Biomarkers of Blood Glucose Regulation: HbA1C

Optimal Takeaways

Hemoglobin A1C levels reflect the percentage of hemoglobin that has become glycosylated, i.e., bound with glucose or fructose over time. Once hemoglobin becomes glycosylated, it can no longer function optimally, including its vital job of oxygenating tissues. Even a 1% change in HbA1C reflects a significant change in blood glucose levels and must be addressed. Elevated levels are associated with chronic hyperglycemia and increased cardiovascular risk. Low HbA1C may be caused by chronic hypoglycemia, blood loss, or chronic renal failure.

Standard Range: 0 - 5.7%

The ODX Range: 4.6 - 5.3%    

Low HbA1C may reflect chronic hypoglycemia. It can also be falsely decreased with increased RBC turnover, blood loss, hemolysis, hemolytic anemia, chronic renal failure (Pagana 2022), erythropoietin administration, or treatment with iron, B12, or folate for anemia (Lee 2015).

High HbA1C is associated with newly diagnosed or poorly controlled diabetes, cardiovascular disease risk, non-diabetic hyperglycemia related to corticosteroid use, Cushing syndrome, splenectomy, pregnancy, and increased stress (Pagana 2022).

Falsely elevated levels can occur when RBC turnover is decreased, which can occur with iron, B12, and folate anemias (Lee 2015). Higher HbA1C is also associated with atherosclerosis (Fernandez-Friera 2017), elevated red cell distribution width (Bhutto 2019), and metabolic syndrome (Cavero-Redondo 2019).

Overview

Hemoglobin A1C (HbA1C) reflects the chronic exposure of red blood cell hemoglobin to circulating glucose over the past 100-120 days, basically the lifespan of the RBC. The test is primarily used to help diagnose prediabetes and diabetes, to monitor blood glucose control over time, and to evaluate the efficacy of therapeutic interventions.

Chronically elevated glucose will bind to hemoglobin in a process called glycosylation and interfere with its function, a process that is not easily reversed. Each 1% increase or decrease in HbA1C reflects an estimated 35 mg/dL (1.94 mmol/L) change in mean plasma glucose. (Pagana 2022). One drawback of using HbA1C is that it does not reflect postprandial spikes and general variability in blood glucose, factors that contribute to metabolic dysfunction even if HbA1C appears to be “well-regulated” (Bonora 2006).

Traditional diagnostic guidelines classify HbA1C of 6.5% or above as diabetic (ADA 2021). However, maintaining a lower HbA1C of 4.6-5.5%, a level found in young, healthy controls, can help reduce the risk of blood sugar dysregulation (Harrington 2010). Evaluating HbA1C with fasting glucose, OGTT, and other glucose regulation biomarkers provides a clearer clinical picture of diabetes risk and control and overall atherosclerosis and cardiovascular risk. Increased HbA1C of 5.7-6.4% is conventionally associated with prediabetes and increased cardiovascular risk (Vistisen 2018).

However, in a cohort study of apparently healthy people, such a cut-off was not sensitive or effective for identifying prediabetes. The cut-off of 5.7% failed to identify dysglycemia in half the patients evaluated by OGTT. Researchers propose a lower cut-off of 5.3% for pre-diabetes and dysglycemia, as well as a cut-off of 5.25% for identifying impaired fasting glucose (Adamska 2012).

A review of NHANES data comprising 13,792 participant records found that those without diabetes had an HbA1C of 5.2%, while those with undiagnosed prediabetes maintained an HbA1C of 5.9%, and those with undiagnosed diabetes had an HbA1C of 7.6% (Bowen 2015).

Higher levels of HbA1C are significantly associated with increased risk of cardiovascular disease and all-cause mortality. A prospective observational study of 10,232 individuals aged 45-79 without diagnosed diabetes found that those with HbA1C below 5% had the lowest cardiovascular disease and mortality rates. Researchers also note a 1.24-1.28 increased relative mortality risk from any cause with each percentage point increase in HbA1c. Associations were independent of traditional cardiovascular risk factors including smoking, serum cholesterol, systolic blood pressure, BMI, waist-to-hip ratio, and history of CVD (Khaw 2004).

References

Adamska, E et al. “The usefulness of glycated hemoglobin A1c (HbA1c) for identifying dysglycemic states in individuals without previously diagnosed diabetes.” Advances in medical sciences vol. 57,2 (2012): 296-301. doi:10.2478/v10039-012-0030-x

American Diabetes Association. “2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021.” Diabetes care vol. 44,Suppl 1 (2021): S15-S33. doi:10.2337/dc21-S002

Bhutto, Abdul Rabb et al. “Correlation of Hemoglobin A1c with Red Cell Width Distribution and Other Parameters of Red Blood Cells in Type II Diabetes Mellitus.” Cureus vol. 11,8 e5533. 30 Aug. 2019, doi:10.7759/cureus.5533

Bonora, E et al. “Prevalence and correlates of post-prandial hyperglycaemia in a large sample of patients with type 2 diabetes mellitus.” Diabetologia vol. 49,5 (2006): 846-54. doi:10.1007/s00125-006-0203-x

Bowen, Michael E et al. “Random blood glucose: a robust risk factor for type 2 diabetes.” The Journal of clinical endocrinology and metabolism vol. 100,4 (2015): 1503-10. doi:10.1210/jc.2014-4116

Cavero-Redondo, Iván et al. “Metabolic Syndrome Including Glycated Hemoglobin A1c in Adults: Is It Time to Change?.” Journal of clinical medicine vol. 8,12 2090. 1 Dec. 2019, doi:10.3390/jcm8122090

Fernandez-Friera, Leticia et al. “Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors.” Journal of the American College of Cardiology vol. 70,24 (2017): 2979-2991. doi:10.1016/j.jacc.2017.10.024

Harrington, Jennifer et al. “Aortic intima media thickness is an early marker of atherosclerosis in children with type 1 diabetes mellitus.” The Journal of pediatrics vol. 156,2 (2010): 237-41. doi:10.1016/j.jpeds.2009.08.036

​Khaw, Kay-Tee et al. “Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk.” Annals of internal medicine vol. 141,6 (2004): 413-20. doi:10.7326/0003-4819-141-6-200409210-00006 

Lee, Ji-Eun. “Alternative biomarkers for assessing glycemic control in diabetes: fructosamine, glycated albumin, and 1,5-anhydroglucitol.” Annals of pediatric endocrinology & metabolism vol. 20,2 (2015): 74-8. doi:10.6065/apem.2015.20.2.74

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.

Vistisen, Dorte et al. “Risk of Cardiovascular Disease and Death in Individuals With Prediabetes Defined by Different Criteria: The Whitehall II Study.” Diabetes care vol. 41,4 (2018): 899-906. doi:10.2337/dc17-2530