Association Between Haemoglobin A1c and All-Cause and Cause-Specific Mortality in Middle-Aged and Older Koreans: A Prospective Cohort Study

Abstract

Background This study aimed to examine associations between haemoglobin A1c (HbA_1c) levels over time and all-cause and cause-specific mortality in middle-aged and older Koreans.

Methods Using data from the Korean Genome and Epidemiology Study, we analysed 9,294 40–69-year-old participants with no history of cardiovascular disease (CVD) or cancer. HbA_1c levels were measured at baseline and at each biennial follow-up examination. Participants were divided into one group of participants with known diabetes and five groups of participants without known diabetes classified according to HbA_1c levels: <31 mmol/mol (5.0%), 31–36 mmol/mol (5.0%–5.4%), 37–41 mmol/mol (5.5%–5.9%), 42–47 mmol/mol (6.0%–6.4%), and ≥48 mmol/mol (6.5%). Hazard ratios (HRs) for all-cause and cause-specific mortality associated with HbA_1c levels were calculated using a time-dependent Cox proportional hazards model adjusting for several variables. Restricted cubic spline models were fitted to investigate the relationship between continuous HbA_1c levels and mortality among people without known diabetes. Subgroup analyses were performed for age, sex, smoking, hypertension, liver diseases, and red blood cell (RBC) counts.

Results During a median follow-up period of 15.7 years, there were 944 deaths, including 185, 359, and 400 from CVD, cancer, and other causes, respectively. Compared with participants with HbA_1c levels of 37–41 mmol/mol, multivariate-adjusted HRs and 95% confidence intervals for all-cause death of participants with levels <31 mmol/mol, 31–36 mmol/mol, 42–47 mmol/mol, and ≥48 mmol/mol and participants with known diabetes were 1.84 (1.35–2.51), 1.13 (0.95–1.34), 1.30 (1.04–1.62), 1.37 (0.97–1.93), and 2.03 (1.70–2.44), respectively. There was a U-shaped association between HbA_1c levels over time and all-cause and cause-specific mortality. When we performed diverse subgroup analyses, low HbA_1c levels were strongly associated with mortality in participants with low RBC counts or liver diseases.

Conclusions We found U-shaped associations between HbA_1c levels over time and all-cause and cause-specific mortality in middle-aged and older Koreans. In particular, people with low RBC counts or liver diseases and low HbA_1c levels had a high risk of mortality. Therefore, more careful management of these groups is recommended to decrease the risk of mortality.

Background

The prevalence of diabetes, a major cause of premature death and disability, is increasing worldwide, especially in Asia [1–3]. Glycated haemoglobin (HbA_1c) represents the average glycemia for the preceding two to three months and is an established biomarker for monitoring glycaemic control in patients with diabetes [4]. Compared with fasting blood glucose, HbA_1c has the advantages that it provides higher repeatability and can be assessed in the non-fasting state [4, 5]. In 2010, the American Diabetes Association (ADA) and the World Health Organization added an HbA_1c threshold of ≥48 mmol/mol (6.5%) as a standard criterion for the diagnosis of diabetes [6, 7]. Previous research suggests that high HbA_1c levels predict cardiovascular diseases (CVDs) and mortality from all causes among people with and without diabetes [8, 9]. However, the association between low HbA_1c levels and mortality is equivocal. Some studies have observed a positive linear relationship between HbA_1c levels and mortality [10–12]; however, others have observed U- or J-shaped associations, with increased mortality at both low and high HbA_1c levels [13–16]. This inconsistency in the association between low HbA_1c levels and mortality might be due to differences in the characteristics of the study populations, causes of death, control for important confounders, and analytic methods. Furthermore, racial differences have also been reported, with Blacks, Hispanics, and Asians having higher HbA_1c levels than those in Whites [17, 18]. Specifically, HbA_1c levels were higher in Asians than in Whites in individuals without diabetes [18], patients with impaired glucose tolerance [17], and patients with type 2 diabetes [19]. However, most studies on the association between HbA_1c and mortality were conducted in Western countries, with only a few exceptions targeting the Asian population [10, 20, 21]. Moreover, most of the previous studies used a single HbA_1c measurement; therefore, could not reflect the change in HbA_lc levels during follow up.

Therefore, we examined the relationship between HbA_1c levels, measured repeatedly every 2 years for 16 years, and all-cause and cause-specific mortality in middle-aged and older Koreans.

Methods

Results

Table 1 presents the baseline characteristics of the study population stratified by HbA_1c levels at baseline. The mean age and HbA_1c level for all participants at baseline were 52.0 years and 39.8 mmol/mol (5.8%), respectively. Participants with higher HbA_1c levels tended to be older and had higher BMIs, waist circumferences, RBC counts, hypertension and dyslipidaemia prevalences, proportion of current smokers, and fasting glucose, haemoglobin, haematocrit, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and a lower total bilirubin level, prevalence of anaemia, proportion of current alcohol drinkers, and education level. On the other hand, participants with lower HbA_1c levels tended to have lower RBC counts and higher prevalences of anaemia and liver diseases.

Mortality rates and the risk of death according to HbA_1c levels are presented in Table 2. The total and median follow-up times for the 9,294 participants were 139,960 person-years and 15.7 years, respectively. By 31 December 2017, there had been 944 deaths (10.2%), of which 185, 359, and 400 were due to CVD, cancer, and other causes, respectively. All-cause mortality was 6.7 deaths per 1,000 person-years and showed a J-shaped pattern according to HbA_1c level. Compared with participants with baseline HbA_1c levels of 37–41 mmol/mol (5.5–5.9%), those with baseline HbA_1c levels <31 mmol/mol (5.0%), 31–36 mmol/mol (5.0–5.4%), 42–47 mmol/mol (6.0–6.4%), ≥48 mmol/mol (6.5%), and known diabetes were at a 74%, 20%, 50%, 62%, and 130%, respectively, increased risk of all-cause mortality. This was after adjusting for age, sex, residential area, BMI, smoking, alcohol use, regular exercise, education, hypertension, and dyslipidaemia. When we considered changes in HbA_1c levels and other covariates during follow-up in a time-dependent Cox regression analysis, HbA_1c levels <31 mmol/mol (5.0%) were associated with 84% and 121% increased risks of all-cause and cancer deaths, respectively. Risks of all-cause and non-CVD/non-cancer mortality were significantly elevated in patients with HbA_1c levels of 42–47 mmol/mol (6.0–6.4%). A significantly increased risk of CVD mortality was associated with HbA_1c levels ≥48 mmol/mol (≥6.5%). Known diabetes significantly increased the risk of all-cause and cause-specific mortality.

For sensitivity analysis, we additionally adjusted for RBC count, haemoglobin level, anaemia, and liver diseases, and the results were similar to those obtained before further adjustments (Additional File 1). We also investigated the association between HbA_1c levels and mortality after excluding 171 people who died within one year of HbA_1c measurement, and the results were similar to our original models (Additional File 2). Additionally, we adjusted for waist circumference instead of BMI and the results were similar overall (data not shown).

We evaluated the associations between baseline HbA_1c levels and all-cause mortality after stratification by age, sex, smoking, hypertension, liver diseases, and RBC count (Table 3). In people with liver diseases or below median RBC counts (4.72 Mil/µL for men and 4.15 Mil/µL for women), low HbA_1c levels were strongly associated with mortality. However, no significant association was observed between low HbA_1c levels and all-cause mortality in participants with high RBC counts or without liver diseases. The results in the other subgroups were similar to those obtained before stratification.

Restricted cubic spline regression models for individuals without known diabetes revealed a J-shaped association between continuous baseline HbA_1c levels and all-cause (p-nonlinearity = 0.032) (Fig. 2a) and non-CVD/noncancer (p-nonlinearity = 0.024) mortality (Fig. 2d).

Discussion

In the present study of the general Korean population with neither a history of cancer nor CVD, non-diabetic adults with very low HbA1c were at significantly higher risk of all-cause and cancer mortality than were individuals with HbA1c of 37–41 mmol/mol (5.5–5.9%).

Higher HbA_1c levels in the prediabetic and diabetic ranges were associated with an increased risk of all-cause, cancer, and non-CVD/noncancer mortality in a dose-response manner.

Furthermore, when stratified by the median RBC count or by having liver diseases, there was a strong association between low HbA_1c levels and all-cause death among individuals with low RBC counts or liver diseases.

Most previous studies agree that high HbA_1c levels increase the risk of death. However, the association between low HbA_1c levels and mortality is equivocal. Several studies have reported that only high HbA_1c levels increase mortality [10–12, 20]. In the general Japanese population, compared with HbA_1c levels <31 mmol/mol (5.0%), high HbA_1c levels (>42 mmol/mol; 6.0%) in individuals without treatment for diabetes were significantly associated with an increased risk of all-cause mortality and death from CVD [10]. In Singaporean Chinese adults without diagnosed diabetes, compared with HbA_1c levels of 36–38 mmol/mol (5.4–5.6%), only HbA_1c levels ≥48 mmol/mol (6.5%) were significantly associated with all-cause (HR, 1.96; 95% CI, 1.56–2.46), CVD (HR, 2.63; 95% CI, 1.77–3.90), and cancer (HR, 1.51; 95% CI, 1.04–2.18) mortality [20]. In Australian adults (aged ≥25 years) without diagnosed diabetes, HbA_1c levels exhibited a linear relationship with all-cause and CVD mortality [12]. Our findings of an increased risk of all-cause mortality in the pre-diabetic and diabetic HbA_1c ranges are in line with these previous reports. On the other hand, consistent with our findings, some epidemiologic studies [8, 13–16] have observed U- or J-shaped associations between HbA_1c levels and the risk of mortality. In the Atherosclerosis Risk in Communities (ARIC) study, non-diabetic participants with HbA_1c levels < 31 mmol/mol (5.0%), as well as those with HbA_1c levels ≥37 mmol/mol (5.5%), were at a significantly increased risk of death from any cause (HR, 1.48; 95% CI, 1.21-1.81) [8]. In the general German population without known diabetes, restricted cubic spline models showed a U-shaped association between HbA_1c levels and all-cause mortality: the lowest risk was at HbA_1c levels of 36–38 mmol/mol (5.4–5.6%) and a significantly increased risk at ≤31 mmol/mol (5.0%) and ≥46 mmol/mol (6.4%) [13]. The association between extremely low HbA_1c levels and mortality were assessed in several studies. In US adults without diabetes, compared with HbA_1c levels of 31–36 mmol/mol (5.0–5.4%), HbA_1c levels <20 mmol/mol (4.0%) were associated with an increased risk of all-cause mortality (HR, 2.90; 95% CI, 1.25–6.76) [14]. In the general New Zealand population, individuals with HbA_1c levels <20 mmol/mol (4.0%) had a higher risk of mortality (HR, 2.90; 95% CI, 0.91–9.19) than did those with HbA_1c levels of 20–30 mmol/mol (4.0–4.9%), with marginal statistical significance [15]. In the current study, we were unable to examine extremely low HbA_1c levels because the number of participants with HbA_1c levels <20 mmol/mol (4.0%) was very small (n = 2).

Hyperglycaemia has been associated with an increased risk of cardiovascular morbidity [24–26] and mortality [10, 12] in the general population. This may be due to the vascular damage caused by increased oxidative stress and endothelial dysfunction in individuals with impaired fasting glucose or impaired glucose tolerance [27, 28]. Moreover, elevated HbA_1c levels influences cancer progression through an increase in the levels of insulin, insulin-like growth factor-1 (IGF-1), and inflammatory cytokines in circulation [29, 30]. However, the potential mechanism underlying the association between low HbA_1c levels and increased mortality remains unclear. Low HbA_1c levels have been correlated with impaired RBC related indices and increased liver function indices [14, 23]. These factors, in turn, were shown to correlate with inflammatory processes and increased morbidity and mortality [31, 32]. In other words, low HbA_1c levels are considered a marker of deteriorated health condition. Thus, the association between low HbA_1c levels and higher mortality may be explained by a result of reverse causation due to comorbid conditions [14, 23]. In our study sample, participants with HbA_1c levels <31 mmol/mol (5%) had lower RBC, haemoglobin, and haematocrit levels and higher total bilirubin levels and prevalence of liver diseases than did those with HbA_1c levels of 37–41 mmol/mol (5.5–5.9%), the reference group. Moreover, low HbA_1c levels, <31 mmol/mol (5%), were associated with an increased risk of all-cause mortality only among people with pre-existing liver disease or less than median RBC counts. These results suggest potential roles of RBC and liver function markers in the association between low HbA_1c levels and increased mortality. However, after we extensively adjusted for various RBC and liver function markers, the association between low HbA_1c levels and all-cause mortality persisted. Further studies on the mechanism leading to low HbA_1c levels and the association with mortality are warranted.

To the best of our knowledge, this is the first study to find an increased risk of mortality in the Asian population with low HbA_1c levels and to evaluate the association between HbA_1c levels and mortality in the general Korean population. The other unique feature of this analysis was the time-dependent modelling of the association between HbA_1c levels over time and mortality. Nearly all previous studies on this question utilized time-fixed methods using a single HbA_1c measurement at baseline [8, 10–16, 20].

Time-fixed analyses use a single measurement of HbA_1c levels; therefore, changes in HbA_1c levels during follow up cannot be considered, and there is a possibility of misclassification. In contrast, time-dependent analysis makes use of all the available HbA_1c data, and the risk is assessed considering each HbA_1c data point during follow-up. This approach is more reflective of clinical practice. Coherent results from both time-fixed and time-dependent analyses strengthen the association of low HbA_1c levels with an increased risk of all-cause mortality. An additional strength of this study lies in the long-term population-based cohort design (16-year follow-up) and the use of extensive data on RBC related indices and disease history.

Despite its strengths, the current study had some limitations. First, the participants were aged 40–70 years at the baseline examination and were enrolled from two communities. Therefore, the findings of this study may not be directly generalizable to younger adults or the entire Korean population. However, general characteristics and HbA_1c level distribution were similar when we compared our study population with the KNHANES participants, who are a representative sample. Specifically, among the KNHANES participants aged 40–70 in 2019, 44% were men, the mean age was 55.0 years, and the mean HbA_1c level was 40.9 mmol/mol (5.9%). Second, among the 9,294 participants who met the inclusion criteria at baseline, 14.5% did not attend any follow-up examination until 2016. However, reassuringly, the major variables, such as HbA_1c levels, age, sex, and comorbidities, were similar between participants and nonparticipants in the follow-up examinations (data not shown). Therefore, it is unlikely that the association between HbA_1c levels and mortality found in the time-dependent analysis using follow-up data is severely underestimated or overestimated. Third, there was a small number of participants with extremely low HbA_1c levels; therefore, we were unable to analyse the relationship between low HbA_1c levels and detailed cause-specific mortality. Finally, information on the diagnosis and treatment of diabetes, hypertension, dyslipidaemia, and liver diseases was obtained from questionnaires. Participants omitting to report existing diseases or having undiagnosed health conditions could have limited our ability to classify people with diabetes or other existing diseases. However, we collected data on the disease history using a structured questionnaire with questions about each disease asked separately by trained interviewers. Moreover, missing rates of related variables were very low (0.04%).

Conclusions

In summary, there was a U-shaped association between HbA_1c levels over time and all-cause and cause-specific mortality in middle-aged and older Koreans. These findings suggest that people with low HbA_1c levels, as well as those with high HbA_1c levels, have an increased risk of mortality. HbA_1c testing may improve the identification of individuals with a high risk of mortality. In particular, for people with low RBC counts or liver diseases and low HbA_1c levels, more careful management is recommended to decrease the risk of mortality. Causal mechanisms underlying the increased cause-specific mortality risk in the lower HbA_1c range warrant investigation. Thus, further studies with a large number of individuals with very low HbA_1c levels and a detailed assessment of morbid conditions are needed. In addition, further studies to identify the usefulness and appropriate cut-off HbA_1c level for predicting mortality are needed.

Declarations

Ethics approval and consent to participate

All participants provided written informed consent, and the study protocol was approved by the Institutional Review Board of National Institute of Health, Korea.

Consent for publication

Not applicable

Availability of data and materials

The KoGES data and biospecimens are available for research purposes from https://www.nih.go.kr/ on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This research received no specific grant. 

Authors’ contributions

BMS analysed the data and wrote the paper under the supervision of SSK. JHL, HDW, MJC, and SSK aided in the interpretation of the data and provided critical revision of the manuscript for important intellectual content. SSK had primary responsibility for the final content. All authors read and approved the final manuscript.

Acknowledgements

The data in this study were from the Korean Genome and Epidemiology Study (KoGES 4851-302), National Institute of Health, Korea Disease Control and Prevention Agency, Republic of Korea. The authors thank the participants and staff of the KoGES.

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