When used to diagnose diabetes or prediabetes, the A1c level performs differently among persons of African descent, depending upon their specific ethnicity, new research suggests.

Findings from a meta-analysis by Lakshay Khosla, BA, and colleagues of 12 US studies were published online March 11 in Preventing Chronic Disease.

The studies evaluated the use of recommended A1c cutoff levels to diagnose diabetes and prediabetes among Americans who are descended from African people (African Americans), Afro-Caribbean people, and people who immigrated from Africa (Africans). Overall, the currently used cutoff levels of 6.5% or higher for diabetes and 5.7% to 6.5% for prediabetes tended to overestimate glycemia in African Americans and to underestimate it in Afro-Caribbean and African people.

“We suggest using both A1c and fasting plasma glucose [FPG ] or, better yet, a 2-hour oral glucose tolerance test [OGTT],” senior author Margrethe F. Horlyck-Romanovsky, DrPH, told Medscape Medical News. “Because of the underperformance in both directions, particularly in Africans, and because of the absence of evidence in the Afro-Caribbean populations, fasting plasma glucose appears to be a better test…. The idea is to use two different tests instead of a repeat of one test,” she said.

The limitations of the use of A1c to assess glycemic status in people with certain nutritional deficiencies, anemia, or genetic hemoglobinopathies, including sickle cell trait, have been well described.

But recent data suggest that A1c underperforms among people of African descent in the absence of those conditions, and few studies have examined differences by subethnic groups.

These issues are mentioned in the American Diabetes Association’s (ADA’s) guidelines for diagnosing diabetes. The ADA recommends that “for patients with a hemoglobin variant but normal red blood cell turnover, such as those with the sickle cell trait, an A1C assay without interference from hemoglobin variants should be used.”

Horlyck-Romanovsky commented, “We know now that the diabetes risk is one of those transgenerational risks that is carried forward…. Once we can demonstrate that the current tools do not actually perform particularly well in detecting what we think they detect, then we have to reevaluate and rethink it instead of continuing to say it works just fine.”

Asked to comment, M. Sue Kirkman, MD, professor of medicine and medical director of the Diabetes Care Center’s Clinical Trials Unit, the University of North Carolina at Chapel Hill, told Medscape Medical News, “There are three different tests to diagnose diabetes, and we’ve known that they don’t identify exactly the same people. Whichever one you say is the gold standard, the other ones are going to look less sensitive or less specific.”

Kirkman, who was senior vice president for medical affairs at the ADA and who oversaw the committee that developed the first US guidelines for use of A1c in diagnosing diabetes in 2009, explained that although the OGTT is often considered the gold standard because it’s the most sensitive, its use can lead to overdiagnosis in comparison with FPG. “When A1c is added into the mix, it’s an additional piece of the Venn diagram…. They don’t overlap completely. You are going to get differences among the three tests, even leaving out the race issue,” she said.

Moreover, Kirkman said that although studies of the use of continuous glucose monitoring have not demonstrated differences between the average A1c levels and average glucose levels between races, “if you look at individuals, there’s a lot more variation from individual to individual than there is between Blacks on average and Whites on average. So, it’s very complicated.”

Despite its limitations, Kirkman advised continuing to use A1c because it’s the most effective at predicting long-term complications regardless of race, “and we know Black people are more likely to develop diabetes and to develop many of the complications of diabetes than White people.”

Regarding use of a different test for confirmation, Kirkman said that doing so might make sense for individuals whose conditions are on the borderline between glycemia categories. “If their A1c is 8.5% and repeated, they don’t need another test. But I think around the margins with either glucose or A1c, keep an eye on them. If the A1c is 6.6%, it might be reasonable to do other tests to see,” she said.

Kirkman also cautioned in general about categorizing patients on the basis of race. She referred to the recent controversy regarding the use of a race modifier in the formula for estimated glomerular filtration rate (eGFR), which appears to result in people of African descent being less likely to qualify for kidney transplants and other nephrologic care.

“I think we need to be careful about saying we need to put in race corrections for A1c, because then are we going to get into the same problem that we have with eGFR?…. There are biracial people and just completely different genetics even within the same race. It gets very fraught and complicated…. Are we going to have a different A1c cutpoint if you’re African American or Caribbean or moved here from Africa? It can get a little bit ridiculous.”

Horlyck-Romanovsky agrees that it’s complicated.

“We’re using a social construct in comparing clinical outcomes. We really need to think about the heterogeneity within these racial groups that we think of as monolithic. The heritage of any person is a story of admixture…. Genetics only indicates what we’re at risk for, not of what we have.”

A1c Differs Among Africans, African Americans, and Afro-Caribbeans

Of the meta-analysis reported by Khosla, of the College of Medicine, SUNY Downstate Health Sciences University, New York City, and colleagues, seven of the 12 studies analyzed A1c performance among African-American people; four analyzed A1c performance in Africans; and one analyzed performance in Afro-Caribbeans. Study populations ranged from 83 to 16,056 participants, and the mean age of participants was between 37 and 64 years when reported.

The studies compared A1c performance in people of African descent either to other ethnic groups (ie, White people), to the 2-hour OGTT, FPG, and/or previous diagnosis in the same individuals.

In five of the studies of African Americans, the A1c test was associated with a greater risk for false positive results as assessed by either OGTT or FBG compared to White people across a range of glycemia levels. In one of those studies, the risk was greater compared to Hispanic individuals as well.

In two of the studies, use of an A1c level of 6.5% or higher in African Americans resulted in overdiagnosis of type 2 diabetes when compared to OGTT results. Another showed that African Americans may be overdiagnosed with prediabetes at A1c values of 5.7% to 6.4%. Another study showed that an A1c value less than 5.7% doesn’t eliminate the possibility of a type 2 diabetes diagnosis.

In contrast, in the one study of Afro-Caribbeans, the A1c cutoff of 6.5% or higher was associated with a greater risk for false negative results using FPG as the diagnostic standard. In that study, more participants were accurately diagnosed with type 2 diabetes using an A1c cutoff of 6.26% or higher.

Among African-born adults now living in the United States, the results were more similar to those of the Afro-Caribbean group: In the four studies, A1c was assocaited with a greater risk for false negative results for prediabetes at cutoffs of 5.7% to 6.4% and for type 2 diabetes at a cutoff level of 6.5% or greater when compared to OGTT results.

The study was funded by the National Institutes of Health. The authors have disclosed no relevant financial relationships. Kirkman receives NIH funding and is a consultant for Encore Medical Education.

Prev Chronic Dis. Published online March 11, 2021. Full text

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker.

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