Major Finding: A rule-out value of 5.8% or below and a rule-in value of 6.8% or above reduced the size of the “impaired HbA1c” category from 55% to 28% of the cohort.
Data Source: A study of 8,696 adults identified from two systematic screening programs during 2002-2008.
Disclosures: Dr. Mostafa stated that he had no relevant financial disclosures.
STOCKHOLM — Use of a “rule-in” hemoglobin A1c cut point of 6.8% and a “rule-out” value of 5.8%, with glucose testing for individuals who fall in the middle of the diagnostic cutoff, was more accurate in diagnosing type 2 diabetes than was a single cutoff value of 6.5%.
The finding from a multiethnic cohort study of 8,696 previously undiagnosed primary care patients addresses some of the concerns about false-positive and false-negative diagnoses associated with using a single measure of HbA1c. Multiple studies have shown that the 6.5% cutoff can conflict with the results of an oral glucose tolerance test (OGTT), said Dr. Samiul A. Mostafa, a clinical research fellow in the diabetes research unit of the University of Leicester (England).
Last year, an international expert committee recommended the use of HbA1c for diagnosing diabetes, with a cutoff of 6.5% or above following a repeat confirmatory HbA1c test. In January, the American Diabetes Association endorsed that recommendation. The EASD and the World Health Organization are expected to issue similar statements soon.
The study participants were identified from two systematic screening programs during 2002-2008. Three-quarters (75%) were white Europeans and 23% were South Asians. The mean HbA1c for the entire cohort was 5.7%. All underwent an OGTT and also had their HbA1c levels measured. With the WHO criteria (a 2-hour plasma glucose level of 200 mg/dL or above, following a 75-g glucose load), the OGTT detected 291 persons (3.3% of 8,696 study participants) with type 2 diabetes.
Among the white Europeans, use of the 6.5% HbA1c cutoff had a sensitivity of 62% and a positive predictive value of 45%. The investigators compared those values with a rule-out cutoff of 5.5% and a rule-in cutoff of 7.0%, with a confirmatory OGTT used for those falling in between (Diabetes Care 2010;33:817-9).
That method gave an improved sensitivity of 98% and positive predictive value of 76% in the white European group. With either method, specificity and negative predictive values were close to 100%. For the South Asians, the 6.5% cutoff gave a sensitivity of 79% and positive predictive value of 36%, both of which improved to 99% and 68%, respectively, with the two–cut-point criteria. Again, specificity and negative predictive values were strong with either method, Dr. Mostafa reported.
“Impaired HbA1c,” the term used for the values between the two cutoffs (5.6%-6.9%), was found in 59% of the total cohort, who thus required confirmatory tests. Noting that those in the impaired HbA1c group (55% of the total cohort) had A1c values between 5.6% and 6.4%, they tried various cut points and arrived at a rule-out value of 5.8% or below and a rule-in value of 6.8% or above. That left 28% of the total cohort in the “impaired HbA1c” category when defined as an A1c of 5.9%-6.7%.
“We believe [a rule-out value of 5.8% and a rule-in value of 6.8%] would be a more feasible strategy to implement in clinical practice,” Dr. Mostafa said.
These cutoffs gave sensitivities of 92% for white Europeans and 98% for South Asians, and positive predictive values of 70% and 54%, respectively, while maintaining the nearly 100% specificity and negative predictive values for both groups. Despite the slight reductions in positive predictive values, “overall, we feel using the cut points of 5.8% and 6.8% is still diagnostically accurate, with the major advantage that only a quarter of the population would have to return for a subsequent test,” he said.
In a final analysis, the investigators looked at mean HbA1c values in various undiagnosed populations. Compared with the U.K. cohort's mean of 5.7%, the Australian cohort had a mean of 5.1%, which resulted in 24% falling into their 5.6%-6.9% “impaired HbA1c” category. That led to the hypothesis that broader cut points are acceptable when mean HbA1c is relatively low, but a tighter range is required when mean HbA1c is higher.
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Glucose Testing Should Continue to Play a Role in Diagnosing Diabetes
This study assesses a strategy that I think is quite reasonable, and was suggested in the American Association of Clinical Endocrinologists' position statement a number of months ago.
One must recognize that a “negative” hemoglobin A1c level (below 6.5%) misses from one-third to one-half of those with diabetes by glucose tolerance test criteria, whereas a “positive” value (6.5% or greater) may not be the result of diabetes in persons who have greater degrees of hemoglobin glycation. Because high glycation is present in blacks, older populations, and people with iron deficiency, and also is a common variant in the overall population, I would even suggest that blood glucose confirmation – although not necessarily with glucose tolerance testing – should be done in all persons with high HbA1c, regardless of the level.