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identification of Those at Risk for Diabetes Mellitus (HbA1c): (Commentary)
  Can Comparative Effectiveness Research Provide the Answer?
American Journal of Preventive Medicine
January 2011
Daniela Geba, MD, Thomas A. Pearson, MD, MPH, PhD From the Rochester Clinical and Translational Research institute (Geba, Pearson), and the Department of Community and Preventive Medicine (Pearson), University of Rochester Medical Center, Rochester, New York
impaired fasting glucose (iFG) and impaired glucose tolerance (iGT) were formally recognized as risk factors for diabetes in 1997, when they were included in the updated classification of hyperglycemic conditions.1 Collectively labeled as prediabetes, these categories include individuals whose fasting or stimulated glucose levels are above the normal limit but below the diabetes criterion levels. Encouraging consistent results from clinical trials showing lifestyle changes and pharmacologic intervention as efficacious in preventing, or at least in delaying the development of, diabetes in similar people have been published soon thereafter.2, 3, 4 Now, more than a decade later, 57 million U.S. adults, who represent about 29.5% of the entire adult population, are considered prediabetics, or at risk to develop type 2 diabetes,5 with age, racial, and ethnic subgroups having substantially higher prevalence rates. From the limited data available, it is estimated that, despite the existence of screening recommendations, only a small percentage of these individuals are aware of their status,6 and, among them, only a limited number receive interventions to prevent progression to diabetes and its complications.
The addition of the hemoglobin A1c (HbA1c) assay to the panel of glycemic measures used for screening and diagnosis of diabetes as proposed by the international Expert Committee in 20097 has drawn considerable attention. Although an HbA1c level of 6.5% or greater was clearly stated as a diabetes diagnostic criterion, the recommendations for prediabetes were less precise, as a reflection of still accumulating evidence that the risk of diabetes complications is a continuum along the HbA1c values lower than 6.5%, without a clear threshold. Although aggressive treatment with proven cost-effective interventions to prevent disease development was recommended for individuals with HbA1c levels between 6.0% and 6.5%, no clear recommendations were made for those with HbA1c levels lower than 6.0%, implying that the use of preventive interventions in this group should be guided by other risk determinants. However, analysis8 of data from the National Health and Nutrition Examination Survey (NHANES) has shown that only 10% of the individuals traditionally considered to have prediabetes, based on iFG and/or iGT, are identified by restricting the HbA1c screening criteria to the 6.0%-6.5% range. Even a more inclusive HbA1c range of 5.7%-6.5%, as suggested in an American Diabetes Association 2010 position statement,9 fails to categorize as such three quarters of the cases of prediabetes defined by other criteria.10 These results explain the concerns expressed lately regarding the use of HbA1c for screening, as a large percentage of the individuals otherwise identifiable as having prediabetes by traditional methods would be classified as normal and would not receive preventive interventions.
in this issue of the American Journal of Preventive Medicine, Ackermann et al.11 examine the use of the HbA1c assay for prediabetes screening from a population perspective. Using data from the 2005-2006 NHANES and a previously published prediction model, the authors have calculated the risk of developing diabetes over a period of 7.5 years for the entire 5.0%-6.5% range, providing the results for 0.1% increments of HbA1c. Of individuals with HbA1c levels between 6.0% and 6.5%, more than half (56%) are likely to develop diabetes during the follow-up period, whereas 41% of those in the 5.7%-6.5% range are at risk. The authors suggest caution in interpretation of the results, as the risk estimations were calculated based on a mathematical model using cross-sectional data rather than prospective incidence rates. Moreover, the model for diabetes risk used has been developed based on data from a cohort with a different ethnic composition than the general U.S. population12 and has not been validated so far in other populations.
However, the results presented by Ackermann and colleagues11 are consistent with those from a systematic review13 of 16 prospective studies examining the risk of developing diabetes according to HbA1c levels published recently. Although obtained using different methods in different populations, the studies generally agree that the risk of developing diabetes increases progressively with the HbA1c level above 5.0% and also that roughly half of the individuals with HbA1c levels between 6.0% and 6.5% will develop diabetes over the next 5-7 years. Using HbA1c assay for risk stratification among those with prediabetes would therefore allow the tailoring of the preventive measures according to each individual's risk level, with potentially positive effects on cost effectiveness.
The more optimistic view shared by those who propose the use of HbA1c as a risk-stratification tool rather than a simple screening method is based on the limitations of iFG and iGT in defining diabetes risk and guiding preventive interventions. First, the prediabetes category, which includes a very large proportion of the U.S. adult population, is extremely heterogeneous regarding the actual risk of developing diabetes, and implementation of the same preventive measures for all individuals would prove cost prohibitive, if not logistically impossible. Second, some characteristics of the actual tests, such as the requirement for a fasting blood sample or the need for repeated phlebotomies, negatively affect the screening rate. Although the use of HbA1c will identify fewer individuals, the concomitant risk estimation would permit a tailoring of the preventive measures, and possibly a more efficient use of already limited resources. Further, convenience for the screened individuals and familiarity of the clinicians with the assay-key factors for the implementation of any screening guidelines-have the potential to increase screening rates. Additionally, as HbA1c appears to be an as good, or a better, predictor of diabetes complications as the other glycemic measures,14 targeting individuals with higher HbA1c levels for aggressive interventions may result in long-term reduction of complications.
Although cross-sectional studies as such that of Ackermann et al.11 and prospective studies13 provide observational evidence for a role of HbA1c in diabetes screening, is it actually superior to traditional tests (fasting blood glucose, 2-hour postprandial glucose) in multiple subgroups and in real clinical settings? Do the convenience of a nonfasting sample and the familiarity of clinicians with HbA1c translate into higher rates of detection of people with prediabetes and their inclusion in prevention programs? Are there meaningful differences in the laboratory and clinical costs of the alternative strategies? These questions of HbA1c versus traditional screening tests seem appropriate for comparative effectiveness research to inform patients and their healthcare providers about the best strategy to use in typical clinical settings and in their demographic group, in order to identify those who would benefit from interventions proven to prevent diabetes. indeed, conventional versus intensive interventions in the medical management of diabetes was one of the 100 priority topics of the iOM report on Comparative Effectiveness Research, based on the magnitude of the burden of the human, economic, and healthcare costs of diabetes in the U.S.15
The recent increase in knowledge pertaining to the prevention of type 2 diabetes has not been translated into a reduction in the prevalence of diabetes thus far. For diabetes prevention, the optimization of the screening process to identify the high-risk beneficiary of an intervention must be part of the overall strategy. The identification of efficacious and cost-effective screening methods that compare favorably to alternate strategies is essential to any comprehensive approach to reducing the relentlessly growing burden of this disease.
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