Algorithm Improves Diagnostic Value of HbA1c

STOCKHOLM – Use of a “rule-in” hemoglobin A_1c 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 hemoglobin A_1c. Multiple studies have shown that the 6.5% cutoff may be discordant with the results of an oral glucose tolerance test (OGTT), which is considered to be the standard diagnostic test for type 2 diabetes, said Dr. Samiul A. Mostafa, a clinical research fellow in the diabetes research unit of the University of Leicester (England).

In July 2009, an international expert committee recommended the use of hemoglobin A_1c for diagnosing diabetes, with a diagnostic cutoff of 6.5% or above following a repeat confirmatory A_1c test (Diabetes Care 2009;32:1327-34). In January 2010, the American Diabetes Association endorsed that recommendation (Diabetes Care 2010;33[suppl. 1]:S62-9). The European Association for the Study of Diabetes 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 from Pakistan, Bangladesh, and India. The mean HbA_1c for the entire cohort was 5.7%. All underwent an OGTT and also had their HbA_1c levels measured. Using 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 individuals (3.3% of 8,696 study participants) with type 2 diabetes.

Among the white Europeans, use of the 6.5% A_1c cutoff had a sensitivity of 62% and a positive predictive value of 45%. Based on an Australian study published earlier this year, the investigators chose to compare those values with a rule-out A_1c 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 HbA_1c,” 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 HbA_1c group (55% of the total cohort) had A_1c values between 5.6% and 6.4% (that is, lower than 6.5%), 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 HbA_1c” category when defined as an HbA_1c 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 ethnicities. 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.

Dr. Mostafa stated that he had no disclosures.

View on the News

Blood Glucose Tests Are Still Crucial

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 A_1c 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 HbA_1c, regardless of the level.

Similarly, there are people whose degree of hemoglobin glycation is lower than average. Thus, if there is clinical reason to look for diabetes, it is reasonable to perform glucose tolerance testing even with rather low HbA_1c levels.

Given this inherent variability in glycation, just as the 6.5% diagnostic cutoff is incorrect for many persons whose diabetes status is being ascertained, the use of a specific HbA_1c goal of, say, 6.5% or 7.0%, may not be appropriate for all patients with known diabetes. Again, assessment of actual blood glucose levels is crucial in the management of diabetes.

ZACHARY T. BLOOMGARDEN, M.D., of the Mount Sinai School of Medicine in New York, is on the speakers bureau for Merck, Novo Nordisk, and GlaxoSmithKline; serves on an advisory panel for Merck, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, and Biodel; is a consultant for Merck, Novartis, Dainippon Sumitomo Pharma America, and Forest Laboratories; and is a stock shareholder of Covidien, C.R. Bard, Novartis, Roche, and Stryker Corp.

STOCKHOLM – Use of a “rule-in” hemoglobin A_1c 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 hemoglobin A_1c. Multiple studies have shown that the 6.5% cutoff may be discordant with the results of an oral glucose tolerance test (OGTT), which is considered to be the standard diagnostic test for type 2 diabetes, said Dr. Samiul A. Mostafa, a clinical research fellow in the diabetes research unit of the University of Leicester (England).

In July 2009, an international expert committee recommended the use of hemoglobin A_1c for diagnosing diabetes, with a diagnostic cutoff of 6.5% or above following a repeat confirmatory A_1c test (Diabetes Care 2009;32:1327-34). In January 2010, the American Diabetes Association endorsed that recommendation (Diabetes Care 2010;33[suppl. 1]:S62-9). The European Association for the Study of Diabetes 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 from Pakistan, Bangladesh, and India. The mean HbA_1c for the entire cohort was 5.7%. All underwent an OGTT and also had their HbA_1c levels measured. Using 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 individuals (3.3% of 8,696 study participants) with type 2 diabetes.

Among the white Europeans, use of the 6.5% A_1c cutoff had a sensitivity of 62% and a positive predictive value of 45%. Based on an Australian study published earlier this year, the investigators chose to compare those values with a rule-out A_1c 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 HbA_1c,” 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 HbA_1c group (55% of the total cohort) had A_1c values between 5.6% and 6.4% (that is, lower than 6.5%), 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 HbA_1c” category when defined as an HbA_1c 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 ethnicities. 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.

Dr. Mostafa stated that he had no disclosures.

View on the News

Blood Glucose Tests Are Still Crucial

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 A_1c 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 HbA_1c, regardless of the level.

Similarly, there are people whose degree of hemoglobin glycation is lower than average. Thus, if there is clinical reason to look for diabetes, it is reasonable to perform glucose tolerance testing even with rather low HbA_1c levels.

Given this inherent variability in glycation, just as the 6.5% diagnostic cutoff is incorrect for many persons whose diabetes status is being ascertained, the use of a specific HbA_1c goal of, say, 6.5% or 7.0%, may not be appropriate for all patients with known diabetes. Again, assessment of actual blood glucose levels is crucial in the management of diabetes.

ZACHARY T. BLOOMGARDEN, M.D., of the Mount Sinai School of Medicine in New York, is on the speakers bureau for Merck, Novo Nordisk, and GlaxoSmithKline; serves on an advisory panel for Merck, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, and Biodel; is a consultant for Merck, Novartis, Dainippon Sumitomo Pharma America, and Forest Laboratories; and is a stock shareholder of Covidien, C.R. Bard, Novartis, Roche, and Stryker Corp.

STOCKHOLM – Use of a “rule-in” hemoglobin A_1c 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 hemoglobin A_1c. Multiple studies have shown that the 6.5% cutoff may be discordant with the results of an oral glucose tolerance test (OGTT), which is considered to be the standard diagnostic test for type 2 diabetes, said Dr. Samiul A. Mostafa, a clinical research fellow in the diabetes research unit of the University of Leicester (England).

In July 2009, an international expert committee recommended the use of hemoglobin A_1c for diagnosing diabetes, with a diagnostic cutoff of 6.5% or above following a repeat confirmatory A_1c test (Diabetes Care 2009;32:1327-34). In January 2010, the American Diabetes Association endorsed that recommendation (Diabetes Care 2010;33[suppl. 1]:S62-9). The European Association for the Study of Diabetes 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 from Pakistan, Bangladesh, and India. The mean HbA_1c for the entire cohort was 5.7%. All underwent an OGTT and also had their HbA_1c levels measured. Using 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 individuals (3.3% of 8,696 study participants) with type 2 diabetes.

Among the white Europeans, use of the 6.5% A_1c cutoff had a sensitivity of 62% and a positive predictive value of 45%. Based on an Australian study published earlier this year, the investigators chose to compare those values with a rule-out A_1c 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 HbA_1c,” 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 HbA_1c group (55% of the total cohort) had A_1c values between 5.6% and 6.4% (that is, lower than 6.5%), 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 HbA_1c” category when defined as an HbA_1c 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 ethnicities. 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.

Dr. Mostafa stated that he had no disclosures.

View on the News

Blood Glucose Tests Are Still Crucial

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 A_1c 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 HbA_1c, regardless of the level.

Similarly, there are people whose degree of hemoglobin glycation is lower than average. Thus, if there is clinical reason to look for diabetes, it is reasonable to perform glucose tolerance testing even with rather low HbA_1c levels.

Given this inherent variability in glycation, just as the 6.5% diagnostic cutoff is incorrect for many persons whose diabetes status is being ascertained, the use of a specific HbA_1c goal of, say, 6.5% or 7.0%, may not be appropriate for all patients with known diabetes. Again, assessment of actual blood glucose levels is crucial in the management of diabetes.

ZACHARY T. BLOOMGARDEN, M.D., of the Mount Sinai School of Medicine in New York, is on the speakers bureau for Merck, Novo Nordisk, and GlaxoSmithKline; serves on an advisory panel for Merck, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, and Biodel; is a consultant for Merck, Novartis, Dainippon Sumitomo Pharma America, and Forest Laboratories; and is a stock shareholder of Covidien, C.R. Bard, Novartis, Roche, and Stryker Corp.