Add Glycated Proteins to HbA1c for Diabetes Risk Prediction?

Nancy A. Melville

January 17, 2014

Measurements of fructosamine and glycated albumin could help identify people at risk of developing diabetes and diabetic complications such as retinopathy, with independent associations that are similar to the HbA1c test, new research published online in Lancet Diabetes & Endocrinology suggests.

This is the largest long-term study to evaluate these novel markers in relation to diabetes outcomes, offering important support to their potential value in a clinical setting.

"Our findings suggest that fructosamine and glycated albumin can be used to predict diabetes, chronic kidney disease, and retinopathy in the community," the authors write.

"These results suggest that measurement of these nontraditional markers of hyperglycemia might be useful in clinical practice."

The need for alternative measures of hyperglycemia has been emphasized in recent years as a result of the growing awareness of the limitations of HbA1c in various situations, including among patients with anemia and kidney disease, said lead author Elizabeth Selvin, PhD, MPH, an associate professor with the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

"Limitations of HbA1c are widely acknowledged and have become of particular concern following the 2010 recommendations by the American Diabetes Association for the use of HbA1c for diagnosis of diabetes," she told Medscape Medical News. "HbA1c testing is problematic in the setting of anemia, recent transfusion, pregnancy, blood loss, liver disease, and kidney disease or in persons with certain hemoglobinopathies."

In addition, HbA1c, which measures 2- to 3-month glycemic control, doesn't change rapidly in response to treatment, and diabetes patients usually have their HbA1c measured only every 6 months.

Importantly, fructosamine and glycated albumin reflect short-term, 2- to 4-week glycemic control. "They will change far more rapidly in response to changes in treatment," Dr. Selvin said.

Fructosamine, Glycated Albumin, in Addition to HbA1c?

For the study, Dr. Selvin and colleagues with the University of Wisconsin and University of Minnesota measured glycated albumin and fructosamine in the blood samples of 11,348 adults without diabetes and 958 adults diagnosed with diabetes mellitus, types 1 and 2, who were participants in the Atherosclerosis Risk in Communities (ARIC) study in 1990 through 1992.

Over the course of a 20-year follow-up, the adjusted hazard ratios (HR) for the incidence of diabetes were 4.96 among patients whose fructosamine levels were above the 95th percentile and 6.17 for patients whose glycated albumin was above the 95th percentile.

The associations were similar after adjustment for HbA1c.

Fructosamine and glycated albumin were both strongly associated with retinopathy (P < .0001 for trend).

Among those with fructosamine and glycated-albumin levels above the 95th percentile, multivariable-adjusted hazard ratios for chronic kidney disease were 1.50 and 1.48, respectively, in comparison to those with no diabetes and fructosamine or glycated-albumin levels below the 75th percentile.

"Our findings suggest that fructosamine or glycated-albumin testing could add complementary information to HbA1c, and these tests might be particularly useful in settings where HbA1c testing or interpretation is problematic or in research settings where whole-blood samples are not available (fructosamine and glycated albumin can be measured in serum or plasma)," the authors state.

Fructosamine Test Available but Albumin Not as Widespread

Fructosamine testing is currently available in many countries, including the United States, but the lack of long-term outcomes in patients with diabetes has prevented its widespread use.

And while glycated-albumin measurement is commonly used in Japan, an assay is not widely available elsewhere and there is no Food and Drug Administration–approved test in the United States.

Dr. Selvin couldn't comment on how the new findings could play a role in the introduction of a glycated-albumin assay in the United States. But she noted that the simplicity of the tests make them ideal for a clinical setting.

"These are straightforward tests and can be conducted on standard autoanalyzers," she said. "Fructosamine testing is already available in most major laboratories, but it is simply not commonly used."

In an accompanying editorial, Robert M. Cohen, MD, from the University of Cincinnati Medical Center, Ohio, and William H. Herman, MD, from the University of Michigan, Ann Arbor, note that the important question that the research leaves open is how well the fructosamine and glycated-albumin tests will fare compared with HbA1c on the individual level.

"All 3 tests seem to work well in populations, especially for predicting complications, but it remains to be seen how well they perform in individuals, especially for the diagnosis of diabetes," they say, adding that "it will not always be obvious for whom these indirect measures of average glycemia do not work."

More Measures Should Improve Clinical Practice

The editorialists add that more work is required. "Studying the glycation gap, a measure of discordance between HbA1c and glycated serum proteins, provides one strategy for examining consistency among these measures and in highlighting areas where further research needs to be done.

"In the meantime, as multiple indirect tests allowing measurement of average glycemia enter clinical practice, clinicians will need to use multiple sources of information to assess glycemia and maintain a high index of suspicion when an indirect measure does not seem correct."

Ultimately, the availability of more glycemic measures should only improve clinical practice, they add, noting that clinicians "should not be afraid to employ multiple measures of glycemic control.

"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 glycemia disagree."

The study received funding from the National Heart, Lung, and Blood Institute. The authors have reported no relevant financial relationships. Drs. Cohen and Herman received grant support from the US Department of Veterans Affairs and the National Institute of Diabetes and Digestive and Kidney Diseases.

Lancet Diabetes Endocrinol . Published online January 15, 2014. Abstract Editorial

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