New Biomarkers May Be More Accurate than HbA1c in Diabetes Screening

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Although widely used to monitor glucose control and — more recently — to diagnose diabetes, HbA1c screening lacks accuracy in a range of patients with hemoglobinopathies, kidney issues or HIV. A new study, supported by the VA, lays out the benefits of alternative biomarkers to determine hyperglycemia.

By Annette M. Boyle

BALTIMORE — Despite its nearly universal use for monitoring glucose control in diabetics and increasing use in diagnosing diabetes, HbA1c screening has some serious limitations.

As the product of glycation of hemoglobin in erythyrocytes, HbA1c indicates exposure to glucose over the approximately three-month lifespan of red blood cells but does not accurately indicate hyperglycemia in patients with hemoglobinopathies such as those occurring in anemia, malaria, pregnancy, major blood loss, uremia, smoking, hemolysis or transfusion. It also is problematic for patients on dialysis, in renal failure or with human immunodeficiency virus (HIV). Further, in patients whose glucose levels fluctuate a great deal, HbA1C results often are misleading.

Now, a new study partly funded by the VA suggests that two new biomarkers might help clinicians more accurately screen for diabetes and assess risk for complications in thousands of patients.

Naval Health Clinic-Hawaii's Health Promotion mobile "Wellness on Wheels" van was on site at Tripler Army Medical Center's diabetes wellness fair. HbA1c tests were offered to patients who wanted to know their numbers.

Naval Health Clinic-Hawaii’s Health Promotion mobile “Wellness on Wheels” van was on site at Tripler Army Medical Center’s diabetes wellness fair. HbA1c tests were offered to patients who wanted to know their numbers.

Fructosamine and glycated albumin levels can be used to improve diabetes detection and provide better indications of treatment effectiveness and the risk of developing retinopathy, chronic kidney disease and other microvascular complications, according to a recent study funded by the VA, National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases and published in The Lancet.1

“Our study is the first to demonstrate that the predictive ability of fructosamine and glycated albumin for microvascular disease is actually quite similar to that of HbA1c. Fructosamine and glycated albumin also strongly predict future diabetes,” said lead author Elizabeth Selvin, PhD, MPH, associate professor of Epidemiology and Medicine, Welch Center for Prevention, Epidemiology and Clinical Research and the Johns Hopkins Bloomberg School of Public Health in Baltimore.

The researchers measured glycated albumin and fructosamine in blood samples from more than 12,000 participants in the Atherosclerosis Risk in Communities (ARIC) study. Since 1987, the study has tracked a community-based cohort with participants in Washington County, MD, Jackson, MS, Forsyth County, NC, and suburban Minneapolis.

The second examination period, 1990-1992, was used as the baseline, and participants were followed for two decades to determine the association between levels of the two glycated proteins and the risk of developing diabetes, retinopathy or chronic kidney disease. Those results were compared to the association of HbA1c and incident diabetes, retinopathy or chronic kidney disease. Of the participants, 11,348 did not and 958 did have diabetes at initiation.

Over the study period, the adjusted hazard ratios for the incidence of diabetes was 4.96 for patients in the 95th percentile for fructosamine and 6.17 for those with glycated albumin in the 95th percentile, a result that remained stable after adjustment for HbA1c. At the 95th percentile, the hazard ratios for chronic kidney disease were 1.5 for fructosamine and 1.48 for glycated albumin, compared to nondiabetics with glycated serum protein levels below the 75th percentile.

“A major advantage to these tests is that they may be useful for monitoring glucose control in persons in whom HbA1c is known to be problematic,” Selvin said. Fructosamine and glycated albumin levels represent the glycation of serum proteins, which turn over in about two weeks and are not affected by genetic variations in hemoglobin or altered red blood cell turnover. The tests can be performed using serum or plasma unlike HbA1c, which requires whole blood.

While widely available, fructosamine assays have not been commonly used in clinical practice, something the researchers said they hope their findings will change.

“The lack of evidence linking fructosamine to long-term outcomes in patients with diabetes has been cited as a major barrier to the use and interpretation of these assays,” they noted. Glycated albumin testing is used to monitor short-term glycemic control in Japan, but is has not been adopted elsewhere.

“These biomarkers respond rapidly to treatment changes [within one to two weeks], whereas response of HbA1c to changes in treatment won’t be observed for a few months,” Selvin told U.S. Medicine. Consequently, the two tests could enable clinicians to quickly determine the impact of a new treatment regimen or therapy and allow relatively rapid adjustments of therapies to obtain glycemic control. “They may be useful as complements to provide additional information to HbA1c in clinical practice,” she added.

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An accompanying editorial focused on “several new and potentially unexpected findings” in the study, particularly that in nondiabetic participants with HbA1c levels between 5.4% and 5.8%, “there was a proportionately greater increase in glycated albumin and fructosamine concentrations compared with HbA1c” and other indications that the glycated proteins “might perform better that HbA1c in the non-diabetic-diabetic transition point.”

If so, glycated albumin and fructosamine may be better diagnostic tests for diabetes, wrote the editorial co-authors, Robert Cohen, MD, endocrinologist, Cincinnati VA Medical Center and professor of medicine at the University of Cincinnati Medical Center, and William Herman, MD, MPH, director of the Michigan Center for diabetes translational research and professor of medicine at the University of Michigan Health System in Ann Arbor.

The commentators note that “all three tests seem to work well in populations, especially for predicting complications, but it remains to be seen how well they perform in individuals.”

Selvin said she expects the results to hold up in clinical use. “At the patient level, there will sometimes be discordance between biomarkers, but glycated albumin and fructosamine are highly correlated with HbA1c, particularly in persons with diabetes and as glucose levels rise.”

Cohen and Herman urge more study of that discordance to determine where more research is required and for which patients the newer measures of average glycemia will not work.

While additional research continues on these potential alternative predictors of diabetes and its complications, Cohen and Herman encourage clinicians to use multiple indirect tests to assess their patients’ glycemia and to “maintain a high index of suspicion when an indirect measure does not seem correct. … Not only will they do better by their patients, but they might be intrigued and frustrated by how often and by how much alternative indirect measures of glycaemia disagree.”

1Selvin E, Rawlings AM, Grams M, Klein R, Sharrett AR, Steffes M, Coresh J. Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular complications: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. The Lancet Diabetes & Endocrinology. Published online Jan. 15, 2014, ahead of print.

2Cohen RM and Herman WH. Are glycated serum proteins ready for prime time? Lancet Diabetes & Endocrinology. Published online Jan. 15, 2014, ahead of print.

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