The optimal screening strategies for diabetes in terms of sensitivity, specificity, and cost may vary among different populations based on demographics and other risk factors for diabetes. We found that iron deficiency, a common condition among reproductive-age women, was associated with shifts in A1C distribution to higher levels, but this shift occurred primarily between <5.5 and 5.5–6.0%. Although we did not find an association between iron deficiency and shifts in A1C between <6.5 and ≥6.5%, few women and men had both iron deficiency and A1C elevations ≥6.5, and therefore conclusions regarding iron deficiency and the higher cut point are limited.
Previous studies of the influence of iron deficiency and glucose control have documented the high prevalence of iron deficiency in pregnancy (19
) and the association with erythrocyte indexes (20
). In a premenopausal nonpregnant population, Koga et al. (20
) found that red cell counts and A1C were associated in premenopausal women with otherwise normal glucose tolerance. Hashimoto et al. (19
) found that A1C levels were significantly increased in the third trimester compared with earlier in pregnancy, but serum glycated albumin did not change; A1C was negatively correlated with serum ferritin and transferrin saturation, suggesting that A1C was influenced by iron stores rather than by glucose control. Furthermore, replacement with iron is associated with decreases in A1C, independent of glucose changes. Coban et al. (21
) found that among nondiabetic adults with iron-deficiency anemia, the A1C was 7.4 ± 0.3% before treatment and 6.2 ± 0.6% after treatment. Likewise, Tarim et al. (22
) found that A1C in iron-deficient patients decreased from 7.6 ± 2.6 to 6.2 ± 1.4% after iron therapy (P
< 0.05), despite similar glucose levels. We did not find such large shifts in A1C associated with iron deficiency, either because of the population-based nature of the sample or differences in A1C assays. In addition, we did not examine pregnant patients, and the previous studies of nonpregnant patients may have included some adults with undiagnosed diabetes, as suggested by the A1C levels. In this respect, our results are similar to a subanalysis of the Diabetes Control and Complications Trial, in which comparisons of A1C and glucose associations were similar between premenopausal women and men (23
), suggesting that iron deficiency might not be influential in larger samples, although actually iron measurements were not available in that study.
When we examined only women who underwent a fasting glucose measurement and included fasting glucose as an adjuster, iron deficiency was still associated with a greater mean level of A1C after adjustment as well as a greater odds of having an A1C ≥5.5%. When we excluded women who were likely to have undiagnosed diabetes by fasting glucose value, iron deficiency was still associated with a higher mean level of A1C after adjustment, but the increased odds of having an A1C ≥5.5% was no longer significant. When we included adults with renal impairment, the association between iron deficiency and A1C was attenuated. This result is consistent with the observation that factors contributing to shorter erythrocyte half-life such as renal disease may lower the range of A1C values and reduce the strength of the association between A1C and factors such as iron deficiency.
The strengths of our report include its population-based sampling frame, size, and standardized A1C measurements that accounted for factors that might alter A1C measures such as hemoglobinopathies. Our study has several limitations. Iron studies may be affected by inflammation, and we have limited ability to assess such inflammation. Whereas previous studies have not shown that adjustment for C-reactive protein affected estimates of iron deficiency, it is possible that adults more prone to glucose intolerance and higher A1C levels were also prone to inflammation that was not detected. However, inflammation would be expected to raise ferritin levels so that adults with iron deficiency would be less likely to be diagnosed with iron deficiency, thus biasing estimates of association between A1C and iron deficiency to the null, and we used a low cutoff for ferritin (15 mg/dl). We were also unable to account for other factors that might affect red cell production, including malignancies and aplastic anemia. These factors might act as effect modifiers by decreasing red cell half-life and thus artificially lower A1C, thus reducing the magnitude of the association and might also act as confounders through influencing iron resorption, although we expect that these conditions were probably uncommon and would bias any associations to the null. As with any observational study, residual confounding from measurement error may account for the observed associations, and multiple testing may have contributed to chance positive findings.
In summary, we found that iron deficiency was common among women, this iron deficiency was not necessarily accompanied by anemia, and iron deficiency shifted the A1C slightly upward independent of fasting glucose level. However, the shift occurred at the lower end of the A1C spectrum, and we were unable to conclude whether iron deficiency affected A1C distributions at a higher cut point of <6.5 vs. ≥6.5%, a new recommended diagnostic cut point (1
). Similar relationships were observed in men, although the proportion of men with iron deficiency was fairly low, prohibiting more definitive conclusions. Although younger populations are generally at low risk for diabetes compared with older populations, the incidence and prevalence of diabetes are increasing among younger women and pregnant women with the obesity epidemic as well as advancing maternal age (24
). Research needs to be done to confirm that iron deficiency does not affect A1C readings in the population with known diabetes as well as at diagnostic cut points ≥5.5%.