Introduction

The World Health Organization estimates that annually 3.4 million deaths are due to high levels of glucose in the blood.[1] The prevalence of diabetes, the disease most closely associated with chronic hyperglycaemia, currently totals 366 million worldwide and this figure is expected to rise to over 550 million by 2030.[2] In England, around 3.1 million adults over the age of 16 are estimated to be living with diabetes, equating to 7.4% of the population, and the Association of Public Health Observatories projected that this will increase to 4.6 million (9.5%) by 2030.[3] Glycated haemoglobin (HbA1_C) is a reliable biomarker of long term blood glucose levels. The International Expert Committee recommended in 2009 that HbA1_C is appropriate for the clinical diagnosis of diabetes: with HbA1_C levels ≥6.5% (≥48 mmol/mol) being indicative of diabetes, and HbA1_C between 5.7-<6.5% (39 and <48mmol/mol) indicating a pre-diabetic state within which an individual is at a high risk of developing diabetes.[4]

There is heterogeneity within the results of studies which have sought to explore the associations between raised HbA1_C and all-cause mortality; with some finding an increased risk of mortality when compared with those who are normoglycaemic, while others demonstrate no difference[5–9]. The evidence is suggestive of a continuous association between HbA1_C and cardiovascular disease (CVD), including for myocardial infarction and stroke.[10,11] Khaw et al. found that the association between HbA1_C and mortality from all-causes and cardiovascular disease was not only continuous but occurred at measurements lower than the diabetic threshold.[12] A small number of published epidemiological studies have focussed upon HbA1_C and cancer mortality, with the majority demonstrating a positive association between the two,[13–15] although some did not.[16] Joshu et al. found that women with raised HbA1_C were at an increased risk of both cancer incidence and mortality, but this association was not present for men.[14]

There is also inconsistency in current research in a number of areas related to HbA1C and mortality, including whether there are differences in excess mortality related to HbA1_C between the sexes,[17–20] whether HbA1_C begins to impact upon mortality within the normoglycaemic range,[17,21,22] how raised HbA1_C impacts upon mortality among those with and without diagnosed diabetes—the latter being an indicator of how well an individual is controlling their diabetes,[22] and how it might impact upon mortality from site-specific cancers.[17,19,21] The impact that socioeconomic status has upon the excess mortality experienced by those with raised HbA1_C/diagnosed diabetes has also yet to be fully assessed.[23]

We explored the associations between raised HbA1_C (within both the pre-diabetic and diabetic ranges) and mortality from all-causes, cancer and CVD. The impact of confounding factors, such as BMI and socioeconomic status, upon the associations were also assessed. Finally, in order to evaluate whether raised HbA1_C and diabetes impart mortality risks that differ between men and women, we performed sex-stratified analyses.

Materials and Methods

Results

Characteristic of the study sample

In total, 22,106 individuals aged ≥16 years within the HSE had a valid measurement for HbA1_C. The average number of follow-up years was 7 (±SD 2.2). 54% of the sample were women. The sample was evenly split between never regular cigarette smokers and ex or current smokers. 15,476 (70) had neither a raised HbA1_C measurement nor diagnosed diabetes (see Table 1). Among those who reported diagnosed diabetes, 732 were in the uncontrolled diabetes category (HbA1_C ≥48mmol/mol (≥6.5)), 53 had controlled diabetes (HbA1_C <5.7% (<39mmol/mol)), and 234 had diabetes and moderately raised HbA1_C 5.7-<6.5% (39-<48mmol/mol). Of those without diagnosed diabetes, 15,476 had an HbA1_C within the normoglycaemic range 5.7% (<39mmol/mol). This category was used as our reference group. 413 had undiagnosed diabetes (HbA1_C ≥6.5% (≥48mmol/mol) but no diagnosis of diabetes) and 5,198 had pre-diabetes (HbA1_C 5.7-<6.5% (39mmol/mol-<48mmol/mol) and no diagnosis of diabetes). Those with raised HbA1_C tended to be older than those with a lower measurement; for example the mean age of those within the normoglycaemic range, and who did not report diabetes, was 47 years (±SD 0.14), while among those with uncontrolled diabetes the mean age was 64 (0.50). BMI was raised among those in either the diabetic or pre-diabetic groups when compared with those who were normoglycaemic.

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Table 1. Characteristics of the study sample.

https://doi.org/10.1371/journal.pone.0119882.t001

1,509 participants (6.8% of the sample) had died by the end of the follow-up period; 506 participants had died of CVD and 466 from cancer.

All-cause mortality

Compared with those without diabetes, participants with undiagnosed, uncontrolled, or diabetes with moderately raised HbA1_C had an increased HR in relation to all-cause mortality; although those with pre-diabetes or controlled diabetes did not (see Table 2). When the analyses were stratified by sex, women who had either undiagnosed or uncontrolled diabetes were at an increased risk of all-cause mortality 1.61 (1.12–2.30) and 2.27 (1.72–3.01), respectively) while only men with uncontrolled diabetes were found to have an increased HR (1.62, 1.27–2.05) (Table 3). Results were not significantly altered by adjustment for SES and BMI. Fig. 1 demonstrates the fully adjusted (age, sex, smoking status, SES and BMI) survival curves for cancer mortality HbA1_C and diabetes category.

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Table 2. HRs for all-cause and cause-specific mortality by glycated haemoglobin and self-reported diabetes category.

https://doi.org/10.1371/journal.pone.0119882.t002

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Table 3. HRs for all-cause and cause-specific mortality by glycated haemoglobin and diagnosed diabetes category, stratified by sex.

https://doi.org/10.1371/journal.pone.0119882.t003

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Fig 1. Fully adjusted (age, sex, smoking, SES and BMI) all-cause mortality survival curves by HbA1_C and diabetes category (whole sample).

https://doi.org/10.1371/journal.pone.0119882.g001

Cancer and cardiovascular disease mortality

Raised HbA1_C and/or diabetes did not confer an increased risk of cancer mortality when compared with those without diabetes; this result was also found within the sex-stratified analyses (Table 2). Fig. 2 details the survival curves for cancer mortality by HbA1_C/diabetes category.

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Fig 2. Fully adjusted survival curves for cancer mortality by HbA1_C and diabetes category (whole sample).

https://doi.org/10.1371/journal.pone.0119882.g002

The situation was different for cardiovascular mortality (Table 2). Compared with those without diabetes, each group categorised as having abnormal HbA1_C or diabetes had a statistically significant excess in mortality from CVD apart from those with pre-diabetes. For each group (undiagnosed, controlled diabetes, uncontrolled, and those with diabetes and moderately raised HbA1_C) the HRs were substantially increased (1.99 (1.35–2.94), 3.22 (1.32–7.84), 2.63 (1.97–3.51), and 1.89 (1.20–2.97), respectively). The elevation in risk survived adjustment for SES and BMI. Fig. 3 details the survival curves for CVD mortality by HbA1_C/diabetes category. When the analyses were sex-stratified, we observed a mixed pattern. Women with undiagnosed or uncontrolled diabetes had an increased risk of mortality from CVD, while for men, controlled diabetes, diabetes with moderately raised HbA1_C and uncontrolled diabetes were associated with excess CVD mortality. The elevated mortality risk for men with controlled diabetes was particularly striking. None of these results were materially altered by adjustment for SES or BMI.

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Fig 3. Fully adjusted survival curves for CVD mortality by HbA1_C and diabetes category (whole sample).

https://doi.org/10.1371/journal.pone.0119882.g003

Discussion

Our study demonstrated an excess in mortality from all-causes among those with raised HbA1_C, including within the pre-diabetes range among those with diagnosed diabetes. Raised HbA1_C among people with diabetes was also strongly associated with mortality from CVD, but not cancer. BMI and socioeconomic status did not affect the associations.

These results support those of Skriver et al. who found increased all-cause mortality among those with an HbA1_C measurement ≥7% (53 mmol/mol) (HR 1.26 (95% CI 1.15, 1.39)) and a U-shaped relationship between increasing HbA1_C and all-cause mortality.[8] A 2013 study also found an increased HR in relation to HbA1_C and all-cause mortality that was marginally non-significant (HR 1.21, 95% CI 0.99–1.47).[5] Within the current study, among those with diabetes only those with raised HbA1_C had an increased risk of all-cause mortality, while for mortality from CVD all diabetes/raised HbA1_C categorieshad an increased risk. The only exception to this was pre-diabetes, which was not associated with any of the causes of mortality under investigation; this result contradicts those of a recent meta-analysis, which found associations between pre-diabetes and mortality from all-causes and CVD, suggesting the need for further analyses in this area.[29]

The results of our current study support those of previous research in finding HbA1_C to be more strongly associated with mortality from all-causes and CVD rather than cancer.[5,10,15] Compared with normoglycaemic participants, those with raised HbA1_C and/or diabetes (uncontrolled, undiagnosed or with a moderately raised HbA1_C) had an increased risk of mortality from all-causes and CVD; those with controlled diabetes had an increased risk of CVD mortality only. Earlier studies found that impaired glucose metabolism impacts upon CVD mortality for women to a greater extent than for men[30]; our results indicate differences in risk by sex dependent upon HbA1_C/diabetes category analysed.

We found HbA1_C and diabetes were not significantly associated with cancer mortality, although an earlier cohort study found a 1mmol/l increment in glucose increased the risk of fatal cancer for both men (1.15, 1.07–1.22) and women (1.21, 1.11–1.33).[18] Joshu et al. also found that raised HbA1_C was not associated with increased cancer mortality among men, but was among women.[31] Research able to utilise larger datasets with a greater number of cancer mortality endpoints is needed to further assess the association between HbA1_C and cancer mortality. One reason for the lack of association between HbA1_C and cancer mortality within our results, but found in those of earlier studies, may be the differing rates of site-specific cancers within the all-cancers outcome variable used within each study. Although limited in number, previous studies have suggested that increased blood glucose is associated with increased mortality from a number of site-specific cancers, but is not associated with others.[32] Therefore results related to a grouped, all-cancers variable may be concealing differences in site-specific cancer mortality risk. Further research is required which explores the associations between HbA1_C and site-specific cancer mortality and incidence. The larger sample size utilised by Stocks et al.,[18] and the longer follow-up time and corresponding greater number of cancer deaths in the research undertaken by Joshu et al.,[31] compared with our study may also have given these studies the power needed to find a small, statistically significant difference. Although a power calculation undertaken before commencement of this current study suggested that our analyses were not underpowered, future studies which are able to utilise larger samples and investigate the sex differences within the associations between impaired glucose metabolism and mortality are required.

A number of plausible pathways have been proposed for the relationship between HbA1_C, diabetes and cause-specific mortality. Increased rates of atherosclerosis appear to explain much of the association between diabetes and cardiovascular disease; raised HbA1_C has been found to be strongly associated with carotid intima-media thickness, a marker of atherosclerosis.[33,34]. Although the epidemiological evidence related to HbA1_C and cancer is limited, the key biological causal factors relate to the anti-apoptotic, proliferative and mitogenic nature of insulin and insulin-like growth factor (IGF) and the impact that hyperglycaemia has upon mortality risk.[35–37] If a causal association were to be found between raised HbA1_C and mortality from CVD and other causes then some of the differences found in mortality between those with and without diabetes could be overcome through stricter glycaemic control. At the same time the potential deleterious impact of tighter control—for example the increased mortality found within the strict glucose control group of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the risk of hypoglycaemia [9,38–40]—would have to be balanced against any such reductions in mortality and take into account the specific characteristics of each individual with raised blood glucose.[9,41]

A strength of this study was its utilisation of a nationally-representative, general population sample of over 22,000 participants with a recorded HbA1_C measurement and comprehensive linked mortality data. The use of HSE data enabled the inclusion of a detailed HbA1_C and self-reported diabetes variable and a range of confounding factors within the analyses. Further, unlike a number of studies which have utilised only self-reported diabetes as an indicator of the presence of the disease, this study used a valid measure of HbA1_C to explore the association between diabetes, blood glucose and mortality. The recording of the use of diabetes-related medications, within the nurse visit, also enabled the further verification of diagnosed diabetes information.

The majority of the study sample self-identified as white—around 85%—a similar percentage to the general, free-living population of England.[42] Although the results of earlier analyses (not shown) were suggestive of ethnicity not having a significant impact upon the excess mortality found among those with raised HbA1_C/diabetes, the small number of deaths among those from Black and Minority Ethnic populations and the corresponding lack of power made interpretation of the results difficult. Studies utilising larger datasets, with a corresponding larger number of mortality endpoints, could further explore the impact of ethnicity.

The current study did not assess the impact that the use of different types of diabetes-related medications may have upon the excess risk experienced by those with diabetes. Those with diabetes may change drug regimens regularly and may switch from oral medications to insulin as their disease progresses. Because of this, research in this area favours the use of randomised controlled trials to explore this issue further.

Our results demonstrate that diabetes/raised HbA1_C are associated with mortality from CVD and all-causes. This result was found among those with and without diagnosed diabetes and, if confirmed, suggests that the monitoring of impaired blood glucose could be an important tool in relation to reducing mortality from these causes. The results also support the introduction of clinical practices which aim to prevent and detect pre-diabetes, diagnose previously undiagnosed diabetes, and optimise HbA1_C levels among people with diagnosed diabetes.

Conclusion

This study—utilising data from a nationally representative sample—demonstrates an association between HbA1_C and all-cause and cardiovascular disease mortality among those with and without diagnosed diabetes that remains after adjustment for a range of confounding factors including adiposity. If these result were to be replicated within further studies, the lowering of HbA1_C within populations could become an important public health goal.

Acknowledgments

Vanessa Gordon-Dseagu is the acting corresponding author of this article.

All authors are located in the Department of Epidemiology and Public Health, UCL (University College London), 1–19 Torrington Place, London, WC1E 6BT, UK.

We thank colleagues at UCL, NatCen Social Research and the field-staff for collecting and processing the data, and participants in the HSE. The HSE was funded in 2003 by the Department of Health and since 2004 by the Health and Social Care Information Centre. The funders played no part in this study nor the decision to publish the findings and there are no relevant conflicts of interest to disclose.