Photo by Juan D. Alfonso
A new study suggests that hemoglobin A1c (HbA1c), a biomarker used to measure blood sugar over time, may not perform as accurately among African-Americans with sickle cell trait (SCT) and could be leading to a systemic underestimation of blood sugar control in that population.
Researchers analyzed data from more than 4600 people and found that HbA1c readings were significantly lower in individuals with SCT than in those without it, even after accounting for several possible confounding factors.
The team reported these findings in JAMA.
“We found that HbA1c was systematically lower in African-Americans with sickle cell trait than those without sickle cell trait, despite similar blood sugar measurements using other tests,” said study author Mary Lacy, a doctoral candidate at the Brown University School of Public Health in Providence, Rhode Island.
“We might be missing an opportunity for diagnosis and treatment of a serious disease.”
Lacy and her co-authors found that using standard clinical HbA1c cutoffs resulted in identifying 40% fewer potential cases of prediabetes and 48% fewer potential cases of diabetes in people with SCT than in people without SCT.
However, when the researchers used other blood glucose measures as the diagnostic criteria, they found no significant difference in the likelihood of diabetes and prediabetes among patients with or without SCT.
The questions the study raises about using HbA1c among SCT carriers matter for treatment as well as diagnosis, said study author Wen-Chih Wu, MD, of Brown University.
“The clinical implications of these results are highly relevant,” Dr Wu said. “For patients with diabetes, HbA1c is often used as a marker of how well they are managing their diabetes, so having an underestimation of their blood sugars is problematic because they might have a false sense of security, thinking they are doing okay when they are not.”
Study details
For this study, the researchers analyzed data from 2 major public health studies—the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). Of the 4620 participants included in the analysis, 367 had SCT.
Among all the patients included in the analysis, HbA1c readings came from either of 2 widely used, clinically accepted assays made by Tosoh Bioscience Inc. that rely on a process called high-performance liquid chromatography.
In addition to those measures, the researchers also compared fasting and 2-hour blood glucose and statistically controlled for demographic and medical factors, such as gender, age, body-mass index, whether diabetes had already been diagnosed, and whether it was being treated.
Study author Gregory Wellenius, ScD, of Brown University, said the study’s scale and breadth allowed for the most definitive comparison to date of HbA1c readings in patients with and without SCT. Two previous, smaller studies had not detected a similar discrepancy.
“The strengths of the study are that it’s the largest sample size ever used, it’s across 2 different studies with somewhat different populations, and it’s a more thorough evaluation than prior studies,” Dr Wellenius said.
While the study showed that HbA1c readings were significantly different between people with and without SCT, it also showed that blood glucose readings were not, suggesting that glucose metabolism is not necessarily different between the 2 groups, as the HbA1c readings alone would suggest.
Implications for practice
The study does not explain why the HbA1c readings differ. While it could be related to the assay method, which is approved by the NGSP (formerly National Glycohemoglobin Standardization Program) for use in patients with SCT, it could also be a consequence of the underlying biology of SCT.
Hypothetically, according to the researchers, if the hemoglobin variant of the trait endows red blood cells with a shorter lifespan, the cells’ hemoglobin would carry less accumulated blood glucose, leading to falsely low HbA1c readings.
“Irrespective of the reason of the underestimation, the underestimation is very real, and clinicians should consider screening for sickle cell trait and account for the difference in HbA1c,” Dr Wu said.
Yet not many people with SCT in the US know they carry the variant, especially those born before routine screenings at birth began, Lacy said.
The researchers therefore recommend that practitioners following African-American patients whose HbA1c levels are within 0.3 percentage points of a diagnostic cutoff also consider using additional blood glucose measures. Current diagnostic thresholds for A1C are ≥5.7% for prediabetes and ≥6.5% for diabetes.
