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HbA1c is an indicator of long-term glucose levels and has been recommended for diagnosing diabetes by the American Diabetes Association. Increased HbA1c in nondiabetics, apart from being a risk factor for diabetes, is also associated with cardiovascular disease and elevated all-cause mortality. Ideally, you would want to keep your HbA1c low, but also stable. Read on to find out why, and to learn about all the factors that can help you improve your HbA1c levels.

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HbA1c 2-Part Series

What is HbA1c

Glycated hemoglobin (HbA1c) is an important indicator for long-term glucose levels and has been recommended for use in the diagnosis of diabetes mellitus (DM) by the American Diabetes Association (ADA) and World Health Organization (WHO) (R).

HbA1c results from the attachment of glucose to hemoglobin, which is found in red blood cells (R).

How Our Blood Glucose Levels Relate to HbA1c

Red blood cells are exposed to glucose in the blood. The higher the blood glucose level gets, the more HbA1c forms throughout the lifespan of a red blood cell. The lifespan of a red blood cell varies from person to person but averages out to approximately 117 days in men and 106 days in women. Therefore, the HbA1c is an index of average blood sugar levels over the preceding 2 to 3 months. Of this 2 – 3 month period, the immediately preceding 30 days contribute 50% to HbA1c (R).

Normal adult hemoglobin consists predominantly of HbA1, of which HbA1c comprises approximately 5% (R).

However, HbA1c does not always correlate with blood glucose levels. It is possible to have high blood glucose but low HbA1c due to the presence of hemoglobin variants, inflammation, or other factors that increase red blood cell turn over.

If your Red Blood Cells live longer than 90 days or your RBCs are smaller (as measured by MCV in blood test), then your HbA1C will be artificially higher.

Optimal Range for HbA1c

In healthy people, optimal HbA1c values range between 4.0% and 5.6% (R).

American Diabetes Association that people with HbA1c values of 5.7–6.4% (39–46 mmol/mol) be considered high risks for diabetes (R).

Values ≥ 6.5% may indicate diabetes (R).

However, HbA1c as a single measurement is not adequate to diagnose diabetes (R). In one study HbA1c resulted in a significantly lower diabetes detection (3.6%) compared with diabetes defined by a 2-hour post-meal blood glucose test (9.2%) (R).

HbA1c can be measured in percent or mmol/mol.

HbA1c Testing

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How Often Should One Test for HbA1c?

Diabetic patients with stable blood glucose levels should test HbA1c twice a year (R).

Quarterly monitoring might be indicated in patients with newly diagnosed or pregnancy associated diabetes, rapidly changing HbA1c levels, treatment changes, insulin use, or history of hypoglycemia (low blood sugar) (R).

Testing HbA1c five or more times per year is redundant because HbA1c is a measure of average blood sugar over three months (R).

Advantages of HbA1C Over Other Blood Glucose Tests

  • The HbA1c test can be taken at any time and does not require fasting (R).
  • It is unaffected by physical activity or stress prior to testing (R).
  • As a marker of longer-term blood sugar levels, it is unaffected by short-term hormonal surges (R).
  • As a test, HbA1c has a low variability, both when measured in a single individual, and among people (R).
  • HbA1c is more stable than glucose at 37°C (R).
  • Symptomatic patients can be tested immediately at the same visit, saving costs (R).

How HbA1c Naturally Varies

1) Seasonal variation

HbA1c levels were reported to be higher in colder (January-March) than in warmer (July-September) months (R).

This variation amounts to about 0.3% (3.3 mmol/mol). These differences may be due to differences in exercise, carbohydrate intake, and the number of illness events between summer and winter months (R).

2) Ethnic differences

HbA1c levels are often reported to be different depending on race, ethnicity, and ancestry.

African-Caribbean and South Asian subjects were reported to have HbA1c levels 0.27-0.4% higher compared to those with European ancestry, despite lower fasting blood glucose in oral glucose tolerance tests (R,R).

In South Africa, Black African patients with diabetes were more likely to reach the HbA1c target (<7%) and less likely to have eye, kidney or cardiovascular diabetic complications (R).

3) Genetic Variants of Hemoglobin

HbA1c results can be inaccurate in persons with elevated amounts of hemoglobin variants. These variants (Hemoglobin S, C, E, and F) are more prevalent in non-caucasians (R).

Hemoblobin S is found in approximatel one in 12 African Americans, one in 100 hispanics and other races (R).

Hemoglobin C is found in approximately one in 50 African Americans (R).

Hemoglobin E is associated with Asian descents, particularly southeast coastal Asia, with up to 30% in some areas (R).

Hemoglobin F is the normal hemoglobin typically found in fetus and in low concentration in adults. In some genetic diseases like Hereditary Persistence of Fetal Hemoglobin, Sickle Beta Thalassemia and some other diseases, hemoglobin F can be elevated (R).

4) Sex Differences

Men have to undergo a greater metabolic deterioration and put on more visceral fat to develop HbA1c-defined diabetes than do women (R).

5) Age

HbA1c increases with age, even in the absence of diabetes (R,R,R,R).

Patients with aged over 70 have a 0.47% higher HbA1c compared to those under 30 (R).

Age results in an increase of 0.074% – 0.094% in HbA1c per decade (R,R). This age-dependent increase in HbA1c is greater in subjects with a family history of diabetes, and higher BMI (R).

One study argues against the increase of HbA1c with age though (R).

HbA1c in Diseases and Disorders

6) HbA1c is Elevated in Diabetes

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HbA1c ≥ 6.5% is a reliable indicator of the presence of diabetes (R).

In non-diabetic Japanese health-check examinees who were 30-79 years old, the incidence of diabetes increased with increasing baseline HbA1c (R). In this and other studies, a HbA1c above 5.7% was a suitable value for predicting future diabetes (R,R).

In 2015, the American Diabetic Association (ADA) suggested that an HbA1c of 5.7–6.4% (39–46 mmol/mol) was reasonable for the diagnosis of pre-diabetes and that patients with HbA1c > 6.0% (>42 mmol/mol) should be considered to be at very high risk for developing diabetes (R).

According to the ADA, 9.3% of the American population is diabetic (R).

7) High HbA1c Predicts Diabetes Complications

A study showed that the incidence of eye and kidney dysfunction in patients with type 1 diabetes increased sharply and occurred earlier with increasing HbA1c. None of the patients developed these complications when HbA1c was below 7.6% (R).

However, not only HbA1c levels but also their variability (instability), can increase the risk of the development of kidney and eye disease in type 1 diabetes (T1DM) patients (R,R).

The odds for lower extremity amputation in patients with diabetes increased with increasing HbA1c levels (R,R).

High HbA1c was also associated with pain. Participants reporting pain in diabetes were more than twice as likely to have HbA1c levels > 8% (64 mmol/mol) (R).

8) HbA1c is Elevated in Kidney Disease

High HbA1c in nondiabetics can be associated with chronic kidney disease (R).

However, not only HbA1c levels but also their variability (instability), could predict the development of kidney disease in T1DM (R) and T2DM patients (R).

In patients with elevated blood urea due to kidney failure, there is an elevated production of carbamylated hemoglobin, which can make HbA1c results inaccurate (R, R2).

9) High HbA1c is Associated with Hearing Impairment

High HbA1c was associated with increased hearing loss in nondiabetics (R).

10) High HbA1c is Associated with Cognitive Impairment

High HbA1c was associated with poor cognitive performance in healthy middle-aged people (R).

Higher HbA1c levels were associated with poorer baseline episodic memory and greater episodic memory decline in adults (R,R). This association was more pronounced in women (R).

Memory and learning problems in children and adolescents were associated with HbA1c > 8.8% (73 mmol/mol) (R).

11) High HbA1c is Associated with Dementia

Higher levels of HbA1c are associated with an increased risk of dementia and Alzheimer’s in the elderly.

HbA1c levels ≥6.5% were associated with a 2.8-fold increased risk of all-cause dementia and Alzheimer’s. HbA1c levels ≥7% were associated with a 5-fold increased risk of all-cause dementia and a 4.7-fold increased risk of Alzheimer’s (R).

12) Periodontal Disease Can Increase HbA1c Levels

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There is an association between oral hygiene practice and blood glucose levels in diabetes (R). Individuals with better self-reported toothbrushing practice tended to have lower levels of blood glucose and HbA1c (R,R).

HbA1c control was associated with toothbrushing everyday. An Indian study reported that percentage of twice-daily toothbrushing was significantly higher in people with good diabetes control (HbA1c <6.0%) than in people with poor diabetes control (HbA1c > 7.5%) in both male and female adults with type 2 diabetes (R).

HbA1c is significantly elevated with periodontal (gum) deterioration in nondiabetics (R,R). Treatments that improve gum inflammatory conditions resulted in decreased HbA1c levels (R,R).

13) Iron Deficiency and Anemia Impact HbA1c Levels

Iron deficiency and anemia may interfere with the classification of diabetes and prediabetes using HbA1c (R). The effect may be dependent on the degree of anemia, as subjects with mild anemia did not show significant effects on HbA1c (R).

Although many forms of anemia are associated with lowering of HbA1c, iron deficiency anemia has been shown to shift HbA1c upward (R,R,R,R).

Similarly, patients with anemia due to the deficiency of vitamin B12 have higher HbA1c levels (R).

In both iron and B12 deficiency, the administration of the deficient factor decreases the HbA1c back to normal (R,R).

14) HbA1c Can be Associated with Fatigue

About three-quarters of patients with type 1 diabetes suffer from persistent fatigue. Higher HbA1c was weakly associated with fatigue (R).

In patients with type 2 diabetes, with a HbA1c greater than 7%, fatigue was indirectly related to HbA1C. This relationship was mediated through diabetic symptoms, depression and diabetes distress (R).

15) High HbA1c is Associated with Anxiety and Depression in Diabetics

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In diabetics, depressed mood, sleeping difficulties, appetite problems and suicidal ideation correlate with higher baseline HbA1c levels and higher HbA1c values at 1-year follow-up. These associations were more pronounced in type 1 diabetes than in type 2 diabetes patients (R).

Suicidal ideation was significantly more prevalent among patients with HbA1c levels ≥6.5% (R).

High levels of HbA1c (HbA1c≥9.0%) were associated with a greater risk of anxiety and depression in African men (R).

In 18-21-year-old patients with type 1 diabetes, higher HbA1c levels is associated with psychomotor agitation/retardation (women), overeating/poor appetite (men/women), lethargy (men), and sleep difficulty (men) (R).

16) High HbA1c in ADHD

HbA1c values were higher in children with ADHD, suggesting an association between ADHD and an altered blood glucose balance (R).

17) High HbA1c is Associated with Atherosclerosis

There is an interwoven relationship between unsatisfactory blood sugar levels, low-grade inflammation and low HDL cholesterol on the hardening of the arteries in type 2 diabetes (R).

In adolescents with T1DM, a significant association was observed between arterial stiffness and high HbAc1 (R).

Arterial stiffness positively correlated with both HbA1c and the duration of diabetes in subjects with diabetes and elevated blood pressure (R).

High HbA1c was also associated with higher atherosclerotic burden in nondiabetic patients (R). In nondiabetics, high-normal HbA1c levels were independently associated with arterial stiffness (R).

18) High HbA1c is Associated with Cardiovascular Risk and All-Cause Mortality

Increased risk of cardiovascular complications was found with higher HbA1c levels in both those with established diabetic and in non-diabetic adults (R,R,R).

A 1% increase in HbA1c levels is associated with a 17% – 35% increase in the risk of cardiovascular disease and a 15% – 25% increase in the risk of mortality in subjects with type 2 diabetes. In nondiabetics, a 1% increase in HbA1c, increases all-cause mortality risk by 26% (R,R).

A significant increase in the number of diseased blood vessels was observed as HbA1c level increased (R).

HbA1c showed a direct correlation with blood cholesterol, triglycerides and LDL in diabetic patients at high risk of developing cardiovascular diseases (R).

Chronically elevated glucose, measured by HbA1c, was also disruptive for the heart function (R).

However, lower HbA1c was also reported to increase the risk of cardiovascular disease in some studies. In one study, both HbA1c <6% as well as HbA1c> 10% were independently associated with the risk of heart failure (R).

19) H. pylori Infection May Increase HbA1c

Chronic H. pylori infection was associated with high levels of HbA1c and type 2 diabetes in the elderly (R).

H. pylori eradication treatment had beneficial effects on insulin resistance and favorably changed HbA1c in patients with normal glucose concentrations (R).

20) High HbA1c May be Associated with Gastrointestinal Abnormalities

Higher HbA1c levels were associated with an increase of digestive tract abnormalities (R).

The incidence of colorectal adenomatous polyps increased with increasing HbA1C in male subjects over 50 (R).

21) High HbA1c is Associated with Fatty Liver

Fatty liver is associated with higher HbA1c (R).

In nondiabetic individuals, the risk for non-alcoholic fatty liver disease (NAFLD) increased with increasing HbA1c levels, independent of obesity and other metabolic components (R,R).

The prevalence of NAFLD was significantly higher in subjects with HbA1c ≥6.5% (R).

22) High HbA1c May Affect the Immune Response

In diabetic patients who were vaccinated against influenza (flu), subjects with the highest HbA1c levels (≥7.6%) showed a lower immune response to the virus, because diabetics may have impaired immune system (R).

23) High HbA1c is Associated with Chronic Inflammation

Chronic low-grade inflammation is a common feature of insulin resistant states, including obesity, polycystic ovary syndrome and type 2 diabetes (R).

In patients with type 2 diabetes, HbA1c levels correlated with CRP levels. HbA1c levels were significantly higher in patients who had higher CRP levels (R,R).

In patients with polycystic ovary syndrome, HbA1c correctly classified patients with elevated CRP, and may serve as a marker of chronic inflammation (R).

24) High HbA1c is Associated with Sleep Disorders

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Both short and long sleep durations were associated with an increased HbA1c. Similarly, poor sleep quality was associated with a higher HbA1c (R).

The presence of sleep apnea and lower levels of oxygen in the blood were associated with higher HbA1c levels in patients with T2DM (R). Sleep apnea is a sleep disorder characterized by pauses in breathing or periods of shallow breathing during sleep.

T1DM patients with moderate-to-severe obstructive sleep apnea had a trend toward higher HbA1c (R).

Even in nondiabetic men with obstructive sleep apnea, high HbA1c levels were associated with a more severe disorder (R).

25) High HbA1c is Associated with Irregular Menstrual Cycle

Girls with T1DM and HbA1c levels of 7.6% – 8.9% exhibit increased cycle duration, menstrual cycle variability, and infrequent periods (oligomenorrhea). For each point of increase in HbA1c, the menstrual cycle duration increases by 5.1 days (R).

26) High HbA1c is Associated with Bone Loss

Bone loss is a complication of diabetes characterized by osteoporosis, increased risk for bone fractures and alterations in bone metabolism (R).

Osteocalcin (OC) is a bone-specific protein produced by bone cells, involved in the regulation of glucose and energy metabolism (R). This is a bone-building protein and correlates well with a person’s bone mineral density (BMD). In T1DM of long duration, lower osteocalcin in the blood was associated with higher HbA1c (R).

Similarly, in type 2 diabetic patients, lower bone mineral density was associated with higher HbA1c (R).

Also, higher bone resorption was independently associated with higher HbA1c in women (R).

27) High HbA1c is Associated with Metabolic Syndrome

Many studies have reported an association between HbA1c and metabolic syndrome in nondiabetic patients (R).

HbA1c levels in nondiabetics were associated with the number of metabolic syndrome components (R).

28) High HbA1c is Associated with Obesity

Obesity is associated with an increased risk of impaired glucose tolerance (R). A positive energy balance, when there are more calories consumed than spent, is associated with higher HbA1c (R).

Higher body mass index (BMI), waist-to-hip ratio, and waist circumference were all linked to significantly higher HbA1c (R).

An interesting finding is that weight discrimination exacerbated the effects of waist-to-hip ratio on HbA1c, suggesting that psychosocial factors can increase vulnerability to diabetes in nondiabetic subjects (R).

High HbA1c is Associated with Cancer

Studies report that higher HbA1c levels are associated with higher incidence and/or mortality risk of cancers. Elevated HbA1c levels were associated with a higher risk of developing colorectal, pancreatic, respiratory and female genital tract cancers (R).

HbA1c levels were observed to be higher in patients who had high-grade prostate cancer (R).

Patients with poorly controlled T2DM, with HbA1c > 7.5, had more advanced colorectal cancer, a younger age of onset and a poorer 5-year survival. Additionally, in patients with T2DM who have colorectal cancer, unsatisfactory blood sugar levels are associated with a clinically more aggressive course of the disease (R).

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401751/

HbA1c and Mortality

Several studies observed that high HbA1c levels (≥6.5%, 48 mmol/mol) were associated with increased mortality, whereas others failed to find any significant associations with mortality across the whole HbA1c range. Furthermore, some studies also found increased mortality in people with lower HbA1c values (R).

29) High HbA1c is Associated with All-Cause Mortality in Diabetics

Higher HbA1c levels are associated with increased mortality from all causes among nondiabetic subjects (R). One study reported that the risk for all-cause mortality was significantly increased in HbA1c level >5.5% compared to HbA1c <5.5%, and it further dramatically increased 2-3 times in the highest HbA1c group ≥ 7.2% (R).

The American Diabetes Association (ADA) estimated that the risk of diabetes-related mortality increased 25% for each 1% increase in HbA1c. It has also been estimated that each percentage point increase in HbA1c corresponds to a 35% increase in the risk of cardiovascular complication and an 18% increase in the risk of myocardial infarction (R).

Why does elevated HbA1c relate to mortality? Ample evidence shows that elevated glucose can result in oxidative stress. Oxidative stress then damages blood vessels, contributing to cardiovascular disease. Oxidative stress can also damage DNA, potentially resulting in gene mutation and cancer development (R).

30) Below Optimal HbA1c is Also Associated with Increased Mortality

Increased mortality was also reported for HbA1c levels below optimal range in diabetics. Some reported an increased risk for cardiovascular outcomes or death among nondiabetic subjects with HbA1c levels below 4.0 % (20 mmol/mol), 4.8 % (29 mmol/mol), 4.9 % (30 mmol/mol) or 5.0 % (31 mmol/mol) (R,R).

In diabetic subjects, the HbA1c cutoff value was reported to be as high as 7.5%. In these subjects, mortality increased both with values over and values under 7.5% (R,R).  It was suggested, therefore, that diabetes guidelines should be revised to include a minimum HbA1c (R).

Some explanations for the low HbA1c – mortality relationship, include: underweight, inflammation, anemia, high alcohol consumption, liver disease and chronic renal failure (R).

It appears that malnutrition, inflammation, and functional decline are characteristics shared by the populations that showed increased mortality and low HbA1c. Thus, frailty or decline may be the main confounding factor explaining the relationship between increased mortality risk and low HbA1c (R).

In one study, where HbA1c < 5% was associated with adverse outcomes in nondiabetic people, a link to inflammation and autoimmunity was suggested (R). Very low HbA1c (1.4%) in a diabetic patient with fairly high plasma glucose was associated with autoimmune destruction of red blood cells (R).

HbA1c and Pregnancy

31) HbA1c in Normal Pregnancy

HbA1c levels fluctuate very slightly during pregnancy. HbA1c levels decrease during the second trimester of a normal non-diabetic pregnancy and rise during the third trimester (R).

32) Higher HbA1c and Pregnancy Risks

An HbA1c of 5.9-6.7% (41-49 mmol/mol) identifies a higher-risk group of women with gestational diabetes (R).

HbA1c>5.9% (41 mmol/mol) is associated with increased risk of large infants, cesarean section and high blood pressure (R).

One study showed that women with HbA1c over 5.9% showed a 3-fold higher rate of large infants and high blood pressure (preeclampsia) (R).

Another study showed that not obtaining HbA1c within the normal range before delivery was associated with a 6 fold increased risk of infants with low blood sugar levels (hypoglycemia) (R).

HbA1c is a good predictor of congenital malformations. The rate of congenital malformations among those who had HbA1c in diabetic range, pre-diabetic range or normal range was 27.8%, 9.8% and 3.0%, respectively (R).

33) HbA1c and Post-partum Weight Loss in Diabetic Women

Pre-pregnancy BMI and weight retention after delivery were positively associated with HbA1c levels during the first year after delivery in women with Type 1 diabetes. Interventions to modify the behaviors associated with these body weight factors before pregnancy and after delivery may help women with Type 1 diabetes maintain good blood sugar and HbA1c levels after pregnancy (R).

Continued

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2 COMMENTS

  • Keith

    What would be a reason(s) for a low HbA1C? How would you go about correcting it?

    1. Nattha Wannissorn

      fast red blood cell turn over or maybe you just genetically have low HbA1C. If there’s no diagnosis I’d say rely on other markers for blood sugar.

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