Lower HbA1c seen with sickle trait, but questions remain

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Dr. Sacks

To address the single-method weakness of the JAMA study, he says, another retrospective study could still suffice, “as long as there is enough properly stored blood that one can actually analyze it by different methods.”

The JAMA study is likely to stoke discussion about whe-ther the cutoff for HbA_1c should be different in different racial groups, Dr. Sacks says. As the study authors write: “These findings raise the possibility of benefit from incorporating information on hemoglobin variants into clinical guidelines for interpreting HbA_1c values for screening and diagnosis of prediabetes and diabetes.”

“One of the actually intriguing implications of the study is evidence that’s well documented that HbA_1c in African Americans born in the U.S. is higher than that of whites. And this has been shown in several studies,” Dr. Sacks says.

“What is hotly debated and contested and is unresolved is whether this is clinically meaningful—whether this difference is related to glycemia. Is the higher HbA_1c in blacks a reflection of higher glucose or is it independent of glucose? I think that’s the critical question and that’s not known.” The JAMA study further complicates the debate by showing that people with sickle cell trait have lower HbA_1c. “That makes the clinical findings very difficult—the whole nuance of this is that the implications are potentially large.”

Studies in other countries have shown conflicting results. “One study in Asian Indians suggested they may have higher HbA_1c than whites, but a study in Japan of about 20,000 people found that whites and Japanese had the same HbA_1c.” A meta-analysis that combined data from 300,000 people on five continents compared HbA_1c to fasting glucose and glucose tolerance tests, he adds, but there wasn’t enough information regarding the ethnic composition of participants to reach a conclusion.

The number of people potentially affected by a racial or ethnic component to HbA_1c has made the research questions more urgent. “This whole issue really only surfaced when HbA_1c became recommended for diagnosis in 2010. People had been using it for monitoring people with diabetes for years and years and nobody raised this concern,” Dr. Sacks points out. He hopes that ongoing studies addressing racial differences might resolve some of the issues. The study authors suggest that future studies that include biracial populations further investigate HbA_1c differences by race in relation to hemoglobinopathies. Future studies should also investigate, they say, whether a possible delay in the diagnosis and treatment of prediabetes and diabetes in those with SCT could explain their lower kidney function.

A definitive answer would not be possible without a more precise indication of the average glucose in the blood, obtained by continuous glucose monitoring, for example. “Many of the studies have just looked at one or two fasting glucose values and done a glucose tolerance test, but those only indicate the glucose concentration in the blood at a specific point in time—not 10 minutes before you put the needle in the patient or 20 minutes after you drew the blood—whereas HbA_1c reflects a longer period of time, around eight to 12 weeks.”

Looking at the broader context, Dr. Sacks says, “For 25 years, HbA_1c has been used for monitoring treatment of people with diabetes, and there’s very clear evidence that HbA_1c correlates very, very well with the risk of microvascular complications, such as blindness and kidney failure, much better than glucose.” Tens of millions of patients have benefited from this type of monitoring, he adds.

The available diagnostics for HbA_1c are also performing well. “I think the manufacturers have been remarkable in working with the NGSP to improve the assays and reduce the interference from hemoglobin variants.” In fact, he says, the recommendation that spurred the 2010 guidelines clearly conveyed that after the many years in which it was advised that HbA_1c not be used for diagnosis, it was because the assay had improved that the standard-setting organizations were now recommending its use for diagnosis.

Amid the controversies, the most important thing for laboratorians to keep in mind, Dr. Sacks says, is that “it would be premature to be changing guidelines based on one paper.”

“It remains an open question as to whether HbA_1c values are significantly different in people with sickle cell trait and whether the cutoffs for diagnosis and perhaps targets for treatment should be changed in these individuals.” He hopes that the JAMA study will spur further studies that will find the answers that can improve patient care.
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Anne Paxton is a writer and attorney in Seattle.