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Diabetes Care Volume 41, Supplement 1, January 2018 S55

American Diabetes Association


6. Glycemic Targets: Standards of
Medical Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S55–S64 | https://doi.org/10.2337/dc18-S006

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

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

ASSESSMENT OF GLYCEMIC CONTROL


Patient self-monitoring of blood glucose (SMBG) and A1C are available to health
care providers and patients to assess the effectiveness and safety of a manage-
ment plan on glycemic control. Continuous glucose monitoring (CGM) also has
an important role in assessing the effectiveness and safety of treatment in sub-
groups of patients with type 1 diabetes and in selected patients with type 2 di-
abetes. Data indicate similar A1C and safety with the use of CGM compared with
SMBG (1).

Recommendations
c Most patients using intensive insulin regimens (multiple-dose insulin or in-
sulin pump therapy) should perform self-monitoring of blood glucose (SMBG)
prior to meals and snacks, at bedtime, occasionally postprandially, prior to
exercise, when they suspect low blood glucose, after treating low blood
glucose until they are normoglycemic, and prior to critical tasks such as
driving. B
c When prescribed as part of a broad educational program, SMBG may help to
guide treatment decisions and/or self-management for patients taking less fre-
quent insulin injections B or noninsulin therapies. E
c When prescribing SMBG, ensure that patients receive ongoing instruction and
regular evaluation of SMBG technique, SMBG results, and their ability to use
SMBG data to adjust therapy. E Suggested citation: American Diabetes Associa-
tion. 6. Glycemic targets: Standards of Medical
c When used properly, continuous glucose monitoring (CGM) in conjunction with
Care in Diabetesd2018. Diabetes Care 2018;
intensive insulin regimens is a useful tool to lower A1C in adults with type 1 41(Suppl. 1):S55–S64
diabetes who are not meeting glycemic targets. A © 2017 by the American Diabetes Association.
c CGM may be a useful tool in those with hypoglycemia unawareness and/or Readers may use this article as long as the work
frequent hypoglycemic episodes. C is properly cited, the use is educational and not
c Given the variable adherence to CGM, assess individual readiness for continuing for profit, and the work is not altered. More infor-
CGM use prior to prescribing. E mation is available at http://www.diabetesjournals
.org/content/license.
S56 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

should be advised against purchasing or most CGM devices include alarms for hypo-
c When prescribing CGM, robust di-
reselling preowned or secondhand test and hyperglycemic excursions. The inter-
abetes education, training, and sup-
strips, as these may give incorrect results. mittent or “flash” CGM device, very re-
port are required for optimal CGM
Only unopened vials of glucose test strips cently approved for adult use only (18),
implementation and ongoing use. E
should be used to ensure SMBG accuracy. differs from previous CGM devices. Spe-
c People who have been successfully
For Patients on Intensive Insulin Regimens cifically, it does not have alarms, does not
using CGM should have continued
Most patients using intensive insulin require calibration with SMBG, and does
access after they turn 65 years of
not communicate continuously (only on
age. E regimens (multiple-dose insulin or insulin
pump therapy) should perform SMBG demand). It is reported to have a lower
prior to meals and snacks, at bedtime, oc- cost than traditional systems. A study in
Self-monitoring of Blood Glucose
casionally postprandially, prior to exercise, adults with well-controlled type 1 diabe-
Major clinical trials of insulin-treated pa-
when they suspect low blood glucose, af- tes found that flash CGM users spent less
tients have included SMBG as part of
ter treating low blood glucose until they time in hypoglycemia than those using
multifactorial interventions to demon-
are normoglycemic, and prior to critical SMBG (19). However, due to significant
strate the benefit of intensive glycemic
tasks such as driving. For many patients, differences between flash CGM and other
control on diabetes complications. SMBG
this will require testing 6–10 (or more) CGM devices, more discussion is needed
is thus an integral component of effective
times daily, although individual needs on outcomes and regarding specific rec-
therapy (2). SMBG allows patients to eval-
may vary. A database study of almost ommendations.
uate their individual response to therapy
27,000 children and adolescents with For most CGM systems, confirmatory
and assess whether glycemic targets are
type 1 diabetes showed that, after adjust- SMBG is required to make treatment de-
being achieved. Integrating SMBG results
ment for multiple confounders, increased cisions, though a randomized controlled
into diabetes management can be a
daily frequency of SMBG was significantly trial of 226 adults suggested that an en-
useful tool for guiding medical nutrition
associated with lower A1C (–0.2% per ad- hanced CGM device could be used safely
therapy and physical activity, preventing
ditional test per day) and with fewer and effectively without regular confirma-
hypoglycemia, and adjusting medications
acute complications (8). tory SMBG in patients with well-controlled
(particularly prandial insulin doses). Among
type 1 diabetes at low risk of severe hy-
patients with type 1 diabetes, there is a
For Patients Using Basal Insulin and/or Oral poglycemia (1). Two CGM devices are now
correlation between greater SMBG fre-
Agents approved by the U.S. Food and Drug Ad-
quency and lower A1C (3). The patient’s
The evidence is insufficient regarding ministration (FDA) for making treatment
specific needs and goals should dictate
when to prescribe SMBG and how often decisions without SMBG confirmation
SMBG frequency and timing.
testing is needed for patients who do not use (18,20), including the flash CGM device.
Optimization intensive insulin regimens, such as those Although performed with older gener-
SMBG accuracy is dependent on the instru- with type 2 diabetes using oral agents ation CGM devices, a 26-week random-
ment and user, so it is important to evalu- and/or basal insulin. For patients using ized trial of 322 patients with type 1
ate each patient’s monitoring technique, basal insulin, assessing fasting glucose diabetes showed that adults aged $25 years
both initially and at regular intervals with SMBG to inform dose adjustments using intensive insulin therapy and CGM
thereafter. Optimal use of SMBG requires to achieve blood glucose targets results experienced a 0.5% reduction in A1C
proper review and interpretation of the in lower A1Cs (9,10). (from ;7.6% to 7.1% [;60 mmol/mol
data, by both the patient and the pro- For individuals with type 2 diabetes on to 54 mmol/mol]) compared with those
vider. Among patients who check their less intensive insulin therapy, more fre- using intensive insulin therapy with SMBG
blood glucose at least once daily, many quent SMBG (e.g., fasting, before/after (21). The greatest predictor of A1C lower-
report taking no action when results are meals) may be helpful, as increased fre- ing for all age-groups was frequency of
high or low. In a yearlong study of insulin- quency is associated with meeting A1C sensor use, which was highest in those
naive patients with suboptimal initial targets (11). aged $25 years and lower in younger
glycemic control, a group trained in struc- Several randomized trials have called age-groups. Two clinical trials in adults
tured SMBG (a paper tool was used at into question the clinical utility and cost- with type 1 diabetes not meeting A1C
least quarterly to collect and interpret effectiveness of routine SMBG in noninsu- targets and using multiple daily injections
7-point SMBG profiles taken on 3 consec- lin-treated patients (12–15). Meta-analyses also found that the use of CGM compared
utive days) reduced their A1C by 0.3 per- have suggested that SMBG can reduce A1C with usual care resulted in lower A1C levels
centage points more than the control by 0.25–0.3% at 6 months (16,17), but the than SMBG over 24–26 weeks (22,23).
group (4). Patients should be taught effect was attenuated at 12 months in Other small, short-term studies have
how to use SMBG data to adjust food in- one analysis (16). A key consideration is demonstrated similar A1C reductions us-
take, exercise, or pharmacologic therapy that performing SMBG alone does not ing CGM compared with SMBG in adults
to achieve specific goals. The ongoing lower blood glucose levels. To be useful, with A1C levels $7% (53 mmol/mol)
need for and frequency of SMBG should the information must be integrated into (24,25).
be reevaluated at each routine visit to clinical and self-management plans. A registry study of 17,317 participants
avoid overuse (5–7). SMBG is especially confirmed that more frequent CGM use is
important for insulin-treated patients to Continuous Glucose Monitoring associated with lower A1C (26), whereas
monitor for and prevent asymptomatic CGM measures interstitial glucose (which another study showed that children
hypoglycemia and hyperglycemia. Patients correlates well with plasma glucose), and with .70% sensor use (i.e., $5 days per
care.diabetesjournals.org Glycemic Targets S57

week) missed fewer school days (27). A1C TESTING when the A1C result does not correlate
Small randomized controlled trials in with the patient’s SMBG levels. Options
Recommendations
adults and children with baseline A1C for monitoring include more frequent and/
c Perform the A1C test at least two
,7.0–7.5% (53–58 mmol/mol) have con- or different timing of SMBG or CGM use.
times a year in patients who are
firmed favorable outcomes including a Other measures of average glycemia such
meeting treatment goals (and who
reduced frequency of hypoglycemia (de- as fructosamine and 1,5-anhydroglucitol
have stable glycemic control). E
fined as a blood glucose level ,70 mg/dL are available, but their translation into
c Perform the A1C test quarterly in
[3.9 mmol/L]) and maintaining A1C ,7% average glucose levels and their prog-
patients whose therapy has changed
(53 mmol/mol) during the study period in nostic significance are not as clear as
or who are not meeting glycemic
groups using CGM, suggesting that CGM for A1C. Though some variability exists
goals. E
may provide further benefit for individu- among different individuals, generally
c Point-of-care testing for A1C provides
als with type 1 diabetes who already have the association between mean glucose
the opportunity for more timely
good glycemic control (28–30). and A1C within an individual correlates
treatment changes. E
A meta-analysis suggests that com- over time (42).
pared with SMBG, CGM is associated A1C reflects average glycemia over A1C does not provide a measure of
with short-term A1C lowering of ;0.26% approximately 3 months and has strong glycemic variability or hypoglycemia. For
in insulin-treated patients (31). The long- predictive value for diabetes complica- patients prone to glycemic variability,
term effectiveness of CGM needs to be tions (39,40). Thus, A1C testing should especially patients with type 1 diabetes
determined. This technology may be par- be performed routinely in all patients or type 2 diabetes with severe insulin de-
ticularly useful in insulin-treated patients with diabetesdat initial assessment and ficiency, glycemic control is best evalu-
with hypoglycemia unawareness and/or as part of continuing care. Measurement ated by the combination of results from
frequent hypoglycemic episodes, although approximately every 3 months deter- A1C and SMBG or CGM. A1C may also
studies have not shown consistent reduc- mines whether patients’ glycemic targets confirm the accuracy of the patient’s me-
tions in severe hypoglycemia (31–33). A have been reached and maintained. The ter (or the patient’s reported SMBG re-
CGM device equipped with an automatic frequency of A1C testing should depend sults) and the adequacy of the SMBG
low glucose suspend feature has been on the clinical situation, the treatment testing schedule.
approved by the FDA. The Automation regimen, and the clinician’s judgment.
to Simulate Pancreatic Insulin Response The use of point-of-care A1C testing may A1C and Mean Glucose
(ASPIRE) trial of 247 patients with type 1 provide an opportunity for more timely Table 6.1 shows the correlation between
diabetes and documented nocturnal hypo- treatment changes during encounters be- A1C levels and mean glucose levels based
glycemia showed that sensor-augmented tween patients and providers. Patients on two studies: the international A1C-
insulin pump therapy with a low glucose with type 2 diabetes with stable glycemia Derived Average Glucose (ADAG) study,
suspend function significantly reduced well within target may do well with A1C which assessed the correlation between
nocturnal hypoglycemia over 3 months testing only twice per year. Unstable or A1C and frequent SMBG and CGM in
without increasing A1C levels (34). intensively managed patients (e.g., preg- 507 adults (83% non-Hispanic whites)
These devices may offer the opportunity nant women with type 1 diabetes) may with type 1, type 2, and no diabetes (43),
to reduce hypoglycemia for those with require testing more frequently than every and an empirical study of the average
a history of nocturnal hypoglycemia. 3 months (41). blood glucose levels at premeal, post-
The FDA has also approved the first meal, and bedtime associated with spec-
hybrid closed-loop system. The safety of A1C Limitations ified A1C levels using data from the
hybrid closed-loop systems has been sup- The A1C test is an indirect measure of ADAG trial (37). The American Diabetes
ported in the literature (35) and may have average glycemia and, as such, is subject Association (ADA) and the American As-
advantages over sensor-augmented to limitations. As with any laboratory test, sociation for Clinical Chemistry have de-
pump therapy in specific populations, there is variability in the measurement of termined that the correlation (r 5 0.92) in
such as pregnant women with type 1 A1C. Although such variability is less on an the ADAG trial is strong enough to justify
diabetes (36). intraindividual basis than that of blood reporting both the A1C result and the es-
Due to variable adherence, optimal glucose measurements, clinicians should timated average glucose (eAG) result
CGM use requires an assessment of indi- exercise judgment when using A1C as the when a clinician orders the A1C test. Clini-
vidual readiness for the technology as sole basis for assessing glycemic control, cians should note that the mean plasma
well as initial and ongoing education particularly if the result is close to the glucose numbers in the table are based on
and support (26,37). Additionally, pro- threshold that might prompt a change in ;2,700 readings per A1C in the ADAG
viders need to provide robust diabetes medication therapy. Conditions that affect trial. In a recent report, mean glucose
education, training, and support for opti- red blood cell turnover (hemolytic and measured with CGM versus central labo-
mal CGM implementation and ongoing other anemias, recent blood transfusion, ratory–measured A1C in 387 participants
use. As people with type 1 or type 2 use of drugs that stimulate erythropo- in three randomized trials demonstrated
diabetes are living longer, healthier lives, esis, end-stage kidney disease, and that A1C may underestimate or overesti-
individuals who have been successfully pregnancy) may result in discrepancies mate mean glucose. Thus, as suggested, a
using CGM should have continued access between the A1C result and the pa- patient’s CGM profile has considerable
to these devices after they turn 65 years tient’s true mean glycemia. Hemoglobin potential for optimizing his or her glyce-
of age (38). variants must be considered, particularly mic management (42).
S58 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

A1C Differences in Ethnic Populations

Data in parentheses represent 95% CI, unless otherwise noted. A calculator for converting A1C results into eAG, in either mg/dL or mmol/L, is available at http://professional.diabetes.org/eAG. *These estimates are
and Children

12.3 (10.9–13.8)

based on ADAG data of ;2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92 (43).
9.8 (9.2–10.4)
9.7 (9.0–10.4)
7.5 (7.3–7.8)
8.5 (8.0–8.9)
In the ADAG study, there were no signif-

mmol/L
icant differences among racial and ethnic

Mean bedtime glucose


groups in the regression lines between
A1C and mean glucose, although the
study was underpowered to detect a
difference and there was a trend toward

136 (131–141)
153 (145–161)

177 (166–188)
175 (163–188)

222 (197–248)
a difference between the African/African
mg/dL

American and non-Hispanic white co-


horts, with higher A1C values observed
in Africans/African Americans compared
with non-Hispanic whites for a given
10.5 (10.0–10.9)

11.4 (10.8–12.0)
9.8 (9.4–10.2)
8.0 (7.7–8.2)
9.1 (8.8–9.4)

mean glucose. Other studies have also


mmol/L
Mean postmeal glucose

demonstrated higher A1C levels in African


Americans than in whites at a given mean
glucose concentration (44,45). Moreover,
African Americans heterozygous for the
144 (139–148)
164 (159–169)

176 (170–183)
189 (180–197)

206 (195–217)

common hemoglobin variant HbS may


have, for any level of mean glycemia,
mg/dL

lower A1C by about 0.3 percentage points


than those without the trait (46). Another
genetic variant, X-linked glucose-6-phosphate
dehydrogenase G202A, carried by 11% of
9.9 (9.3–10.6)
6.5 (6.4–6.7)
7.7 (7.4–8.0)

8.4 (8.2–8.7)
8.6 (8.2–8.9)
mmol/L

African Americans, was associated with a


Mean premeal glucose

decrease in A1C of about 0.8% in hemi-


zygous men and 0.7% in homozygous
women compared to those without the
trait (47).
118 (115–121)
139 (134–144)

152 (147–157)
155 (148–161)

179 (167–191)

A small study comparing A1C to CGM


mg/dL

data in children with type 1 diabetes


found a highly statistically significant cor-
relation between A1C and mean blood glu-
cose, although the correlation (r 5 0.7) was
9.9 (9.1–10.7)
6.8 (6.5–7.0)
7.9 (7.5–8.3)

8.4 (7.9–9.0)
9.3 (8.7–9.8)

significantly lower than in the ADAG trial


mmol/L
Mean fasting glucose

(48). Whether there are clinically mean-


ingful differences in how A1C relates to
average glucose in children or in different
ethnicities is an area for further study
122 (117–127)
142 (135–150)

152 (143–162)
167 (157–177)

178 (164–192)

(44,49,50). Until further evidence is avail-


Table 6.1—Mean glucose levels for specified A1C levels (37,43)

mg/dL

able, it seems prudent to establish A1C


goals in these populations with consider-
ation of both individualized SMBG and
A1C results.
13.4 (10.7–15.7)
14.9 (12.0–17.5)
16.5 (13.3–19.3)
10.2 (8.1–12.1)

11.8 (9.4–13.9)
8.6 (6.8–10.3)
7.0 (5.5–8.5)
mmol/L

A1C GOALS
Mean plasma glucose*

For glycemic goals in children, please refer to


Section 12 “Children and Adolescents.”
For glycemic goals in pregnant women,
please refer to Section 13 “Management
126 (100–152)

154 (123–185)

183 (147–217)

212 (170–249)
240 (193–282)
269 (217–314)
298 (240–347)

of Diabetes in Pregnancy.”
mg/dL

Recommendations
c A reasonable A1C goal for many
nonpregnant adults is ,7% (53
mmol/mol). A
5.5–6.49 (37–47)
6.5–6.99 (47–53)

7.0–7.49 (53–58)
7.5–7.99 (58–64)

8.0–8.5 (64–69)
% (mmol/mol)

c Providers might reasonably suggest


more stringent A1C goals (such
12 (108)
10 (86)
11 (97)

as ,6.5% [48 mmol/mol]) for se-


6 (42)

7 (53)

8 (64)

9 (75)
A1C

lected individual patients if this


care.diabetesjournals.org Glycemic Targets S59

curvilinear relationship between A1C and death compared with those previously ran-
can be achieved without significant
microvascular complications. Such anal- domized to the standard arm (62). The
hypoglycemia or other adverse ef-
yses suggest that, on a population level, benefit of intensive glycemic control in
fects of treatment (i.e., polyphar-
the greatest number of complications will this cohort with type 1 diabetes has
macy). Appropriate patients might
be averted by taking patients from very been shown to persist for several decades
include those with short duration of
poor control to fair/good control. These (63) and to be associated with a modest
diabetes, type 2 diabetes treated
analyses also suggest that further lower- reduction in all-cause mortality (64).
with lifestyle or metformin only,
ing of A1C from 7% to 6% [53 mmol/mol
long life expectancy, or no signifi- Cardiovascular Disease and Type 2 Diabetes
to 42 mmol/mol] is associated with fur-
cant cardiovascular disease. C In type 2 diabetes, there is evidence that
ther reduction in the risk of microvascular
c Less stringent A1C goals (such more intensive treatment of glycemia in
complications, although the absolute risk
as ,8% [64 mmol/mol]) may be ap- newly diagnosed patients may reduce
reductions become much smaller. Given
propriate for patients with a history long-term CVD rates. During the UKPDS,
the substantially increased risk of hypo-
of severe hypoglycemia, limited life there was a 16% reduction in CVD events
glycemia in type 1 diabetes trials and
expectancy, advanced microvascu- (combined fatal or nonfatal MI and sud-
with polypharmacy in type 2 diabetes,
lar or macrovascular complications, den death) in the intensive glycemic con-
the risks of lower glycemic targets out-
extensive comorbid conditions, or trol arm that did not reach statistical
weigh the potential benefits on microvas-
long-standing diabetes in whom significance (P 5 0.052), and there was
cular complications.
the goal is difficult to achieve de- no suggestion of benefit on other CVD
spite diabetes self-management ACCORD, ADVANCE, and VADT outcomes (e.g., stroke). However, after
education, appropriate glucose Three landmark trials (Action to Control 10 years of observational follow-up, those
monitoring, and effective doses of Cardiovascular Risk in Diabetes [ACCORD], originally randomized to intensive glyce-
multiple glucose-lowering agents Action in Diabetes and Vascular Disease: mic control had significant long-term re-
including insulin. B Preterax and Diamicron MR Controlled ductions in MI (15% with sulfonylurea or
Evaluation [ADVANCE], and Veterans Af- insulin as initial pharmacotherapy, 33%
A1C and Microvascular Complications fairs Diabetes Trial [VADT]) showed that with metformin as initial pharmacother-
Hyperglycemia defines diabetes, and gly- lower A1C levels were associated with re- apy) and in all-cause mortality (13% and
cemic control is fundamental to diabetes duced onset or progression of some micro- 27%, respectively) (56).
management. The Diabetes Control and vascular complications (58–60). ACCORD, ADVANCE, and VADT sug-
Complications Trial (DCCT) (2), a prospec- The concerning mortality findings in gested no significant reduction in CVD
tive randomized controlled trial of inten- the ACCORD trial (61), discussed below, outcomes with intensive glycemic control
sive versus standard glycemic control in and the relatively intense efforts required in participants followed for 3.5–5.6 years
patients with type 1 diabetes, showed de- to achieve near-euglycemia should also who had more advanced type 2 diabetes
finitively that better glycemic control is be considered when setting glycemic tar- than UKPDS participants. All three trials
associated with significantly decreased gets. However, on the basis of physician were conducted in relatively older partic-
rates of development and progression of judgment and patient preferences, select ipants with longer known duration of di-
microvascular (retinopathy [51], neurop- patients, especially those with little co- abetes (mean duration 8–11 years) and
athy, and diabetic kidney disease) compli- morbidity and long life expectancy, may either CVD or multiple cardiovascular risk
cations. Follow-up of the DCCT cohorts in benefit from adopting more intensive gly- factors. The target A1C among intensive
the Epidemiology of Diabetes Interven- cemic targets (e.g., A1C target ,6.5% control subjects was ,6% (42 mmol/mol)
tions and Complications (EDIC) study [48 mmol/mol]) as long as significant hy- in ACCORD, ,6.5% (48 mmol/mol) in
(52) demonstrated persistence of these poglycemia does not become a barrier. ADVANCE, and a 1.5% reduction in A1C
microvascular benefits despite the fact compared with control subjects in VADT,
that the glycemic separation between A1C and Cardiovascular Disease with achieved A1C of 6.4% vs. 7.5%
the treatment groups diminished and dis- Outcomes (46 mmol/mol vs. 58 mmol/mol) in ACCORD,
appeared during follow-up. Cardiovascular Disease and Type 1 Diabetes 6.5% vs. 7.3% (48 mmol/mol vs. 56
The Kumamoto Study (53) and UK Pro- Cardiovascular disease (CVD) is a more mmol/mol) in ADVANCE, and 6.9% vs.
spective Diabetes Study (UKPDS) (54,55) common cause of death than microvascular 8.4% (52 mmol/mol vs. 68 mmol/mol) in
confirmed that intensive glycemic control complications in populations with diabetes. VADT. Details of these studies are re-
significantly decreased rates of microvas- There is evidence for a cardiovascular ben- viewed extensively in “Intensive Glycemic
cular complications in patients with type 2 efit of intensive glycemic control after long- Control and the Prevention of Cardiovas-
diabetes. Long-term follow-up of the term follow-up of cohorts treated early in cular Events: Implications of the ACCORD,
UKPDS cohorts showed enduring effects the course of type 1 diabetes. In the DCCT, ADVANCE, and VA Diabetes Trials” (65).
of early glycemic control on most micro- there was a trend toward lower risk of CVD The glycemic control comparison in
vascular complications (56). events with intensive control. In the 9-year ACCORD was halted early due to an in-
Therefore, achieving A1C targets post-DCCT follow-up of the EDIC cohort, creased mortality rate in the intensive
of ,7% (53 mmol/mol) has been shown participants previously randomized to the compared with the standard treatment
to reduce microvascular complications of intensive arm had a significant 57% reduc- arm (1.41% vs. 1.14% per year; hazard ra-
diabetes. Epidemiological analyses of the tion in the risk of nonfatal myocardial in- tio 1.22 [95% CI 1.01–1.46]), with a similar
DCCT (2) and UKPDS (57) demonstrate a farction (MI), stroke, or cardiovascular increase in cardiovascular deaths. Analysis
S60 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

Table 6.2—Summary of glycemic recommendations for many nonpregnant adults have been associated with increased car-
with diabetes diovascular risk independent of fasting
A1C <7.0% (53 mmol/mol)* plasma glucose in some epidemiological
Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L) studies, but intervention trials have not
Peak postprandial capillary plasma glucose† <180 mg/dL* (10.0 mmol/L) shown postprandial glucose to be a cardio-
*More or less stringent glycemic goals may be appropriate for individual patients. Goals should be
vascular risk factor independent of A1C. In
individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD subjects with diabetes, surrogate measures
or advanced microvascular complications, hypoglycemia unawareness, and individual patient of vascular pathology, such as endothelial
considerations. †Postprandial glucose may be targeted if A1C goals are not met despite reaching dysfunction, are negatively affected by post-
preprandial glucose goals. Postprandial glucose measurements should be made 1–2 h after the
beginning of the meal, generally peak levels in patients with diabetes. prandial hyperglycemia. It is clear that post-
prandial hyperglycemia, like preprandial
hyperglycemia, contributes to elevated
of the ACCORD data did not identify a proposes optimal targets, but each target A1C levels, with its relative contribution be-
clear explanation for the excess mortality must be individualized to the needs of each ing greater at A1C levels that are closer to
in the intensive treatment arm (61). patient and his or her disease factors. 7% (53 mmol/mol). However, outcome
Longer-term follow-up has shown no ev- When possible, such decisions should be studies have clearly shown A1C to be the
idence of cardiovascular benefit or harm in made with the patient, reflecting his or her primary predictor of complications, and
the ADVANCE trial (66). The end-stage re- preferences, needs, and values. Fig. 6.1 landmark trials of glycemic control such as
nal disease rate was lower in the intensive is not designed to be applied rigidly but the DCCT and UKPDS relied overwhelmingly
treatment group over follow-up. However, to be used as a broad construct to guide on preprandial SMBG. Additionally, a ran-
10-year follow-up of the VADT cohort clinical decision-making (72), in both type 1 domized controlled trial in patients with
(67) showed a reduction in the risk of car- and type 2 diabetes. known CVD found no CVD benefit of insulin
diovascular events (52.7 [control group] Recommended glycemic targets for regimens targeting postprandial glucose
vs. 44.1 [intervention group] events per many nonpregnant adults are shown in compared with those targeting preprandial
1,000 person-years) with no benefit in Table 6.2. The recommendations include glucose (74). Therefore, it is reasonable for
cardiovascular or overall mortality. Hetero- blood glucose levels that appear to corre- postprandial testing to be recommended
geneity of mortality effects across studies late with achievement of an A1C of ,7% for individuals who have premeal glucose
was noted, which may reflect differences (53 mmol/mol). The issue of preprandial values within target but have A1C values
in glycemic targets, therapeutic approaches, versus postprandial SMBG targets is com- above target. Measuring postprandial
and population characteristics (68). plex (73). Elevated postchallenge (2-h oral plasma glucose 1–2 h after the start of a
Mortality findings in ACCORD (61) and glucose tolerance test) glucose values meal and using treatments aimed at
subgroup analyses of VADT (69) suggest
that the potential risks of intensive glyce-
mic control may outweigh its benefits in
higher-risk patients. In all three trials, se-
vere hypoglycemia was significantly more
likely in participants who were randomly
assigned to the intensive glycemic control
arm. Those patients with long duration of
diabetes, a known history of hypoglyce-
mia, advanced atherosclerosis, or ad-
vanced age/frailty may benefit from less
aggressive targets (70,71).
Providers should be vigilant in preventing
hypoglycemia and should not aggressively
attempt to achieve near-normal A1C levels
in patients in whom such targets cannot be
safely and reasonably achieved. Severe or
frequent hypoglycemia is an absolute indi-
cation for the modification of treatment
regimens, including setting higher glycemic
goals.
Many factors, including patient prefer-
ences, should be taken into account when
developing a patient’s individualized
goals (Table 6.2).

A1C and Glycemic Targets Figure 6.1—Depicted are patient and disease factors used to determine optimal A1C targets.
Numerous aspects must be considered Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those
when setting glycemic targets. The ADA toward the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (72).
care.diabetesjournals.org Glycemic Targets S61

Table 6.3—Classification of hypoglycemia*


Level Glycemic criteria Description
Hypoglycemia alert value (level 1) #70 mg/dL (3.9 mmol/L) Sufficiently low for treatment with fast-acting carbohydrate and dose
adjustment of glucose-lowering therapy
Clinically significant hypoglycemia (level 2) ,54 mg/dL (3.0 mmol/L) Sufficiently low to indicate serious, clinically important hypoglycemia
Severe hypoglycemia (level 3) No specific glucose threshold Hypoglycemia associated with severe cognitive impairment requiring
external assistance for recovery
*Adapted from ref. 75.

reducing postprandial plasma glucose val- Hypoglycemia may be inconvenient or


c Hypoglycemia unawareness or one
ues to ,180 mg/dL (10.0 mmol/L) may frightening to patients with diabetes. Se-
or more episodes of severe hypo-
help to lower A1C. vere hypoglycemia may be recognized or
glycemia should trigger reevalua-
An analysis of data from 470 participants unrecognized and can progress to loss of
tion of the treatment regimen. E
in the ADAG study (237 with type 1 diabe- consciousness, seizure, coma, or death. It is
c Insulin-treated patients with hy-
tes and 147 with type 2 diabetes) found reversed by administration of rapid-acting
poglycemia unawareness or an
that actual average glucose levels associ- glucose or glucagon. Clinically significant
episode of clinically significant hy-
ated with conventional A1C targets were hypoglycemia can cause acute harm to
poglycemia should be advised to
higher than older DCCT and ADA targets the person with diabetes or others, espe-
raise their glycemic targets to
(Table 6.1) (37,39). These findings support cially if it causes falls, motor vehicle acci-
strictly avoid hypoglycemia for at
that premeal glucose targets may be relaxed dents, or other injury. A large cohort study
least several weeks in order to par-
without undermining overall glycemic con- suggested that among older adults with
tially reverse hypoglycemia un-
trol as measured by A1C. These data promp- type 2 diabetes, a history of severe hypo-
awareness and reduce risk of future
ted the revision in the ADA-recommended glycemia was associated with greater risk
episodes. A
premeal glucose target to 80–130 mg/dL of dementia (77). Conversely, in a sub-
c Ongoing assessment of cognitive
(4.4–7.2 mmol/L) but did not affect the study of the ACCORD trial, cognitive
function is suggested with increased
definition of hypoglycemia. impairment at baseline or decline in cog-
vigilance for hypoglycemia by the
nitive function during the trial was sig-
clinician, patient, and caregivers if
HYPOGLYCEMIA nificantly associated with subsequent
low cognition or declining cognition
episodes of severe hypoglycemia (78). Ev-
Recommendations is found. B
idence from DCCT/EDIC, which involved
c Individuals at risk for hypoglycemia
adolescents and younger adults with
should be asked about symptom-
Hypoglycemia is the major limiting factor type 1 diabetes, found no association be-
atic and asymptomatic hypoglyce-
in the glycemic management of type 1 tween frequency of severe hypoglycemia
mia at each encounter. C
and type 2 diabetes. Recommendations and cognitive decline (79), as discussed in
c Glucose (15–20 g) is the preferred
from the International Hypoglycemia Study Section 12 “Children and Adolescents.”
treatment for the conscious individ-
Group regarding the classification of hypo- Severe hypoglycemia was associated
ual with blood glucose #70 mg/dL
glycemia in clinical trials are outlined in Ta- with mortality in participants in both the
[3.9 mmol/L]), although any form of
ble 6.3 (75). Of note, this classification standard and the intensive glycemia arms
carbohydrate that contains glucose
scheme considers a blood glucose ,54 of the ACCORD trial, but the relationships
may be used. Fifteen minutes after
mg/dL (3.0 mmol/L) detected by SMBG, between hypoglycemia, achieved A1C,
treatment, if SMBG shows contin-
CGM (for at least 20 min), or laboratory and treatment intensity were not straight-
ued hypoglycemia, the treatment
measurement of plasma glucose as suffi- forward. An association of severe hypo-
should be repeated. Once SMBG
ciently low to indicate clinically significant glycemia with mortality was also found
returns to normal, the individual
hypoglycemia that should be included in in the ADVANCE trial (80). An association
should consume a meal or snack to
reports of clinical trials of glucose-lowering between self-reported severe hypoglyce-
prevent recurrence of hypoglycemia. E
drugs for the treatment of diabetes (75). mia and 5-year mortality has also been
c Glucagon should be prescribed for
However, a hypoglycemia alert value reported in clinical practice (81).
all individuals at increased risk of
of #70 mg/dL (3.9 mmol/L) can be impor- Young children with type 1 diabetes and
clinically significant hypoglycemia,
tant for therapeutic dose adjustment of the elderly, including those with type 1 and
defined as blood glucose ,54 mg/dL
glucose-lowering drugs in clinical care and type 2 diabetes (77,82), are noted as par-
(3.0 mmol/L), so it is available should
is often related to symptomatic hypogly- ticularly vulnerable to clinically significant
it be needed. Caregivers, school
cemia. Severe hypoglycemia is defined as hypoglycemia because of their reduced
personnel, or family members of
severe cognitive impairment requiring as- ability to recognize hypoglycemic symp-
these individuals should know
sistance from another person for recov- toms and effectively communicate their
where it is and when and how to
ery (76). needs. Individualized glucose targets, pa-
administer it. Glucagon administra-
Symptoms of hypoglycemia include, tient education, dietary intervention (e.g.,
tion is not limited to health care
but are not limited to, shakiness, irritabil- bedtime snack to prevent overnight hypo-
professionals. E
ity, confusion, tachycardia, and hunger. glycemia when specifically needed to treat
S62 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

low blood glucose), exercise management, with hypoglycemia-prone diabetes (fam- prone patients also require urine or
medication adjustment, glucose monitor- ily members, roommates, school person- blood ketone monitoring. If accompa-
ing, and routine clinical surveillance may nel, child care providers, correctional nied by ketosis, vomiting, or alteration in
improve patient outcomes (76). CGM with institution staff, or coworkers) should be the level of consciousness, marked hyper-
automated low glucose suspend has been instructed on the use of glucagon kits in- glycemia requires temporary adjustment of
shown to be effective in reducing hypogly- cluding where the kit is and when and the treatment regimen and immediate in-
cemia in type 1 diabetes (34). For patients how to administer glucagon. An individual teraction with the diabetes care team. The
with type 1 diabetes with severe hypogly- does not need to be a health care pro- patient treated with noninsulin therapies or
cemia and hypoglycemia unawareness fessional to safely administer glucagon. medical nutrition therapy alone may tem-
that persists despite medical treatment, Care should be taken to ensure that glu- porarily require insulin. Adequate fluid and
human islet transplantation may be an op- cagon kits are not expired. caloric intake must be ensured. Infection or
tion, but the approach remains experimen- Hypoglycemia Prevention
dehydration is more likely to necessitate
tal (83,84). Hypoglycemia prevention is a critical com- hospitalization of the person with diabetes
In 2015, the ADA changed its prepran- ponent of diabetes management. SMBG than the person without diabetes.
dial glycemic target from 70–130 mg/dL and, for some patients, CGM are essential A physician with expertise in diabetes
(3.9–7.2 mmol/L) to 80–130 mg/dL (4.4– tools to assess therapy and detect incipient management should treat the hospital-
7.2 mmol/L). This change reflects the results hypoglycemia. Patients should understand ized patient. For further information on
of the ADAG study, which demonstrated situations that increase their risk of hypo- the management of diabetic ketoacidosis
that higher glycemic targets corresponded glycemia, such as fasting for tests or pro- and the hyperglycemic nonketotic hyper-
to A1C goals (37). An additional goal of cedures, delayed meals, during or after osmolar state, please refer to the ADA con-
raising the lower range of the glycemic intense exercise, and during sleep. Hypo- sensus report “Hyperglycemic Crises in
target was to limit overtreatment and glycemia may increase the risk of harm to Adult Patients With Diabetes” (87).
provide a safety margin in patients titrat- self or others, such as with driving. Teach-
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