Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Epidemiology/Health Services Research

Association Between Hemoglobin A1c and All-Cause Mortality: Results of the Mortality Follow-up of the German National Health Interview and Examination Survey 1998

  1. Rebecca Paprott1,
  2. Angelika Schaffrath Rosario1,
  3. Markus A. Busch1,
  4. Yong Du1,
  5. Silke Thiele2,
  6. Christa Scheidt-Nave1 and
  7. Christin Heidemann1⇑
  1. 1Department of Epidemiology and Health Monitoring, Robert Koch Institute, Berlin, Germany
  2. 2Department of Food Economics and Consumption Studies, Christian-Albrechts-University Kiel, Kiel, Germany
  1. Corresponding author: Christin Heidemann, heidemannc{at}rki.de.
Diabetes Care 2015 Feb; 38(2): 249-256. https://doi.org/10.2337/dc14-1787
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

Abstract

OBJECTIVE This study examined the association of HbA1c-defined glycemic status and continuous HbA1c with all-cause mortality.

RESEARCH DESIGN AND METHODS The study population comprised 6,299 participants (aged 18–79 years) of the German National Health Interview and Examination Survey 1998, who were followed up for mortality for an average of 11.6 years. Glycemic status was defined as known diabetes (self-reported diagnosis or intake of antidiabetic medication) and based on HbA1c levels according to American Diabetes Association diagnostic criteria as undiagnosed diabetes (≥6.5% [≥48 mmol/mol]), prediabetes with very high (6.0–6.4% [42–46 mmol/mol]) or high diabetes risk (5.7–5.9% [39–41 mmol/mol]), and normoglycemia (<5.7% [<39 mmol/mol]). Associations between glycemic status and mortality were examined by Cox regression adjusting for age, sex, education, lifestyle factors, anthropometric measures, and history of chronic diseases (reference: normoglycemia). Spline models were fitted to investigate associations between continuous HbA1c and mortality among participants without known diabetes.

RESULTS Excess mortality risk was observed for participants with known diabetes (hazard ratio 1.41 [95% CI 1.08–1.84]) and undiagnosed diabetes (1.63 [1.23–2.17]) but not for those with high (1.02 [0.80–1.30]) or very high diabetes risk (0.87 [0.67–1.13]). Spline models revealed a U-shaped association, with lowest risk at HbA1c levels 5.4–5.6% (36–38 mmol/mol) and a significantly increased risk at ≤5.0% (≤31 mmol/mol) and ≥6.4% (≥46 mmol/mol).

CONCLUSIONS Unlike known and undiagnosed diabetes, HbA1c levels in the prediabetic range were not associated with an increased mortality risk. The observed U-shaped relationship adds to existing evidence that not only high but also low HbA1c levels might be associated with all-cause mortality.

Introduction

Glycated hemoglobin A1c (HbA1c) reflects the individual average blood glucose concentration within the past 2–3 months and is an established biomarker for monitoring glycemic control in diabetic patients (1,2). The American Diabetes Association (ADA) and the World Health Organization (WHO) also recently recommended HbA1c (≥6.5% [≥48 mmol/mol]) for diabetes diagnosis (3,4). In addition, the ADA has recommended HbA1c for the identification of individuals at high (HbA1c 5.7–5.9% [39–41 mmol/mol]) or very high (HbA1c 6.0–6.4% [42–46 mmol/mol]) diabetes risk, also referred to as prediabetes (3,5).

There is evidence that increased HbA1c levels predict not only diabetes but also cardiovascular morbidity among people with and without diabetes (6,7). Moreover, a number of studies have analyzed the relationship between HbA1c and all-cause mortality. Most of these previous studies observed an increased risk of death from all-causes at diabetic HbA1c levels among adults without known diabetes, independent of other known cardiovascular risk factors (6–11), whereas some studies found no significant association (12–14). Whether the risk for all-cause mortality is already increased at HbA1c levels in the prediabetic range is unclear. Former studies showed contradictory results and differed in applied HbA1c cutoffs (6,9–13,15–17). So far, only one previous study assessing all-cause mortality in relation to HbA1c in the prediabetic range applied ADA recommendations. However, this study did not differentiate between HbA1c categories related to a high risk versus a very high risk for diabetes (15).

Several studies have assessed the risk of all-cause mortality independently of predefined cutoffs by modeling HbA1c levels continuously in adults without known diabetes. Although some studies reported a linear association between HbA1c and all-cause mortality (17–19), others observed a J-shaped relationship (6,14,16). Further, it is possible that the association between HbA1c and mortality changes with aging and thus might no longer be detectable in studies of older populations (12).

Given the wide application of diagnostic HbA1c testing in clinical practice, we investigated the association of HbA1c-defined glycemic status and continuous HbA1c with all-cause mortality in a nationwide sample of adults in Germany. In categoric analyses, we applied ADA cutoff criteria for undiagnosed diabetes and subcategories of prediabetes and also considered different reference groups to define normoglycemia. Spline models were fitted to test for nonlinearity of the relationship between HbA1c and mortality among people without known diabetes. Further, we investigated the modification of the association between HbA1c and mortality by age.

Research Design and Methods

The Mortality Follow-up of the German National Health Interview and Examination Survey 1998

The nationwide German National Health Interview and Examination Survey 1998 (GNHIES98) was conducted between October 1997 and March 1999, targeting the residential, noninstitutionalized German population aged 18–79 years. A two-stage stratified clustered sampling technique was used. First, a representative sample of communities stratified by federal state and community size was drawn. Second, a random sample of adults stratified by age and sex was selected from local population registries proportional to the age and sex structure of the German population. The overall response rate was 61.4%, equivalent to 7,124 participants (20).

Study participants were recontacted between October 2008 and October 2011 and invited to participate in the first wave of the German Health Interview and Examination Survey for Adults (DEGS1). For those who did not respond or could no longer be contacted at the most current address, vital status and the exact date of death for deceased individuals were obtained from local population registries. Follow-up for death was complete for 6,979 participants (98.0%). After excluding participants with missing information regarding known diabetes (n = 22), HbA1c level (n = 398), or covariates (n = 260) at baseline, the study population for the present analysis comprised 6,299 people. The GNHIES98 was approved by the Federal Commissioner for the Protection of Data and Freedom of Information. All study participants provided written informed consent before participation (20).

Assessment of Glycemic Status

Known diabetes was determined as 1) self-reported history of physician-diagnosed diabetes in standardized interviews conducted by specifically trained physicians or 2) intake of antidiabetic medication within the 7 days preceding the interview documented through a detailed medication review and coding of unique product identifiers (Pharmazentralnummer [PZN]) on original drug containers. Among participants without known diabetes, normoglycemia (HbA1c <5.7% [<39 mmol/mol]), prediabetes (HbA1c 5.7–6.4% [39–46 mmol/mol]), and undiagnosed diabetes (HbA1c ≥6.5% [≥48 mmol/mol]) were defined according to recent ADA recommendations (21). Prediabetes was further categorized as prediabetes with high (HbA1c 5.7–5.9% [39–41 mmol/mol]) or very high (HbA1c 6.0–6.4% [42–46 mmol/mol]) risk for diabetes (5,21).

HbA1c was measured in fresh whole blood specimens with a Diamat high-performance liquid chromatography analyzer (Bio-Rad Laboratories, Munich, Germany) and reagents of Recipe (Recipe Chemicals and Instruments, Munich, Germany) in the Robert Koch Institute Central Epidemiological Laboratory (20). The interassay coefficients of variation were 2.0–2.8%. The Bio-Rad HbA1c analysis system was certified by the National Glycohemoglobin Standardization Program (NGSP) ensuring standardization of HbA1c test results to the Diabetes Control and Complications Trial (22).

Assessment of Covariates

A standardized self-administered questionnaire was used to obtain information on age, sex, educational level, sport activity, and smoking status. Trained interviewers checked all completed questionnaires for plausibility and completeness (20). Educational level (low, medium, or high) was classified by the Comparative Analysis of Social Mobility in Industrial Nations (CASMIN), encompassing general as well as vocational training (23). Sport activity was assessed by five categories as no sport, <1 h/week, regularly 1–2 h/week, regularly 2–4 h/week, or regularly >4 h/week. This information was aggregated into two categories (<2 h/week or ≥2 h/week) for analyses. Smoking status was categorized as never, former, and current smoking. Alcohol intake (g/day) was obtained by a semiquantitative food frequency questionnaire (24). Moderate alcohol intake was defined as >0–20 g/day for men and >0–10 g/day for women. History of physician-diagnosed chronic diseases (hypertension, hyperlipidemia, myocardial infarction, stroke, cancer, hepatitis, chronic liver disease) was obtained by trained study physicians conducting standardized interviews (20). Hb was measured in EDTA-blood with a Coulter HmX Hematology Analyzer (Beckman Coulter, Krefeld, Germany), and anemia was defined by Hb <13 g/dL for men and <12 g/dL for women (25). Creatinine was measured in serum with an Architect analyzer (Abbott, Wiesbaden, Germany), and chronic kidney disease was defined by an estimated glomerular filtration rate <60 mL/min/1.73 m2 (26). Trained health professionals used standardized operational procedures to obtain measures of height, weight, and waist circumference. BMI was calculated as the ratio of body weight (kg) and height squared (m2).

Statistical Analysis

Cox proportional hazards regression was performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for death during follow-up according to the glycemic status at baseline using normoglycemia as the reference category. Follow-up time, as a dependent time variable, was defined as the interval in days between the date of the baseline examination in GNHIES98 and the date of recontact during follow-up or the date of death. We verified that the proportional hazards assumption was met by including a product term of each independent variable and the log of survival time in the Cox model. Model 1 was adjusted for sex and age (years). Model 2 was further adjusted for established mortality risk factors: educational level (low, medium, high), smoking status (never, former, current), sport activity (≥2 h/week, <2 h/week), moderate alcohol consumption (yes, no), BMI (kg/m2), and waist circumference (cm). Model 3 was additionally adjusted for chronic diseases, including selfreported history of myocardial infarction, stroke, or cancer (yes, no) and hypertension or hyperlipidemia (yes, no). Sensitivity analyses were performed excluding 1) participants with <2 years of follow-up (n = 52) to account for potential influence of prevalent diseases influencing HbA1c levels; 2) participants with a history of self-reported myocardial infarction, stroke, or cancer (n = 393); and 3) participants with baseline conditions known to affect HbA1c, including pregnancy, anemia, chronic kidney disease, and self-reported history of hepatitis or chronic liver disease (n = 444). In an additional sensitivity analysis, the reference group was confined to HbA1c levels of 5.0% to <5.7% (31 to <39 mmol/mol), because HbA1c levels <5.0% (<31 mmol/mol) may be associated with increased mortality risk (15).

Spline regression analyses excluded participants with known diabetes at baseline (n = 313). The shape of the association between continuous HbA1c levels and mortality was modeled by restricted cubic splines in the fully adjusted model, with four knots set at the 5th, 25th, 75th, and 95th percentile. Knots were equivalent to an HbA1c level of 4.7% (28 mmol/mol), 5.1% (32 mmol/mol), 5.8% (40 mmol/mol), and 6.3% (45 mmol/mol), respectively. The reference was set at the median HbA1c level of 5.4% (36 mmol/mol), and the plot was truncated at the 1st and the 99th percentile. The number of deceased individuals at specific HbA1c values was limited (e.g., 22 deceased at an HbA1c level of 5.4% [36 mmol/mol)]). To test the robustness of results, the reference was hence set at alternate HbA1c levels, including 5.3% (34 mmol/mol) and 5.5% (37 mmol/mol). Because HbA1c has been shown to increase in older age in nondiabetic individuals (27,28), a test for interaction was conducted by including a product term with age (<55 vs. ≥55 years) and HbA1c in the spline model. Interaction with sex was tested in a separate model by including a product term with sex and HbA1c.

SAS 9.3 software (SAS Institute Inc., Cary, NC) was used for all statistical analyses. The level of statistical significance was set at P = 0.05 based on two-sided tests.

Results

Baseline characteristics of the study population stratified by glycemic status are presented in Table 1. Participants with undiagnosed diabetes and with known diabetes were similar in most characteristics. However, those with known diabetes showed a higher prevalence of hypertension and were less likely current smokers. With increasing HbA1c from normoglycemia to a high and very high risk for diabetes to undiagnosed diabetes, individuals were older and more likely to have a lower educational level and a higher BMI. Moreover, the prevalence of hypertension increased in a stepwise fashion with deteriorating glycemic status. When the normoglycemic group was subdivided into individuals with an HbA1c level <5.0% (<31 mmol/mol) and those with an HbA1c level of 5.0 to <5.7% (31 to <39 mmol/mol), those with a lower HbA1c level were more likely female, younger, had a higher educational level, a lower BMI and waist circumference, and a lower prevalence of hypertension, hyperlipidemia, and myocardial infarction (data not shown).

View this table:
  • View inline
  • View popup
Table 1

Baseline characteristics for participants of the Mortality Follow-up of the GNHIES98 according to categories of glycemic status (n = 6,299)

Overall, 552 of 6,299 eligible study participants were confirmed to have died during an average follow-up of 11.6 years, amounting to 73,299 person-years. Compared with participants with normoglycemia, mortality rates were approximately two to three times higher among participants with a high and a very high diabetes risk and approximately seven times higher among subjects with known or undiagnosed diabetes (Table 2). In Cox proportional hazards models adjusting for age and sex, undiagnosed diabetes and known diabetes, but not the prediabetic states, were associated with a significantly higher mortality risk compared with normoglycemia. The risk was 87% higher among subjects with undiagnosed diabetes and 66% higher among subjects with known diabetes compared with those with normoglycemia. Further adjustment for established mortality risk factors moderately attenuated risk estimates among all groups. In the model additionally adjusted for chronic diseases at baseline, mortality risk was still significantly increased by 63% (23–117%) among individuals with undiagnosed diabetes and by 41% (8–84%) in those with known diabetes. These results were confirmed in several sensitivity analyses (Table 3). Determining the reference group as an HbA1c level of 5.0 to <5.7% (31 to <39 mmol/mol) slightly increased risk estimates among all groups. Among subjects with an HbA1c level <5.0% (<31 mmol/mol), mortality risk was significantly increased by 70% (16–150%). The latter finding did not change materially after exclusion of 1) individuals who died within the first 2 years of follow-up (66% [10–151%]); 2) those with a history of myocardial infarction, stroke, or cancer (64% [6–153%]); or 3) those with baseline conditions known to affect HbA1c (66% [10–152%]) (data not shown).

View this table:
  • View inline
  • View popup
Table 2

Mortality rate and risk for all-cause mortality (HR [95% CI]) according to categories of glycemic status

View this table:
  • View inline
  • View popup
Table 3

Sensitivity analyses for risk for all-cause mortality (HR [95% CI]) according to categories of glycemic status

Restricted cubic spline regression modeled for subjects without known diabetes revealed a U-shaped association (Fig. 1A). Risk for all-cause mortality was lowest at HbA1c levels of 5.4–5.6% (36–38 mmol/mol), whereas HbA1c levels ≤5.0% (≤31 mmol/mol) and ≥6.4% (≥46 mmol/mol) were both associated with a significantly increased risk. In sensitivity analyses with the reference set at HbA1c levels 5.3% (34 mmol/mol) or 5.5% (37 mmol/mol) instead of 5.4% (36 mmol/mol), the overall shape of the curve remained essentially the same, and the HbA1c range related to the lowest mortality risk was comparable (5.3–5.6% [34–38 mmol/mol] or 5.4–5.6% [36–38 mmol/mol], respectively; data not shown). However, the spline reacted slightly flexible before the first and after the last knot, with an increased mortality risk at HbA1c levels ≤5.1% (≤32 mmol/mol) and ≥6.6% (≥49 mmol/mol) for the reference of 5.3% (34 mmol/mol) or ≤4.9% (≤30 mmol/mol) and ≥6.3% (≥45 mmol/mol) for the reference of 5.5% (37 mmol/mol), respectively. Spline regression stratified by age group indicated a steeper increase in mortality risk in both the low and high range of HbA1c among participants aged <55 years compared with those aged at least 55 years (Fig. 1B and C), although a test for interaction between age group and HbA1c was not significant (P = 0.51). There was also no evidence for a significant interaction between HbA1c and sex (P = 0.24).

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Risk for all-cause mortality (HR [95% CI]) according to restricted cubic spline regression among participants without known diabetes. Knots were set at the 5th, 25th, 75th, and 95th percentile. Reference was set at the median HbA1c level. Plot is truncated at the 1st and 99th percentile. Total population (N = 5,986 including 461 deaths) (A), population aged <55 years (n = 4,146 including 92 deaths) (B), and population aged ≥55 years (n = 1,840 including 369 deaths) (C). HRs (95% CIs) are shown on a natural log scale.

Conclusions

In the current study, known diabetes and HbA1c-defined undiagnosed diabetes (HbA1c ≥6.5% [≥48 mmol/mol]), but not prediabetes, in the high or the very high diabetes risk category (HbA1c 5.7–6.4% [39–46 mmol/mol]), were significantly associated with an increased risk of all-cause mortality compared with normoglycemia (HbA1c <5.7% [<39 mmol/mol]). Results persisted in various sensitivity analyses, excluding individuals with preexisting chronic diseases or conditions with a possible effect on HbA1c and resetting the normoglycemic reference category to HbA1c levels of 5.0 to <5.7% [31 to <39 mmol/mol]. A U-shaped association was found between continuous HbA1c and all-cause mortality, with the lowest risk at HbA1c levels of 5.4–5.6% (36–38 mmol/mol) and a significantly increased risk at HbA1c levels ≤5.0% (≤ 31 mmol/mol) and ≥6.4% (≥46 mmol/mol).

In accordance with evidence from previous studies, we observed an excess mortality risk among participants with known diabetes and HbA1c-defined undiagnosed diabetes compared with normoglycemic individuals (6,9,10,29,30). In the main and sensitivity analyses, the risk for all-cause mortality was consistently slightly lower among people with known diabetes than among those with undiagnosed diabetes. This might be due to diabetes treatment and might also reflect the effect of disease consciousness (11). In our study, additional subgroup analyses revealed similar mortality risks among individuals with undiagnosed diabetes (n = 238; HR 1.63 [95% CI 1.23–2.17]) and those with known diabetes treated by antidiabetic medication (n = 220; HR 1.65 [95% CI 1.24–2.20]). Because the mean baseline HbA1c value was higher (8.1% [65 mmol/mol] vs. 7.1% [54 mmol/mol]) and the diabetes duration was probably longer in the latter group, this observation might at least partially be due to diabetes treatment. In individuals with known diabetes but without antidiabetic medication, mortality risk was not increased (n = 93; HR 0.85 [95% CI 0.50–1.42]). According to their mean baseline HbA1c value (6.7% [50 mmol/mol]), these individuals were at a less progressed stage of diabetes development.

With respect to a lack of an increased mortality risk among participants without diabetes but at high (HbA1c 5.7–5.9% [39–41 mmol/mol]) or very high diabetes risk (HbA1c 6.0–6.4% [42–46 mmol/mol]), our results are in line with findings from the German Cooperative Health Research in the Region of Augsburg (KORA) Survey. This study showed no association between HbA1c levels of 5.8–6.0% (40–42 mmol/mol) and all-cause mortality (reference: HbA1c 5.4–5.5% [36–37 mmol/mol]) (11). Neither did the Cardiovascular Health Study (HbA1c 5.61–6.20% [38–44 mmol/mol], reference: ≤5.60% [≤38 mmol/mol]) (12) or the Hoorn Study (HbA1c 5.6–5.9% [38–41 mmol/mol], reference: ≤5.1% [≤32 mmol/mol]) (13) find an association with all-cause mortality. However, these previous studies included participants within a limited age range (11–13) and applied criteria to define reference and risk categories that were different from ADA recommendations.

The Atherosclerosis Risk in Communities (ARIC) study, in contrast, used the same cutoff criteria to define prediabetes (HbA1c 5.7–6.4% [39–46 mmol/mol]) as applied in the current study but observed a significant association between prediabetes and all-cause mortality (reference: 5.0 to <5.7% (31 to <39 mmol/mol) (15). An increased mortality risk was also found in National Health and Nutrition Examination Survey (NHANES) III and the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study in relation to HbA1c levels of 5.5–5.9% (37–41 mmol/mol) and 6.0–6.4% (42–47 mmol/mol) compared with HbA1c levels of 5.0–5.4% (31–36 mmol/mol) as a reference (9,16). HbA1c levels of 6.0–6.4% (42–47 mmol/mol) were also predictive of an increased mortality risk in a study of the Japanese general adult population; in that study, the reference group was set at HbA1c levels of <5.0% (<31 mmol/mol) (10).

Inconclusive results regarding the relationship between prediabetic HbA1c levels and mortality are likely to result from varying definitions of prediabetes and reference categories as well as differences in main characteristics of the study population, such as age range and inclusion or exclusion of individuals with prevalent cardiovascular disease or undiagnosed diabetes according to glucose criteria. In sensitivity analyses, we therefore redefined our reference category according to the ARIC study (HbA1c 5.0 to <5.7% [31 to <39 mmol/mol]). However, there was still no association between a high or very high risk for diabetes and mortality. Notably, the ARIC analysis was based on an age range other than in the current study, included different ethnicities, and did not exclude or consider in adjusted models individuals with a history of myocardial infarction, stroke, or cancer. Despite the finding of no association between prediabetes and all-cause mortality in the current study, prediabetes might still be relevant for other clinical outcomes. HbA1c levels in the prediabetic range have been shown to be associated with an increased risk for coronary heart disease and stroke in some but not all studies (6,7,31).

Similar to the current study, some other studies determined nonlinear relationships between HbA1c and all-cause mortality (6,9,16). J-shaped associations were found among adults without known diabetes in a study based on NHANES III data (16) and in the ARIC study (6). Consistent with our findings, mortality risk in both studies was significantly increased at low and high HbA1c levels. For example, the risk in NHANES III was significantly increased at HbA1c levels ≤4.1% (≤21 mmol/mol) and ≥6.1% (≥43 mmol/mol) (16). Further, results of Cox models showed a significantly increased mortality risk in the ARIC study at HbA1c levels <5.0% (<31 mmol/mol) compared with HbA1c levels of 5.0–5.5% (31–37 mmol/mol) (6) or 5.0 to <5.7% (31 to <39 mmol/mol) (15), respectively, and in NHANES III at HbA1c levels <4.0% (<20 mmol/mol) compared with HbA1c levels of 5.0–5.4% (31–36 mmol/mol) (16). These findings are in concordance with results from our sensitivity analysis of an increased mortality risk at HbA1c levels <5.0% (<31 mmol/mol) compared with HbA1c levels of 5.0 to <5.7% (31 to <39 mmol/mol). In contrast, the EPIC-Norfolk study did not detect an increased mortality risk in the lower HbA1c range; risk was similar for HbA1c values <5.5% (<37 mmol/mol) and significantly increased afterward (9). Some other studies also tested for nonlinearity of the association between HbA1c levels and all-cause mortality but confirmed linear relationships (17–19).

Therefore, whether low HbA1c levels are a predictor of increased mortality risk remains controversial. Low HbA1c has been considered as a general marker of disease and a correlate of impaired red blood cell indices, unfavorable measures of iron storage, and increased liver function indices (15,16,32). These factors, in turn, were shown to correlate with inflammatory processes and increased morbidity and mortality (33–35). However, in our main and sensitivity analyses considering several comorbid conditions, the increased mortality risk in the lower HbA1c range persisted, which is also in accordance with a study based on NHANES III data (16). Residual confounding (36) and reliance on self-report for most chronic diseases have to be considered for discussing this observation but are unlikely to entirely explain the robust result. Therefore, future studies with a large number of individuals with low HbA1c levels and detailed assessment of morbid conditions would be important to further investigate mechanisms underlying the increased mortality risk in the lower HbA1c range (16).

There is evidence that older age is associated with higher HbA1c levels independent of fasting plasma glucose and glucose measured 2 h after an oral glucose tolerance test (27,28). Studies investigating the association between increased HbA1c levels and mortality among elderly individuals showed diverging results (11–13,37). Our results indicate that the mortality risk associated with increased HbA1c levels might be more pronounced among younger than older persons without known diabetes, although the test for interaction between HbA1c and age was not significant. However, this might be due to the relatively small number of deceased individuals aged <55 years (n = 92) and low statistical power. Future studies with a larger sample size should focus on potential differences in risk among younger and older individuals.

The current study was based on a nationwide sample of the noninstitutional, residential population covering a wide age range from 18–79 years. Information on a large number of confounding variables was available. Besides, our study is among the few studies that have defined categories of glycemic status according to recently recommended HbA1c cutoffs following ADA diagnostic criteria for diabetes and prediabetes. However, HbA1c measurements may be influenced by a number of physiological and pathophysiological conditions affecting red cell and iron metabolism, such as pregnancy, iron deficiency, chronic liver disease, alcoholism, chronic renal failure, and intake of large doses of aspirin (4,5). Nevertheless, results remained materially unchanged in sensitivity analyses that considered most of these factors. In addition, we only measured HbA1c once at baseline and due to random variability in HbA1c levels, misclassification of participants might have occurred. However, the within-subject variation has been shown to be minimal (38), and HbA1c measurement in the current study could be done with high precision using an established high-performance liquid chromatography analytic system. Further, we do not have information on changes in lifestyle, glycemic status, or drug treatment during follow-up. Thus, the influence of HbA1c on mortality might have been under- or overestimated. Moreover, the diagnosis of known diabetes largely relied on self-report, and we did not have the information to exclude women with gestational diabetes. However, we were able to consider information on antidiabetic agent use based on a detailed medication review. Still, misclassification for known diabetes may have occurred. Another limitation is that we were not able to report cause-specific mortality risks. This would have been valuable for the evaluation of potential differences in the proportion of cause-specific deaths across HbA1c categories.

In summary, known diabetes and HbA1c-defined undiagnosed diabetes were both associated with an increased risk for all-cause mortality after 11.6 years of follow-up in this nationwide German cohort. However, adults with prediabetes, as defined by HbA1c, did not differ in their mortality risk from those with normoglycemia. A U-shaped association was found between continuous HbA1c measures and all-cause mortality, suggesting that not only high but also low HbA1c levels might be associated with an increased risk of death.

Article Information

Acknowledgments. The authors thank Ingrid-Katharina Wolf and Michael Lange for conducting the Mortality Follow-up, Julia Truthmann for assistance with data management, Daniel Grams for support with figure formatting, and Wulf Thierfelder for overseeing the laboratory analyses and quality assurance of HbA1c measurements (all affiliated with the Robert Koch Institute).

Funding. The Mortality Follow-up was supported by research grants of the Federal Ministry of Health. R.P. was supported by research grants from the Federal Ministry of Health (FKZ IIA5-2513-FSB-736). Y.D. was supported by research grants from the Kompetenznetz Diabetes mellitus (Competence Network Diabetes mellitus) funded by the Federal Ministry of Education and Research (FKZ 01GI1110F).

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. R.P. performed the statistical analyses and drafted the manuscript. A.S.R., M.A.B., Y.D., S.T., C.S.-N., and C.H. critically revised the manuscript for important intellectual content. A.S.R. and C.H. supported statistical modeling. C.S.-N. and C.H. conceptualized the study. All authors read and approved the final version of the manuscript. R.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were previously published in abstract form in the following publication: Paprott R, Schaffrath Rosario A, Busch MA, et al. Association between HbA1c and all-cause mortality – The Mortality Follow-Up of the German National Health Interview and Examination Survey 1998. Diabetologie 2014,9:S13 (in German).

  • Received July 25, 2014.
  • Accepted October 17, 2014.
  • © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

References

  1. ↵
    1. Goldstein DE,
    2. Little RR,
    3. Lorenz RA,
    4. Malone JI,
    5. Nathan DM,
    6. Peterson CM; American Diabetes Association
    . Tests of glycemia in diabetes. Diabetes Care 2004;27(Suppl. 1):S91–S93pmid:14693937
    OpenUrlCrossRefPubMed
  2. ↵
    1. American Diabetes Association
    . Standards of medical care in diabetes—2014. Diabetes Care 2014;37(Suppl. 1):S14–S80pmid:24357209
    OpenUrlFREE Full Text
  3. ↵
    1. American Diabetes Association
    . Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33(Suppl. 1):S62–S69pmid:20042775
    OpenUrlFREE Full Text
  4. ↵
    1. World Health Organization
    . Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. Abbreviated Report of a WHO Consultation. Geneva, World Health Organization, 2011
  5. ↵
    1. International Expert Committee
    . International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327–1334pmid:19502545
    OpenUrlFREE Full Text
  6. ↵
    1. Selvin E,
    2. Steffes MW,
    3. Zhu H, et al
    . Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010;362:800–811pmid:20200384
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Khaw KT,
    2. Wareham N,
    3. Bingham S,
    4. Luben R,
    5. Welch A,
    6. Day N
    . Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004;141:413–420pmid:15381514
    OpenUrlCrossRefPubMedWeb of Science
    1. Brewer N,
    2. Wright CS,
    3. Travier N, et al
    . A New Zealand linkage study examining the associations between A1C concentration and mortality. Diabetes Care 2008;31:1144–1149pmid:18299440
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Pfister R,
    2. Sharp SJ,
    3. Luben R,
    4. Khaw KT,
    5. Wareham NJ
    . No evidence of an increased mortality risk associated with low levels of glycated haemoglobin in a non-diabetic UK population. Diabetologia 2011;54:2025–2032pmid:21584793
    OpenUrlCrossRefPubMed
  9. ↵
    1. Sakurai M,
    2. Saitoh S,
    3. Miura K, et al, .; NIPPON DATA90 Research Group
    . HbA1c and the risks for all-cause and cardiovascular mortality in the general Japanese population: NIPPON DATA90. Diabetes Care 2013;36:3759–3765pmid:23877989
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Kowall B,
    2. Rathmann W,
    3. Heier M, et al
    . Categories of glucose tolerance and continuous glycemic measures and mortality. Eur J Epidemiol 2011;26:637–645pmid:21785986
    OpenUrlCrossRefPubMed
  11. ↵
    1. Chonchol M,
    2. Katz R,
    3. Fried LF, et al
    . Glycosylated hemoglobin and the risk of death and cardiovascular mortality in the elderly. Nutr Metab Cardiovasc Dis 2010;20:15–21pmid:19364638
    OpenUrlCrossRefPubMed
  12. ↵
    1. van ’t Riet E,
    2. Rijkelijkhuizen JM,
    3. Alssema M, et al
    . HbA1c is an independent predictor of non-fatal cardiovascular disease in a Caucasian population without diabetes: a 10-year follow-up of the Hoorn Study. Eur J Prev Cardiol 2012;19:23–31pmid:20517157
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Saydah S, Tao M, Imperatore G, Gregg E. GHb level and subsequent mortality among adults in the U.S. Diabetes Care 2009;32:1440–1446
  14. ↵
    1. Aggarwal V,
    2. Schneider AL,
    3. Selvin E
    . Low hemoglobin A(1c) in nondiabetic adults: an elevated risk state? Diabetes Care 2012;35:2055–2060pmid:22855733
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Carson AP,
    2. Fox CS,
    3. McGuire DK, et al
    . Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes. Circ Cardiovasc Qual Outcomes 2010;3:661–667pmid:20923991
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Levitan EB,
    2. Liu S,
    3. Stampfer MJ, et al
    . HbA1c measured in stored erythrocytes and mortality rate among middle-aged and older women. Diabetologia 2008;51:267–275pmid:18043905
    OpenUrlCrossRefPubMedWeb of Science
    1. Barr EL,
    2. Boyko EJ,
    3. Zimmet PZ,
    4. Wolfe R,
    5. Tonkin AM,
    6. Shaw JE
    . Continuous relationships between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study. Diabetologia 2009;52:415–424pmid:19130039
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    1. Cohen BE,
    2. Barrett-Connor E,
    3. Wassel CL,
    4. Kanaya AM
    . Association of glucose measures with total and coronary heart disease mortality: does the effect change with time? The Rancho Bernardo Study. Diabetes Res Clin Pract 2009;86:67–73pmid:19671481
    OpenUrlCrossRefPubMed
  18. ↵
    1. Heidemann C,
    2. Scheidt-Nave C,
    3. Richter A,
    4. Mensink GB
    . Dietary patterns are associated with cardiometabolic risk factors in a representative study population of German adults. Br J Nutr 2011;106:1253–1262pmid:21736839
    OpenUrlCrossRefPubMed
  19. ↵
    1. American Diabetes Association
    . Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37(Suppl. 1):S81–S90pmid:24357215
    OpenUrlFREE Full Text
  20. ↵
    1. The Diabetes Control and Complications Trial Research Group
    . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986pmid:8366922
    OpenUrlCrossRefPubMedWeb of Science
  21. ↵
    1. Hoffmeyer-Zlotnik JH,
    2. Wolf C
    1. Brauns H,
    2. Scherer S,
    3. Steinmann S
    . The CASMIN educational classification in international comparative research. In Advances in Cross-National Comparison. Hoffmeyer-Zlotnik JH, Wolf C, Eds. New York, Kluwer, 2003, p. 221–244
  22. ↵
    1. Burger M,
    2. Mensink G,
    3. Brönstrup A,
    4. Thierfelder W,
    5. Pietrzik K
    . Alcohol consumption and its relation to cardiovascular risk factors in Germany. Eur J Clin Nutr 2004;58:605–614pmid:15042128
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    1. World Health Organization
    . Nutritional Anaemias. Report of a WHO Scientific Group. Geneva, World Health Organization, 1968
  24. ↵
    1. Levey AS,
    2. Stevens LA,
    3. Schmid CH, et al, .; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)
    . A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604–612pmid:19414839
    OpenUrlCrossRefPubMedWeb of Science
  25. ↵
    1. Pani LN,
    2. Korenda L,
    3. Meigs JB, et al
    . Effect of aging on A1C levels in individuals without diabetes: evidence from the Framingham Offspring Study and the National Health and Nutrition Examination Survey 2001-2004. Diabetes Care 2008;31:1991–1996pmid:18628569
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Davidson MB,
    2. Schriger DL
    . Effect of age and race/ethnicity on HbA1c levels in people without known diabetes mellitus: implications for the diagnosis of diabetes. Diabetes Res Clin Pract 2010;87:415–421pmid:20061043
    OpenUrlCrossRefPubMed
  27. ↵
    1. Dailey G
    . Overall mortality in diabetes mellitus: where do we stand today? Diabetes Technol Ther 2011;13(Suppl. 1):S65–S74pmid:21668339
    OpenUrlPubMed
  28. ↵
    1. Currie CJ,
    2. Peters JR,
    3. Tynan A, et al
    . Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 2010;375:481–489pmid:20110121
    OpenUrlCrossRefPubMedWeb of Science
  29. ↵
    1. Schöttker B,
    2. Müller H,
    3. Rothenbacher D,
    4. Brenner H
    . Fasting plasma glucose and HbA1c in cardiovascular risk prediction: a sex-specific comparison in individuals without diabetes mellitus. Diabetologia 2013;56:92–100pmid:22986731
    OpenUrlCrossRefPubMedWeb of Science
  30. ↵
    1. Christman AL,
    2. Lazo M,
    3. Clark JM,
    4. Selvin E
    . Low glycated hemoglobin and liver disease in the U.S. population. Diabetes Care 2011;34:2548–2550pmid:21953797
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Montagnana M,
    2. Cervellin G,
    3. Meschi T,
    4. Lippi G
    . The role of red blood cell distribution width in cardiovascular and thrombotic disorders. Clin Chem Lab Med 2012;50:635–641pmid:22505527
    OpenUrlPubMed
    1. Abril-Ulloa V,
    2. Flores-Mateo G,
    3. Solà-Alberich R,
    4. Manuel-y-Keenoy B,
    5. Arija V
    . Ferritin levels and risk of metabolic syndrome: meta-analysis of observational studies. BMC Public Health 2014;14:483pmid:24884526
    OpenUrlCrossRefPubMed
  32. ↵
    1. Lioudaki E,
    2. Ganotakis ES,
    3. Mikhailidis DP
    . Liver enzymes: potential cardiovascular risk markers? Curr Pharm Des 2011;17:3632–3643pmid:22074433
    OpenUrlCrossRefPubMed
  33. ↵
    1. Rutter MK
    . Low HbA1c and mortality: causation and confounding. Diabetologia 2012;55:2307–2311pmid:22806354
    OpenUrlCrossRefPubMed
  34. ↵
    1. Gao L,
    2. Matthews FE,
    3. Sargeant LA,
    4. Brayne C,
    5. Mrc C; MRC CFAS
    . An investigation of the population impact of variation in HbA1c levels in older people in England and Wales: from a population based multi-centre longitudinal study. BMC Public Health 2008;8:54pmid:18267013
    OpenUrlCrossRefPubMed
  35. ↵
    1. Rohlfing C,
    2. Wiedmeyer HM,
    3. Little R, et al
    . Biological variation of glycohemoglobin. Clin Chem 2002;48:1116–1118pmid:12089188
    OpenUrlFREE Full Text
PreviousNext
Back to top
Diabetes Care: 38 (2)

In this Issue

February 2015, 38(2)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Association Between Hemoglobin A1c and All-Cause Mortality: Results of the Mortality Follow-up of the German National Health Interview and Examination Survey 1998
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Association Between Hemoglobin A1c and All-Cause Mortality: Results of the Mortality Follow-up of the German National Health Interview and Examination Survey 1998
Rebecca Paprott, Angelika Schaffrath Rosario, Markus A. Busch, Yong Du, Silke Thiele, Christa Scheidt-Nave, Christin Heidemann
Diabetes Care Feb 2015, 38 (2) 249-256; DOI: 10.2337/dc14-1787

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Association Between Hemoglobin A1c and All-Cause Mortality: Results of the Mortality Follow-up of the German National Health Interview and Examination Survey 1998
Rebecca Paprott, Angelika Schaffrath Rosario, Markus A. Busch, Yong Du, Silke Thiele, Christa Scheidt-Nave, Christin Heidemann
Diabetes Care Feb 2015, 38 (2) 249-256; DOI: 10.2337/dc14-1787
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Research Design and Methods
    • Results
    • Conclusions
    • Article Information
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Comparisons of Polyexposure, Polygenic, and Clinical Risk Scores in Risk Prediction of Type 2 Diabetes
  • Quantifying Variation in Treatment Utilization for Type 2 Diabetes Across Five Major University of California Health Systems
  • Trends in Total and Out-of-pocket Payments for Noninsulin Glucose-Lowering Drugs Among U.S. Adults With Large-Employer Private Health Insurance From 2005 to 2018
Show more Epidemiology/Health Services Research

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.