Clinical Laboratory Strategies: May 13, 2010

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Defining HbA1c's Role in Non-Diabetics
Will This Measurement Become a Risk Assessment Tool for all Adults?
By Genna Rollins


Hemoglobin A1c (HbA1c) increasingly has been recognized as an important tool in monitoring, and more recently, diagnosing, diabetes. Now, new research explores the role of HbA1c in predicting mortality and risk of developing diabetes and cardiovascular disease in a non-diabetic population. The findings are the subject of this issue of Strategies.


Since the landmark Diabetes Control and Complications Trial (DCCT) in 1993 showed that tight glycemic control, measured by decreases in HbA1c levels, lowered the risk of microvascular disease in type 1 diabetes, the body of evidence about a broader role for HbA1c has grown substantially. Most recently, based on accumulated research findings and improved standardization of the HbA1c assay, the American Diabetes Association (ADA) in January endorsed using HbA1c to diagnose type 2 diabetes when testing is performed by a laboratory method certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the DCCT assay. Now a new study has opened the door to a potential role for HbA1c in nondiabetics. The research linked rising HbA1c levels to increasing risk of death and of developing diabetes and cardiovascular disease in nondiabetic adults (N Engl J Med 2010;362:800-11).

“We found that glycated hemoglobin is an extraordinary predictor of who will develop diabetes, and it’s also a marker for cardiovascular disease,” observed lead author, Elizabeth Selvin, PhD, MPH, assistant professor of epidemiology and medicine at the Welch Center for Prevention, Epidemiology and Clinical Research at the Johns Hopkins University Bloomberg School of Public Health in Baltimore. “Our results can help health providers think about how to use the glycated hemoglobin test results among people who don’t have apparent diabetes.”

Selvin and her colleagues analyzed whole blood samples from 11,092 participants in the Artherosclerosis Risk in Communities (ARIC) Study, a community-based prospective trial designed to investigate the etiology and natural history of atherosclerosis and atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, sex, location, and date. ARIC participants had examinations approximately every 3 years, and from the second visit, which took place between 1990 and 1992, Selvin’s research team was able to use stored whole-blood samples to measure HbA1c. These measurements served as the baseline for the study. The research team thawed and assayed the samples using high-performance liquid chromatography with instruments standardized to the DCCT assay. In addition, fasting glucose, plasma lipids, body mass index, waist-to-hip ratio, and blood pressure were measured at the time of each participant’s second visit. Diabetes was defined either based on glucose measurements, patient-reported diagnosis of diabetes, or use of diabetic medications. The median follow-up time was 14 years.

The researchers found a graded relationship between rising HbA1c levels and risk of diabetes. The cumulative incidence of diagnosed diabetes was 6%, 12%, 21%, 44%, and 79% among subjects with HbA1c levels <5%, between 5 and <5.5%, 5.5 and <6.0%; 6% and <6.5%, and ≥6.5%, respectively. They also observed significant trends for rising risk of coronary heart disease, stroke, and all-cause mortality given higher levels of baseline HbA1c, associations that persisted even after adjustment for fasting glucose. For instance, in comparison to the reference group with HbA1c values of 5.0% to <5.5%, hazard ratios for developing coronary heart disease were 0.96, 1.23, 1.78, and 1.95 among individuals with HbA1c values <5%, between 5.5 and <6.0%, 6.0% to <6.5%, and ≥6.5%, respectively. Hazard ratios for ischemic stroke were similar.

The researchers also explored associations among three categories of HbA1c levels (<6%, 6% to <6.5%, and ≥6.5%) and risk of outcomes in participants stratified according to three fasting glucose groups (<100, 100 to <126, and ≥126 mg/dL). They found that for HbA1c values <6%, fasting glucose levels were not significantly associated with coronary heart disease, ischemic stroke, or death from any cause, but for the HbA1c categories of 6% to <6.5% and ≥6.5% there was a significant association with all outcomes in each fasting glucose category. “Overall, our data show that glycated hemoglobin values greater than six percent can be a useful marker of people at risk not only for future diabetes but also all-cause mortality and cardiovascular disease,” said Selvin.

One curious finding was an increased risk of all-cause mortality among participants with lowest HbA1c values <5%. In comparison to those with HbA1c values between 5% and <5.5% these individuals had odds ratios of 1.43-1.48 depending on the multivariate model used. “It’s a very interesting finding that deserves further study. It’s been observed in a number of other studies and there’s an open question about whether it’s  related to a low glycemic state or glycated hemoglobin values specifically,” according to Selvin.

Similar to other studies, Selvin and her colleagues also detected higher baseline HbA1c values in blacks compared to whites. While race did not change the associations between HbA1c values and cardiovascular outcomes or death, blacks were significantly less likely than whites to report a diagnosis of diabetes across all HbA1c categories. “The important thing we show is that higher glycated hemoglobin values in blacks represent higher risk, so these data suggest it’s not an artifact. There have been calls for race-specific glycated hemoglobin values, but I think that’s clearly premature,” said Selvin. “What we saw is a significant difference in the probability of being diagnosed with diabetes, but that probably has more to do with delays in diagnosis than in the biology of glucose homeostasis.”

The study underscores the importance of the role of labs in measuring HbA1c, according to Randie Little, PhD, associate professor and director of the diabetes diagnostic lab at the University of Missouri School of Medicine in Columbia and NGSP lab network coordinator. “The results indicate that glycated hemoglobin is really useful and we need to be measuring it very carefully at the lower levels. That normal range is really important and it’s an indicator for risk, not just for diabetes, but other things,” she said. “Accuracy of the measurement still needs to be improved. We need to keep making it better, which is what we’re trying to do in terms of tightening the criteria for method certification.”

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