David C. Ziemer, MD, MPH; Paul Kolm, PhD; William S. Weintraub, MD; Viola Vaccarino, MD, PhD; Mary K. Rhee, MD, MS; Jennifer G. Twombly, MD, PhD; K.M. Venkat Narayan, MD, MPH, MBA; David D. Koch, PhD; Lawrence S. Phillips, MD
Portions of this work were presented at the 68th Scientific Sessions of the American Diabetes Association, San Francisco, California, 6–10 June 2008.
Acknowledgment: The authors thank Kirsten Herric, MSc, for the NHANES III weighted analyses and Jane Caudle, Circe Tsui, Jack Kaufman, Eileen Osinski, Jade Irving, Rincy Varughese, and Lennisha Pinckney for their assistance.
Grant Support: By the National Institutes of Health and National Center for Research Resources (awards DK07298, DK062668, RR017643, DK066204, and RR00039) and U.S. Department of Veterans Affairs Health Services Research and Development Service (awards SHP 08-144 and IIR 07-138).
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1619.
Reproducible Research Statement:Study protocol: Not available. Statistical code: Code for weighted analyses available from Dr. Ziemer (e-mail, email@example.com). Data set: Collaborative data sharing available from Dr. Phillips (e-mail, firstname.lastname@example.org).
Corresponding Author: David C. Ziemer, MD, MPH, Division of Endocrinology, Emory University, 49 Jesse Hill Jr. Drive SE, Atlanta, GA 30303.
Current Author Addresses: Drs. Ziemer and Rhee: Division of Endocrinology, Emory University, 49 Jesse Hill Jr. Drive SE, Atlanta, GA 30303.
Drs. Kolm and Weintraub: Christiana Care Health System, 130 Continental Drive, Suite 202, Newark, DE 19713.
Dr. Vaccarino: Emory University School of Medicine, Emory Program in Cardiovascular Outcomes Research and Epidemiology (EPICORE), 1256 Briarcliff Road, Building A, Suite 1 N, Atlanta, GA 30306.
Drs. Twombly and Phillips: Division of Endocrinology, Emory University, 101 Woodruff Circle, Woodruff Memorial Research Building, Room 1027, Atlanta, GA 30322.
Dr. Narayan: School of Public Health, Emory University, 1518-002-7AA (SPH: Global Health), Grace C. Rollins Building 730, Atlanta, GA 30322.
Dr. Koch: Grady Clinical Laboratory, D-119, Grady Health System, 80 Jesse Hill Jr. Drive SE, Atlanta, GA 30303.
Author Contributions: Conception and design: D.C. Ziemer, P. Kolm, K.M.V. Narayan, L.S. Phillips.
Analysis and interpretation of the data: D.C. Ziemer, P. Kolm, W.S. Weintraub, V. Vaccarino, J.G. Twombly, K.M.V. Narayan, D.D. Koch, L.S. Phillips.
Drafting of the article: D.C. Ziemer, J.G. Twombly.
Critical revision of the article for important intellectual content: D.C. Ziemer, P. Kolm, W.S. Weintraub, V. Vaccarino, M.K. Rhee, J.G. Twombly, K.M.V. Narayan, L.S. Phillips.
Final approval of the article: D.C. Ziemer, P. Kolm, W.S. Weintraub, V. Vaccarino, M.K. Rhee, J.G. Twombly, K.M.V. Narayan, D.D. Koch, L.S. Phillips.
Provision of study materials or patients: V. Vaccarino, L.S. Phillips.
Statistical expertise: D.C. Ziemer, P. Kolm, V. Vaccarino.
Obtaining of funding: D.C. Ziemer, W.S. Weintraub, L.S. Phillips.
Administrative, technical, or logistic support: D.C. Ziemer, V. Vaccarino, L.S. Phillips.
Collection and assembly of data: D.C. Ziemer, W.S. Weintraub, D.D. Koch, L.S. Phillips.
Ziemer D., Kolm P., Weintraub W., Vaccarino V., Rhee M., Twombly J., Narayan K., Koch D., Phillips L.; Glucose-Independent, Black–White Differences in Hemoglobin A1c Levels: A Cross-sectional Analysis of 2 Studies. Ann Intern Med. 2010;152:770-777. doi: 10.7326/0003-4819-152-12-201006150-00004
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Published: Ann Intern Med. 2010;152(12):770-777.
A previous study of participants with prediabetes found that hemoglobin A1c (HbA1c) levels differed between black and white participants with no differences in glucose concentration.
To determine whether blackâ€“white differences in HbA1c level are present in other populations and across the full spectrum of glycemia.
1581 non-Hispanic black and white participants between 18 and 87 years of age without known diabetes in the SIGT (Screening for Impaired Glucose Tolerance) study and 1967 non-Hispanic black and white participants older than 40 years without known diabetes in the NHANES III (Third National Health and Nutrition Examination Survey).
HbA1c levels, anthropometry, and plasma glucose levels during oral glucose tolerance testing.
Hemoglobin A1c levels were higher in black than in white participants with normal glucose tolerance (0.13 percentage point [PÂ < 0.001] in the SIGT sample and 0.21 percentage point [PÂ < 0.001] in the NHANES III sample), prediabetes (0.26 percentage point [PÂ < 0.001] and 0.30 percentage point [PÂ < 0.001], respectively), or diabetes (0.47 percentage point [PÂ < 0.020] and 0.47 percentage point [PÂ < 0.013], respectively) after adjustment for plasma glucose levels and other characteristics known to correlate with HbA1c levels.
The mechanism for the differences is unknown.
Black persons have higher HbA1c levels than white persons across the full spectrum of glycemia, and the differences increase as glucose intolerance worsens. These findings could limit the use of HbA1c to screen for glucose intolerance, indicate the risk for complications, measure quality of care, and evaluate disparities in health.
National Institutes of Health and National Institute of Diabetes, Digestive, and Kidney Diseases.
Rajasree Pai Ramachandra Pai
University of connecticut, Farmington
June 25, 2010
A1c is not the number 1
Apparently, a lot of emphasis is placed on monitoring hba1c levels for glycemic control and even for diagnosis as per the 2010 ADA guidelines. It would be interesting to know whether A1c is influenced by age/gender/medical comorbidities with the same blood glucose levels. In the current clinical scenario, most physicians are chasing the A1c for glycemic control and on the verge of neglecting finger stick checks in the outpatient clinic.
David M. Nathan
MGH Diabetes Center
August 13, 2010
Is the Relationship between HbA1c and Mean Glucose Levels Different by Race: A Call for Scientifically Valid Studies
To the Editor: The glycated hemoglobin assay has been widely accepted as an objective index of chronic glycemia, is universally used for diabetes management (1), and has now been recommended for diagnosis (2). The mathematical relationship between HbA1c and mean glucose levels was established in the 1980s by small studies that compared self-monitored glucose levels during a 5-8 week period and HbA1c measured at the end of that period (1). Recent studies have used more comprehensive measures, such as continuous glucose monitoring, to determine the relationship (3, 4). These studies have demonstrated relatively high correlation coefficients (R> 0.9) compared with previous studies with less frequent monitoring, emphasizing the need for comprehensive measures of glucose to capture true mean glycemia and accurately determine the relationship between mean glucose levels and HbA1c. The largest such study was the A1c-Derived Average Glucose (ADAG) study. (4) Unfortunately, ADAG only included 8% of its population as Africans or African-Americans (AA) and power was limited to appreciate whether the relationship between mean glucose and HbA1c differed among races. The difference in regression lines of mean glucose on HbA1c between the non-hispanic white and AA cohorts had a P-value of 0.07. At the low (diagnostic) end of the glycemic spectrum, HbA1c for a comparable mean glucose level was minimally higher (<0.13) for AA than NHW. This borderline significant difference between races in the relationship between mean glucose and HbA1c has been used to support the notion that HbA1c levels are different for comparable levels of mean glycemia in different races (5). Several cross-sectional studies, including the study by Ziemer et al. (6), have been published supporting this conclusion; however, without exception, they have relied on extremely limited glucose measurements, ranging from a single timed glucose level to a single glucose tolerance test, to measure "mean glucose." All of these studies ignore the well -recognized variability in intra-patient, inter-day glucose values and the possibility that sampling error might explain their findings. Specifically, none of the investigators have considered that glucose levels during every-day existence might differ between different racial groups, independent of the limited glucose levels on the day of testing. There is a clear need to determine whether there is a difference by race in the relationship between mean glucose levels and HbA1c and, if true, the magnitude of the difference and its clinical relevance. A study measuring glucose levels frequently enough to capture mean glucose levels with confidence, such as ADAG, but including a large representation from different races is necessary to address this issue satisfactorily. Until then, the current studies are neither scientifically valid nor compelling.
1. Nathan DM, Singer DE, Hurxthal K, Goodson JD. The clinical information value of the glycosylated hemoglobin assay. N Engl J Med 1984; 310:341-346.
2. Nathan DM, Balkau B, Bonora E, Borch-Johnsen K, Buse JB, Colagiuri S, Davidson MB, et al.. for the International Expert Committee on the Diagnosis of Diabetes. International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes. Diabetes Care 2009; 32: 1327-1334.
3. Nathan DM, Turgeon H, Regan S. Relationship between glycated haemoglobin levels and mean glucose levels over time. Diabetologia 2007; 50:2239-44. 4. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ for the A1c Derived Average Glucose (ADAG) Study Group. Translating the A1c assay into estimated average glucose values. Diabetes Care 2008; 31: 1473-8.
5. Herman WH, Cohen RM. Hemoglobin A1c: teaching a new dog old tricks. Ann Int Med 2010;152: 815-817.
6. Ziemer DC, Kolm P, Weintraub WS, Vaccarino V, Rhee MK, Twombly JG, Naray, Koch DD, Phillips LSan V. Glucose-independent, black-white differences in hemoglobin A1c levels. Ann Int Med 2010;152:770-7.
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