Anemia May Distort Blood Sugar Tests, Clouding Eye Damage Risk in Diabetes

For the millions of people living with type 2 diabetes, a single blood test often shapes the entire conversation about their future health. Glycated hemoglobin, better known as HbA1c, has reigned for decades as the gold standard for measuring long-term blood sugar control, and its value is woven into treatment guidelines worldwide. Yet a new study from researchers at Ziyang Central Hospital in Sichuan, China, adds to mounting evidence that this trusted marker can mislead in certain patients, and it points to an underappreciated alternative that may better flag the earliest threat to vision: diabetic retinopathy.

The research, published in BMC Endocrine Disorders, examined 1,090 hospitalized patients with type 2 diabetes and asked a deceptively simple question: does anemia change how well a lesser-known blood sugar marker, albumin-corrected fructosamine, predicts diabetic retinopathy? The answer was a clear yes. Among patients with anemia, higher fructosamine levels were dramatically more strongly associated with retinopathy than among patients without it, and the marker outperformed HbA1c in identifying those at risk of eye damage.

To understand why this matters, it helps to look at the chemistry behind these tests. HbA1c measures glucose molecules that have permanently bonded to hemoglobin, the oxygen-carrying protein inside red blood cells. Because red blood cells live for roughly three to four months, the test reflects average glucose exposure over that window. But that same biology creates a vulnerability: anything that alters red blood cell survival distorts the reading. Anemia, whether from iron deficiency, chronic disease, or kidney dysfunction, shortens red cell lifespan, which can falsely lower HbA1c and make blood sugar control appear better than it truly is.

Fructosamine takes a different route. It measures glucose bonded to serum proteins, chiefly albumin, which circulate in the blood for only about two to three weeks. That shorter window makes fructosamine a gauge of recent glycemic control, and because it does not depend on red blood cells, it is theoretically immune to the distortions that plague HbA1c in anemic patients. The catch is that fructosamine levels rise or fall with albumin concentrations, so researchers typically correct the value against serum albumin, producing the albumin-corrected fructosamine, or AlbF, used in this study.

Diabetic retinopathy, the condition both markers are being asked to predict, remains one of the most feared complications of diabetes. It develops when chronically elevated glucose damages the delicate blood vessels of the retina, causing them to leak, swell, and eventually grow abnormally. It is a leading cause of blindness in working-age adults, and its earliest stages are silent, detectable only through eye examinations. Finding reliable blood-based markers that signal elevated retinopathy risk could help clinicians intensify monitoring and treatment before irreversible damage occurs.

In the new study, retinopathy was present in 459 of the 1,090 participants, or 42.1 percent, while 366 participants, or 33.6 percent, met World Health Organization criteria for anemia. Using multivariable logistic regression to account for confounding factors, the researchers found that among anemic patients, each 10 μmol/g increase in AlbF was associated with nearly double the odds of having retinopathy, with an adjusted odds ratio of 1.98 and a 95 percent confidence interval of 1.42 to 2.76, a highly statistically significant result. Among patients without anemia, the association was considerably weaker, with an odds ratio of 1.30.

The team went beyond simple comparison, formally testing whether anemia modified the relationship on both multiplicative and additive scales, the two frameworks statisticians use to detect interaction between variables. On the multiplicative scale, the interaction was significant, with a P value of 0.014. On the additive scale, the relative excess risk due to interaction was 2.88, the attributable proportion was 0.49, and the synergy index was 2.42, all indicating that the combined presence of anemia and elevated fructosamine confers risk beyond what either factor alone would predict. In practical terms, nearly half of the retinopathy risk in anemic patients with high AlbF could be attributed to this interaction.

Perhaps the most clinically consequential finding came from the head-to-head comparison of the two glycemic markers within the anemic subgroup. Adding AlbF to a base statistical model significantly improved the model’s ability to discriminate between patients with and without retinopathy, raising the area under the receiver operating characteristic curve from 84.43 percent to 87.07 percent, a difference that reached statistical significance at p equal to 0.012. Adding HbA1c, by contrast, provided no significant improvement. AlbF also improved risk classification beyond HbA1c, with a categorical net reclassification improvement of 0.109, a continuous NRI of 0.461, and an integrated discrimination improvement of 0.039, all statistically significant.

These numbers translate into a concrete clinical message. In anemic patients with type 2 diabetes, a group in which HbA1c is known to be unreliable, albumin-corrected fructosamine appears to carry real, incremental information about retinopathy risk that HbA1c cannot supply. The authors conclude that AlbF deserves consideration as a complementary glycemic marker in this population, not a wholesale replacement for HbA1c, but an additional lens through which to view a patient’s metabolic status when the standard test may be distorted.

The study’s cross-sectional design imposes important limits. Because blood was drawn and eye status assessed at the same time, the findings show association rather than proven prediction over time, and they cannot establish that elevated fructosamine causes retinopathy or that lowering it would protect the retina. The participants were all hospitalized patients at a single Chinese institution, which may limit generalizability to outpatient populations or other ethnic groups. Still, the large sample size, the rigorous dual-scale interaction analysis, and the formal reclassification statistics give the findings unusual statistical weight for a single-center study, and they align with a growing body of literature on the pitfalls of HbA1c in hematological disorders.

For clinicians, the practical takeaway is to think twice before interpreting an HbA1c result in a diabetic patient with known or suspected anemia, and to consider fructosamine-based testing as a cross-check, particularly when retinopathy screening decisions hang in the balance. For researchers, the results open a clear path forward: prospective studies tracking whether AlbF measured today predicts retinopathy progression years later, and trials examining whether correcting anemia restores concordance between the two markers. As diabetes rates continue to climb globally, refining the tools used to judge blood sugar control is not an academic luxury but a matter of preserved eyesight.

Subject of Research: The effect of anemia on the association between albumin-corrected fructosamine and diabetic retinopathy in type 2 diabetes

Article Title: Anemia modifies the association between albumin-corrected fructosamine and diabetic retinopathy in type 2 diabetes: a cross-sectional study

Article References: Anemia modifies the association between albumin-corrected fructosamine and diabetic retinopathy in type 2 diabetes: a cross-sectional study. (n.d.). https://doi.org/10.1186/s12902-026-02571-w

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02571-w

Keywords: diabetic retinopathy, albumin-corrected fructosamine, HbA1c, anemia, type 2 diabetes, glycemic biomarker, effect modification, cross-sectional study, retinopathy screening, serum albumin, hemoglobin, BMC Endocrine Disorders