“Insights into HbA1c: Key Role in Diabetes Screening and Associated Conditions” - A Comprehensive Review

ABSTRACT

Diabetes Mellitus (DM) is a main cause of serious health problems such as stroke, blindness, renal failure, and amputation. Glycated hemoglobin (HbA1c) has emerged as an important biomarker for monitoring long-term glycemic management, representing average glucose levels over the previous 8-12 weeks. The World Health Organization (WHO) recommends HbA1c as the gold standard for monitoring and predicting diabetes-related problems. This review emphasizes how important it is and how accurate interpretation is required to inform therapy decisions that work.

INTRODUCTION

In today’s times, Diabetes Mellitus has become the leading cause of stroke, blindness, amputation, kidney failure, etc., Within the domain of diabetes assessment and management, glycated hemoglobin (HBA1c) has emerged as a pivotal tool in assessing the glycemic function of hemoglobin. According to WHO, it is considered the gold standard test for assessing long-term glycemic control.[1,2,3] Owing to the long lifespan of erythrocytes, it also has the advantage of showcasing average glucose levels for 8–12 weeks. An Australian report also suggested that a model incorporating HBA1c is comparable to fasting plasma glucose in predicting the development of diabetic retinopathy.[4,5]

Even though HBA1C is an effective tool in testing and diagnosing, it is yet known to be influenced by the genetic variation by the genetic variation at the rs560887 locus of the glucose-6-phosphatase catalytic 2 gene (G6PC2). This shows that patients with GCK mutation have a higher chance of being diagnosed with diabetes.[6,7] Our review article aims to give a comprehensive update on the current knowledge of HbA1c concerning different complications and conditions [Table 1].

Table 1.

Comparison of HbA1c levels and associated complications across major diabetes organizations

Organization	HbA1C Levels	Higher HBA1c value	Most severe complication
American Diabetic Association (ADA)	Normal: Below 5.7%	≥6.5%	Diabetic Retinopathy[2]
	Prediabetes: 5.7%–6.4%
	Diabetes: 6.5% or higher
World Health Organisation (WHO)	Normal: Below 6.0%	≥7%	Cardiovascular disorders (Myocardial Infarction)[1]
	Prediabetes: 6.0%–6.4%
	Diabetes: 6.5% or higher
International Diabetic Federation	Normal: Below 5.7%	≥8.5%	Diabetic Neuropathy[19]
	Prediabetes: Between 5.7% and 6.4%
	Diabetes: 6.5% or higher, confirmed by at least two separate tests.
Diabetic Association of India/ICMR	Normal: Below 5.6%	≥9%	Diabetic Ketoacidosis[2]
	Pre-diabetes: Between 5.7% and 6.4%
	Diabetes: Above 6.5%

MATERIAL AND METHODS

A comprehensive search of the literature in PubMed, Scopus, Web of Science, and Embase database using keywords like HbA1c, Diabetes Mellitus, systemic Involvement, Diabetic neuropathy, nephropathy, retinopathy, cardiovascular system, and stroke. For recent updates, all related articles were scrutinized by reading abstracts and full texts wherever possible. The articles for the review were restricted to 2022–2024.

Measurement of HBA1c

Tanaka et al.[8] presented an electrochemical detection of HbA1c utilizing a flow immunoassay device. Hirokawa et al.[9] reported an enzyme-based system for detecting HbA1c utilizing fructose peptide oxidase. However, HbA1c (%) cannot be computed only using these approaches. To calculate HBA1c, total hemoglobin must be measured followed by computation of the HBA1c/Hb ratio. Engbaeck et al.[10] developed a direct adsorption immunoassay for HBA1c but is prone to interference with proteins. Numerous factors affect the value of HBA1c which needs to be properly interpreted through proper analysis. Drugs such as levofloxacin, penicillin, cephalosporins, vitamin E, etc. can reflect a false decrease in the value.[11,12]

Conditions associated with HBA1c

1. Diabetes Mellitus:

   Various studies have demonstrated that HBA1c indicates the prognosis of microvascular problems. HbA1c is disproportionately higher in old age and in women with Symptoms like vaginal itching, unintentional weight loss, and frequent urination also tend to indicate poor glycaemic control[13,14] Sole dependency on HBA1C for diabetes assessment can lead to serious clinical errors. The glycation gap (GGap) measures the difference between calculated A1C and the value predicted by regression on fructosamine.[15,16]

2. Cardiovascular Diseases and Stroke:

   HBA1c is known to be associated with the ratio of total to high-density lipoprotein and hypertension. Increasing HBA1c levels in type 2 diabetic patients and being overweight pose a greater risk of cardiovascular diseases and eventually death[17] A case-control study of 32 nations (n = 26,919) found 26% of stroke patients had diabetes versus the 22% of controls. The incidence of stroke is minimum with HBA1c levels ranging from 6% to 7%.[18]

3. Diabetic Peripheral Neuropathy:

   It is one of the most common complications occurring in at least half of type 2 diabetes patients. Wang et al. found that DPN occurred in 8.4% of non-elderly and 24% of elderly. However, in the initial stages, higher HBA1c levels predicted DPN in the elderly than in the non-elderly.[19]

4. Diabetes Retinopathy:

   It is one of the primary conditions causing blindness in China. Retinopathy is far more common in type 2 diabetic patients as compared to patients with normal HBA1c levels.[20]

5. Diabetic Nephropathy:

   Damage to kidneys starts in the prediabetes stage but it is usually diagnosed when the patient presents with end-stage renal disease. In a recent study conducted by Arnold et al., it was concluded that HBA1c is a strong predictor of the early decline of eGFR.[21]

CONCLUSION

HBA1c measures average glucose exposure over 2–3 months. It independently predicts all-cause and cardiovascular mortality and was recently added to the diabetes screening algorithm. Increased levels of HBA1c can cause vascular stiffness, cause endothelial damage, aggravate endothelin release, and lead to vasomotor dysfunction.[22]

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.