We examined whether A1C increases with age in several ways: by examining two large and racially different nondiabetic populations, by studying a subset of subjects with no evident abnormalities of glucose metabolism, and finally by examining a cohort of nondiabetic subjects over time. The studies that have failed to demonstrate an association between age and A1C used diagnostic criteria to exclude diabetes that are now outdated (14
) or were small and possibly underpowered (15
). In our study we used the most recent criteria for diabetes diagnosis and large population-based cohorts.
We found a consistent increase in A1C with age in the cross-sectional analyses of both FOS and NHANES 2001–2004 nondiabetic populations. Our longitudinal analysis of FOS nondiabetic subjects confirmed an increase in A1C with aging. The 0.03-point increase per year in subjects with no abnormality in glucose homeostasis was greater in magnitude than expected from FOS examination 5 cross-sectional analysis, perhaps related to the relative increase in obesity among individuals of the FOS by the time of examination 7. An increase in BMI was noted in all age-groups, except for the ≥70 years age-group during that period (data not shown). It is also possible that subjects who returned for visit 7 may have been different from subjects who did not return. Results of our longitudinal analysis are comparable with those for a previous analysis of the original Framingham Heart Study, comprising parents of the FOS population, in which a 0.28% point increase in A1C over a 4- to 6-year period was observed, with a greater increase observed with increasing age (30
). Even though we found a small increase in FPG and a more significant increase in 2-h postload glucose values across age categories, we could not translate these into mean blood glucose values to estimate the corresponding rise in A1C across age categories. However, we accounted for variation with age of FPG and 2-h postload glucose levels by performing multivariate analyses. None of these adjustments materially affected the association of age category with change in A1C.
In the current study, the upper limit (97.5th percentile) of A1C could be as high as 6.83% in older nondiabetic subjects and 6.60% in older subjects with no detectable abnormality of glucose homeostasis on standard testing. Despite using similar methodology to determine the 97.5th percentile A1C in the FOS and NHANES nondiabetic populations, the 97.5th percentile A1C was slightly higher in the FOS population than in the NHANES population, even though statistically significant increases with age were noted in both populations. Differences in assays and in the study populations, including their different racial compositions, and differences in the proportion of subjects with dysglycemic states (supplemental Table A1) may have contributed to the difference observed. The similar relative increase with age in both cohorts strengthens the conclusion that A1C levels increase with age. Moreover, the data from both the NHANES and the FOS enhance the generalizability of our results.
The age-related increase in A1C observed in our study is similar in magnitude to that in two previous studies: one in Japan (8
) and one in a very small (n
= 109) convenience cohort in the U.S. (10
). Of the studies that have demonstrated an association between A1C and older age, many have been performed in selected samples (6
). Some have inadvertently included subjects with diabetes by not screening the populations for diabetes with fasting or postchallenge glucose levels (6
). Inclusion of subjects with IGT and/or IFG in previous studies may have contributed to the rise in A1C observed. In the current study, even after excluding subjects with the categorical dysglycemic states of IGT and IFG and controlling for the rise in FPG and 2-h postload glucose with age, we still observed an increase in A1C with age.
A possible explanation for the observed association of higher A1C with increasing age in individuals with NGT is that factors unrelated to glucose metabolism are affecting A1C levels. One such explanation may be changes in the rate of glycation associated with aging (12
). There is no evidence for decreased red cell turnover owing to decreased clearance with aging as a possible explanation. A 2-h OGTT may not adequately capture postprandial glycemic excursions in elderly individuals. It is possible that other factors such as worsening kidney function with aging or anemia could be playing a role; however, these are less likely to play a significant role in healthy aging adults.
As in other studies (9
), sex differences were noted in the relationship between A1C and age. It is possible that this finding is related to lower hemoglobin levels in menstruating women with more rapid erythrocyte turnover, as suggested previously (9
). Women in peri- and postmenopausal age-groups had a steeper slope than men.
Even though the association of A1C with complications is well established in individuals with diabetes (31
) and in nondiabetic subjects (32
), the clinical significance of increased A1C in the subset of older individuals who have no evidence of glucose intolerance is unknown. Current treatment targets for patients with diabetes are similar regardless of age. A study designed to address the question of age-specific treatment targets would be necessary to determine whether treatment targets should be different.
There are several limitations of this study. First, the differences in sampling strategies for the two studies precluded combining the data from both. Second, although both studies used an A1C assay that was standardized by the National Glycohemoglobin Standardization Program (27
), different laboratories performed the FOS and NHANES assays and a comparison of the absolute A1C values may be problematic. Furthermore, the age distribution and prevalence of dysglycemic states in the two studies differed, and this may also have affected the absolute A1C levels in the two studies. Our sample size was smaller at the extremes of age, and we therefore combined all subjects who were ≥70 years old to have an analyzable sample size in all age categories. Finally, we did not account for the prevalence of other conditions that could affect A1C in either study population, including anemia and its treatment and kidney dysfunction; however, their effect is likely to be small overall. Despite these limitations, the similar impact of increasing age on A1C in both populations provides confirmation of the relationship between age and A1C in the nondiabetic population.
In summary, in the current study, the uniform results between FOS and NHANES establish clearly that A1C increases with age even after multivariate adjustments for sex, fasting, and 2-h postload glucose. The finding of higher upper limits of normal A1C in older individuals suggests that nonglycemic factors may contribute to the relationship of A1C with age. If we bear in mind the fact that elderly individuals have an increased risk for hypoglycemia and other medication side effects (22
), the adoption of A1C targets that are lower than age-appropriate nondiabetic values may be associated with more medication-associated complications; however, a clinical study directly addressing the question of whether A1C should be age adjusted is needed. We recommend that further studies be undertaken to determine whether the increase in A1C associated with age in subjects with normal glucose tolerance is of clinical significance and to clarify whether age-specific diagnostic and treatment criteria would be appropriate.