Received: 29 September 2021 Revised: 20 December 2021 Accepted: 1 January 2022

DOI: 10.1111/dom.14638

REVIEW ARTICLE

Understanding the clinical implications of differences between

glucose management indicator and glycated haemoglobin

Fernando Gomez-Peralta MD, PhD1 | Pratik Choudhary MD, PhD2 |

3,4 5
Emmanuel Cosson MD, PhD | Concetta Irace MD, PhD |
Birgit Rami-Merhar MD, PhD6 | Alexander Seibold MD, PhD7

1
Department of Endocrinology and Nutrition,
Segovia General Hospital, Segovia, Spain Abstract
2
Leicester Diabetes Centre – Bloom, Laboratory measured glycated haemoglobin (HbA1c) is the gold standard for
University of Leicester, Leicester General
assessing glycaemic control in people with diabetes and correlates with their risk of
Hospital, Leicester, UK
3
Department of Endocrinology-Diabetology- long-term complications. The emergence of continuous glucose monitoring (CGM)
Nutrition, AP-HP, Avicenne Hospital, has highlighted limitations of HbA1c testing. HbA1c can only be reviewed infre-
Université Paris 13, Bobigny, France
4
quently and can mask the risk of hypoglycaemia or extreme glucose fluctuations.
Paris 13 University, Sorbonne Paris Cité,
UMR U557 INSERM/U11125 INRAE/CNAM/ While CGM provides insights in to the risk of hypoglycaemia as well as daily fluctua-
Université Paris13, Unité de Recherche
tions of glucose, it can also be used to calculate an estimated HbA1c that has been
Epidémiologique Nutritionnelle, Bobigny,
France used as a substitute for laboratory HbA1c. However, it is evident that estimated
5
Department of Health Science, University HbA1c and HbA1c values can differ widely. The glucose management indicator
Magna Graecia, Catanzaro, Italy
6
(GMI), calculated exclusively from CGM data, has been proposed. It uses the same
Department of Pediatrics and Adolescent
Medicine, Medical University Vienna, Vienna, scale (% or mmol/mol) as HbA1c, but is based on short-term average glucose values,
Austria rather than long-term glucose exposure. HbA1c and GMI values differ in up to 81%
7
Abbott Diabetes Care, Wiesbaden, Germany
of individuals by more than ±0.1% and by more than ±0.3% in 51% of cases. Here,
Correspondence we review the factors that define these differences, such as the time period being
Alexander Seibold, MD PhD, Abbott Diabetes
assessed, the variation in glycation rates and factors such as anaemia and
Care, Wiesbaden, Germany.
Email: alexander.seibold@abbott.com haemoglobinopathies. Recognizing and understanding the factors that cause differ-
ences between HbA1c and GMI is an important clinical skill. In circumstances when
Funding information
Abbott Diabetes Care, Grant/Award Number: HbA1c is elevated above GMI, further attempts at intensification of therapy based
Abbott has provided writing support
solely on the HbA1c value may increase the risk of hypoglycaemia. The observed
difference between GMI and HbA1c also informs the important question about the
predictive ability of GMI regarding long-term complications.

KEYWORDS
average glucose, continuous glucose monitoring, diabetes, glucose management indicator,
HbA1c

1 | I N T RO DU CT I O N hyperglycaemia was targeted in the landmark Diabetes Control and

Since the introduction of insulin therapy, type 1 diabetes (T1D) has
been accompanied by the morbidity and mortality of long-term micro-
vascular and macrovascular complications.1 Among possible factors
responsible for the rate of long-term complications, the role of
Complications Trial (DCCT),2 which asked whether the risk of compli-
cations could be significantly reduced by lowering blood glucose
levels to near normal.
Glycated haemoglobin (HbA1c) is the glycated fraction of the
haemoglobin in circulating red blood cells (RBC) during the previous

Diabetes Obes Metab. 2022;24:599–608. wileyonlinelibrary.com/journal/dom © 2022 John Wiley & Sons Ltd. 599

600
F I G U R E 1 Glycated haemoglobin (HbA1c) formation and red
blood cell (RBC) longevity. Plasma glucose (G) enters the RBCs in
proportion to plasma concentration. Intracellular glucose (Gi) reacts
with the amino group on a haemoglobin (Hb) molecule, forming the
ketoamine HbA1c. Average life of an RBC is approximately 120 days;
therefore, HbA1c level reflects the average plasma G level during that
period
2-4 months, equivalent to the life of RBCs (Figure 1). Elevated HbA1c
levels were first associated with diabetes in 19693 and it became clear
that there was a relationship between HbA1c, mean fasting glucose
and mean daily glucose. The DCCT was initiated in 1982 and the
availability of the HbA1c assay allowed a reliable and convenient
assessment of average blood-glucose levels over the previous
2-4 months.4 Although the goal of the DCCT was to investigate the
impact of blood glucose levels on complications of T1D, HbA1c was
perceived to be a reliable surrogate marker for average glucose and
the limitations of HbA1c for interpreting long-term glucose levels
were not understood at that point. The widespread use of continuous
glucose monitoring (CGM) during the last decade has enabled us to
track glycaemic control directly, including the metrics of estimated
A1c (eA1c) and subsequently the glucose management indicator
(GMI).5 This has also led to a widespread assumption that eA1c or
GMI are intended to approximate HbA1c as closely as possible. How-
ever, it is important to correct this assumption. These measures of
short-term glucose exposure are most useful when they are compared
alongside long-term HbA1c, but without implying that the two mea-
sures should be identical. The aim of this review is to clarify why eA1c
and GMI can be expected to differ from laboratory-tested HbA1c in
the majority of instances, and highlight the clinical importance of
understanding this difference for changes to diabetes therapy and
predictions about long-term complications of diabetes.
2 | I M P A C T O F T H E D C CT A ND U K P D S
S T U D I E S A N D T H E ST R E N G T H OF GL Y C A T E D
HAEMOGLOBIN FOR DIABETES
MANAGEMENT
The DCCT followed 1441 people with T1D during the period
1983-1989, and compared conventional insulin therapy against inten-
sive insulin therapy with multiple daily insulin injections or using an
insulin pump.2 The intensive regimen was designed to achieve
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GOMEZ-PERALTA ET AL.
blood glucose levels as close as possible to the ‘normal’ physiological
range, specifically preprandial levels between 70 and 120 mg/dl
(3.9-6.7 mmol/L), postprandial concentrations <180 mg/dl (10 mmol/L)
and HbA1c <6.05% (42.6 mmol/mol). During the DCCT study, HbA1c
was measured each month.
The DCCT conclusively showed that intensive insulin therapy
reduced the risk of developing retinopathy by 76%, the incidence of
microalbuminuria or albuminuria by 39% and 54% respectively, and
clinical neuropathy by 60%. These significant risk reductions were
seen in people with T1D who maintained their average HbA1c levels
close to 7.0% (53 mmol/mol) in the mean 6.5-year study period, com-
pared with people with an average 9.0% (75 mmol/mol) HbA1c in the
conventional treatment arm.
The important outcomes in T1D were followed by the
United Kingdom Prospective Diabetes Study (UKPDS) in type
2 diabetes (T2D).6 The UKPDS investigated intensive control of
blood glucose after the diagnosis of T2D, which achieved a median
HbA1c of 7.0% (53 mmol/mol) compared with 7.9% (63 mmol/mol)
in those randomized to conventional treatment over a median
10.0 years of follow-up, from 1977 to 1997. UKPDS showed that
every 1% reduction in HbA1c was associated with a reduction of
43% in risk of developing peripheral vascular disease, a 37%
reduced risk of developing diabetic eye disease or kidney disease
and a 14% reduction in risk of diabetes-related heart attacks.
Importantly, risk of death from any diabetes-related cause was
reduced by 21%.6,7
Based on these and subsequent studies, HbA1c has become
established as an objective measure of glycaemic control and the ‘gold
standard’ marker for risk of morbidity and mortality for people with
diabetes. This long-term association between HbA1c and diabetes
health has led most physicians and people with diabetes to assume
that HbA1c reflects a 1-to-1 concordance with average glucose and
can be interpreted in the same way for each person with diabetes.
The advent of CGM has allowed us to challenge this assumption and
better understand the limitations of HbA1c as a marker of diabetes
health.
3 | HBA1C, THE HAEMOGLOBIN
GLYCATION INDEX AND THE GLYCATION
GAP HYPOTHESIS
HbA1c is perceived to reflect the weighted average of blood-glucose
levels during the lifetime of RBCs, but HbA1c has several limitations
that must be acknowledged, as described in Table 1. Historical obser-
vations that some individuals have HbA1c values that are higher or
lower than expected from measurements of their blood glucose gave
rise to the concept of a so-called glycation gap, calculated as the dif-
ference between observed HbA1c and the value calculated from its
regression with fructosamine.8 This also helped to explain studies that
have consistently shown that the assumed strong relationship
between HbA1c and chronic diabetes complications indicated an
important interindividual variation.9
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GOMEZ-PERALTA ET AL. 601

The haemoglobin glycation index (HGI) has been proposed to data for every patient, along with automatically computed
explain biological variation in HbA1c predictions for risk of retinopa- glucometrics, including mean glucose descriptors, the HGI and the
thy and nephropathy (Figure 2).10,11 HGI is the difference between glycation gap can be assessed more readily.
observed HbA1c and the value calculated from its regression with
mean plasma glucose obtained from a reference population. With the
extended use of CGM, access to measurements of complete glucose 4 | D E R I V A T I O N OF E S T I M A T E D A 1 C A S A
MEASURE OF AVERAGE GLUCOSE
EX POSURE
TABLE 1 Limitations of HbA1c as a measure of glucose control

• Does not measure glucose levels directly and neglects other
influencing factors.
• Laboratory testing for HbA1c is typically undertaken only every
3 months or less.
• Conveys no information about short-term glycaemic control,
including frequency of hypoglycaemia or day-to-day glycaemic
variability.
• Relationship between daily mean glucose over time and a final
HbA1c value is not linear. Mean glucose in the month immediately
before an HbA1c test represents approximately 50% of the HbA1c
value, with diminishing contributions in the preceding
2-3 months.12
• Clinically, HbA1c (% units or mmol/mol) does not relate to the day-
to-day glucose meter readings in mmol/L or mg/dl that are used in
day-to-day management of diabetes.
• Non-glycaemic pathophysiological conditions issues can alter
haemoglobin bioavailability such that HbA1c levels do not
accurately reflect mean glucose exposure over 2-4 months.
• Red blood cell lifespan and individual glycation rates determine
HbA1c formation, affecting how average plasma glucose exposure
is reflected in the periodic HbA1c measurements.13 Different
glycation rates will generate different HbA1c readings for the same
mean glucose value.
• Individual factors, including age, comorbid disease, and ethnic and
racial differences, can also influence glycation rates.14
Abbreviation: HbA1c, glycated haemoglobin.
The eA1c was developed as a metric that could track glycaemic expo-
sure between the laboratory test measurement of HbA1c by using
mean glucose values. Linear regression analysis of HbA1c and average
glucose was used to develop a standard formula whereby mean glu-
cose values could be correlated with long-term HbA1c but could be
estimated more easily and frequently15 (Table 2). This calculation was
subsequently updated to calculate eA1c from CGM data alone, using
the mean glucose value in mg/dl or mmol/L and expressing eA1c as a
% (DCCT units) or mmol/mol (IFCC units) value that people were
familiar with.16
At this point the perception became widespread that eA1c could
replace HbA1c readings as an absolute measure of glucose exposure.
However, there were problems with this assumption. First, the original
linear regression analysis15 included just 39 days of seven-point daily
self-monitoring of blood glucose tests performed at least 3 days per
week over 90 days, only 36% of which were completed (mean 5.1
tests/day). Consequently, many glucose excursions were not docu-
mented, resulting in imprecise mean glucose calculations. Secondly,
although the original calculations also included CGM data, these were
collected in 2/3-day packages every 4 weeks over 3 months. These
imprecise original calculations were amended using CGM data only.16
However, an absolute correlation between eA1c and HbA1c was not

F I G U R E 2 HbA1c, haemoglobin glycation index and risk of complications of diabetes. HbA1c is not a direct measure of glucose exposure and
is influenced by factors that modify the formation and bioavailability of HbA1c in RBCs. Haemoglobin glycation index is the difference between
observed HbA1c and the value calculated from its regression with mean plasma glucose obtained from a reference population. Glycation gap is
calculated as the difference between the laboratory tested HbA1c and the CGM-derived value calculated from mean glucose. AG, average
glucose; CGM, continuous glucose monitoring; eA1c, estimated A1c; GMI, glucose management indicator; HbA1c, glycated haemoglobin; RBC,
red blood cells
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602 GOMEZ-PERALTA ET AL.

T A B L E 2 Evolution from estimated HbA1c to glucose

management indicator

Calculation Evolutionary milestones

eAG (mmol/
L) = 1.5944  HbA1c –
2.5944
eA1c (%) = 3.38
+ 0.02345  [mean
glucose in mg/dl]
GMI (%) = 3.31
+ 0.02392  [mean
glucose in mg/dl]
• Intended to allow measurement of
mean glucose to infer periodic
HbA1c status15
• Mix of SMBG and CGM data used
in derivation makes calculation
imprecise
• Designed to use mean glucose
levels to derive an estimated
HbA1c to map glucose trends
based on average glucose without
a formal HbA1c test16 F I G U R E 3 eA1c and GMI are not parallel estimates of mean
• Single eA1c can be associated with glucose. Relationship between eA1c, GMI for a given HbA1c and
a wide range of different test mean glucose. Slopes were drawn from eA1c and GMI formula
HbA1c readings (shown in Table 2). eA1, estimated HbA1c; GMI, glucose management
• International guidance confirms indicator; HbA1c, glycated haemoglobin
intention to be used alongside
HbA1c (14)
• eA1c incorrectly assumed by many
to describe a 1:1 concordance with might be helpful for safe and effective clinical management16 and
HbA1c that should include understanding the difference between eA1c
• Deliberately created to avoid and HbA1c. Although additional computational approaches have
misinterpretation that this metric attempted to minimize discrepancies between measured short-term
should closely approximate a
glucose exposure and long-term HbA1c, for example the calculated
corresponding laboratory
measured A1C.5 HbA1c approach,19 the clinical value of knowing how average glucose
• Derived from regression of mean and HbA1c differ is established.
glucose concentration and
contemporaneously measured A1C
values from 4 RCTs using
CGM data. 5 | DE VE L OPME N T O F T H E G L UCO SE
• Not a parallel for eA1c despite MANAGEMENT INDICATOR
common basis in mean glucose

Note: Goal of each step along the evolution from eAG to GMI has been to
derive a measure of overall glycaemic performance, which has the same
utility as HbA1c but that can be measured more frequently.
Abbreviations: eA1c, estimated A1c; eAG, estimated average glucose;
CGM, continuous glucose monitoring; GMI, glucose management
indicator; HbA1c, glycated haemoglobin; RCT, randomized controlled
trials; SMBG, self-monitoring of blood glucose.
the intended outcome (see Table 2), as a single lab-measured HbA1c
value could be associated with a range of mean glucose values as cal-
culated by eA1c.16 This lack of precision resulted in confusion, as the
descriptive terminology of eA1c and HbA1c tended to imply a close
and direct relationship.
International consensus recommendations for using CGM
included eA1c among a list of 14 key metrics for assessing glycaemic
control based on availability of 10-14 consecutive days of CGM
17
data. It should be noted that extending the period of data collection
up to 3 months does not significantly increase the correlation with
longer-term mean glucose.18 Within these recommendations, it was
recognized that eA1C and laboratory-measured HbA1c may differ for
any person with diabetes because of the number of non-glycaemic
factors involved in each calculation. Therefore, it was proposed that
knowing how an eA1c value compares with lab-measured HbA1c
In 2018, the concept of using CGM-derived mean glucose was
adapted to generate a different measure of short-term glucose con-
trol that could be compared alongside long-term HbA1c but without
implying that the two measures should be identical in value. This
was the ‘glucose management indicator’ (GMI; Table 2),5 which is
intended to convey information about overall glucose exposure over
the assessment period. GMI is still a measure of average glucose,
but is based on a regression analysis of mean glucose and contem-
poraneously measured HbA1c using data from four RCTs,
REPLACE-BG,20 DIAMOND studies (in T1D21 or in T2D22) and
HypoDE,23 each of which exclusively used CGM data from people
with T1D or T2D. Each of these studies used CGM systems from
the same manufacturer (Dexcom, San Diego, CA, USA) but have
subsequently been validated using data from trials using Guardian
Sensor 3 (Medtronic Inc., Northridge, CA, USA) and Freestyle Navi-
gator II (Abbott Diabetes Care, Alameda, CA, USA).24 It is important
to note that the accuracy of all CGM systems is subject to recurrent
updating, such that different systems will report slightly different
metrics of average glucose exposure, with slightly differing relation-
ships with laboratory HbA1c.25 As the original derivation of GMI
was based on early generations of the Dexcom G4 sensor,5 the for-
mula for derivation of GMI might also require systematic updating.
However, this does not alter the fact that the non-glycaemic factors

GOMEZ-PERALTA ET AL.
that influence HbA1c formation will continue to influence the rela-
tionship with GMI.
It is also important to recognize that GMI and eA1c are not paral-
lel measures even though they are both derived from mean glucose. A
comparison of the regression analysis of GMI and eA1c datasets
against the lab-measured HbA1c data in each study shows that GMI
has a lower slope than eA1c (Figure 3). At a mean glucose <153 mg/dl
(8.5 mmol/L) eA1c tends to be lower than the corresponding GMI,
whereas as mean glucose rises above 153 mg/dl (8.5 mmol/L) eA1c
becomes relatively higher than GMI26 with a progressively larger gap
as mean glucose increases. Given that GMI is based solely on CGM
data with regression to contemporaneous HbA1c values, eA1c is reg-
arded as obsolete and GMI is now the reference metric when
reviewing CGM data for any patient.
6 | C L I N I C A L I M P L I C A T I O N S O F U SI N G
T H E G LU C O S E M A N A G E M E N T I N D I C A T O R
I N C O N J U N C T I O N WI T H L A B O R A T O R Y -
MEASURED GLYCATED HAEMOGLOBIN
The major risk for progression of retinopathy as identified in the
DCCT study is conveyed by updated mean blood glucose.27,28 As GMI
and time in range (TIR) are both correlated with mean glucose,29 it is
highly plausible that an updated GMI along with TIR for an individual
or group of people with diabetes, when correlated with HbA1c, may
be effective in individualizing glycaemic targets and predict chronic
complications.
It is important to recognize that GMI and HbA1c values are
expected to differ. The relationship between GMI and HbA1c is
influenced by glycation kinetics and the lifespan of RBCs in each
individual that result in HbA1c formation (Table 3, Figure 2). A
consistent difference between HbA1c and GMI effectively
defines the HGI13 and provides an informative assessment of the
so-called glycation gap between average glucose and HbA1c
(Figure 2).
When HbA1c is consistently higher than GMI, these individuals
are probably ‘high’ glycators. When HbA1c is consistently lower
than GMI, we may consider these as ‘low’ glycators. High glycators
have the potential for more glucose-mediated damage in their renal
and retinal cells, as well as in other cells and tissues, despite the
same average glucose levels as measured by GMI. By this we mean
that it is the high rate of glycation that creates the risk of complica-
tions, rather than a prolonged RBC lifespan, which can occur in cer-
tain pathological conditions. High glycators have to aim for a tighter
glucose control than low glycators, to keep their risk for complica-
tions under control. This is why HbA1c is such an important measure
of long-term diabetes health and shows why it has a complementary
role with average glucose levels or GMI calculations to give a more
complete picture of the risks for long-term complications. Therefore,
it will be clinically important to continue to recommend periodic
testing of HbA1c for comparison with GMI, as the glycation gap will
be defined by consistent differences between HbA1c and GMI,
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603
TABLE 3 Factors that influence HbA1c values
Temporal factors
• Time point when the blood sample is obtained.
• Assay selection and operation
Physiological factors
• Average glucose in the short- and long-term
• Glycation rate (or HGI), which can vary significantly between
individuals, resulting in different degrees of post-translational
modification of haemoglobin by glucose over the same period9
• Average production rate (erythropoiesis) and half-life of RBCs
• Haemoglobinopathies
• Ethnic and racial genotype: studies suggest that GMI will
typically be higher than HbA1c in white people but lower than
HbA1c in black African Americans30,31 or in Chinese Asians.30,32
This may indicate a difference in the glycation kinetics in each of
these populations, alongside other non-glycaemic genetic factors
• Comorbid conditions, such as haemolytic anaemia, cirrhosis and
chronic kidney disease
• Action of any drug or treatment that changes these factors; for
example, treatment with metformin has been shown to increase
glucose transport through the RBC membrane and raise
HbA1c33
• Age: glycation rates and RBC turnover change with older age,
increasing the likelihood that older people would probably have
a higher laboratory HbA1c compared with GMI19
Note: Table is categorized into factors that are temporal, i.e. those that are
a function of assay timings or periods over which calculations are made,
and physiological, i.e. those that are a function of genetic, molecular or
cellular differences or changes.
Abbreviations: GMI, glucose management indicator; HbA1c, glycated
haemoglobin; HGI, haemoglobin glycation index; RBCs, red blood cells.
which can be associated with variation in risk of diabetes-related
complications, including nephropathy,34 retinopathy35 and mortal-
ity.36 From a clinical perspective, if the glycation gap is observed to
change over time, this might indicate a change in another health
condition.
7 | PREDICTING THE DIFFERENTIAL
B E T W E E N G L Y C A T ED H A E M O G L O B I N A N D
GLUCOSE MANAGEMENT INDICATOR
Based on the regression analysis by Bergenstal and colleagues,5 for a
given HbA1c we can calculate corridors of probability that GMI will
differ from the lab-measured HbA1c (Table 4). Thus, for a given
HbA1c, GMI will approximate HbA1c only with a 19% probability,
i.e. the difference between the HbA1c value and the GMI calculation
will be within ±0.1% (2 mmol/mol) in ≤19% of cases. The probability
that GMI will be within ±0.3% (3-4 mmol/mol) of the measured
HbA1c is 49% and this rises to 81% that GMI will only be within
±0.6% (6-7 mmol/mol). A different way of looking at this is shown in
Figure 4. This clarifies that the expected difference between GMI and
HbA1c will be between 0.1% and 0.2% for 14% of individuals,
between 0.2% and 0.3% for 16% and 0.3% and 0.4% for 12% of peo-
ple with diabetes. Cumulatively, 28% of people with T1D will have a
GMI that differs from their HbA1c by ≥0.5%. Given that a difference
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604 GOMEZ-PERALTA ET AL.

TABLE 4 Corridors of probability for laboratory-measured HbA1c for any calculated GMI

Average glucose GMI11 eHbA1c7 95% CI for lab-measured HbA1c range and probability

mg/dl mmol/L % mmol/mol % mmol/mol 97% 81% 49% 19%

80 4.4 5.2 33.4 4.4 24.3 4.2-6.2 4.6-5.8 4.9-5.5 5.1-5.3
100 5.5 5.7 38.6 5.1 31.9 4.7-6.7 5.1-6.3 5.4-6.0 5.6-5.8
120 6.7 6.2 44.2 5.8 40.2 5.2-7.2 5.6-6.8 5.9-6.5 6.1-6.3
140 7.8 6.7 49.4 6.5 47.8 5.7-7.7 6.1-7.3 6.4-7.0 6.6-6.8
150 8.3 6.9 51.8 6.9 51.2 5.9-7.9 6.3-7.5 6.6-7.2 6.8-7.0
160 8.9 7.1 54.6 7.2 55.3 6.1-8.1 6.5-7.7 6.8-7.4 7.0-7.2
180 10 7.6 59.8 7.9 62.9 6.6-8.6 7.0-8.2 7.3-7.9 7.5-7.7
200 11.1 8.1 64.9 8.6 70.5 7.1-9.1 7.5-8.7 7.8-8.4 8.0-8.2
220 12.2 8.6 70.1 9.3 78.1 7.6-9.6 8.0-9.2 8.3-8.9 8.5-8.7
240 13.3 9.1 75.3 10.0 85.7 8.1-10.1 8.5-9.7 8.8-9.4 9.0-9.2
260 14.4 9.5 80.5 10.7 93.3 8.5-10.5 8.9-10.1 9.2-9.8 9.4-9.6
280 15.5 10.0 85.7 11.4 100.9 9.0-11.0 9.4-10.6 9.7-10.3 9.9-10.1
300 16.6 10.5 90.8 12.1 108.5 9.5-11.5 9.9-11.1 10.2-10.8 10.4-10.6
320 17.8 11.0 96.5 12.8 116.8 10-12 10.4-11.6 10.7-11.3 10.9–11.1

Note: Any given GMI calculated from CGM glucose data is associated with the probability of lying within a range of laboratory HbA1c readings.5 Only 19%
of GMI values will be within ±0.1% of the predicted HbA1c based on CGM-measured average glucose. Probability that any calculated GMI value will be
within ±1.0% of the predicted HbA1c is 97%. Lab-measured HbA1c values given in DCCT units (%) are dependent on multiple factors associated with RBC
life span and glycation status, as well as other physiological and pharmacological variables (see Table 3).
Abbreviations: CGM, continuous glucose monitoring; GMI, glucose management indicator; HbA1c, glycated haemoglobin.

of ≥0.4% in HbA1c is seen as clinically meaningful,37 it is understand-
able that both for patients and for clinicians these observed differ-
ences may cause concern. In fact, the differences between GMI and a
contemporaneous HbA1c indicate wider variation than that predicted
based on RCT data. A recent real-world analysis38 found that only
11% of patients in the real-world setting had GMI and HbA1c levels
that differed by <0.1%. In fact 50% of the study group had a differ-
ence between GMI and HbA1c of >0.5% and 22% had a difference
>1%. This emphasizes the importance of understanding the relevance
of such differences in real-world clinical practice.
8 | CLINICAL IMPORTANCE OF
D I F F E R E N C E A N D D I R E C T I O N BE T W E E N
T H E G LU C O S E M A N A G E M E N T I N D I C A T O R
A N D GL Y CA T ED H A E M OG LO BI N
As the magnitude of the difference between the GMI and the HbA1c in
any one person with diabetes (effectively a marker of the HGI) can help
to define the risk of diabetes complications, it is critical to know this
status. As discussed below, for the 81% of people for whom GMI and
HbA1c are expected to differ by >0.1%, the magnitude of the differ-
ence and whether the GMI calculation is below the HbA1c value is
particularly important. Established clinical practice is to intensify diabe-
tes therapy based predominantly on laboratory-measured HbA1c, using
2,6,7
the learnings from the landmark DCCT and UKPDS studies. How-
ever, individuals with identical HbA1c levels may have different levels
of hypoglycaemia risk based on different GMI values; as GMI is directly
derived from average glucose levels, those with lower GMI levels would
be at greater risk for hypoglycaemia than those with higher GMI levels.
As HbA1c reflects glycation rates that affect all tissues, it can be used
as a marker of the need to lower average glucose levels, while GMI can
be used in conjunction to identify a realistic glycaemic target in this
context, while minimizing the risk of hypoglycaemia (Table 5).
Apart from temporal factors and changes that may occur in comor-
bid conditions (Table 3), glycation rates and glycation status are proba-
bly constant within an individual. The relative difference between GMI
and HbA1c allows us to identify three categories of patients who use
CGM, these are: (1) average glycators (where the GMI and HbA1c of
patients are closely approximated); (2) low glycators (GMI of patients is
consistently higher than their measured HbA1c); and (3) high glycators
(GMI of patients is consistently lower than their measured HbA1c). As
cells other than RBCs are exposed to the same glycation kinetics,
including cells that are in organs and tissues affected by diabetes com-
plications, high glycators have the potential for more glucose-mediated
damage than low glycators, despite the same average glucose exposure,
with known increased risk of diabetes-related nephropathy,31,34 reti-
nopathy31,35 and mortality.36 This increased risk of diabetes complica-
tions among high glycators suggests that treatment intensification is
emphasized for this group and that an increased risk of hypoglycaemia
must be carefully managed during this period. This is particularly true
for high glycators who do not show abnormally long RBC half-lives, and
will experience genuinely high glycation in diabetes-affected tissues.
For ‘average’ and ‘low’ glycators, treatment intensification will not

GOMEZ-PERALTA ET AL.
F I G U R E 4 Prevalence and magnitude of observed differences
between glucose management indicator (GMI) and glycated
haemoglobin (HbA1c). Expected difference between GMI and HbA1c
is quantified for each 0.1% degree of variation, based on the analysis
by Bergenstal et al.5 Percentage of people with type 1 diabetes who
will have an increasingly wide difference between their GMI and
HbA1c values is shown. For example, 14% of individuals will have an
observed difference of 0.2%-0.3% between their HbA1c and HbA1c
values, and 11% will have an observed difference of 0.4%-0.5%.
Whether GMI is lower or higher than HbA1c for any individual will
help define the clinical approach to intensifying their glycaemic
control. Bars cumulatively reflect 100% of people with type
1 diabetes
increase their risk of adverse hypoglycaemia, as their average short-
term glucose as measured by GMI will fall in line with that predicted by
their HbA1c or exceed it.
These categorizations must be taken into account when setting an
individual's therapeutic goals for HbA1c. Therefore, it will be clinically
important to continue to recommend periodic testing of HbA1c for com-
parison with GMI. The glycation gap will be stable over time for most
people with diabetes and their glycation status will be defined by predict-
able differences between their HbA1c and GMI. For example, if a
patient's HbA1c is 8.5% (69 mmol/mol) but their GMI is 7.9% (63 mmol/
mol), it can be inferred that this person is a ‘high’ glycator and will tend to
have a consistently higher HbA1c than their mean glucose suggests, as
indicated by their GMI. Thus, efforts to intensify therapy to reduce
HbA1c may lower their day-to-day average glucose (GMI) such that it can
result in more episodes of hypoglycaemia than if their GMI was closer to
8.5% as reflected by their HbA1c. This increased risk of hypoglycaemia in
high glycators suggests that using HbA1c itself should not be a factor in
intensifying therapy when GMI is available. This rationale is reversed in
‘low’ glycators when GMI is higher than HbA1c, in which case more
intensive glucose control may be targeted based on the HbA1c reading,
with less risk of adverse hypoglycaemia.
A further consideration is that we know that the comparative rela-
tionship between GMI and HbA1c is expected to remain relatively stable
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605
T A B L E 5 Clinical implications of using contemporaneous GMI and
HbA1c readings
• GMI is expected to be noticeably different from laboratory HbA1c,
this difference is an important factor to take into account when
setting HbA1c goals and intensifying therapy.
• If HbA1c is consistently higher than GMI, HbA1c itself should not
be a factor in intensifying therapy, particularly for people at
increased risk of hypoglycaemia.
• When GMI is higher than HbA1c, more-intensive glucose control
may be targeted based on the HbA1c reading, with less risk of
adverse hypoglycaemia.
• The comparative relationship between GMI and HbA1c is
relatively stable over time. If the relationship changes significantly,
this should be investigated. Consider using a longer 30-day
window over which to assess GMI in circumstances where the
relationship between GMI and HbA1c may be compromised.
• Always review other CGM-derived components of the AGP
alongside GMI, such as % time in range, % time below range and %
coefficient of variation.
Abbreviations: AGP, ambulatory glucose profile; CGM, continuous glucose
monitoring; GMI, glucose management indicator; HbA1c, glycated
haemoglobin.
over time as overall glycaemic control changes.19 Therefore, if the rela-
tionship changes significantly this would also be a concern: for example,
during intercurrent illness or drug treatment that may affect glycation
rates, RBC lifespan or both. Instability in the relationship might also indi-
cate the need to investigate a new comorbid condition, such as anaemia,
liver or kidney disease (Table 3). A continuous 14-day window of CGM
sensor-glucose readings is acknowledged to be sufficient for calculating
most CGM-derived metrics of glucose control, including GMI. In circum-
stances where the relationship between GMI and HbA1c may show insta-
bility, a longer assessment of mean glucose may be necessary to generate
a GMI for comparison with HbA1c, possibly ≥30 days.26
Lastly, it must also be acknowledged that neither eA1c nor GMI
take into account glycaemic variability that occurs within or between
days. Therefore, the other available measures of glycaemic perfor-
mance available from CGM data should always be reviewed as part of
a thorough assessment, including %TIR, % time below range and %
coefficient of variation.39 %TIR is now an established standard of care
for people with diabetes who use CGM39 and reflects both average
glucose exposure and glycaemic variability. Improving %TIR is a diabe-
tes management goal that will ultimately be reflected in reductions
both in GMI and HbA1c. Percentage time below range is also of note
in this context, as it also indicates the level of risk for hypoglycaemia
during treatment intensification, as previously discussed. The dynamic
interplay between these factors can also be reviewed using the ambu-
latory glucose profile format.40
9 | DI SCU SSION
Periodic laboratory measurement of HbA1c is the gold standard for
assessing glycaemic control in people with diabetes and managing
their risk of long-term complications. Given that lab-tested HbA1c can

606
only be reviewed infrequently, eA1c was developed as a way to moni-
tor glycaemic control in between HbA1c tests, by using mean glucose
values that were more readily available. However, partly because of
the nomenclature, it became widely assumed that eA1c was intended
to track HbA1c itself, with many publications and then directed to
highlighting the fact that eA1c tended to differ from HbA1c, often by a
25,30-32
wide margin. The understanding that eA1c should be expected
to differ from HbA1c became lost in translation. Several of these publi-
cations and others have noted the tendency of average glucose and
HbA1c to differ based on ethnicity, with eA1c commonly being higher
10,32
than HbA1c in Caucasian subjects and lower than HbA1c in black
and Asian people with diabetes.10,25,31 By replacing eA1c with GMI,
routinely captured from the last 14 days, it has been possible to dis-
tance the role of a short-term measure of average glucose from that of
long-term HbA1c but there is still a need for diabetes health care pro-
fessionals to acknowledge that GMI and long-term HbA1c are expected
to differ. The full value of GMI can only be realized when it is viewed
alongside the lab-tested HbA1c in any person with diabetes.
Because of the glycation biology that generates HbA1c within
RBCs, GMI will differ from HbA1c in 81% of cases.5 In the category of
people with diabetes who have a high glycation status, GMI will tend
to be lower than HbA1c, indicating that short-term glucose levels
need to be taken into consideration when intensifying treatment
targeting a lower HbA1c, to avoid hypoglycaemia. This clinical
approach is emphasized in high glycators with normal RBC turnover
who may be more at-risk for diabetes complications. A low glycation
status implies that GMI will be greater than the HbA1c in these indi-
viduals and allow for intensification of therapy without the same need
for caution against the risk of hypoglycaemia. This also applies in the
19% of individuals in whom GMI approximates HbA1c to within
±0.1%, so-called ‘average’ glycators.
5
Periodic testing of HbA1c and comparison with GMI is rec-
ommended for effective diabetes care. Understanding the principles
and practice for evaluating the paired measures of GMI and HbA1c is
an important clinical skill, one that is centred on understanding each
individual with diabetes. When HbA1c is elevated above GMI, as the
difference between them increases then the risk for complications is
also increased because of the higher HGI and its impact on cellular
functions. Periodic haematological assessment of erythropoiesis and
RBC turnover may also potentially strengthen the clinical decision-
making process here. People with T1D who have a high HGI and a
wide difference between HbA1c and GMI have a three-fold increase
in retinopathy and a six-fold increased risk of nephropathy compared
with those with a low HGI and a small difference between GMI and
HbA1c,14,34,35 which is probably because of higher glycation of struc-
tures and glucose-mediated damage in these tissues and organs. How-
ever, in striving to reduce HbA1c and reduce the risk of complications
for these individuals, care is needed to avoid hypoglycaemia, which
has its own short-term adverse consequences.
From a clinical perspective, attempting to derive measures of
short-term glucose control that can closely predict lab-measured
HbA1c has proven to be a thankless task, unable to account
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GOMEZ-PERALTA ET AL.
adequately for the unique glycation biology within each individual.
However, this misses the point. The clinical value in GMI is that by
knowing how short-term glucose experience can be mapped and com-
pared with long-term HbA1c, a decision can be made regarding the
need for more-intensive therapy and the potential risks can be man-
aged by understanding the relationship between GMI and HbA1c.
ACKNOWLEDG MENTS
Editorial assistance in the preparation of this manuscript was provided
by Dr Robert Brines of Bite Medical Consulting.
CONFLIC T OF INT ER E ST
FG-P has taken part in advisory panels for Abbott Diabetes, Insulcloud
S.L., Novartis, Astra Zeneca, Sanofi and Novo Nordisk; has participated as
principal investigator in Clinical Trials funded by Sanofi, Novo Nordisk,
Boehringer Ingelheim Pharmaceuticals and Lilly; and has acted as a
speaker for Abbott Diabetes, Novartis, Sanofi, Novo Nordisk, Boehringer
Ingelheim Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Bristol-
Myers Squibb Co. and Lilly. PC has received personal fees from Abbott,
Medtronic, Dexcom, Lilly, Sanofi, Novo Nordisk, Insulet. Emmanuel
Cosson has received personal fees from Abbott, Astra-Zeneca, Bristol-
Myers Squibb, Lifescan, Lilly, Merck-Sereno, Novartis, Novo-Nordisk,
Roche diagnostics, Sanofi Avantis. CI has received personal fees from,
and taken part in advisory panel for Novo Nordisk, Abbott and Sen-
seonics. She has also participated as principal investigator in clinical trials
funded by Novo Nordisk, and accepted to be a speaker for Novo Nordisk,
Abbott, Senseonics, Lilly and Boehringer Ingelheim Pharmaceuticals.
BR-M has received speaker honoraria from Abbott Diabetes Care, Eli Lilly,
Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi and Menarini and
has been on the advisory boards of Eli Lilly, Roche Diabetes Care and
Abbott Diabetes Care. She has also participated as principal investigator
in clinical trials funded by Roche Diabetes Care. AS is an employee of
Abbott Diabetes Care division. The other authors declare that they have
no competing interests.
AUTHOR CONTRIBU TIONS
All named authors contributed to the concept and design of the man-
uscript and worked collaboratively to review and prepare the final
manuscript.
PE ER RE VIEW
The peer review history for this article is available at https://publons.
com/publon/10.1111/dom.14638.
DATA AVAILABILITY STAT EMEN T
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
ET HICS S TAT E MENT
This article is based on previously conducted studies and does not
contain any new studies with human participants or animals per-
formed by any of the authors.

GOMEZ-PERALTA ET AL.
ORCID
Fernando Gomez-Peralta https://orcid.org/0000-0003-0106-0091
Pratik Choudhary https://orcid.org/0000-0001-7635-4735
Emmanuel Cosson https://orcid.org/0000-0002-8785-3385
Concetta Irace https://orcid.org/0000-0001-5182-5473
Birgit Rami-Merhar https://orcid.org/0000-0001-5575-5222
Alexander Seibold https://orcid.org/0000-0002-2008-4593
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How to cite this article: Gomez-Peralta F, Choudhary P,
Cosson E, Irace C, Rami-Merhar B, Seibold A. Understanding
the clinical implications of differences between glucose
management indicator and glycated haemoglobin. Diabetes
Obes Metab. 2022;24(4):599-608. doi:10.1111/dom.14638