarkers and continuous glucose monitoring (CGM).