Your hemoglobin A1c (HbA1c) indicates your long-term glucose levels and is used along with other markers to diagnose diabetes. Increased HbA1c in nondiabetics, apart from being a risk factor for diabetes, is also associated with heart disease and elevated all-cause mortality. Read on to learn about the causes and health risks of high HbA1c.

High Hemoglobin A1c (HbA1c) Causes

1) Diabetes

HbA1c ≥ 6.5% is a reliable indicator of diabetes [1].

In non-diabetic Japanese health-check examinees who were 30 – 79 years old, the incidence of diabetes increased with increasing baseline HbA1c [2]. In this and other studies, an HbA1c above 5.7% was a suitable value for predicting future diabetes [2, 3].

According to the American Diabetes Association (ADA), 9.3% of the American population is diabetic [4].

High HbA1c levels may reveal ongoing diabetes, while slightly higher levels predict future diabetes.

2) Sleep Disorders

Both short and long sleep durations were associated with an increased HbA1c. Similarly, poor sleep quality was associated with a higher HbA1c [5].

The presence of sleep apnea and lower levels of oxygen in the blood were associated with higher HbA1c levels in patients with T2DM [6]. 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 [7].

Even in nondiabetic men with obstructive sleep apnea, high HbA1c levels were associated with a more severe disorder [8].

Getting too little or too much sleep is linked with higher HbA1c. Diabetics with sleep apnea also tend to have higher levels.

3) Gum Disease

There is an association between oral hygiene practice and blood glucose levels in diabetes [9]. Individuals with better self-reported toothbrushing practice tended to have lower levels of blood glucose and HbA1c [9, 10].

HbA1c control was associated with toothbrushing every day. 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 [9].

HbA1c is significantly elevated with periodontal (gum) deterioration in nondiabetics [11, 12]. Treatments that improve gum inflammatory conditions resulted in decreased HbA1c levels [13, 14].

Diabetics who maintain good oral hygeine have lower HbA1c levels, while nondiabetics with untreated gum disease have higher HbA1c levels.

4) Iron Deficiency and Anemia

Iron deficiency and anemia may interfere with the classification of diabetes and prediabetes using HbA1c [15]. The effect may be dependent on the degree of anemia, as subjects with mild anemia did not show significant effects on HbA1c [16].

Although many forms of anemia are associated with lowering of HbA1c, iron deficiency anemia has been shown to shift HbA1c upward [17, 16, 18, 19].

Similarly, patients with anemia due to the deficiency of vitamin B12 have higher HbA1c levels [20].

In both iron and B12 deficiency, the administration of the deficient factor decreases the HbA1c back to normal [18, 20].

Anemia due to iron or vitamin B12 deficiency can increase HbA1c levels, which go back to normal once the deficiency is corrected.

5) H. pylori Infection

Chronic H. pylori infection was associated with high levels of HbA1c and type 2 diabetes in the elderly [21].

H. pylori eradication treatment had beneficial effects on insulin resistance and favorably changed HbA1c in patients with normal glucose concentrations [22].

6) Gastrointestinal Abnormalities

Higher HbA1c levels were associated with increased digestive tract abnormalities [23].

The incidence of colorectal adenomatous polyps increased with increasing HbA1C in male subjects over 50 [24].

High HbA1c levels have been linked with H. pylori infections and gut problems.

7) Chronic Inflammation

Chronic low-grade inflammation is a common feature of insulin-resistant states, including obesity, polycystic ovary syndrome and type 2 diabetes [25].

In patients with type 2 diabetes, HbA1c levels correlated with CRP levels. HbA1c levels were significantly higher in patients who had higher CRP levels [26, 27].

In patients with polycystic ovary syndrome, HbA1c correctly classified patients with elevated CRP and may serve as a marker of chronic inflammation [25].

Diabetics and women with polycystic ovary syndrome who have high HbA1c levels are more likely to have high CRP, a marker of chronic inflammation.

8) Metabolic Syndrome

Many studies have reported an association between HbA1c and metabolic syndrome in nondiabetic patients [28].

HbA1c levels in nondiabetics were associated with the number of metabolic syndrome components [29].

9) Obesity

Obesity is associated with an increased risk of impaired glucose tolerance [30]. A positive energy balance, when there are more calories consumed than spent, is associated with higher HbA1c [31].

Higher body mass index (BMI), waist-to-hip ratio, and waist circumference were all linked to significantly higher HbA1c [32].

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 [32].

High HbA1c is linked with metabolic syndrome and obesity, even in nondiabetics.

Health Risks of High Hemoglobin A1c (HbA1c)

1) Diabetes Complications

A study showed that the incidence of eye and kidney dysfunction in patients with type 1 diabetes increased sharply and earlier on with increasing HbA1c. None of the patients developed these complications when HbA1c was below 7.6% [33].

The variability of HbA1c levels is equally important. Unstable levels increase the risk of kidney and eye disease and even lower extremity amputation in patients with diabetes [34, 35, 36, 37].

High HbA1c was also associated with nerve pain. Participants reporting pain in diabetes were more than twice as likely to have HbA1c levels > 8% (64 mmol/mol) [38].

People with diabetes and unstable or high HbA1c levels are at a greater risk of complications, such as kidney disease, eye disease, and chronic nerve pain.
.

2) Kidney Disease

High HbA1c in nondiabetics can be associated with chronic kidney disease [28].

However, not only HbA1c levels but also their variability (instability), could predict the development of kidney disease in T1DM [34] and T2DM patients [34].

In patients with elevated blood urea due to kidney failure, there is an elevated production of carbamylated hemoglobin, which can make HbA1c results inaccurate [39, 40].

High and unstable HbA1c levels predit kidney problems in diabetics; high HbA1c levels have also been linked with kidney disease in nondiabetics.

3) Hearing Loss

High HbA1c was associated with increased hearing loss in nondiabetics [29].

4) Cognitive Impairment

High HbA1c was associated with poor cognitive performance in healthy middle-aged people [41].

Higher levels were also associated with poorer baseline episodic memory and greater episodic memory decline in adults [42, 43]. This association was more pronounced in women [43].

Memory and learning problems in children and adolescents were associated with HbA1c > 8.8% (73 mmol/mol) [44].

High levels of HbA1c have been linked with hearing loss, poor cognition, forgetfulness, and learning problems.

5) 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 [45].

Higher HbA1c levels are linked with a three- to five-fold increased risk of demetia and Alzheimer’s disease.

6) Fatigue

About three-quarters of patients with type 1 diabetes suffer from persistent fatigue. Higher HbA1c was weakly associated with fatigue [46].

In patients with type 2 diabetes, with an HbA1c greater than 7%, fatigue was indirectly related to HbA1C. This relationship was mediated through diabetic symptoms, depression and diabetes distress [47].

People with type 1 and 2 diabetes who have high HbA1c levels are more likely to suffer from fatigue.

7) Anxiety and Depression in Diabetics

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 [48].

Suicidal ideation was significantly more prevalent among patients with HbA1c levels ≥ 6.5% [49].

High levels of HbA1c (HbA1c≥9.0%) were associated with a greater risk of anxiety and depression in African men [50].

In 18-21-year-old patients with type 1 diabetes, higher HbA1c levels are associated with psychomotor agitation/retardation (women), overeating/poor appetite (men/women), lethargy (men), and sleep difficulty (men) [51].

Diabetics with higher HbA1c levels are at an increased risk of anxiety, suicidality, and sleep disorders.

8) ADHD

HbA1c values were higher in children with ADHD, suggesting an association between ADHD and an altered blood glucose balance [52].

9) 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 [53].

In adolescents with T1DM, arterial stiffness was directly related to high HbAc1 [54].

Arterial stiffness positively correlated with both HbA1c and the duration of diabetes in subjects with diabetes and elevated blood pressure [55].

High HbA1c was also associated with a higher atherosclerotic burden in nondiabetic patients [56]. In nondiabetics, high-normal HbA1c levels were independently associated with arterial stiffness [57].

Both diabetics and nondiabetics with higher HbA1c values are likely to have hardened arteries.

10) Cardiovascular Risk

Increased risk of cardiovascular complications was found with higher HbA1c levels in both those with established diabetic and in non-diabetic adults [58, 59, 60].

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% [58, 61].

A significant increase in the number of diseased blood vessels was observed as HbA1c level increased [59].

HbA1c showed a direct correlation with blood cholesterol, triglycerides and LDL in diabetic patients at high risk of developing cardiovascular diseases [61].

Chronically elevated glucose, measured by HbA1c, was also disruptive for the heart function [62].

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 [63].

Even slight increases in HbA1c levels can greatly increase the risk of heart disease and high blood fats in people with diabetes.

11) Fatty Liver

Fatty liver is associated with higher HbA1c [64].

In nondiabetic individuals, the risk for non-alcoholic fatty liver disease (NAFLD) increased with increasing HbA1c levels, independent of obesity and other metabolic components [65, 66].

The prevalence of NAFLD was significantly higher in subjects with HbA1c ≥ 6.5% [66].

12) 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 [67].

People with higher HbA1c levels may have a less effective response to flu vaccines; they may also be at an increased risk of fatty liver disease.

13) Irregular Menstrual Cycles

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 [68].

Girls with type 1 diabetes and high HbA1c levels are more likely to experience irregular or long menstrual cycles.

14) Bone Loss

Bone loss is a complication of diabetes characterized by osteoporosis, increased risk for bone fractures and alterations in bone metabolism [69].

Osteocalcin (OC) is a bone-specific protein produced by bone cells, involved in the regulation of glucose and energy metabolism [69]. 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 [69].

Similarly, in type 2 diabetic patients, lower bone mineral density was associated with higher HbA1c [70].

Also, higher bone resorption was independently associated with higher HbA1c in women [71].

Higher HbA1c levels are linked with bone loss, which is especially dangerous for people with diabetes.

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 [72].

HbA1c levels were observed to be higher in patients who had high-grade prostate cancer [73].

Patients with poorly controlled T2DM, with HbA1c > 7.5, had more advanced colorectal cancer, a younger age of onset and 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 [74].

hba1c_levels

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

According to some studies, both diabetics and nondiabetics with high HbA1c are at an increased risk of cancer. High levels might also predict worse cancer outcomes.

Hemoglobin A1c and Lifespan

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 [75].

High HbA1c May Increase Mortality

Higher HbA1c levels are associated with increased mortality from all causes among nondiabetic subjects [75]. 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% [76].

The American Diabetes Association (ADA) estimated that the risk of diabetes-related mortality increased by 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 [61].

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 [75].

High HbA1c points to high glucose, which increases oxidative damage and may reduce lifespan in both diabetics and nondiabetics.

Low HbA1c May Also Increase 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) [77, 78].

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% [79, 80]. It was suggested, therefore, that diabetes guidelines should be revised to include a minimum HbA1c [80].

Some explanations for the low HbA1c – mortality relationship, include: underweight, inflammation, anemia, high alcohol consumption, liver disease and chronic renal failure [77].

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 [81].

In one study, where HbA1c < 5% was associated with adverse outcomes in nondiabetic people, a link to inflammation and autoimmunity was suggested [78]. Very low HbA1c (1.4%) in a diabetic patient with fairly high plasma glucose was associated with autoimmune destruction of red blood cells [82].

Lower than normal HbA1c levels have been linked with increased mortality, possibly because they point to frailty, autoimmune inflammation, or inadequate nutrition.

Irregular HbA1c Levels?

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Takeaway

Though HbA1c is a direct measure of long-term sugar levels, diabetes is not the only cause of high values.

Sleep disorders, gum disease, H. pylori infections, chronic inflammation, and anemia can also increase HbA1c. Additionally, high levels are linked with metabolic syndrome and obesity, which often progress to type 2 diabetes.

High HbA1c levels can have many negative effects on your health, whether you have diabetes or not.

People with high levels are at an increased risk of dementia, heart disease, kidney disease, mental health problems, fatigue, and bone loss.

Scientists think HbA1c levels might also impact a person’s lifespan. Both above and below normal levels have been linked with increased mortality, but it’s still too early to say why or to what extent.

Keeping your levels in the normal range is the best step you can take to lower your overall risk of health problems.

About the Author

Biljana Novkovic - PHD (ECOLOGICAL GENETICS) - Writer at Selfhacked

Dr. Biljana Novkovic, PhD

PhD (Ecological Genetics)

Biljana received her PhD from Hokkaido University.

Before joining SelfHacked, she was a research scientist with extensive field and laboratory experience. She spent 4 years reviewing the scientific literature on supplements, lab tests and other areas of health sciences. She is passionate about releasing the most accurate science & health information available on topics, and she's meticulous when writing and reviewing articles to make sure the science is sound. She believes that SelfHacked has the best science that is also layperson-friendly on the web.

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