*Corresponding Author: Dr. Manjusha Hivre, Associate Professor, Department of Biochemistry, MGM Medical College, Chhatrapati Sambhajinagar, Maharashtra, India. Email: drmanjushahivre@gmail.com
Background: Glycated hemoglobin (HbA1c) remains the gold standard for glycemic assessment, yet significant limitations exist in populations with altered erythrocyte kinetics, hemoglobin variants, or rapid metabolic changes. These limitations can lead to misdiagnosis and inappropriate treatment decisions.
Objectives: To comprehensively review HbA1c limitations in hemoglobinopathies, hemolytic anemias, and malignancy; evaluate alternative glycemic biomarkers (glycated albumin, fructosamine, 1,5-anhydroglucitol); examine hyperglycemia-cancer relationships; and provide evidence-based clinical algorithms.
Methods: Systematic literature search across PubMed, Embase, Web of Science, and Scopus through January 2025, prioritizing 2020-2025 publications, randomized trials, systematic reviews, and prospective cohorts.
Results: Analysis of 156 studies revealed: HbA1c underestimation of 0.3-1.5% in hemoglobinopathies/hemolytic anemias; spurious elevation of 0.5-1.0% in iron deficiency; assay-dependent interference in 0.71% of patients with hemoglobin variants; elevated HbA1c associated with increased cancer risk (pancreatic HR 1.21, colorectal HR 1.15, liver HR 1.28 per 1% increase); glycated albumin superior correlation with time-in-range (r=0.76 vs 0.62); diagnostic cutoffs established (GA 13.9%, fructosamine 278 μmol/L, 1,5-AG 13.3 μg/mL); alternatives maintained accuracy where HbA1c failed.
Conclusions: Clinicians must recognize HbA1c limitations and deploy alternatives appropriately. Glycated albumin excels in CKD and hemoglobinopathies; fructosamine in pregnancy and short-term assessment; 1,5-AG for postprandial excursions. The hyperglycemia-cancer bidirectional relationship necessitates accurate assessment in oncology. Evidence-based algorithms enhance precision in complex populations.
Keywords: Glycated hemoglobin, HbA1c, Glycated albumin, Fructosamine, 1,5-anhydroglucitol, Hemoglobinopathies, Sickle cell disease, Thalassemia, Hemolytic anemia, Cancer, Hyperglycemia, Alternative biomarkers, Precision medicine.
How to cite this article: Hivre M, Holkar S, Vaishnav D, Surkar P. Beyond HbA1c: alternative glycemic biomarkers in hemoglobinopathies, malignancy, and special clinical populations - a review. Int J Drug Deliv Technol. 2026;16(7s): 303-327; DOI: 10.25258/ijddt.16.7s.34
Source of support: Nil.
Conflict of interest: None