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Should the Hemoglobin A1c Diagnostic Cutoff Differ Between Blacks and Whites?: A Cross-sectional Study

Yusuke Tsugawa, MD, MPH; Kenneth J. Mukamal, MD, MPH; Roger B. Davis, ScD; William C. Taylor, MD; and Christina C. Wee, MD, MPH
[+] Article and Author Information

From Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Disclaimer: Dr. Tsugawa had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgment: The authors thank the National Center for Health Statistics for providing the data and Ms. Karen Huskey (Beth Israel Deaconess Medical Center) for her assistance with some of the statistical analyses.

Financial Support: Dr. Tsugawa is supported by the Shigeaki Hinohara, MD, Primary Care Fellowship at Beth Israel Deaconess Medical Center; the Joint Japan/World Bank Graduate Scholarship Program; and St. Luke's Life Science Institute, Tokyo, Japan. Dr. Davis is supported by Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Institutes of Health Award UL1 RR 025758), and financial contributions from Harvard University and its affiliated academic health care centers. Dr. Wee is supported by a midcareer mentorship award from the National Institutes of Health (K24DK087932).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2083.

Reproducible Research Statement:Study protocol: Not available. Statistical code: Available from Dr. Tsugawa (e-mail, ytsugawa@bidmc.harvard.edu). Data set: Available from the National Center for Health Statistics (www.cdc.gov/nchs/nhanes.htm).

Requests for Single Reprints: Yusuke Tsugawa, MD, MPH, Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Harvard Medical School, 1309 Beacon Street, Brookline, MA 02446; e-mail, ytsugawa@bidmc.harvard.edu.

Current Author Addresses: Drs. Tsugawa, Mukamal, Davis, Taylor, and Wee: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215.

Author Contributions: Conception and design: Y. Tsugawa, C.C. Wee, K.J. Mukamal, W.C. Taylor.

Analysis and interpretation of the data: Y. Tsugawa, K.J. Mukamal, R.B. Davis, C.C. Wee.

Drafting of the article: Y. Tsugawa, C.C. Wee.

Critical revision of the article for important intellectual content: Y. Tsugawa, K.J. Mukamal, R.B. Davis, W.C. Taylor, C.C. Wee.

Final approval of the article: Y. Tsugawa, K.J. Mukamal, R.B. Davis, W.C. Taylor, C.C. Wee.

Statistical expertise: R.B. Davis.

Administrative, technical, or logistic support: Y. Tsugawa.

Collection and assembly of data: Y. Tsugawa.


Ann Intern Med. 2012;157(3):153-159. doi:10.7326/0003-4819-157-3-201208070-00004
Text Size: A A A

Background: Hemoglobin A1c (HbA1c) levels are known to be consistently higher in black persons than in white persons at any given glycemic level. Whether the optimal diagnostic threshold of HbA1c should differ between blacks and whites is unclear.

Objective: To compare the relationships between HbA1c level and the prevalence of retinopathy in black and white U.S. adults.

Design: Cross-sectional study.

Setting: A nationally representative sample of the National Health and Nutrition Examination Survey from 2005 through 2008.

Patients: 2804 white persons and 1008 black persons aged 40 years or older in the United States.

Measurements: Prevalence of retinopathy. Logistic regression models and restricted cubic spline models were constructed separately for white and black populations to test the HbA1c levels at which risk for retinopathy begins to increase.

Results: After adjustment for age, sex, hypertension, body mass index, family history of diabetes, and use of antidiabetes medications or insulin, the lowest HbA1c category for which the prevalence of retinopathy was significantly higher than the reference category (<5.5%) was 6.0% to 6.4% for white persons (risk difference, 4.8% [95% CI, 0.5% to 9.1%]) and 5.5% to 5.9% for black persons (risk difference, 5.3% [CI, 1.0% to 9.5%]). The restricted cubic spline models indicated that the risk for retinopathy increased at lower HbA1c levels in black persons than in white persons.

Limitation: The cross-sectional design of the study precluded examining the effect of the duration at each HbA1c level.

Conclusion: The prevalence of retinopathy begins to increase at a lower HbA1c level in black Americans than in white Americans. The findings do not support increasing the diagnostic threshold of HbA1c in black persons.

Primary Funding Source: None.

Figures

Grahic Jump Location
Figure 2.

Receiver-operating characteristic curves of hemoglobin A1c for detecting the prevalence of retinopathy at each possible threshold in U.S. adults aged 40 years or older not treated for diabetes.

Adjusted for age, sex, hypertension, body mass index, and family history of diabetes.

Grahic Jump Location
Grahic Jump Location
Figure 1.

Results of restricted cubic spline models showing the association between hemoglobin A1c level and the probability of retinopathy in U.S. adults aged 40 years or older not treated for diabetes.

The lines represent the probability determined from restricted cubic spline models, with knots specified at hemoglobin A1c levels of 5.5%, 6.0%, 6.5%, and 7.0%.

Grahic Jump Location

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Should the Hemoglobin A1c Diagnostic Cutoff Differ Between Blacks and Whites?
Posted on August 10, 2012
Samuel Dagogo-Jack, MD, FRCP, FACP
University of Tennessee
Conflict of Interest: None Declared

Based on their analysis of the NHANES 2005-2008 data, Tsugawa et al. (1) report a retinopathy prevalence of 6.3% for white persons and 13.1% for black persons. Referenced to a control group with HbA1c levels <5.5%, Tsugawa et al. (1) report that white persons showed a significantly higher adjusted prevalence of retinopathy at HbA1c levels of 6.0% to 6.4% or higher, compared to HbA1c levels of 5.5% to 5.9% for black persons. This report (1) that African Americans develop “diabetic retinopathy” at lower HbA1c levels (and presumably lower glycemic burden) than whites suggests a leftward shift in the retinal toxicity curve for glycemic burden in blacks compared to whites. Among persons with diabetes, the higher relative risk for retinopathy in blacks compared to whites may be attributed to disparities in glycemic control, as it is abrogated by improved access to care (2).

Interpretation of the report by Tsugawa et al. (1) is complicated by the fact that African Americans and other ethnic groups have higher HbA1c levels compared to white persons at similar blood glucose levels (3). Contrary to the inaccurate assertion by Tsugawa et al. (1) that “the disparity in HbA1c level did not extend to other measures of glycemia, such as glycated albumin,” black/white differences exist in glycated albumin and other glycemic markers (4). In Fig. 1 of the report by Tsugawa et al. (1) the curves show no black/white difference in the probability of retinopathy at HbA1c levels of <5%, diverge between levels of ~5.5% and ~ 7.5%, and converge again at HbA1c levels >7.5%, with blacks showing a lower trend for retinopathy among persons with HbA1c > 8%. Such a pattern is inconsistent with physiological or clinical logic, or a process driven primarily by glycemia. The cross-sectional design does not allow assessment of cumulative exposure to hyperglycemia and the contribution of nonglycemic factors (e.g., blood pressure) to the findings by is Tsugawa et al. (1). The smaller number of blacks compared to whites in some of the HbA1c strata (255 vs. 1242 among persons with HbA1c <5.5%; 352 vs. 1034 among those with HbA1c 5.5-5.9%) also could affect validity of estimate.

Furthermore, lesions resembling “diabetic retinopathy” can be found in millions of healthy people (~3% of NHANES III population) with perfectly normal glucose values, and in nondiabetic persons with sickle cell disease (5). The natural history and prognosis of such lesions is unclear. Current understanding identifies sustained hyperglycemia as the etiological factor for diabetic retinopathy. The notion of lower HbA1c thresholds for bona fide diabetic retinopathy in African Americans can only be confirmed in a longitudinal study. Until then, the report by Tsugawa et al. (1) must be interpreted with caution, especially since they showed no independent interactions among HbA1c, retinopathy and race.

 References

1. Tsugawa Y, Mukamal KJ, Davis RB, Taylor WC, Wee CC. Should the hemoglobin A1c diagnostic cutoff differ between blacks and whites? A cross-sectional study. Ann Intern Med. 2012;157:153-159.

2. Karter AJ, Ferrara A, Liu JY, Moffet HH, Ackerson LM, Selby JV. Ethnic disparities in diabetic complications in an insured population. JAMA. 2002;287:2519-2527

3. Dagogo-Jack S. Pitfalls in the use of HbA1c as a diagnostic test: the ethnic conundrum.Nat Rev Endocrinol 2010; 6:589-593.

4. Selvin E, Steffes MW, Ballantyne CM, Hoogeveen RC, Coresh J, Brancati FL. Racialdifferences in glycemic markers: a cross-sectional analysis of community-based data.Ann Intern Med 2011;154:303-309.

5. Kennedy JJ, Clyde BC. Intraocular lesions associated with sickle-cell disease. Arch Ophthalmol. 1957;58:163-168.

 

Author's Response
Posted on September 20, 2012
Yusuke Tsugawa, MD, MPH, Kenneth J. Mukamal, MD, MPH, Christina C. Wee, MD, MPH
Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215
Conflict of Interest: None Declared

We thank Dr. Dagogo-Jack for his comments. We agree that the design of our study has important limitations --many of which we acknowledged in our paper—and that our results must be interpreted with appropriate caution. Our main conclusion was that our findings do not support increasing the diagnostic threshold of HbA1c in black persons, given that HbA1c values appear higher in blacks than in whites (1). While our study did suggest the possibility that the risk of retinopathy begins to increase at lower HbA1c in blacks compared to whites, we were cautious not to overinterpret these results and suggested future longitudinal studies with repeated measurements of HbA1c to confirm these findings (2). We agree that racial differences may exist in some other measures of glycemia including glycated albumin (3).In stating that the pattern of the relationship linking HbA1c level and retinopathy does not appear physiological, Dr. Dagogo-Jack may be overinterpreting the results of our restricted cubic spline models. Both multivariate regression models using HbA1c as a categorical variable and restricted cubic spline curves tended to corroborate our primary findings of similar non-linear associations between HbA1c and retinopathy in blacks and whites. Indeed, diagnostic thresholds for glycemia dichotomizing diabetes and non-diabetes have historically been based on (linear or curvilinear) relationships between glycemia level and risk of retinopathy (4). Our recent longitudinal study examining the association between HbA1c level and 3-year incidence of retinopathy also found a curvilinear relationship with an inflection point where the risk for retinopathy begins to increase (5).Dr. Dagogo-Jack also argues that the smaller number of blacks compared to whites could potentially affect the validity of our findings. Despite smaller numbers, the risk of retinopathy was significantly higher for blacks with HbA1c 5.5-5.9% (n=335) compared to HbA1c <5.5% (n=245); whereas white persons with same HbA1c category (n=995) did not exhibit higher risk compared with HbA1c <5.5% (n=1,232), even though the sample sizes were much larger for whites.Lastly, Dr. Dagogo-Jack argues that lesions resembling diabetic retinopathy can be found in those with normal glucose values. The risk of retinopathy (nor of other microvascular diseases) does not exhibit a dramatic increase once glucose levels surpass a certain threshold. Rather, risk increases continuously, with thresholds set at levels where risk tends to increase more notably (4). Hence, it is unsurprising for a subset of those with “normal” glucose levels to exhibit signs of diabetic retinopathy.

References

1. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-independent, black-white differences in hemoglobin A1c levels: a cross-sectional analysis of 2 studies. Ann Intern Med. 2010;152(12):770-7.

2. Tsugawa Y, Mukamal KJ, Davis RB, Taylor WC, Wee CC. Should the Hemoglobin A1c Diagnostic Cutoff Differ Between Blacks and Whites?: A Cross-sectional Study. Ann Intern Med. 2012;157(3):153-9.

3. Selvin E, Steffes MW, Ballantyne CM, Hoogeveen RC, Coresh J, Brancati FL. Racial Differences in Glycemic Markers: A Cross-sectional Analysis of Community-Based Data. Ann Intern Med. 2011;154(5):303-9.

4. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20(7):1183-97.

5. Tsugawa Y, Takahashi O, Meigs JB, et al. New Diabetes Diagnostic Threshold of Hemoglobin A1c and the 3-Year Incidence of Retinopathy. Diabetes. 2012.

Multiple Factors Modulating of blood HbA1C level and Diabetic retinopathy demands different cut of values in different racial groups
Posted on March 14, 2013
Kanjaksha Ghosh, MD
Institute of Immunohaematology
Conflict of Interest: None Declared

Comments of Dagogo Jack (1) on a paper published by Tsugawa et al (2) deserves detailed discussion.  Retinopathy is one of the important complication of diabetics, however the prevalence of this complication is not only dependent on degree of control of hypertension, viscosity of blood, ischaemic pathology in the retinal vasculature and over all other hormonal milieu like growth hormone levels.  Ateliotic dwarfs with diabetes do not develop diabetic retinopathy (3) and unilateral constriction of carotid artery also prevents development of diabetic retinopathy in that eye supplied by stenotic vessel (4).  Patient’s with Down syndrome almost never develops diabetic retinopathy (5).  Moreover certain unrelated conditions like Hb S-C disease, sickle cell anemia, hyperviscosity syndrome due to paraproteins, post retinal venous occlusion produce some of the retinal pathology like diabetic retinopathy even though none of the above mentioned condition are associated with diabetes. 

 Moreover as discussed in the letter 3% of healthy NHANES III population showed lesion resembling diabetic retinopathy.  The salutary effect of photocoagulation shows that retinal ischaemia is a predominant cause of retinal vascular change in diabetics mellitus.

HbA1C level in the blood on the other hand  depends on levels of hyperglycaemia and period through which hyperglycaemia tests.  This level is  also dependent upon mean red cell life span, so that HbA1C levels are reduced in haemolytic states. Moreover structural haemoglobinopathy like Hb S, Hb C etc are glycosylated but on HPLC based techniques for measurement of HbA1C level may not quantitate variant hemoglobins which is glycosylated.   Variant Hb like Hb S may not be glycosylated at the same rate as adult Hb levels.  Hb S also alters the oxygen  dissociation curve of Hb and shifts the curve to right as a result more oxygen  is available  to retina and this property is likely to have opposite effect on retinopathy. Black population has higher prevalence of hemoglobinopathies, essential hypertension and probably also has less tight glycaemic control (6).

 

Hence there are multiple reasons why Caucasian and black race may have different  values of blood HbA1C levels above which retinopathy risk increases.  In this discussion we have not discussed the differences in the biology of endothelial cell health markers and angiogenic gene and HIF and related gene polymorphism which may predispose to differential tendency of developing diabetic retinopathy at similar levels of hyperglycaemic compared to Caucasian population. VEGF also has many polymorphisms and association of diabetic retinopathy with levels of circulating VEGF is now firmly established. Anti VEGF monoclonal antibody Bevacijumab is also success fully used to treat diabetic retinopathy. Moreover many of these VEGF polymorphisms which determines amount of VEGF produced has differential distribution in different populations. All these suggests that there are many other variables which determines development of retinopathy in diabetes and these variables are variably distributed in different races making racial comparison of HbA1c levels for diabetic retinopathy on a single cut off value of HbA1c unrealistic.

Preanalytic and analytic variables (7) (Techniques measuring more labile Aldimine linked HbA1C along with more stable keto-amine linked HbA1C  or only stable Ketoamine product) in measurement of HbA1C may also be important but that is likely to be similar for both Caucasian and black population in US.  Hence we have to understand that plasma (serum) Hb A1C level is only a surrogate marker of degree of glycaemic control and diabetic retinopathy in two different population may be modulated by many different factors hence between two populations HbA1C may not strictly be comparable with relation to some of the diabetic complication like retinopathy.

 

References :

  1. Dagogo –Jack S.   Haemoglobin A1c  Diagnostic  cut off differences between black and while persons.  Ann.  Intern. Med 2013;  158:73.
  2. Tsugawa Y, Mukamalk J,  Davis RB,  Taylor WC, Wec CC:   Should the hemoglobin A (1c)  diagnostic cut off differ between blacks  and whites ?   a cross sectional study.  Ann.  Intern. Med 2012;  157:153-9.
  3. Merimee TJ,  Fineburg SE,  Mckusick  VA,  Hall J.    Diabetes mellitus and sexual ateligtic dwarfism:  a comparative study.   J  Clin. Invest.  1970; 49:1096-1102.
  4. Patel V,  Rassam S,  Newsom R,  Wiek J,  Kohner E.   Retinal Blood flow in diabetic retiropathy.  Br.Med.J. 1992, 305:678-83.
  5. Ryeom D, Folkman J.   Role of endogenous angiogenesis inhibitors in  down syndrome.   J. Craniofac. Surg.  2009;  20(S1): 595-96.
  6. Karter   AJ,  Ferrara A,  Liu Ly, Noffel A,  Ackerson LM, Selby JV,  Ethnic disparities in diabetic complications in an insured population.   JAMA 2002, 287:2519-27.
  7. Goldstein DE,  Peth SB, England JD,  Hess RL, Da-Costa J.   Effects  of  acute changes in Blood glucose on HbA1C.    Diabetes  1980, 29:623-627.

 

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