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J Clin Endocrinol Metab. 2010 Dec; 95(12): 5203–5206.

doi: 10.1210/jc.2010-2352
PMCID: PMC2999978

HbA1c for the Diagnosis of Diabetes and

Prediabetes: Is It Time for a Mid-Course
Correction?
Robert M. Cohen, Shannon Haggerty, and William H. Herman
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.

An estimated 6.2 million people in the United States have undiagnosed diabetes. The average
time between onset and diagnosis of type 2 diabetes is 7 yr (1). Diagnosing diabetes is the
first step in assuring that appropriate lifestyle, glycemic, and nonglycemic interventions are
implemented (2) to reduce the toll that end-organ complications take on the life of the
individual and on the health of the nation. The 2010 American Diabetes Association (ADA)
standards of care for diabetes, based largely on the opinion of an international expert
committee, added hemoglobin A1c (HbA1c) as diagnostic criteria for diabetes (≥6.5%) and
prediabetes (5.7–6.4%) (3,4). In theory, wider application of this new approach should reduce
the delay in diagnosing diabetes by adding a straightforward test to complement fasting
glucose and oral glucose tolerance testing. However, if HbA1c is not sensitive, that is, if it
does not identify individuals who truly have diabetes, and if its limitations are not fully
appreciated by those implementing it, this new approach could fail to achieve this goal or
further delay the diagnosis of diabetes. HbA1c has long been used as a marker of glycemic
control in established diabetes. In affected patients, the rate of HbA1c formation is a direct
function of the average blood glucose concentration. Compared with glucose measurements,
the use of HbA1c as a diagnostic test has advantages, including convenience, less day-to-day
variability, greater preanalytical stability, and international standardization (3,4).
Disadvantages are: HbA1c is more costly than fasting plasma glucose (FPG), guidelines do
not adequately reflect the accuracy of HbA1c measurements available across the nation at the
current level of standardization, and more importantly perhaps, it may not correlate
adequately with actual glucose levels (5,6). For more than a decade, it has been recognized
that there may be a discordance between HbA1c and other measures of glycemia. The study
in this issue of JCEM by Lipska et al. (7) highlights the limitations and strengths of HbA1c as
a diagnostic test.

Lipska et al. (7) examine the performance of HbA1c in comparison to FPG in diagnosing
diabetes and prediabetes in older adults. The participants in the study were between the ages
of 70 and 79 yr, and 42% were black. Median HbA1c levels were higher among blacks
compared with whites despite the fact that there was no difference in median FPG levels.
When the authors compared the newly specified HbA1c cutoff of 6.5% or greater for diabetes
to a prior reference standard, i.e. FPG of at least 126 mg/dl, the sensitivity was 57%, and the
specificity was 98%. As the authors point out, this confirms that HbA1c misses many true
positive cases of diabetes in older adults (3,5). Limitations are that only single measurements
of HbA1c and FPG were performed and there was no measurement of 2-h post-glucose load
glucose levels. The latter is important because post-challenge glucose and insulin levels
deteriorate more rapidly than fasting levels as people age (8,9,10). Hence, when the standard
is 2 h postprandial glucose, the diagnosis of diabetes based on HbA1c of 6.5% or greater
might be expected to be more sensitive, rather than less sensitive, for diabetes when
compared with FPG alone in an elderly cohort.

The authors report similar findings to others regarding racial/ethnic differences between
HbA1c and FPG (11,12,13,14,15,16,17) and reinforce that these differences also occur in
older adults (18). The use of HbA1c for diabetes diagnosis is based on the hypothesis that
HbA1c is a true and consistent measure of mean blood glucose. The best published data
describing the relationship were reported in the HbA1c-derived average glucose study (19).
HbA1c, averaged across four methods calibrated to the recently developed International
Federation of Clinical Chemists standard, was analyzed by regression against mean blood
glucose, measured by both blood glucose meter and continuous glucose monitoring calibrated
against the HemoCue analyzer to improve continuous glucose monitoring accuracy. Even
with all these efforts to minimize measurement variability, a close examination of the
relationship reveals substantial uncertainty in the HbA1c predicted from mean glucose or vice
versa. This may be disturbing to some, but is not surprising to us. Our view is that the vast
proportion of the variance in the HbA1c-mean glucose relationship results from
interindividual differences in the biological determinants of hemoglobin glycation. That
variation also explains why there is likely to be a trade-off between sensitivity and specificity
for a simple HbA1c-based diagnostic cut-off compared with any fasting, 2 h post-glucose
load or mean blood glucose determination. Greater precision may be possible if we can better
define the biological determinants of hemoglobin glycation and use that understanding to
adjust the cutpoints based on demographic, anthropometric, or laboratory measurements.
Such approaches are routinely used in clinical medicine, for example, in diagnostic scoring
for rheumatoid arthritis or in multivariate risk assessment in osteoporosis.

What are the biological determinants of hemoglobin glycation? We can consider them at the
levels of epidemiology (age, race, intercurrent disease), genetics, and physiology. For the
sake of this discussion, we will pass lightly over factors that affect red cell turnover such as
hemoglobinopathies and thalassemia, and dramatic shifts in red blood cell (RBC) life span
such as hemolytic disease and acute blood loss. Gould et al. (20) demonstrated that there are
hematologically normal individuals who have a distinct relationship between HbA1c and
glucose tolerance that is maintained for up to 4 yr, which they termed “high glycators” and
“low glycators.” Although these descriptors are appealing, they imply a greater understanding
of mechanism than justified either then or now. Quantification of the degree of difference
between HbA1c and either glucose or glycated serum proteins has shown that this is
widespread in populations without direct or indirect (e.g. mediated by chronic kidney disease)
red cell disease (21,22,23). The strongest evidence for epidemiological differences was
related to age (10) and race (11,12,13,14,15,16,17). Kirk et al. (24) demonstrated by meta-
analysis 0.65% higher HbA1c levels in African-Americans compared with non-Hispanic
whites but did not adjust for potential differences in blood glucose levels. They assumed that
the differences in HbA1c levels were due to differences in glycemic control. In contrast, we
observed differences in HbA1c by race in three multicenter clinical trials after adjusting for
differences in glycemia. The first trial was in a population (n = 3819) with impaired glucose
tolerance (11); the second, a population (n = 4360) with recent onset, drug-naive type 2
diabetes (12); and the third, a population (n = 2094) with long-standing, treated type 2
diabetes (13). Despite the differences in the three populations and the different stages of
disease, the common finding was a consistent difference in the mean HbA1c-blood glucose
relationship by race and ethnicity. These findings were confirmed by subsequent studies
(14,15,16,17). Evidence that race introduces heterogeneity into the HbA1c-blood glucose
relationship beyond the level of heterogeneity found in the A1c-derived average glucose
dataset, which had only a 17% representation (19) of all races apart from Caucasian/white,
makes it likely that a single set of HbA1c criteria for all will indeed change what we call
diabetes.

The concept of race embodies a wide variety of genetic, environmental, social, and cultural
factors, any number of which may be associated with variation in hemoglobin glycation. It
will be difficult if not impossible to establish evidence-based, race-specific criteria for the
diagnosis of diabetes until the impact of these factors on hemoglobin glycation is better
understood. The importance of genetics was first established in studies demonstrating
heritability of HbA1c in twins (25,26) and the concept that heritability was notably associated
with nonglycemic determinants of HbA1c (27). There is growing literature on genetic
determinants. A number of large population studies are providing important new findings on
genetic linkage for both glycemic and nonglycemic determinants of HbA1c (28,29). Such
studies, however, depend very heavily on the limitations to the methods of phenotyping that
are applied.

Identifying and quantifying the physiological mechanisms underlying potential racial

differences provides a more rational basis for expressing the determinants of the HbA1c-
blood glucose relationship. It is well known that the formation of HbA1c is progressive
throughout the life span of a RBC, such that younger cells have lower amounts and older
cells have higher amounts of HbA1c. A single clinical measurement of HbA1c represents an
average across the RBCs of all ages in a given individual. Therefore, RBC life span is a key
determinant of HbA1c because this reflects the time of reaction for glucose and hemoglobin.
It has been assumed that RBC life span varies little among individuals except in disease states
such as hemolytic anemias. Recent studies using a precise biotin RBC label have documented
substantial heterogeneity in RBC life span in hematologically normal people with and
without diabetes, with sufficient variation to alter HbA1c by more than ±15% (30). Variation
in the rate of hemoglobin glycation was detected (30) and will be of interest in relation to
integrated glycemic control. Also, it has long been assumed that the rapid transit of glucose
across the RBC membrane would result in a constant and common relationship between the
glucose concentration outside the cell and that inside the cell. However, it appears that there
is sufficient heterogeneity between people in the steady-state relationship between glucose
inside and outside the RBC to produce measureable differences in glycation of hemoglobin
compared with glycation of plasma proteins (31). Although methods for these determinations
are complex, they should allow us to better define the basis for age, race, and other
differences in hemoglobin glycation. It is likely that simple means for clinical translation to
diagnostic criteria will then follow.

So where do we go from here? It is evident that we are asking more of HbA1c than it can do.
We are now attempting to use it to make decisions beyond the limits of biological variability
and measurement error. In this territory, it is likely that “one size does not fit all.” In the
critical range, unexplained interindividual differences in hemoglobin glycation may have a
disproportionately greater impact on the relationship with glycemia than in more advanced
diabetes. The diabetes community has focused on improving the technical performance of the
assay; however, the laboratory standardization acceptable for certification by the American
College of Pathologists through 2012 (http://www.ngsp.org/news.asp) still will only require a
quality control sample to give a result within 7%. For example, the lab’s result on a quality
control sample with a reference value of 6.5 HbA1c percentage points would be acceptable
within the range 6.0–7.0%. Hence, the laboratory could generate an individual patient report
of 6.5% when the “true value” is as low as 6.0% or as high as 7.0%. There is concern with
these laboratory sources of error, but now there is also increasing recognition of the
interindividual physiological variability in HbA1c, whether on a racial or other basis. It is
essential to further elucidate these determinants, to improve the sensitivity of HbA1c, and to
facilitate its use as a diagnostic test for diabetes.

If our aim is to accurately recognize diabetes early to prevent or delay complications, it is

imperative that we address these limitations of HbA1c more precisely than is currently
defined in the ADA recommendations (6). We are not asking to “throw the baby out with the
bath water”; rather we believe it is time to plot a mid-course correction to define at a more
basic level the variables that determine HbA1c and work to include these in its use for
diagnosis of diabetes. In the meantime, a “rule-in, rule-out approach” as presented at the 2010
European Diabetes meetings (32) represents one alternative that provides a practical strategy
which can also take account of local variations in HbA1c assay performance. Defining
HbA1c of at least 5.5 as normal and at least 7.0 as diabetes, and defining HbA1c of 5.6 to 6.9
as “impaired HbA1c” with a recommendation for follow-up fasting glucose or oral glucose
tolerance testing both in that interval and when clinically indicated in any hemoglobinopathy
or known disorder of red cell turnover would reduce the frequency of classification error
while allowing the major benefits that HbA1c has to offer.

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Footnotes
For article see page 5289

This work was supported by the U.S. Department of Veterans Affairs (Cincinnati Veterans
Affairs Medical Center, and Merit Award 5I01CX000121-02), the Ursich Family Award, and
the Michigan Diabetes Research and Training Center (National Institutes of Health Grant
DK020572).

Disclosure Summary: R.M.C. has served as a consultant for Roche Diagnostics. S.H. and
W.H.H. have nothing to declare.

Abbreviations: FPG, Fasting plasma glucose; HbA1c, hemoglobin A1c; RBC, red blood cell.

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References
1. Harris MI, Klein R, Welborn TA, Knuiman MW 1992 Onset of NIDDM occurs at
least 4–7 yr before clinical diagnosis. Diabetes Care 15:815–819 [PubMed]
2. Webb DR, Khunti K, Srinivasan B, Gray LJ, Taub N, Campbell S, Barnett J,
Henson J, Hiles S, Farooqi A, Griffin SJ, Wareham NJ, Davies MJ 2010
Rationale and design of the ADDITION-Leicester study, a systematic screening
programme and randomised controlled trial of multi-factorial cardiovascular risk
intervention in people with type 2 diabetes mellitus detected by screening. Trials
11:16 [PMC free article] [PubMed]
3. International Expert Committee 2009 International Expert Committee report on the
role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32:1327–1334
[PMC free article] [PubMed]
4. American Diabetes Association 2010 Diagnosis and classification of diabetes
mellitus. Diabetes Care 33(Suppl 1):S62–S69 [PMC free article] [PubMed]
5. Saudek CD, Herman WH, Sacks DB, Bergenstal RM, Edelman D, Davidson MB
2008 A new look at screening and diagnosing diabetes mellitus. J Clin Endocrinol
Metab 93:2447–2453 [PubMed]
6. Cohen RM 2007 A1C: does one size fit all? Diabetes Care 30:2756–2758 [PubMed]
7. Lipska KJ, De Rekeneire N, Van Ness PH, Johnson KC, Kanaya A, Koster A,
Strotmeyer ES, Goodpaster BH, Harris T, Gill TM, Inzucchi SE 2010 Identifying
dysglycemic states in older adults: implications of the emerging use of hemoglobin
A1c. J Clin Endocrinol Metab 95:5289–5295 [PMC free article] [PubMed]
8. Fritsche A, Madaus A, Stefan N, Tschritter O, Maerker E, Teigeler A, Haring H,
Stumvoll M 2002 Relationships among age, proinsulin conversion, and β-cell
function in nondiabetic humans. Diabetes 51(Suppl 1):S234–S239 [PubMed]
9. Kohrt WM, Holloszy JO 1995 Loss of skeletal muscle mass with aging: effect on
glucose tolerance. J Gerontol A Biol Sci Med Sci 50(Spec No.):68–72 [PubMed]
10. Seals DR, Hagberg JM, Allen WK, Hurley BF, Dalsky GP, Ehsani AA, Holloszy
JO 1984 Glucose tolerance in young and older athletes and sedentary men. J Appl
Physiol 56:1521–1525 [PubMed]
11. Herman WH, Ma Y, Uwaifo G, Haffner S, Kahn SE, Horton ES, Lachin JM,
Montez MG, Brenneman T, Barrett-Connor E 2007 Differences in A1C by race
and ethnicity among patients with impaired glucose tolerance in the Diabetes
Prevention Program. Diabetes Care 30:2453–2457 [PMC free article] [PubMed]
12. Viberti G, Lachin J, Holman R, Zinman B, Haffner S, Kravitz B, Heise MA,
Jones NP, O'Neill MC, Freed MI, Kahn SE, Herman WH 2006 A Diabetes
Outcome Progression Trial (ADOPT): baseline characteristics of type 2 diabetic
patients in North America and Europe. Diabet Med 23:1289–1294 [PubMed]
13. Herman WH, Dungan KM, Wolffenbuttel BH, Buse JB, Fahrbach JL, Jiang H,
Martin S 2009 Racial and ethnic differences in mean plasma glucose, hemoglobin
A1c, and 1,5-anhydroglucitol in over 2000 patients with type 2 diabetes. J Clin
Endocrinol Metab 94:1689–1694 [PubMed]
14. Ziemer DC, Kolm P, Weintraub WS, Vaccarino V, Rhee MK, Twombly JG,
Narayan KM, Koch DD, Phillips LS 2010 Glucose-independent, black-white
differences in hemoglobin A1c levels. Ann Intern Med 152:770–777 [PubMed]
15. Araneta MR, Grandinetti A, Chang HK 10 September 2010 A1C and Diabetes
Diagnosis among Filipino-Americans, Japanese-Americans, and Native Hawaiians.
Diabetes Care doi: 10.2337/dc10-0958 [PMC free article] [PubMed]
16. Li-nong J, Wei L, Wei L, Jing L, Yan-hu D, Chang-jiang W, Da-long Z, Qi-fu L,
Lu-lu C, Zhang-rong X, Hao-ming T, Ning X, Fan Z, Hong L, Jie L, Zhong-yan
S, Xiao-li Y, Ben-li S, Zhi-guang Z, Ping F 2010 Impact of newly recommended
 HbA1c-based diabetes diagnostic criteria on the prevalence of diabetes and high risk
individual in clinical and community population in China. Chin Med J Engl
123:1103–1104 [PubMed]
17. Jørgensen ME, Bjerregaard P, Borch-Johnsen K, Witte D 25 August 2010 New
diagnostic criteria for diabetes: is the change from glucose to HbA1c possible in all
populations? J Clin Endocrinol Metab doi:10.1210/jc.2010-0710 [PubMed]
18. Kramer CK, Araneta MR, Barrett-Connor E 2010 A1C and diabetes diagnosis:
the Rancho Bernardo Study. Diabetes Care 33:101–103 [PMC free article] [PubMed]
19. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ 2008
Translating the A1C assay into estimated average glucose values. Diabetes Care
31:1473–1478 [PMC free article] [PubMed]
20. Gould BJ, Davie SJ, Yudkin JS 1997 Investigation of the mechanism underlying the
variability of glycated haemoglobin in non-diabetic subjects not related to glycaemia.
Clin Chim Acta 260:49–64 [PubMed]
21. Hudson PR, Child DF, Jones H, Williams CP 1999 Differences in rates of
glycation (glycation index) may significantly affect individual HbA1c results in type
1 diabetes. Ann Clin Biochem 36:451–459 [PubMed]
22. Cohen RM, Holmes YR, Chenier TC, Joiner CH 2003 Discordance between
hemoglobin A1c and fructosamine: evidence for a glycosylation gap and its relation to
nephropathy in longstanding type 1 diabetes. Diabetes Care 26:163–167 [PubMed]
23. McCarter RJ, Hempe JM, Gomez R, Chalew SA 2004 Biological variation in
HbA1c predicts risk of retinopathy and nephropathy in type 1 diabetes. Diabetes Care
27:1259–1264 [PubMed]
24. Kirk JK, D'Agostino Jr RB, Bell RA, Passmore LV, Bonds DE, Karter AJ,
Narayan KM 2006 Disparities in HbA1c levels between African-American and non-
Hispanic white adults with diabetes: a meta-analysis. Diabetes Care 29:2130–2136
[PMC free article] [PubMed]
25. Snieder H, Sawtell PA, Ross L, Walker J, Spector TD, Leslie RD 2001 HbA(1c)
levels are genetically determined even in type 1 diabetes: evidence from healthy and
diabetic twins. Diabetes 50:2858–2863 [PubMed]
26. Simonis-Bik AM, Eekhoff EM, Diamant M, Boomsma DI, Heine RJ, Dekker JM,
Willemsen G, van Leeuwen M, de Geus EJ 2008 The heritability of HbA1c and
fasting blood glucose in different measurement settings. Twin Res Hum Genet
11:597–602 [PubMed]
27. Cohen RM, Snieder H, Lindsell CJ, Beyan H, Hawa MI, Blinko S, Edwards R,
Spector TD, Leslie RD 2006 Evidence for independent heritability of the glycation
gap (glycosylation gap) fraction of HbA1c in non-diabetic twins. Diabetes Care
29:1739–1743 [PubMed]
28. Paterson AD, Waggott D, Boright AP, Hosseini SM, Shen E, Sylvestre MP,
Wong I, Bharaj B, Cleary PA, Lachin JM, Below JE, Nicolae D, Cox NJ, Canty
AJ, Sun L, Bull SB 2010 A genome-wide association study identifies a novel major
locus for glycemic control in type 1 diabetes, as measured by both A1C and glucose.
Diabetes 59:539–549 [PMC free article] [PubMed]
29. Soranzo N, Sanna S, Wheeler E, Gieger C, Radke D, Dupuis J, Bouatia-Naji N,
Langenberg C, Prokopenko I, Stolerman E, Sandhu MS, Heeney MM, Devaney
JM, Reilly MP, Ricketts SL, Stewart AF, Voight BF, Willenborg C, Wright B,
Altshuler D, Arking D, Balkau B, Barnes D, Boerwinkle E, Bohm B, Bonnefond
A, Bonnycastle LL, Boomsma DI, Bornstein SR, Bottcher Y, Bumpstead S,
Burnett-Miller MS, Campbell H, Cao A, Chambers J, et al. 21 September 2010
Common variants at ten genomic loci influence hemoglobin A1C levels via glycemic
 and non-glycemic pathways. Diabetes doi: 10.2337/db10-0502 [PMC free article]
[PubMed]
30. Cohen RM, Franco RS, Khera PK, Smith EP, Lindsell CJ, Ciraolo PJ, Palascak
MB, Joiner CH 2008 Red cell lifespan heterogeneity in hematologically normal
people is sufficient to alter HbA1c. Blood 112:4284–4291 [PMC free article]
[PubMed]
31. Khera PK, Joiner CH, Carruthers A, Lindsell CJ, Smith EP, Franco RS, Holmes
YR, Cohen RM 2008 Evidence for interindividual heterogeneity in the glucose
gradient across the human red blood cell membrane and its relationship to hemoglobin
glycation. Diabetes 57:2445–2452 [PMC free article] [PubMed]
32. Mostafa SA, Khunti K, Webb DR, Srinivasan B, Gray LG, Davies MJ 2010 A
comparison of performance from using two HbA1c cut-points (a ‘rule-in, rule-out’
spectrum) and one HbA1c cut-point to detect type 2 diabetes in a multi-ethnic cohort.
Diabetologia 53(Suppl 1):S86

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