Glucose-HbA1c Link Differs in Blacks by Sickle-Cell Status 

Miriam E Tucker

February 07, 2017

The relationship between glucose levels and HbA1c in African Americans differs from that of whites, as has been noted previously. Now research suggests blacks with the sickle-cell trait (SCT) have lower HbA1c than African Americans in general, perhaps more akin to that of whites.

In a new retrospective analysis of data from two prior cohort studies, published in the February 7, 2017 issue of the Journal of the American Medical Association, epidemiologist Mary E Lacy, MPH, of Brown University, Providence, Rhode Island, and colleagues indicate that the 8% to 10% of African Americans who carry the SCT have lower levels of HbA1c at any given concentration of fasting or 2-hour glucose than do those without the trait.

The phenomenon is thought to be due to the fact that red blood cells of people with the SCT contain a lower proportion of hemoglobin A and higher levels of hemoglobin S, resulting in overall shorter red blood cell life-spans and less available time for glycation, thereby throwing off the established glucose-glycated hemoglobin relationship.

"As a screening tool, an HbA1c value that systematically underestimates long-term glucose levels may result in a missed opportunity for intervention," the authors write, pointing out that in the current study, using standard HbA1c cutoffs resulted in identifying 40% fewer people with prediabetes and 48% fewer with diabetes among those with the SCT, compared with those without it. At the same time, glucose-based methods resulted in similar prevalences of diabetes and prediabetes regardless of SCT status.

"Because black people typically have a higher prevalence of diabetes and experience a number of diabetic complications at higher rates than white people, the cost of inaccurately assessing risk and treatment response is high," Ms Lacy and colleagues say.

Blacks Have Higher HbA1c at Any Given Glucose

In an accompanying editorial, nephrologist Anthony J Bleyer, MD, and endocrinologist Joseph A Aloi, MD, of Wake Forest School of Medicine, Winston-Salem, North Carolina, point out in addition that Bleyer and others have previously shown that African Americans overall have higher HbA1c levels than whites at a given blood glucose level.

When taken together, they say, these findings cement the idea that the relationship of HbA1c to glucose among black people with the SCT is similar to that of whites, whereas blacks without the trait have higher HbA1c for any given blood glucose level.

Thus, they assert, the concern centers on African Americans without the sickle cell trait, particularly when their HbA1c values place them near the cutoffs for prediabetes and diabetes.

"There may be some overdiagnosis of diabetes, and this could make African American patients more prone to hypoglycemia if aggressively treated," Dr Bleyer told Medscape Medical News.

Based on that, "If you have an African American patient with diabetes, I think it would be reasonable to know their sickle-cell-trait status....If the patient doesn't have the trait, you need to be more careful in diagnosing them with diabetes if they're near the cutoff for diagnosis and should consider an oral glucose tolerance test," he advised.

Sickle-Cell Trait Reduces HbA1c for Given Glucose Levels

Ms Lacy and colleagues used data on a total of 4620 participants in two community-based study cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study, from 2005 to 2011, and the Jackson Heart Study (JHS), from 2000 to 2013.

Of those, 7.9% (367) of participants had the SCT,and they were slightly but not significantly more likely to report having a diagnosis of diabetes and to be using diabetes medications.

From 9062 concurrent measures of HbA1c and fasting glucose and 2001 concurrent measures of HbA1c with 2-hour oral glucose-tolerance test results, the mean HbA1c was 5.7% among those with the trait and 6.0% in those without the trait, despite nearly identical mean fasting glucose levels (103.0 vs 102.9 mg/dL, P = .88) and similar oral glucose-tolerance test results (118.5 vs 113.0 mg/dL, P = .19)

Mean HbA1c values were lower among those with, vs without, the trait across all categories of fasting and 2-hour glucose measures, the authors report.

In adjusted analysis, HbA1c remained significantly lower among those with the trait (mean difference -0.32%, P < .001), with greater difference by trait status seen at higher fasting glucose levels (P = .01 for adjusted analysis). Results for the 2-hour glucose measurements revealed similar differences from HbA1c by SCT status, Ms Lacy and colleagues report.

Ability to Diagnose Prediabetes, Diabetes Altered

Among the 3935 participants without a prior diabetes diagnosis, the prevalence detected with prediabetes and diabetes was not significantly different among participants with and without the SCT when defined using either fasting glucose or 2-hour oral glucose-tolerance test.

In contrast, both prediabetes and diabetes were detected significantly less often among those with the trait when HbA1c values of 5.7% to 6.4% for prediabetes and ≥6.5% for diabetes were used (29.2% with trait vs 48.6% without the trait for prediabetes and 3.8% with trait vs 7.3% without the trait for diabetes, P < .001 for all comparisons).

The ability of HbA1c to identify participants with prediabetes or diabetes was also significantly lower among those with the SCT, the authors report.

Blacks Without the SCT May Be at Risk for Hypoglycemia if Treated to Same Target as Whites

Dr Bleyer pointed to data from several studies showing higher HbA1c levels overall in African Americans for given blood glucose levels, a phenomenon that has puzzled physicians, as previously reported by Medscape Medical News.

In his own study (Diabet Med. 2008; DOI:10.1111/j.1464-5491.2008.02646.x), including 4215 black patients and 6359 white patients with identical blood glucose values of 150 mg/dL, an HbA1c value of 7.0% in whites was equivalent to an HbA1c of 7.4% in blacks.

Indeed, according to the American Diabetes Association's 2017 Standards of Medical Care in Diabetes, "A1c levels may vary with race/ethnicity independently of glycemia. For example, African Americans may have higher A1c levels than non-Hispanic whites despite similar fasting and post–glucose load glucose levels. Although there is some conflicting data, African Americans may also have higher levels of fructosamine and glycated albumin and lower levels of 1,5-anhydroglucitol, suggesting that their glycemic burden (particularly postprandially) may be higher."

Dr Bleyer also noted that in the ACCORD trial, blacks had a nearly 50% increased risk of hypoglycemia requiring medical assistance vs whites in both the standard and intensive-control groups.

Thus, "for the same hemoglobin A1c level, the African American will have a lower blood glucose than a white patient. So, they're more likely to have hypoglycemia if you try to hit the same target," he said.

Thus, he advised, "If you're trying to target A1c to goal and they're getting a lot of hypoglycemic events, believe the blood glucose levels and don't try to get such stringent targets as with whites."

And he urged caution regarding using hemoglobin A1c for diagnosis of prediabetes and diabetes among African Americans: "It could lead to overdiagnosis, which can affect insurance, how people feel, and what they do."

The study was funded by grants to the individual investigators from the National Heart, Lung, and Blood Institute, the National Institute on Aging (NIA), and the National Institute on Minority Health and Health Disparities. The authors have no further relevant financial relationships. Dr Bleyer and Dr Aloi have no relevant financial relationships.

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JAMA. 2017;317:508-515, 461-482. Article, Editorial

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