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Diabetes Care Volume 46, Supplement 1, January 2023 S97

6. Glycemic Targets: Standards of Nuha A. ElSayed, Grazia Aleppo,


Vanita R. Aroda, Raveendhara R. Bannuru,
Care in Diabetes—2023 Florence M. Brown, Dennis Bruemmer,
Billy S. Collins, Marisa E. Hilliard,
Diabetes Care 2023;46(Suppl. 1):S97–S110 | https://doi.org/10.2337/dc23-S006 Diana Isaacs, Eric L. Johnson,
Scott Kahan, Kamlesh Khunti, Jose Leon,

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Sarah K. Lyons, Mary Lou Perry,
Priya Prahalad, Richard E. Pratley,
Jane Jeffrie Seley, Robert C. Stanton, and
Robert A. Gabbay, on behalf of the
American Diabetes Association

The American Diabetes Association (ADA) “Standards of Care in Diabetes” in-

6. GLYCEMIC TARGETS
cludes the ADA’s current clinical practice recommendations and is intended to
provide the components of diabetes care, general treatment goals and guide-
lines, and tools to evaluate quality of care. Members of the ADA Professional
Practice Committee, a multidisciplinary expert committee, are responsible for up-
dating the Standards of Care annually, or more frequently as warranted. For a de-
tailed description of ADA standards, statements, and reports, as well as the
evidence-grading system for ADA’s clinical practice recommendations and a full
list of Professional Practice Committee members, please refer to Introduction
and Methodology. Readers who wish to comment on the Standards of Care are
invited to do so at professional.diabetes.org/SOC.

ASSESSMENT OF GLYCEMIC CONTROL


Glycemic control is assessed by the A1C measurement, continuous glucose moni-
toring (CGM) using time in range (TIR) and/or glucose management indicator
(GMI), and blood glucose monitoring (BGM). A1C is the metric used to date in clini-
cal trials demonstrating the benefits of improved glycemic control. Individual glu-
cose monitoring (discussed in detail in Section 7, “Diabetes Technology”) is a useful
tool for diabetes self-management, which includes meals, physical activity, and
medication adjustment, particularly in individuals taking insulin. CGM serves an in-
creasingly important role in the management of the effectiveness and safety of
treatment in many people with type 1 diabetes and in selected people with type 2
diabetes. Individuals on a variety of insulin treatment plans can benefit from CGM
with improved glucose control, decreased hypoglycemia, and enhanced self-efficacy
(Section 7, “Diabetes Technology”) (1).

Glycemic Assessment
Recommendations
6.1 Assess glycemic status (A1C or other glycemic measurement such as time Disclosure information for each author is
in range or glucose management indicator) at least two times a year in available at https://doi.org/10.2337/dc23-SDIS.
patients who are meeting treatment goals (and who have stable glycemic Suggested citation: ElSayed NA, Aleppo G, Aroda
control). E VR, et al., American Diabetes Association. 6.
6.2 Assess glycemic status at least quarterly and as needed in patients whose Glycemic targets: Standards of Care in Diabetes—
2023. Diabetes Care 2023;46(Suppl. 1):S97–S110
therapy has recently changed and/or who are not meeting glycemic
goals. E © 2022 by the American Diabetes Association.
Readers may use this article as long as the
work is properly cited, the use is educational
and not for profit, and the work is not altered.
A1C reflects average glycemia over approximately 3 months. The performance of the More information is available at https://www.
test is generally excellent for National Glycohemoglobin Standardization Program diabetesjournals.org/journals/pages/license.
S98 Glycemic Targets Diabetes Care Volume 46, Supplement 1, January 2023

(NGSP)-certified assays (ngsp.org). The most assays in use in the U.S. are accu-
Table 6.1—Estimated average glucose
test is the primary tool for assessing gly- rate in individuals who are heterozygous (eAG)
cemic control and has a strong predictive for the most common variants (ngsp.
A1C (%) mg/dL* mmol/L
value for diabetes complications (2–4). org/interf.asp). Other measures of aver-
5 97 (76–120) 5.4 (4.2–6.7)
Thus, A1C testing should be performed age glycemia such as fructosamine and
routinely in all people with diabetes at 1,5-anhydroglucitol are available, but 6 126 (100–152) 7.0 (5.5–8.5)
initial assessment and as part of continu- their translation into average glucose 7 154 (123–185) 8.6 (6.8–10.3)
ing care. Measurement approximately levels and their prognostic significance 8 183 (147–217) 10.2 (8.1–12.1)
every 3 months determines whether pa- are not as clear as for A1C and CGM.
tients’ glycemic targets have been reached Though some variability in the relation- 9 212 (170–249) 11.8 (9.4–13.9)
and maintained. A 14-day CGM assess- ship between average glucose levels 10 240 (193–282) 13.4 (10.7–15.7)

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ment of TIR and GMI can serve as a and A1C exists among different individ- 11 269 (217–314) 14.9 (12.0–17.5)
surrogate for A1C for use in clinical uals, in general the association between
12 298 (240–347) 16.5 (13.3–19.3)
management (5–9). The frequency of mean glucose and A1C within an indi-
A1C testing should depend on the clin- vidual correlates over time (12). Data in parentheses are 95% CI. A calcula-
ical situation, the treatment plan, and A1C does not provide a measure of tor for converting A1C results into eAG, in
glycemic variability or hypoglycemia. For either mg/dL or mmol/L, is available at
the clinician’s judgment. The use of
professional.diabetes.org/eAG. *These esti-
point-of-care A1C testing or CGM- patients prone to glycemic variability, es- mates are based on ADAG data of 2,700
derived TIR and GMI may provide an pecially people with type 1 diabetes or glucose measurements over 3 months per
opportunity for more timely treatment type 2 diabetes with severe insulin defi- A1C measurement in 507 adults with type 1,
changes during encounters between pa- ciency, glycemic control is best evaluated type 2, or no diabetes. The correlation be-
tients and health care professionals. by the combination of results from BGM/ tween A1C and average glucose was 0.92
(13,14). Adapted from Nathan et al. (13).
People with type 2 diabetes with stable CGM and A1C. Discordant results be-
glycemia well within target may do well tween BGM/CGM and A1C can be the
with A1C testing or other glucose as- result of the conditions outlined above
sessment only twice per year. Unstable or glycemic variability, with BGM miss- has considerable potential for optimizing
or intensively managed patients or people ing the extremes. their glycemic management (13).
not at goal with treatment adjustments
may require testing more frequently (every Correlation Between BGM and A1C A1C Differences in Ethnic
3 months with interim assessments as Table 6.1 shows the correlation between Populations and Children
needed for safety) (10). CGM parameters A1C levels and mean glucose levels based In the ADAG study, there were no signifi-
can be tracked in the clinic or via tele- on the international A1C-Derived Average cant differences among racial and ethnic
health to optimize diabetes management. Glucose (ADAG) study, which assessed groups in the regression lines between
the correlation between A1C and fre- A1C and mean glucose, although the
A1C Limitations quent BGM and CGM in 507 adults (83% study was underpowered to detect a dif-
The A1C test is an indirect measure of av- non-Hispanic White) with type 1, type 2, ference and there was a trend toward a
erage glycemia and, as such, is subject to and no diabetes (13), and an empirical difference between the African and Afri-
limitations. As with any laboratory test, study of the average blood glucose levels can American and the non-Hispanic White
there is variability in the measurement of at premeal, postmeal, and bedtime asso- cohorts, with higher A1C values observed
A1C. Although A1C variability is lower on ciated with specified A1C levels using in the African and African American co-
an intraindividual basis than that of blood data from the ADAG trial (14). The Amer- horts compared with non-Hispanic White
glucose measurements, clinicians should ican Diabetes Association (ADA) and the cohorts for a given mean glucose. Other
exercise judgment when using A1C as American Association for Clinical Chemis- studies have also demonstrated higher A1C
the sole basis for assessing glycemic con- try have determined that the correlation levels in African American participants than
trol, particularly if the result is close to (r = 0.92) in the ADAG trial is strong in White participants at a given mean glu-
the threshold that might prompt a enough to justify reporting both the A1C cose concentration (15,16). In contrast, a
change in medication therapy. For exam- result and the estimated average glucose recent report in Afro-Caribbean individu-
ple, conditions that affect red blood cell (eAG) result when a clinician orders the als found lower A1C relative to glucose
turnover (hemolytic and other anemias, A1C test. Clinicians should note that the values (17). Taken together, A1C and glu-
glucose-6-phosphate dehydrogenase defi- mean plasma glucose numbers in Table cose parameters are essential for the op-
ciency, recent blood transfusion, use of 6.1 are based on 2,700 readings per timal assessment of glycemic status.
drugs that stimulate erythropoiesis, end- A1C measurement in the ADAG trial. In a A1C assays are available that do not
stage kidney disease, and pregnancy) report, mean glucose measured with demonstrate a statistically significant dif-
may result in discrepancies between the CGM versus central laboratory–measured ference in individuals with hemoglobin
A1C result and the patient’s true mean A1C in 387 participants in three random- variants. Other assays have statistically
glycemia (11). Hemoglobin variants must ized trials demonstrated that A1C may significant interference, but the differ-
be considered, particularly when the underestimate or overestimate mean glu- ence is not clinically significant. Use of
A1C result does not correlate with the cose in individuals (12). Thus, as sug- an assay with such statistically significant
patient’s CGM or BGM levels. However, gested, a patient’s BGM or CGM profile interference may explain a report that
diabetesjournals.org/care Glycemic Targets S99

glycemic targets. Major clinical trials of in-


Table 6.2—Standardized CGM metrics for clinical care
sulin-treated patients have included BGM
1. Number of days CGM device is worn (recommend 14 days)
as part of multifactorial interventions to
2. Percentage of time CGM device is active (recommend 70% demonstrate the benefit of intensive gly-
of data from 14 days)
cemic control on diabetes complications
3. Mean glucose (33). BGM is thus an integral component
4. Glucose management indicator of effective therapy of patients taking in-
5. Glycemic variability (%CV) target #36%*
sulin. In recent years, CGM has become a
standard method for glucose monitoring
6. TAR: % of readings and time >250 mg/dL (>13.9 mmol/L) Level 2 hyperglycemia
for most adults with type 1 diabetes (34).
7. TAR: % of readings and time 181–250 mg/dL (10.1–13.9 mmol/L) Level 1 hyperglycemia Both approaches to glucose monitor-

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8. TIR: % of readings and time 70–180 mg/dL (3.9–10.0 mmol/L) In range ing allow patients to evaluate individ-
ual responses to therapy and assess
9. TBR: % of readings and time 54–69 mg/dL (3.0–3.8 mmol/L) Level 1 hypoglycemia
whether glycemic targets are being safely
10. TBR: % of readings and time <54 mg/dL (<3.0 mmol/L) Level 2 hypoglycemia achieved. The international consensus on
CGM, continuous glucose monitoring; CV, coefficient of variation; TAR, time above range; TIR provides guidance on standardized
TBR, time below range; TIR, time in range. *Some studies suggest that lower %CV targets CGM metrics (Table 6.2) and considera-
(<33%) provide additional protection against hypoglycemia for those receiving insulin or sul- tions for clinical interpretation and care
fonylureas. Adapted from Battelino et al. (35). (35). To make these metrics more action-
able, standardized reports with visual
for any level of mean glycemia, African visual cues, such as the ambula- cues, such as the ambulatory glucose pro-
American individuals heterozygous for tory glucose profile, should be file (Fig 6.1), are recommended (35) and
the common hemoglobin variant HbS considered as a standard summary may help the patient and the health care
had lower A1C by about 0.3 percentage professional better interpret the data to
for all CGM devices. E
points when compared with those with- guide treatment decisions (24,27). BGM
6.4 Time in range is associated with
out the trait (18,19). Another genetic and CGM can be useful to guide medical
the risk of microvascular com-
variant, X-linked glucose-6-phosphate de- nutrition therapy and physical activity,
hydrogenase G202A, carried by 11% of plications and can be used for
assessment of glycemic control. prevent hypoglycemia, and aid medication
African American individuals, was associ- management. While A1C is currently the
ated with a decrease in A1C of about Additionally, time below range
primary measure to guide glucose man-
0.8% in hemizygous men and 0.7% in and time above range are use-
agement and a valuable risk marker for
homozygous women compared with ful parameters for the evaluation
developing diabetes complications, the
those without the trait (20). of the treatment plan (Table
CGM metrics TIR (with time below range
A small study comparing A1C to CGM 6.2). C
and time above range) and GMI provide
data in children with type 1 diabetes
the insights for a more personalized dia-
found a highly statistically significant cor-
CGM is rapidly improving diabetes man- betes management plan. The incorpora-
relation between A1C and mean blood
agement. As stated in the recommenda- tion of these metrics into clinical practice
glucose, although the correlation (r =
tions, time in range (TIR) is a useful is in evolution, and remote access to
0.7) was significantly lower than that in
metric of glycemic control and glucose these data can be critical for telehealth. A
the ADAG trial (21). Whether there are
clinically meaningful differences in how patterns, and it correlates well with A1C rapid optimization and harmonization of
A1C relates to average glucose in chil- in most studies (24–29). New data sup- CGM terminology and remote access is
dren or in different ethnicities is an area port the premise that increased TIR cor- occurring to meet patient and health care
for further study (15,22,23). Until further professional needs (36–38). The patient’s
relates with the risk of complications.
evidence is available, it seems prudent specific needs and goals should dictate
The studies supporting this assertion
to establish A1C goals in these popula- BGM frequency and timing and con-
are reviewed in more detail in Section 7,
tions with consideration of individualized sideration of CGM use. Please refer to
“Diabetes Technology”; they include cross-
CGM, BGM, and A1C results. Limitations Section 7, “Diabetes Technology,” for
sectional data and cohort studies (30–32)
in perfect alignment between glycemic a more complete discussion of the use
demonstrating TIR as an acceptable end of BGM and CGM.
measurements do not interfere with the
usefulness of BGM/CGM for insulin dose point for clinical trials moving forward With the advent of new technology,
adjustments. and that it can be used for assessment CGM has evolved rapidly in both accu-
of glycemic control. Additionally, time be- racy and affordability. As such, many pa-
Glucose Assessment by Continuous low range (<70 and <54 mg/dL [3.9 and tients have these data available to assist
Glucose Monitoring 3.0 mmol/L]) and time above range with self-management and their health
Recommendations
(>180 mg/dL [10.0 mmol/L]) are useful care professionals’ assessment of glycemic
6.3 Standardized, single-page glucose parameters for insulin dose adjustments status. Reports can be generated from
reports from continuous glucose and reevaluation of the treatment plan. CGM that will allow the health care
monitoring (CGM) devices with For many people with diabetes, glu- professional and person with diabetes
cose monitoring is key for achieving to determine TIR, calculate GMI, and
S100 Glycemic Targets Diabetes Care Volume 46, Supplement 1, January 2023

AGP Report: Continuous Glucose Monitoring


Time in Ranges Goals for Type 1 and Type 2 Diabetes Test Patient DOB: Jan 1, 1970
Goal: <5% 14 Days: August 8–August 21, 2021
Very High 20%
Time CGM Active: 100%
44% Goal: <25%
250

High 24% Glucose Metrics

Average Glucose ........................................... 175 mg/dL

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180
Goal: <154 mg/dL

mg/dL Target 46% Goal: >70%


Glucose Management Indicator (GMI) ............... 7.5%
Goal: <7%

70 Low 5%
54
10% Goal: <4% Glucose Variability ............................................ 45.5%
Very Low 5%
Goal: <36%
Goal: <1% Each 1% time in range = ~15 minutes

AGP is a summary of glucose values from the report period, with median (50%) and other percentiles shown as if they occurred in a single day.

350
mg/dL

95%

75%
250
50%

25%
180

Target
Range

70 5%
54

0
12am 3am 6am 9am 12pm 3pm 6pm 9pm 12am

Sunday Monday Tuesday Wednesday Thursday Friday Saturday


8 9 10 11 12 13 14
mg/dL

180
70

12pm 12pm 12pm 12pm 12pm 12pm 12pm


15 16 17 18 19 20 21
mg/dL

180
70

Figure 6.1—Key points included in standard ambulatory glucose profile (AGP) report. Reprinted from Holt et al. (34).
diabetesjournals.org/care Glycemic Targets S101

assess hypoglycemia, hyperglycemia, and parallel goal for many nonpreg- glycemic separation between the treat-
glycemic variability. As discussed in a re- nant adults is time in range of ment groups diminished and disap-
cent consensus document, a report for- peared during follow-up.
>70% with time below range
matted as shown in Fig. 6.1 can be The Kumamoto Study (44) and UK
<4% and time <54 mg/dL
generated (35). Published data from two Prospective Diabetes Study (UKPDS)
<1%. For those with frailty or
retrospective studies suggest a strong cor- (45,46) confirmed that intensive gly-
at high risk of hypoglycemia, a
relation between TIR and A1C, with a cemic control significantly decreased
target of >50% time in range
goal of 70% TIR aligning with an A1C of rates of microvascular complications
with <1% time below range
7% (8,26). Note the goals of therapy in people with short-duration type 2
is recommended. (See Fig. 6.1
next to each metric in Fig. 6.1 (e.g., low, diabetes. Long-term follow-up of the
and Table 6.2.) B
<4%; very low, <1%) as values to guide UKPDS cohorts showed enduring ef-

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changes in therapy. 6.6 On the basis of health care
fects of early glycemic control on most
professional judgment and pa- microvascular complications (47).
tient preference, achievement Therefore, achieving A1C targets of
GLYCEMIC GOALS
of lower A1C levels than the <7% (53 mmol/mol) has been shown
For glycemic goals in older adults, please goal of 7% may be acceptable
refer to Section 13, “Older Adults.” For to reduce microvascular complications
and even beneficial if it can be of type 1 and type 2 diabetes when in-
glycemic goals in children, please refer to achieved safely without signifi-
Section 14, “Children and Adolescents.” stituted early in the course of disease
cant hypoglycemia or other ad- (2,48). Findings from the DCCT (33) and
For glycemic goals during pregnancy,
verse effects of treatment. B UKPDS (49) studies demonstrate a curvi-
please refer to Section 15, “Management
6.7 Less stringent A1C goals (such linear relationship between A1C and mi-
of Diabetes in Pregnancy.” Overall, re-
as <8% [64 mmol/mol]) may crovascular complications. Such analyses
gardless of the population being served,
be appropriate for patients with suggest that, on a population level, the
it is critical for the glycemic targets to be
limited life expectancy or where greatest number of complications will
woven into the overall person-centered
strategy. For example, in a very young the harms of treatment are be averted by taking patients from very
child, safety and simplicity may outweigh greater than the benefits. Health poor control to fair/good control. These
the need for glycemic stability in the care professionals should con- analyses also suggest that further lower-
short run. Simplification may decrease sider deintensification of ther- ing of A1C from 7 to 6% (53 mmol/mol
parental anxiety and build trust and apy if appropriate to reduce to 42 mmol/mol) is associated with
confidence, which could support fur- the risk of hypoglycemia in pa- further reduction in the risk of micro-
ther strengthening of glycemic targets tients with inappropriate strin- vascular complications, although the
and self-efficacy. In healthy older adults, gent A1C targets. B absolute risk reductions become much
there is no empiric need to loosen con- 6.8 Reassess glycemic targets based smaller. The implication of these findings
trol; however, less stringent A1C goals on the individualized criteria in is that there is no need to deintensify
may be appropriate for patients with Fig. 6.2. E therapy for an individual with an A1C
limited life expectancy or where the 6.9 Setting a glycemic goal during between 6 and 7% in the setting of
harms of treatment are greater than consultations is likely to improve low hypoglycemia risk with a long life
the benefits (39,40). patient outcomes. E expectancy. There are now newer agents
However, the health care professional that do not cause hypoglycemia, making
needs to work with an individual and it possible to maintain glucose control
should consider adjusting targets for A1C and Microvascular Complications without the risk of hypoglycemia (see
simplifying the treatment plan if this Hyperglycemia defines diabetes, and gly- Section 9, “Pharmacologic Approaches
change is needed to improve safety and cemic control is fundamental to diabetes
to Glycemic Treatment”).
medication-taking behavior. Setting management. The Diabetes Control and
Given the substantially increased risk of
goals by face-to-face or remote consul- Complications Trial (DCCT) (33), a prospec-
hypoglycemia in type 1 diabetes and with
tive randomized controlled trial of inten-
tations has been shown to be more ef- polypharmacy in type 2 diabetes, the risks
sive (mean A1C about 7% [53 mmol/mol])
fective than usual care for glycemic of lower glycemic targets may outweigh
versus standard (mean A1C about 9%
control in type 2 diabetes for fasting the potential benefits on microvascular
[75 mmol/mol]) glycemic control in peo-
plasma glucose and glycated hemoglo- complications. Three landmark trials (Ac-
ple with type 1 diabetes, showed defini-
bin (41). tion to Control Cardiovascular Risk in Dia-
tively that better glycemic control is
associated with 50–76% reductions in betes [ACCORD], Action in Diabetes and
Recommendations rates of development and progression Vascular Disease: Preterax and Diamicron
6.5a An A1C goal for many non- of microvascular (retinopathy, neurop- MR Controlled Evaluation [ADVANCE],
pregnant adults of <7% (53 athy, and diabetic kidney disease) com- and Veterans Affairs Diabetes Trial [VADT])
mmol/mol) without significant plications. Follow-up of the DCCT cohorts were conducted to test the effects of
hypoglycemia is appropriate. A in the Epidemiology of Diabetes Inter- near normalization of blood glucose
6.5b If using ambulatory glucose ventions and Complications (EDIC) study on cardiovascular outcomes in individ-
(42,43) demonstrated persistence of uals with long-standing type 2 diabe-
profile/glucose management in-
these microvascular benefits over two tes and either known cardiovascular
dicator to assess glycemia, a
decades despite the fact that the disease (CVD) or high cardiovascular
S102 Glycemic Targets Diabetes Care Volume 46, Supplement 1, January 2023

Approach to Individualization of Glycemic Targets


of nonfatal myocardial infarction (MI),
stroke, or cardiovascular death com-
Patient / Disease Features More stringent A1C 7% Less stringent
pared with those previously randomized
Risks potentially associated to the standard arm (54). The benefit of
with hypoglycemia and
other drug adverse effects intensive glycemic control in this cohort
low high
with type 1 diabetes has been shown
to persist for several decades (55) and
Disease duration
to be associated with a modest reduction

Usually not modifiable


newly diagnosed long-standing
in all-cause mortality (56).
Life expectancy
Cardiovascular Disease and Type 2 Diabetes

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long short
In type 2 diabetes, there is evidence
that more intensive treatment of glyce-
Important comorbidities
mia in newly diagnosed patients may
absent few / mild severe
reduce long-term CVD rates. In addition,
Established vascular data from the Swedish National Diabe-
complications tes Registry (56) and the Joint Asia Dia-
absent few / mild severe
betes Evaluation (JADE) demonstrate
greater proportions of people with dia-

Potentially modifiable
Patient preference betes being diagnosed at <40 years of
highly motivated, excellent preference for less
self-care capabilities burdensome therapy
age and a demonstrably increased bur-
den of heart disease and years of life
Resources and support
system
lost in people diagnosed at a younger
readily available limited age (57–60). Thus, to prevent both mi-
crovascular and macrovascular compli-
Figure 6.2—Patient and disease factors used to determine optimal glycemic targets. Character- cations of diabetes, there is a major call
istics and predicaments toward the left justify more stringent efforts to lower A1C; those to-
ward the right suggest less stringent efforts. A1C 7% = 53 mmol/mol. Adapted with permission to overcome therapeutic inertia and
from Inzucchi et al. (71). treat to target for an individual patient
(60,61). During the UKPDS, there was a
16% reduction in CVD events (combined
risk. These trials showed that lower higher versus lower A1C; therefore, fatal or nonfatal MI and sudden death)
A1C levels were associated with reduced beyond post hoc analysis of these tri- in the intensive glycemic control arm
onset or progression of some micro- als, we do not have evidence that it is that did not reach statistical significance
vascular complications (50–52). the glucose lowering by these agents that (P = 0.052), and there was no sugges-
The concerning mortality findings confers the CVD and renal benefit (53). tion of benefit on other CVD outcomes
in the ACCORD trial discussed below As such, based on clinician judgment and (e.g., stroke). Similar to the DCCT/EDIC,
and the relatively intense efforts re- patient preferences, select patients, espe- after 10 years of observational follow-
quired to achieve near euglycemia should cially those with little comorbidity and a up, those originally randomized to in-
also be considered when setting gly- long life expectancy, may benefit from tensive glycemic control had significant
cemic targets for individuals with long- adopting more intensive glycemic targets long-term reductions in MI (15% with
standing diabetes, such as those popula- if they can achieve them safely and with- sulfonylurea or insulin as initial pharma-
tions studied in ACCORD, ADVANCE, and out hypoglycemia or significant thera- cotherapy, 33% with metformin as ini-
VADT. Findings from these studies sug- peutic burden. tial pharmacotherapy) and in all-cause
gest caution is needed in treating diabe- mortality (13% and 27%, respectively)
tes to near-normal A1C goals in people A1C and Cardiovascular Disease (47).
with long-standing type 2 diabetes with Outcomes ACCORD, ADVANCE, and VADT sug-
or at significant risk of CVD. Cardiovascular Disease and Type 1 Diabetes gested no significant reduction in CVD
These landmark studies need to be CVD is a more common cause of death outcomes with intensive glycemic control
considered with an important caveat; than microvascular complications in pop- in participants followed for shorter dura-
glucagon-like peptide 1 (GLP-1) receptor ulations with diabetes. There is evidence tions (3.5–5.6 years) and who had more
agonists and sodium–glucose cotrans- for a cardiovascular benefit of intensive advanced type 2 diabetes and CVD risk
porter 2 (SGLT2) inhibitors were not ap- glycemic control after long-term follow- than the UKPDS participants. All three tri-
proved at the time of these trials. As up of cohorts treated early in the course als were conducted in relatively older par-
such, these agents with established car- of type 1 diabetes. In the DCCT, there ticipants with a longer known duration
diovascular and renal benefits appear to was a trend toward lower risk of CVD of diabetes (mean duration 8–11 years)
be safe and beneficial in this group of events with intensive control. In the and either CVD or multiple cardio-
individuals at high risk for cardiorenal 9-year post-DCCT follow-up of the vascular risk factors. The target A1C
complications. Randomized clinical trials EDIC cohort, participants previously among intensive-control participants
examining these agents for cardiovas- randomized to the intensive arm had was <6% (42 mmol/mol) in ACCORD,
cular safety were not designed to test a significant 57% reduction in the risk <6.5% (48 mmol/mol) in ADVANCE,
diabetesjournals.org/care Glycemic Targets S103

and a 1.5% reduction in A1C compared and mortality (69). Therefore, health engage people with type 1 and type 2 di-
with control participants in VADT, care professionals should be vigilant abetes in shared decision-making. More
with achieved A1C of 6.4% vs. 7.5% in preventing hypoglycemia and should aggressive targets may be recommended
(46 mmol/mol vs. 58 mmol/mol) in not aggressively attempt to achieve if they can be achieved safely and
ACCORD, 6.5% vs. 7.3% (48 mmol/mol near-normal A1C levels in people in with an acceptable burden of therapy
vs. 56 mmol/mol) in ADVANCE, and 6.9% whom such targets cannot be safely and if life expectancy is sufficient to
vs. 8.4% (52 mmol/mol vs. 68 mmol/mol) and reasonably achieved. As discussed reap the benefits of stringent targets.
in VADT. Details of these studies are in Section 9, “Pharmacologic Approaches Less stringent targets (A1C up to 8%
reviewed extensively in the joint ADA to Glycemic Treatment,” addition of spe- [64 mmol/mol]) may be recommended
position statement “Intensive Glycemic cific SGLT2 inhibitors or GLP-1 receptor if the patient’s life expectancy is such
Control and the Prevention of Cardio- agonists that have demonstrated CVD that the benefits of an intensive goal

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vascular Events: Implications of the benefit is recommended in patients may not be realized, or if the risks and
ACCORD, ADVANCE, and VA Diabetes with established CVD, chronic kidney burdens outweigh the potential bene-
Trials” (61). disease, and heart failure. As outlined in fits. Severe or frequent hypoglycemia
The glycemic control comparison in more detail in Section 9, “Pharmacologic is an absolute indication for the modi-
ACCORD was halted early due to an in- Approaches to Glycemic Treatment,” and fication of treatment plans, including
creased mortality rate in the intensive Section 10, “Cardiovascular Disease and setting higher glycemic goals.
compared with the standard treatment Risk Management,” the cardiovascular Diabetes is a chronic disease that pro-
arm (1.41% vs. 1.14% per year; hazard benefits of SGLT2 inhibitors or GLP-1 re- gresses over decades. Thus, a goal that
ratio 1.22 [95% CI 1.01–1.46]), with a ceptor agonists are not contingent upon might be appropriate for an individual
similar increase in cardiovascular deaths. A1C lowering; therefore, initiation can early in the course of their diabetes may
Analysis of the ACCORD data did not be considered in people with type 2 change over time. Newly diagnosed pa-
identify a clear explanation for the excess diabetes and CVD independent of the tients and/or those without comorbidities
current A1C or A1C goal or metformin that limit life expectancy may benefit
mortality in the intensive treatment arm
therapy. Based on these considera- from intensive control proven to prevent
(62).
tions, the following two strategies are microvascular complications. Both DCCT/
Longer-term follow-up has shown no
EDIC and UKPDS demonstrated metabolic
evidence of cardiovascular benefit, or offered (70):
memory, or a legacy effect, in which a fi-
harm, in the ADVANCE trial (63). The end- nite period of intensive control yielded
stage renal disease rate was lower in the 1. If already on dual therapy or multi- benefits that extended for decades after
intensive treatment group over follow-up. ple glucose-lowering therapies and that control ended. Thus, a finite period
However, 10-year follow-up of the VADT not on an SGLT2 inhibitor or GLP-1 of intensive control to near-normal A1C
cohort (64) did demonstrate a reduction receptor agonist, consider switching may yield enduring benefits even if con-
in the risk of cardiovascular events (52.7 to one of these agents with proven trol is subsequently deintensified as pa-
[control group] vs. 44.1 [intervention cardiovascular benefit. tient characteristics change. Over time,
group] events per 1,000 person-years) 2. Introduce SGLT2 inhibitors or GLP-1 comorbidities may emerge, decreasing life
receptor agonists in people with CVD expectancy and thereby decreasing the
with no benefit in cardiovascular or
at A1C goal (independent of met- potential to reap benefits from intensive
overall mortality. Heterogeneity of mor-
formin) for cardiovascular benefit, control. Also, with longer disease dura-
tality effects across studies was noted,
independent of baseline A1C or in- tion, diabetes may become more diffi-
which may reflect differences in glyce- cult to control, with increasing risks and
dividualized A1C target.
mic targets, therapeutic approaches, burdens of therapy. Thus, A1C targets
and, importantly, population characteris- should be reevaluated over time to bal-
Setting and Modifying A1C Goals
tics (65). ance the risks and benefits as patient
Numerous factors must be considered
Mortality findings in ACCORD (62) and when setting glycemic targets. The ADA factors change.
subgroup analyses of VADT (66) suggest proposes general targets appropriate Recommended glycemic targets for
that the potential risks of intensive glyce- for many people but emphasizes the many nonpregnant adults are shown
mic control may outweigh its benefits importance of individualization based in Table 6.3. The recommendations in-
in higher-risk individuals. In all three clude blood glucose levels that appear
on key patient characteristics. Glycemic
trials, severe hypoglycemia was signifi- to correlate with achievement of an
targets must be individualized in the
cantly more likely in participants who A1C of <7% (53 mmol/mol). Pregnancy
context of shared decision-making to recommendations are discussed in more
were randomly assigned to the inten- address individual needs and prefer- detail in Section 15, “Management of
sive glycemic control arm. Individuals ences and consider characteristics that Diabetes in Pregnancy.”
with a long duration of diabetes, a known influence risks and benefits of therapy; The issue of preprandial versus post-
history of hypoglycemia, advanced ath- this approach may optimize engagement prandial BGM targets is complex (72,73).
erosclerosis, or advanced age/frailty may and self-efficacy. Elevated postchallenge (2-h oral glucose
benefit from less aggressive targets The factors to consider in individualiz- tolerance test) glucose values have been
(67,68). ing goals are depicted in Fig. 6.2. This fig- associated with increased cardiovascular
As discussed further below, severe ure is not designed to be applied rigidly risk independent of fasting plasma glu-
hypoglycemia is a potent marker of high but to be used as a broad construct to cose in some epidemiologic studies,
absolute risk of cardiovascular events guide clinical decision-making (71) and whereas intervention trials have not
S104 Glycemic Targets Diabetes Care Volume 46, Supplement 1, January 2023

Table 6.3—Summary of glycemic recommendations for many nonpregnant hypoglycemia avoidance educa-
adults with diabetes tion and reevaluation and ad-
A1C <7.0% (53 mmol/mol)*# justment of the treatment plan
Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L) to decrease hypoglycemia. E
6.14 Insulin-treated patients with hy-
Peak postprandial capillary plasma glucose† <180 mg/dL* (10.0 mmol/L)
poglycemia unawareness, one
*More or less stringent glycemic goals may be appropriate for individual patients. #CGM level 3 hypoglycemic event, or a
may be used to assess glycemic target as noted in Recommendation 6.5b and Fig. 6.1. pattern of unexplained level 2
Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid
hypoglycemia should be advised
conditions, known CVD or advanced microvascular complications, hypoglycemia unaware-
ness, and individual patient considerations (as per Fig. 6.2). †Postprandial glucose may be to raise their glycemic targets

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targeted if A1C goals are not met despite reaching preprandial glucose goals. Postprandial to strictly avoid hypoglycemia
glucose measurements should be made 1–2 h after the beginning of the meal, generally for at least several weeks in or-
peak levels in people with diabetes. der to partially reverse hypogly-
cemia unawareness and reduce
risk of future episodes. A
shown postprandial glucose to be a to 80–130 mg/dL (4.4–7.2 mmol/L) 6.15 Ongoing assessment of cogni-
cardiovascular risk factor independent but did not affect the definition of tive function is suggested with
of A1C. In people with diabetes, surro- hypoglycemia. increased vigilance for hypogly-
gate measures of vascular pathology, cemia by the clinician, patient,
such as endothelial dysfunction, are HYPOGLYCEMIA and caregivers if impaired or
negatively affected by postprandial hy-
declining cognition is found. B
perglycemia. It is clear that postprandial Recommendations
hyperglycemia, like preprandial hyper- 6.10 Occurrence and risk for hypogly-
glycemia, contributes to elevated A1C cemia should be reviewed at ev- Hypoglycemia is the major limiting fac-
levels, with its relative contribution ery encounter and investigated tor in the glycemic management of
being greater at A1C levels that are as indicated. Awareness of hypo- type 1 and type 2 diabetes. Recommen-
closer to 7% (53 mmol/mol). However, glycemia should be considered dations regarding the classification of
outcome studies have shown A1C to using validated tools. C
be the primary predictor of complica- hypoglycemia are outlined in Table 6.4
6.11 Glucose (approximately 15–20 g) (74–83). Level 1 hypoglycemia is defined
tions, and landmark trials of glycemic
is the preferred treatment for as a measurable glucose concentration
control such as the DCCT and UKPDS
the conscious individual with <70 mg/dL (3.9 mmol/L) but $54 mg/dL
relied overwhelmingly on preprandial
BGM. Additionally, a randomized con- blood glucose <70 mg/dL (3.9 (3.0 mmol/L). A blood glucose concentra-
trolled trial in patients with known CVD mmol/L), although any form of tion of 70 mg/dL (3.9 mmol/L) has been
found no CVD benefit of insulin treat- carbohydrate that contains glu- recognized as a threshold for neuroendo-
ment plans targeting postprandial glu- cose may be used. Fifteen mi- crine responses to falling glucose in peo-
cose compared with those targeting nutes after treatment, if blood ple without diabetes. Because many
preprandial glucose (73). Therefore, it glucose monitoring (BGM) shows people with diabetes demonstrate im-
is reasonable to check postprandial glu- continued hypoglycemia, the paired counterregulatory responses to
cose in individuals who have premeal treatment should be repeated. hypoglycemia and/or experience hypo-
glucose values within target but A1C Once the BGM or glucose pat- glycemia unawareness, a measured glu-
values above target. In addition, when tern is trending up, the individ- cose level <70 mg/dL (3.9 mmol/L) is
intensifying insulin therapy, measuring ual should consume a meal or considered clinically important (indepen-
postprandial plasma glucose 1–2 h af- snack to prevent recurrence of
ter the start of a meal (using BGM or dent of the severity of acute hypoglyce-
hypoglycemia. B mic symptoms). Level 2 hypoglycemia
CGM) and using treatments aimed at 6.12 Glucagon should be prescribed
reducing postprandial plasma glucose (defined as a blood glucose concentration
for all individuals at increased <54 mg/dL [3.0 mmol/L]) is the threshold
values to <180 mg/dL (10.0 mmol/L) risk of level 2 or 3 hypoglyce-
may help to lower A1C. at which neuroglycopenic symptoms be-
mia, so that it is available should gin to occur and requires immediate ac-
An analysis of data from 470 partici-
it be needed. Caregivers, school
pants in the ADAG study (237 with tion to resolve the hypoglycemic event. If
personnel, or family members
type 1 diabetes and 147 with type 2 a patient has level 2 hypoglycemia with-
providing support to these indi-
diabetes) found that the glucose ranges out adrenergic or neuroglycopenic symp-
viduals should know where it is
highlighted in Table 6.1 are adequate toms, they likely have hypoglycemia
and when and how to admin-
to meet targets and decrease hypogly- unawareness (discussed further below).
ister it. Glucagon administra-
cemia (14). These findings support that This clinical scenario warrants investiga-
tion is not limited to health
premeal glucose targets may be relaxed tion and review of the treatment plan
care professionals. E
without undermining overall glycemic (75,79). Use Clarke score, Gold score,
6.13 Hypoglycemia unawareness or
control as measured by A1C. These data or Pedersen-Bjergaard score to assess
one or more episodes of level 3
prompted the revision in the ADA- impaired awareness (76). Lastly, level 3
hypoglycemia should trigger
recommended premeal glucose target hypoglycemia is defined as a severe
diabetesjournals.org/care Glycemic Targets S105

In 2015, the ADA changed its prepran-


Table 6.4—Classification of hypoglycemia
dial glycemic target from 70–130 mg/dL
Glycemic criteria/description
(3.9–7.2 mmol/L) to 80–130 mg/dL
Level 1 Glucose <70 mg/dL (3.9 mmol/L) and $54 mg/dL (3.0 mmol/L) (4.4–7.2 mmol/L). This change reflects
Level 2 Glucose <54 mg/dL (3.0 mmol/L) the results of the ADAG study, which
Level 3 A severe event characterized by altered mental and/or physical status requiring demonstrated that higher glycemic tar-
assistance for treatment of hypoglycemia gets corresponded to A1C goals (14).
An additional goal of raising the lower
Reprinted from Agiostratidou et al. (74).
range of the glycemic target was to
limit overtreatment and provide a safety
margin in patients titrating glucose-

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event characterized by altered mental increased risk of level 3 hypoglycemia lowering drugs such as insulin to gly-
and/or physical functioning that re- (88,89). In addition to age and race, cemic targets.
quires assistance from another person other important risk factors found in
for recovery. a community-based epidemiologic co- Hypoglycemia Treatment
Symptoms of hypoglycemia include, hort of older adults with type 2 diabetes Health care professionals should con-
but are not limited to, shakiness, irrita- include insulin use, poor or moderate tinue to counsel patients to treat hypo-
bility, confusion, tachycardia, and hun- versus good glycemic control, albumin- glycemia with fast-acting carbohydrates
ger. Hypoglycemia may be inconvenient uria, and poor cognitive function (88). at the hypoglycemia alert value of
or frightening to people with diabetes. Level 3 hypoglycemia was associated 70 mg/dL (3.9 mmol/L) or less. This
Level 3 hypoglycemia may be recognized with mortality in participants in both should be reviewed at each patient
or unrecognized and can progress to loss the standard and the intensive glyce- visit. Hypoglycemia treatment requires
of consciousness, seizure, coma, or death. mia arms of the ACCORD trial, but the ingestion of glucose- or carbohydrate-
Hypoglycemia is reversed by administra- relationships between hypoglycemia, containing foods (98–100). The acute
tion of rapid-acting glucose or glucagon. achieved A1C, and treatment intensity glycemic response correlates better with
Hypoglycemia can cause acute harm to were not straightforward. An associa- the glucose content of food than with
the person with diabetes or others, espe- tion of level 3 hypoglycemia with mor- the carbohydrate content of food. Pure
cially if it causes falls, motor vehicle acci- tality was also found in the ADVANCE glucose is the preferred treatment, but
dents, or other injury. Recurrent level 2 trial (90). An association between self- any form of carbohydrate that contains
hypoglycemia and/or level 3 hypoglycemia reported level 3 hypoglycemia and 5-year glucose will raise blood glucose. Added
is an urgent medical issue and requires in- mortality has also been reported in clinical fat may retard and then prolong the
tervention with medical treatment plan practice (91). Glucose variability is also acute glycemic response. In type 2 dia-
adjustment, behavioral intervention, and, associated with an increased risk for
betes, ingested protein may increase insu-
in some cases, use of technology to assist hypoglycemia (92).
lin response without increasing plasma
with hypoglycemia prevention and identi- Young children with type 1 diabetes
glucose concentrations (101). Therefore,
fication (76,79–82). A large cohort study and the elderly, including those with
carbohydrate sources high in protein should
suggested that among older adults with type 1 and type 2 diabetes (84,93), are
not be used to treat or prevent hypogly-
type 2 diabetes, a history of level 3 hy- noted as particularly vulnerable to hy-
cemia. Ongoing insulin activity or insulin
poglycemia was associated with greater poglycemia because of their reduced
secretagogues may lead to recurrent hy-
risk of dementia (84). Conversely, in a ability to recognize hypoglycemic symp-
poglycemia unless more food is ingested
substudy of the ACCORD trial, cognitive toms and effectively communicate their
after recovery. Once the glucose returns
impairment at baseline or decline in needs. Individualized glucose targets,
to normal, the individual should be coun-
cognitive function during the trial was patient education, nutrition interven-
seled to eat a meal or snack to prevent
significantly associated with subsequent tion (e.g., bedtime snack to prevent
recurrent hypoglycemia.
episodes of level 3 hypoglycemia (85). overnight hypoglycemia when specifi-
Evidence from DCCT/EDIC, which in- cally needed to treat low blood glu-
Glucagon
volved adolescents and younger adults cose), physical activity management,
The use of glucagon is indicated for the
with type 1 diabetes, found no asso- medication adjustment, glucose moni-
treatment of hypoglycemia in people un-
ciation between frequency of level 3 toring, and routine clinical surveillance able or unwilling to consume carbohy-
hypoglycemia and cognitive decline may improve patient outcomes (94). drates by mouth. Those in close contact
(86). CGM with automated low glucose sus- with, or having custodial care of, people
Studies of rates of level 3 hypoglyce- pend and hybrid closed-loop systems with hypoglycemia-prone diabetes (fam-
mia that rely on claims data for hospi- have been shown to be effective in re- ily members, roommates, school person-
talization, emergency department visits, ducing hypoglycemia in type 1 diabetes nel, childcare professionals, correctional
and ambulance use substantially under- (95). For people with type 1 diabetes institution staff, or coworkers) should be
estimate rates of level 3 hypoglycemia with level 3 hypoglycemia and hypogly- instructed on the use of glucagon, in-
(87) yet reveal a high burden of hypo- cemia unawareness that persists despite cluding where the glucagon product is
glycemia in adults over 60 years of medical treatment, human islet trans- kept and when and how to administer
age in the community (88). African plantation may be an option, but the ap- it. An individual does not need to be
American individuals are at substantially proach remains experimental (96,97). a health care professional to safely
S106 Glycemic Targets Diabetes Care Volume 46, Supplement 1, January 2023

administer glucagon. In addition to tra- diabetes (106). Hence, individuals with insulin dosing can improve A1C with
ditional glucagon injection powder that one or more episodes of clinically signifi- minimal hypoglycemia (133,134).
requires reconstitution prior to injec- cant hypoglycemia may benefit from at
tion, intranasal glucagon and ready-to- least short-term relaxation of glycemic INTERCURRENT ILLNESS
inject glucagon preparations for sub- targets and availability of glucagon (107).
For further information on management
cutaneous injection are available and Any person with recurrent hypoglycemia
may be beneficial in view of safety, ef- or hypoglycemia unawareness should of individuals with hyperglycemia in the
ficacy, and ease of use. Care should be have their glucose management treat- hospital, see Section 16, “Diabetes Care
taken to ensure that glucagon products ment plan adjusted. in the Hospital.”
are not expired (102). Stressful events (e.g., illness, trauma,
Use of CGM Technology in Hypoglycemia surgery) may worsen glycemic control and

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Hypoglycemia Prevention Prevention precipitate diabetic ketoacidosis or nonke-
Hypoglycemia prevention is a critical With the advent of sensor-augmented totic hyperglycemic hyperosmolar state,
component of diabetes management. CGM and CGM-assisted pump therapy, life-threatening conditions that require im-
BGM and, for some individuals, CGM there has been a promise of alarm-based mediate medical care to prevent complica-
are essential tools to assess therapy prevention of hypoglycemia (108,109). To tions and death. Any condition leading to
and detect incipient hypoglycemia. Peo- date, there have been a number of ran- deterioration in glycemic control necessi-
ple with diabetes should understand sit- domized controlled trials in adults with tates more frequent monitoring of blood
uations that increase their risk of type 1 diabetes and studies in adults and glucose; ketosis-prone patients also re-
hypoglycemia, such as when fasting for children with type 1 diabetes using real- quire urine or blood ketone monitoring. If
laboratory tests or procedures, when time CGM (see Section 7, “Diabetes accompanied by ketosis, vomiting, or al-
meals are delayed, during and after the Technology”). These studies had differ-
consumption of alcohol, during and af- teration in the level of consciousness,
ing A1C at entry and differing primary marked hyperglycemia requires tempo-
ter intense physical activity, and during
end points and thus must be inter- rary adjustment of the treatment plan
sleep. Hypoglycemia may increase the
preted carefully. Real-time CGM studies and immediate interaction with the dia-
risk of harm to self or others, such as
can be divided into studies with ele- betes care team. The patient treated with
when driving. Teaching people with dia-
vated A1C with the primary end point
betes to balance insulin use and carbo- noninsulin therapies or medical nutrition
hydrate intake and physical activity are of A1C reduction and studies with A1C
therapy alone may require insulin. Ade-
near target with the primary end
necessary, but these strategies are not quate fluid and caloric intake must be
always sufficient for prevention (77, point of reduction in hypoglycemia (98,
ensured. Infection or dehydration are
103–105). Formal training programs to 109–124). In people with type 1 and
more likely to necessitate hospitaliza-
increase awareness of hypoglycemia type 2 diabetes with A1C above target,
CGM improved A1C between 0.3 and tion of individuals with diabetes versus
and to develop strategies to decrease
0.6%. For studies targeting hypoglyce- those without diabetes.
hypoglycemia have been developed, in-
mia, most studies demonstrated a signifi- A clinician with expertise in diabetes
cluding the Blood Glucose Awareness
Training Program, Dose Adjusted for cant reduction in time spent between 54 management should treat the hospital-
Normal Eating (DAFNE), and DAFNE- and 70 mg/dL. A report in people with ized patient. For further information on
plus. Conversely, some individuals with type 1 diabetes over the age of 60 years the management of diabetic ketoacidosis
type 1 diabetes or type 2 diabetes and revealed a small but statistically signifi- and the nonketotic hyperglycemic hyper-
hypoglycemia who have a fear of hyper- cant decrease in hypoglycemia (125). No osmolar state, please refer to the ADA
glycemia are resistant to relaxation of study to date has reported a decrease in consensus report “Hyperglycemic Crises
glycemic targets (74–83). Regardless of level 3 hypoglycemia. In a single study in Adult Patients With Diabetes” (134).
the factors contributing to hypoglycemia using intermittently scanned CGM, adults
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