The American Diabetes Association’s Standards of Medical Care in Diabetes—2017 states that age should be “taken into consideration” when diagnosing diabetes with HbA1c (1). Nonetheless, it is unclear how this recommendation might be implemented. Population studies demonstrate that HbA1c increases with age, which some experts have suggested may be due to nonglycemic factors like alterations in red cell turnover or hemoglobin glycation (24). However, prior studies lack concurrent comparisons across nonhemoglobin-related markers of hyperglycemia. We evaluated increases with age in fructosamine and glycated albumin—hemoglobin-independent measures of hyperglycemia—in comparison with HbA1c and fasting glucose in the community-based Atherosclerosis Risk in Communities (ARIC) study.

We conducted serial cross-sectional analyses at visit 2 (1990–1992; n = 11,632) and visit 5 (2011–2013; n = 3,876), excluding individuals with diagnosed diabetes. We performed adjusted linear regression of z scores of each biomarker (standardized to visit 2) on age to allow head-to-head comparisons of the associations.

Age was significantly correlated with all biomarkers of hyperglycemia at visit 2 (Fig. 1). In middle age (visit 2), we observed increases in HbA1c with age, comparable increases in fructosamine and glycated albumin, and some increase in fasting glucose, with modest impact of adjustment for sex, race center (white, Minneapolis, MN; black, Jackson, MS; white, Washington County, MD; black, Forsyth County, NC; white, Forsyth County, NC; as defined by the ARIC study design), BMI, and BMI2. At visit 5 among older adults (21 years later), increases with age were less evident for fasting glucose and HbA1c compared with fructosamine and glycated albumin. Associations of age with HbA1c, fructosamine, and glycated albumin at both visits persisted after further adjustment for fasting glucose.

Figure 1

Scatterplots with linear predictions, Pearson correlation coefficients, and unadjusted β coefficients (95% CIs) from linear regressions of z scores of markers of hyperglycemia (standardized to visit 2) on age (visit 2: 1990–1992 and visit 5: 2011–2013). HbA1c (A), fasting glucose (B), fructosamine (C), and glycated albumin (D). Black circles, visit 2 biomarker values; white line, visit 2 linear prediction; white circles, visit 5 biomarker values; black line, visit 5 linear prediction. *P < 0.05, **P < 0.001.

Figure 1

Scatterplots with linear predictions, Pearson correlation coefficients, and unadjusted β coefficients (95% CIs) from linear regressions of z scores of markers of hyperglycemia (standardized to visit 2) on age (visit 2: 1990–1992 and visit 5: 2011–2013). HbA1c (A), fasting glucose (B), fructosamine (C), and glycated albumin (D). Black circles, visit 2 biomarker values; white line, visit 2 linear prediction; white circles, visit 5 biomarker values; black line, visit 5 linear prediction. *P < 0.05, **P < 0.001.

The magnitude of the association we observed between HbA1c and age, particularly in middle age (0.11% [1.2 mmol/mol] per 10 years of age), was similar to that in other studies (24). Prior investigations adjusted for glucose to account for glycemia and attributed associations to nonglycemic hemoglobin-related factors. However, although HbA1c and fasting glucose are highly related, they represent different glycemic constructs. We observed increases in HbA1c, fructosamine, and glycated albumin independent of fasting glucose, suggesting that increases may be primarily glycemic or that putative nonglycemic factors may influence nonhemoglobin biomarkers.

The heterogeneity of dysglycemia across the life span may offer some explanation for the less consistent associations of age across the hyperglycemia biomarkers. Impaired insulin secretion is common in older age. As HbA1c, fructosamine, and glycated albumin reflect postprandial glucose excursions in addition to fasting concentrations, their stronger associations with age as compared with fasting glucose could reflect that impaired glucose tolerance is more common than impaired fasting glucose in this population (5).

Similar to previous investigations, our assessment is limited by its cross-sectional nature. Additionally, our analyses of older adults could be subject to selection bias. Study strengths include the community-based sample, broad age range, and measurements at different time points in the life span.

In conclusion, we observed higher HbA1c at older ages but also saw comparable associations for other (nonhemoglobin-related) biomarkers of hyperglycemia. Our results provide some evidence that the age associations with HbA1c, fasting glucose, fructosamine, and glycated albumin may reflect increases in the prevalence of hyperglycemia in aging.

Ackowledgments. The authors thank the staff and participants of the ARIC study for their important contributions. Reagents for the glycated albumin assays were donated by the Asahi Kasai Pharma Corporation. Reagents for the fructosamine assays were donated by Roche Diagnostics.

Funding. ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. B.W., A.M.R., and A.K.L. were supported by National Institutes of Health National Heart, Lung, and Blood Institute grant T32HL007024. This research was supported by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK089174, and E.S. was also supported by K24DK106414.

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

Author Contributions. B.W. and E.S. designed the study, researched the data, and wrote the manuscript. A.M.R., A.K.L., M.G., and J.C. all provided meaningful contributions to the revision of the manuscript. E.S. 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.

1.
American Diabetes Association
.
Standards of Medical Care in Diabetes—2017
.
Diabetes Care
2017
;
40
(
Suppl. 1
):
S1
S135
2.
Pani
LN
,
Korenda
L
,
Meigs
JB
, et al
.
Effect of aging on A1C levels in persons without diabetes: evidence from the Framingham Offspring Study and the National Health and Nutrition Examination Survey 2001–2004
.
Diabetes Care
2008
;
31
:
1991
1996
3.
Dubowitz
N
,
Xue
W
,
Long
Q
, et al
.
Aging is associated with increased HbA1c levels, independently of glucose levels and insulin resistance, and also with decreased HbA1c diagnostic specificity
.
Diabet Med
2014
;
31
:
927
935
4.
Ravikumar
P
,
Bhansali
A
,
Walia
R
,
Shanmugasundar
G
,
Ravikiran
M
.
Alterations in HbA1c with advancing age in subjects with normal glucose tolerance: Chandigarh Urban Diabetes Study (CUDS)
.
Diabet Med
2011
;
28
:
590
594
5.
Kalyani
RR
,
Egan
JM
.
Diabetes and altered glucose metabolism with aging
.
Endocrinol Metab Clin North Am
2013
;
42
:
333
347
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