Latest HbA_1c debate examines race as nonglycemic factor

As support for this argument, Dr. Herman cited a study of 1,806 patients covered by Harvard Pilgrim Health Care and receiving treatment at Harvard Vanguard Medical Associates. At the start of the study period, the 467 black patients had an average HbA_1cof 9.8 percent, compared with 8.9 percent for the 1,339 white patients. After one year, there remained a 0.5 percent difference in HbA_1c even after adjusting for age, sex, body mass index, hypertension, comorbidities, medication adherence, and many other potential confounders (Adams AS, et al. Diabetes Care. 2008;31[5]:916–921).

“A lot of the studies have been done to tease out these differences and adjust for these [socioeconomic and treatment] differences, but none of those studies have been able to make those [HbA_1c] differences go away,” Dr. Herman said.

For Dr. Herman, also a professor of epidemiology and internal medicine, the concern about hemoglobin A1c is far from academic. If there is some unexplained reason why black patients’ HbA_1c is higher than that of whites, this may prompt overly aggressive medical treatment that could lead to hypoglycemia. He noted a study finding that African-Americans visit the emergency department for hypoglycemia at rates two to four times higher than those of white patients, suggesting that this overtreatment may be happening (Lipska KJ, et al. JAMA Intern Med. 2015;175 [3]:356–362).

“Hemoglobin A1c is not glucose,” Dr. Herman said in concluding his AACC talk. “It is influenced by red-cell survival and by a number of other factors which, unfortunately, we’re not smart enough to understand at this point. The empirical observation stands that HbA_1cs are higher in African-Americans than in whites despite similar or comparable glucose levels.… Interventions to reduce racial disparities in hemoglobin A1c must carefully weigh both the benefits and risks.”

In taking her turn at the lectern, Elizabeth Selvin, PhD, MPH, did not dispute that racial and ethnic differences are seen in hemoglobin A1c measurements. But, she said, the differences are slight and HbA_1c does its principal job of predicting long-term diabetes-related morbidity and mortality.

“In all of these studies, the absolute differences we’re talking about in hemoglobin A1c are small. We have a 4.93 percent average in whites, 5.16 in blacks, 5.05 in Mexican-Americans. At the low levels of A1c there are no differences. Actually, what we see is that the differences are primarily driven by the higher level of the range,” said Dr. Selvin, professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health.
“I do agree we see differences,” she added. “There is a lot of difference between ethnic and racial groups on various laboratory parameters.”

Dr. Selvin offered a potential explanation for the disparities.

“It’s possible that differences in activity, stress, the environment, the neighborhood, lifestyle factors, and exposures might influence HbA_1c via real differences in nonfasting glycemia,” she said. “But this wouldn’t be captured in studies that only have a single glucose measure.”

In an interview with CAP TODAY, Dr. Sacks speculates along similar lines.

“People, before they go to the dentist, they brush their teeth. People with diabetes, before they go to the doctor, if they’ve been eating cake and candy and they know they’re going to the doctor on Wednesday, maybe for a few days they eat better,” he says. “Fasting glucose captures the moment you stick the needle into the arm. HbA_1c is a measure of the last eight to 12 weeks. That’s a very useful thing.”

For Dr. Selvin, the most valuable aspect of HbA_1c is its ability to predict outcomes for patients regardless of their race or ethnicity—for example, the rates at which they develop cardiovascular disease.

“HbA_1c is a measure of average glucose,” she said. “Glucose is not the right gold standard. The right measure is clinical complications. The way to evaluate it is to look at its prognostic value and its relationship to long-term clinical outcomes.”

In a prospective cohort analysis of 2,484 black patients and 8,593 white patients, she and her colleagues found that HbA_1c “is a risk factor for vascular outcomes and mortality in both black and white adults” (Selvin E, et al. Diabetes Care. 2013;36:2995–3001). This was their conclusion after adjusting for age, sex, LDL cholesterol, waist-to-hip ratio, and many other potential confounders.

“HbA_1c was more strongly associated with these outcomes compared with fasting glucose, and it was similarly prognostic for blacks and whites,” Dr. Selvin told the AACC crowd.

“There’s no evidence that race is a modifier of the associations between HbA_1c and the risk of these outcomes,” she added.

“The racial differences in HbA_1c, especially at diagnostic levels, likely reflect true differences in hyperglycemia,” Dr. Selvin concluded. “Blacks and Mexican-Americans are at higher risk of diabetes and complications compared with whites, and differences in stress, diet, etc., may contribute to higher nonfasting glycemia.”

Before the debate began, the standing-room only AACC crowd was asked, by show of hands, to say whether they agreed that race was an independent factor changing HbA_1c levels. About a third of those present said yes, another third said no, and the remainder were undecided.

When Dr. Selvin concluded her presentation, the crowd was surveyed again. A few hands went up to say yes, they believed race alters HbA_1c independently of glycation. About twice as many said no, it does not. But the vast majority of the laboratory professionals now said they were undecided, a testament to the power of the presentations and how much remains to be learned about the phenomenon of race, ethnicity, and hemoglobin glycation.

During the question-and-answer session, Dr. Selvin speculated that certain elements of what is happening may be beyond the ability of epidemiology to capture.

“Epidemiology is not physics,” she said. “We’re observing human beings in their natural settings, and understanding the inherent variability in biomarkers is very important.”

“I’m from Baltimore,” Dr. Selvin added. “There are major differences in the experiences of African-Americans and whites. Anyone who’s been pulled over by a cop can tell you that. We really need not to discount that. These are differences that we can’t adjust away in epidemiological studies. These are differences that go back to the historical origins of our country.”

Drs. Herman and Selvin did agree that more research involving continuous glucose monitoring, rather than fasting plasma glucose tests, could help answer some of the questions at issue in the session.

“One could design a good study that could evaluate that, and I think it would be important to design such a study to have enough individuals to have statistically significant results so you could interpret it, and have a diversity of individuals—healthy people, lots of type 2 diabetic individuals, maybe some type 1s who are stable and control their glucose well,” Dr. Sacks tells CAP TODAY. “Funding the study would be a big problem. It does have intellectual appeal, but the key question is whether this is more important to study than something else.”
In an interview, Dr. Herman says even that type of study would not resolve all the concerns he has about how HbA_1c appears to differ by race and ethnicity.

“What I’m actually beginning to find increasingly frustrating is that there is this debate, but very little progress toward scientific resolution,” he says. “I say what I think, she [Dr. Selvin] says what she thinks, but neither of us has the definitive data to answer the question.”

“There are lots of epidemiological questions to look at, but we need to drill down to the basic scientific and molecular level, which is certainly beyond my expertise,” Dr. Herman says.

To Dr. Selvin, the back-and-forth on this question could have thoroughgoing consequences.

“The stakes are high because what the other side’s arguing is that hemoglobin A1c in African-Americans is artificially high. Take that to its logical conclusion…and that means we should use a higher cutpoint in blacks,” she says. “But I don’t see who’s concerned about overdiagnosis of diabetes in African-Americans. African-Americans have a much higher risk of complications, a higher risk of diabetes, and poor access to care. The idea that we should be more conservative in diagnosis concerns me.”

Dr. Herman says he is not seeking a different HbA_1c cutpoint for African-American or Hispanic patients. For now, he resolves his concerns by seeking multiple measures to confirm a diagnosis.

“I try to mix it up a little,” he says. “If the screening test is A1c, I will follow up with fasting glucose because I can deal with uncertainty. I’d rather think about it and say, ‘Which test do I really believe?’ As a routine practice, before I label someone as diabetic I will confirm with another test, and usually use fasting glucose and A1c—a combination of the two rather than just one.”

Dr. Herman tells his endocrinology residents and fellows to look at multiple measures of glycemia “and if there’s a discrepancy between them, think which is right, why the discordance is there, and not to rely solely on one test.”

At the moment, it appears there is little to discourage Dr. Herman or any clinicians so inclined from taking this approach to diagnostic testing for type 2 diabetes. The NIH’s Dr. Sacks delivered the big picture in closing his AACC talk.

“Hemoglobin A1c can be measured accurately in the vast majority of patients, and it provides valuable clinical information for most individuals,” he said.

“Is HbA_1c the perfect test? No,” he tells CAP TODAY. “But neither is glucose or anything else.”
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Kevin B. O’Reilly is CAP TODAY senior editor.