Latest HbA_1c debate examines race as nonglycemic factor

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Kevin B. O’Reilly

December 2015—In 2010, the American Diabetes Association endorsed the use of hemoglobin A1c to diagnose type 2 diabetes, and fierce arguments over the wisdom of that move have ensued ever since. A 2013 debate at the American Association for Clinical Chemistry’s annual meeting featured a spirited dialogue on the merits of using HbA_1c as a diagnostic marker, compared with the traditional—and still ADA-recommended—alternatives, fasting plasma glucose and two-hour plasma glucose.

Now the discussion is zeroing in on a narrower controversy within the HbA_1c dispute—the role of race and ethnicity. African-Americans regularly have higher HbA_1c values than do whites, even when they have similar fasting plasma glucose levels. Hispanics, too, have exhibited a similar HbA_1c/FPG disparity, though amid a smaller body of research and to a lesser degree than is found among blacks. The questions are what this widely observed trend means and what to do about it.

Do higher HbA_1c concentrations among blacks and Hispanics reflect socioeconomic or lifestyle factors, or are they driven by some as yet unidentified molecular or biological nonglycemic factors present in these patient populations? Should clinicians and laboratories set different diagnostic cutpoints for their black and Hispanic patients than for their white ones? Should laboratories seek race and ethnicity data to help overcome this apparent impediment to HbA_1c interpretation?

These questions and more will come to the fore in an upcoming point-counterpoint on the issue in the ADA’s influential Diabetes Care journal. They also arose as part of a provocative, well-attended session at this year’s AACC meeting.

Dr. Sacks

David Sacks, MB, ChB, FRCPath, helped organize the session—a version of which also was held at this year’s ADA meeting—and in his introductory remarks he provided a contextual understanding of hemoglobin glycation and the nonglycemic factors that have been identified in the medical literature.

“Clearly, there are some factors that influence HbA_1c that are independent of glycemia,” Dr. Sacks tells CAP TODAY. “There aren’t as many as the reviews and the old textbooks have listed because many of the factors that are reported to alter HbA_1c may have interfered in old assays—the measurements that we used in the ’70s or ’80s—but many of these do not occur with current HbA_1c assays.”

Dr. Sacks, senior investigator at the National Institutes of Health and chief of clinical chemistry at the NIH Clinical Center, notes that HbA_1c testing improvements played a big role in encouraging the ADA and the World Health Organization to recommend using HbA_1c as a diagnostic test for type 2 diabetes.

“One of the main reasons for saying that it was OK to use HbA_1c for diagnosis was actually based on the clinical lab community, because they [the ADA and WHO] said the test is good enough now,” he says. “Before, they said the test is not harmonized and not accurate enough and then they changed. And that’s in large part due to the people and the companies who worked hard to harmonize the assay.”

So, conditions such as uremia and hyperbilirubinemia—once identified as nonglycemic factors affecting HbA_1c—are no longer stumbling blocks.

“There’s this one category that interferes with the actual measurement. As the manufacturers improve their methods or new methods are developed, they can eliminate some of these factors. They are basically assay artifacts,” Dr. Sacks says. “And then there is another group of factors that are of much greater concern and interest and really do change the value. Those are the ones that require more thought and discussion. Race would fit into that category.”

Other nonglycemic factors in this category include age, chronic renal failure, iron-deficiency anemia, red blood cell lifespan, and differing hemoglobin glycation rates, Dr. Sacks said in his talk at the AACC meeting. The impact of race as a nonglycemic factor is particularly fascinating because it has yielded differing interpretations among experts surveying the available body of evidence.

“One of the intriguing things to me is that if you look at the literature on race and HbA_1c, while the studies are not designed exactly the same, the question they’re asking is the same and yet they come up with completely opposite conclusions,” Dr. Sacks says.

And so it was during the AACC session. Endocrinologist William H. Herman, MD, MPH, took first to the lectern to argue the case that race does alter HbA_1c independently of glycemia. He cited an array of studies finding differences of between 0.4 and two percentage points in HbA_1c between white patients with type 2 diabetes and their black counterparts (Kirk JK, et al. Diabetes Care. 2006;29[9]:2130–2136).

Dr. Herman pointed to another study showing that 164 black patients and 1,815 white patients had fasting plasma glucose scores only two points apart (153 mg/dL for African-Americans, 151 mg/dL for whites). Yet the average HbA_1c for the two groups differed by 0.7 percentage points—eight percent for blacks, 7.3 percent for whites (Viberti G, et al. Diabet Med. 2006;23 [12]:1289–1294).

“These racial differences are not explained by access to care or quality, and they appear to occur independently of glycemia,” said Dr. Herman, the Stefan S. Fajans/GlaxoSmithKline professor of diabetes at the University of Michigan Medical School and director of the Michigan Center for Diabetes Translational Research.

“We can’t explain why these differences occur,” he added. “And I don’t think we can or should discard the observation, and the observation is incredibly robust that there remain unexplained differences in hemoglobin A1c between African-Americans and whites.”