Hypoglycemia

Javier Morales, MD,a Doron Schneiderb

a
Advanced Internal Medicine Group, P.C., Great Neck, NY; bAbington Health, Abingdon, Pa.

ABSTRACT

Hypoglycemia is a common, potentially avoidable consequence of diabetes treatment and is a major barrier
to initiating or intensifying antihyperglycemic therapy in efforts to achieve better glycemic control. Therapy
regimen and a history of hypoglycemia are the most important predictors of future events. Other risk factors
include renal insufficiency, older age, and history of hypoglycemia-associated autonomic failure. Reported
rates of hypoglycemia vary considerably among studies because of differences in study design, definitions
used, and population included, among other factors. Although occurring more frequently in type 1 diabetes,
hypoglycemia also is clinically important in type 2 diabetes. Symptoms experienced by patients vary among
individuals, and many events remain undiagnosed. The incidence of severe events is unevenly distributed,
with only a small proportion (w5%) of individuals accounting for >50% of events. Consequently, clini-
cians must be conscientious in obtaining thorough patient histories, because an accurate picture of the
frequency and severity of hypoglycemic events is essential for optimal diabetes management. Severe hy-
poglycemia in particular is associated with an increased risk of mortality, impairments in cognitive function,
and adverse effects on patients’ quality of life. Economically, hypoglycemia burdens the healthcare system
and adversely affects workplace productivity, particularly after a nocturnal event. Ongoing healthcare re-
form efforts will result in even more emphasis on reducing this side effect of diabetes treatment. Therefore,
improving patients’ self-management skills and selecting or modifying therapy to reduce the risk of hy-
poglycemia will increase in importance for clinicians and patients alike.
Ó 2014 Elsevier Inc. All rights reserved.
The American Journal of Medicine (2014) 127, S17-S24

KEYWORDS: Blood glucose management; Diabetes; Hypoglycemia; Insulin treatment; Treatment options

Hypoglycemia is a common, potentially avoidable conse-
quence of diabetes treatment and a major barrier to better
metabolic control in type 1 and type 2 diabetes. It is a sig-
nificant concern of primary care practitioners and patients
when it comes to initiating or intensifying antihyper-
glycemic therapy.1 Hypoglycemia can be defined in several
ways: by plasma glucose values (biochemical definition), by
symptoms (type and severity), and by time of day in which
Funding: The publication of this manuscript was funded by Novo
Nordisk Inc.
Conflict of Interest: JM has served on advisory boards for Novo
Nordisk and Boehringer Ingelheim, and is on the speakers bureau for Novo
Nordisk, Boehringer Ingelheim, Ortho Biotec, and Warner Chilcott. DS has
served on advisory boards for Novo Nordisk, Janssen, and Lilly.
Authorship: The authors take full responsibility for the content of this
manuscript. Writing support was provided by Watermeadow Medical.
Requests for reprints should be addressed to Javier Morales, MD,
Advanced Internal Medicine Group, P.C., 310 E Shore Rd, Great Neck, NY
11023, USA.
E-mail address: saxodoc@gmail.com
it occurs (daytime or nocturnal).2 The literature is incon-
sistent in describing biochemical hypoglycemia, and these
definitions may vary in clinical trials in inpatient versus
outpatient settings; thus, an American Diabetes Associa-
tion (ADA) workgroup has proposed 5 classifications
(Table 1).2 As Seaquist et al2 have noted, the ADA standard
of 70 mg/dL (3.9 mmol/L) is an alert value, intended to
provide a margin of error for the limited accuracy of glucose
monitoring devices at lower glucose levels. Because this
value is above the threshold for symptoms, it allows suffi-
cient time for corrective action to be taken.
It has been questioned whether the ADA standard is the
most appropriate cutoff point for the biochemical definition
of hypoglycemia because it is based on glucose-clamp
studies, which measure arterialized venous samples,
whereas it is capillary glucose, which tends to be approxi-
mately 15% lower than venous samples, that is typically
measured in practice. Thus, it has been argued that in
the absence of symptoms, a lower level (eg, 63 mg/dL
[3.5 mmol/L]) should be used for biochemical definition.3

0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjmed.2014.07.004
S18 The American Journal of Medicine, Vol 127, No 10A, October 2014
Table 1 Definitions of Hypoglycemia2
Documented Asymptomatic
Symptomatic (Documented)
Severe Hypoglycemia Hypoglycemia Hypoglycemia
Requires assistance of Typical symptoms Measured plasma
a third party and is accompanied by glucose 70 mg/dL
ameliorated by measured plasma but without
normalization of glucose 70 mg/dL typical symptoms
plasma glucose
With respect to symptomatic definitions, hypoglycemia
may be self-treated (mild) or severe/major (ie, requiring
assistance of a third party).2 Symptoms can be divided into
2 broad groups: autonomic (eg, sweating, heart palpitations,
shaking, dizziness, hunger) and neuroglycopenic (eg, confu-
sion, drowsiness, speech difficulty, odd behavior, incoordi-
nation).4,5 Unfortunately, the symptoms experienced are
inconsistent between individuals, which complicates our ef-
forts in identifying hypoglycemia and in counseling patients
who experience these symptoms.6 Furthermore, symptoms
are not pathognomonic and can occur while a person is bio-
chemically normoglycemic (pseudo-hypoglycemia) or when
normalizing glucose levels in those patients with prolonged
hyperglycemia.7 Assessing the frequency of nocturnal hypo-
glycemia is challenging because of inconsistencies in defining
the beginning and end of the nocturnal period in various
studies. Furthermore, continuous glucose monitoring studies
confirm that many episodes of hypoglycemia are not detected
by patients with type 1 diabetes8 and type 2 diabetes.9
FREQUENCY OF HYPOGLYCEMIA
Data from population-based studies confirm that hypogly-
cemia rates are higher in patients with type 1 diabetes than
in those with type 2 diabetes. For example, in a random
sample of 267 insulin-treated people, 94 with type 1 dia-
betes had a total of 336 hypoglycemic events (42.89 events
per person-year), 9 of which were severe (1.15 events
per person-year). By comparison, 173 people with type 2
diabetes experienced a total of 236 hypoglycemic events
(16.37 events per person-year), 5 of which were severe (0.35
events per person-year).10 Another review estimated that
7% to 25% of patients with type 2 diabetes using insulin
experience at least 1 severe episode annually.4 Hypoglyce-
mia also is commonly reported in people with type 2 dia-
betes using oral medications.4,11
Nevertheless, it is important to recognize the limitations
of making a broad generalization about the comparative
incidence in type 1 diabetes versus type 2 diabetes in
community populations or in randomized trials. Random-
ized trials may titrate patients more ambitiously, but ex-
clude people with a high risk of severe hypoglycemia or
hypoglycemia unawareness. If treated to a very tight glucose
Probable Symptomatic
Hypoglycemia Pseudo-hypoglycemia
Typical symptoms responding Typical symptoms but with
to self-treatment but not a measured plasma glucose
confirmed by biochemical greater than but approaching
documentation but 70 mg/dL
presumably caused by
plasma glucose 70 mg/dL
target, patients with type 2 diabetes conceivably could be at
a similar risk to those with type 1 diabetes. In population
statistics (in type 1 diabetes), the distribution of severe hy-
poglycemia is skewed, with a small proportion (5%) of in-
dividuals accounting for the majority (54%) of events.12 It is
critical that these patients be identified and case managed
more proactively.
RISK FACTORS/BEHAVIORS PREDISPOSING
TO HYPOGLYCEMIA
Antidiabetic therapies, individually and used in combina-
tion, vary substantially in their risk of hypoglycemia.13-16 In
one meta-analysis of intensification after failure of maximal
metformin monotherapy, all noninsulin second-tier medi-
cations provided similar improvements in glycemic control,
but were distinguishable by different rates of hypoglycemia
(Table 2).15
Studies have identified numerous patient-level predictors
of hypoglycemia. In type 1 diabetes, these include a history
of hypoglycemia (P ¼ .006) and co-prescribing of any oral
drug (P ¼ .048), whereas in insulin-treated type 2 diabetes,
predictors included a history of hypoglycemia (P < .0001)
and duration of insulin treatment (P ¼ .014).10 In a study of
patients intensifying therapy because of insufficient control
on 1 or 2 oral medications, after adjustment for confounding
variables, the following factors were significant predictors:
prior anamnestic (remembered) hypoglycemia (odds ratio
[OR], 4.05; 95% confidence interval [CI], 3.04-5.39), pre-
existent retinopathy (OR, 3.27; 95% CI, 1.07-30.02), pre-
existent clinically relevant depression (OR, 1.81; 95% CI,
1.14-2.88), insulin use starting at baseline (OR, 2.99; 95%
CI, 2.27-3.95), and blood glucose self-measurement (OR,
1.72; 95% CI, 1.23-2.41).16 In type 2 diabetes, factors that
have been reported to precede a severe hypoglycemic
episode include a change in food intake, more vigorous
exercise, increase in insulin dose, and cognitive impairment,
among others.13 Caffeine is an example of a commonly
ingested substance that, by virtue of its potential to produce
resting tremors and tachycardia, may enhance the intensity
of warning symptoms, and thus increase the number of mild
episodes reported.17
Morales and Schneider Hypoglycemia
Table 2 Results of Two Methods of Meta-analysis Comparing Noninsulin Antidiabetic Drugs with Placebo on Overall Hypoglycemia15
Risk of Overall Hypoglycemia
Traditional Meta-analysis
No. of Trials Relative Risk
Sulfonylureas 3 2.63
Glinides 2 7.92
Thiazolidinediones 2 2.04
AGIs 2 0.60
DPP4-inhibitors 8 0.67
GLP-1 analogs 2 0.94
AGI ¼ alpha-glucosidase inhibitor; CI ¼ confidence interval; DPP4 ¼ dipeptidyl peptidase-4; GLP-1 ¼ glucagon-like peptide-1.
*I2  75% (significant statistical heterogeneity present).
SUBGROUPS AT RISK
Patients with Renal Insufficiency
Patients with diabetes who have chronic kidney disease
have a higher frequency of hypoglycemia than people with
diabetes who do not have chronic kidney disease. In a
retrospective analysis of more than 200,000 patients cared
for by the Veterans Health Administration, the rate of hy-
poglycemia was approximately twice as high for people
with a diagnosis of diabetes having chronic kidney disease
(glomerular filtration rate <60 mL/min per 1.73 m2) versus
those without chronic kidney disease (glomerular filtration
rate 60 mL/min per 1.73 m2) (10.72 vs 5.33 episodes per
100 patient-months, respectively).18 Reasons for this in-
creased risk include reduced insulin requirements because of
decreased renal clearance of insulin, decreased degradation
of insulin in peripheral tissues, reduced renal gluconeo-
genesis if there is a reduction in renal mass, and prolonged
half-life of other drugs in chronic kidney disease.18
Elderly Patients
Elderly patients are at increased risk of hypoglycemia, partly
because of factors such as deteriorating renal function
affecting drug clearance, occurrence of polypharmacy mak-
ing more drugs available for adverse interactions, and
decreased cognitive functioning.19 This elevated risk com-
pared with nonelderly individuals persists even at compara-
ble glycemic control.20 Glycemic thresholds at which
counter-regulatory responses to hypoglycemia occur are
lowered in elderly persons (eg, <2.0 mmol/L [36 mg/dL]),
decreasing potential reaction time for corrective action and
increasing the risk for asymptomatic hypoglycemia.20,21
Elderly patients also report different symptoms and have
different responses to hypoglycemia (eg, diminished auto-
nomic symptoms and more prominent neuroglycopenic
symptoms). Thus, hypoglycemia can be misdiagnosed as
delirium or neurologic events. Cognitive impairments in the
elderly may contribute to the increased risk of hypoglyce-
mia, and hypoglycemia may further worsen or increase the
risk of cognitive issues.22,23 The joint occurrence of
hypoglycemia unawareness and deteriorated cognitive
S19
Mixed-Treatment Meta-analysis
95% CI Relative Risk 95% Credible Interval
0.76-9.13* 4.57 2.11-11.45
1.45-43.21 7.50 2.12-41.52
0.50-8.23 0.56 0.19-1.69
0.08-4.55 0.42 0.01-9.00
0.30-1.50 0.63 0.26-1.71
0.42-2.12 0.89 0.22-3.96
function is a critical factor to be carefully considered in the
treatment of older patients.24 A recent study of 40 elderly
(mean age, 75 years; 70% had type 2 diabetes), mostly
insulin-using diabetic patients found that after continuous
glucose monitoring for 3 days, 65% (n ¼ 26) of patients had
a blood glucose level <70 mg/dL, and 46% of those (n ¼
12) had an episode with blood glucose <50 mg/dL. It was
worrisome that 93% (95/102) of hypoglycemic events were
not detected, either by finger-stick glucose monitoring or
symptoms.25 Thus, expert guidelines recognize that it may
be prudent to strive for less ambitious targets in many
elderly patients.26
People with Hypoglycemia Unawareness and
Hypoglycemia-Associated Autonomic Failure
Defective glucose counter-regulation and hypoglycemia
unawareness constitute the syndrome of hypoglycemia-
associated autonomic failure, which can occur in people
with type 1 or 2 diabetes. Those with recent antecedent
hypoglycemia are predisposed.27,28 Affected individuals
have loss of forewarning symptoms of hypoglycemia and
decreased response to those symptoms, and thus are at
increased risk of hypoglycemia.27,28 In one study, adults
with type 1 diabetes and impaired awareness of hypogly-
cemia exhibited twice the frequency of all episodes of hy-
poglycemia over a 4-week monitoring period, compared
with those with normal awareness (mean  standard devi-
ation, 7.9  5.4 episodes vs 3.7  3.6 episodes, P ¼ .003).29
Annual prevalence of severe hypoglycemia was 53% in
people with type 1 diabetes and impaired awareness
compared with 5% for people with normal awareness.29
During sleep, physiologic defenses may be further com-
promised, making it less likely that a person will awaken
because of hypoglycemia.30,31
CONSEQUENCES OF HYPOGLYCEMIA
Clinical Consequences
Overall, it has been estimated that 4% to 10% of deaths
of patients with type 1 diabetes are associated with
S20
hypoglycemia.2,32 In a sample of 1013 adults with type 1 or
2 diabetes, self-reports of severe hypoglycemia were asso-
ciated with a 3.4-fold (95% CI, 1.5-7.4) higher mortality
after 5 years compared with those who reported no events or
mild events.33 In a study of 11,140 people with type 2 dia-
betes (Action in Diabetes and Vascular Disease: Preterax and
Diamicron Modified-Release Controlled Evaluation trial
[ADVANCE]), the mortality rate among those reporting
severe hypoglycemia was 19.5%, compared with 9% for
those without severe hypoglycemia, and all-cause mortality
risk remained increased for 4 years after a severe hypogly-
cemic event.11
Much of this mortality may be mediated via increased
risk of cardiovascular death. In the ADVANCE trial, severe
hypoglycemia was associated with significant increases in
the risk of major macrovascular events (hazard ratio [HR],
2.88; 95% CI, 2.01-4.12) and major microvascular events
(HR, 1.81; 95% CI, 1.19-2.74).11 In a large population
(>860,000) of people with type 2 diabetes, those with an
International Classification of Diseases 9th Revisionecoded
hypoglycemic outpatient event and subsequent admission for
cardiovascular event had 79% higher odds of acute cardio-
vascular events, even after adjustment for important con-
founding variables.34
Hypoglycemia-related physiologic effects, which may
increase cardiovascular disease risk, include higher circu-
lating levels of inflammatory markers, vascular adhesion
molecules, and markers of thrombosis and platelet activa-
tion.35-38 Insulin-induced hypoglycemia also is associated
with alterations in cardiac electrical function, which may be
important in generating severe arrhythmias and “dead-in-
bed” syndrome.39 It is interesting to note that in one study
looking particularly at electrocardiographic alterations after
a single bolus of insulin, QT prolongation in subjects was
similar when normoglycemic 15 minutes after injection
and when hypoglycemic at the blood glucose nadir (QTc
prolongation of 27  19 ms and 25  24 ms, respectively,
P ¼ .25), indicating that hypoglycemia alone may not be
responsible for these observed alterations.40
Severe hypoglycemia may permanently impair cognitive
function in the young and in older adults.41,42 Compared
with the general population, people with type 2 diabetes
and hypoglycemia have a 1.5- to 2.5-fold increased risk
of developing dementia, which could be related to the
development of cerebral microvascular disease or other
factors that render brains of older individuals more
vulnerable.23 The risk of dementia in older patients has
been shown to be graded according to the frequency of
severe hypoglycemia (episodes requiring a hospital visit):
1 episode (HR, 1.26; 95% CI, 1.10-1.49); 2 episodes (HR,
1.80; 95% CI, 1.37-2.36); and 3 episodes (HR, 1.94; 95%
CI, 1.42-2.64).42
Economic Consequences
Hypoglycemia poses significant burdens to the healthcare
system, for both emergency services43-45 and increased use
The American Journal of Medicine, Vol 127, No 10A, October 2014
of primary care resources.46 In 1 medical claims database,
the mean cost of a hypoglycemic event managed in an
outpatient setting was $472 (95% CI, 270-674) and the
mean attributable total cost was $1087 (95% CI, 764-
1409).47 An increase in diabetes-related or all causeerelated
costs has been reported in other studies comparing patients
with and without hypoglycemia.48-50 Furthermore, patients
may incur out-of-pocket costs for managing hypoglycemic
events.51
Hypoglycemia can affect next-day functioning, particu-
larly after nocturnal events, and therefore affect produc-
tivity in the workplace.52-54 It may take, on average, half a
day to return to functioning at a normal level after a non-
severe hypoglycemic event.55 In one study, lost produc-
tivity was estimated to range from $15.26 to $93.47 (US
dollars) per nonsevere hypoglycemia event, representing
8.3 to 15.9 hours of lost work time per month.56 Monthly
out-of-pocket costs for test strips and lancets were esti-
mated at $17.23  $19.51.
Psychosocial/Quality of Life Consequences
Numerous studies document the adverse effects of hypo-
glycemia on health-related quality of life and treatment
satisfaction, including how patients with hypoglycemia are
more affected by their diabetes; report lower general health,
physical health, and mental health; and are more anxious
about hypoglycemia or worried than those without hypo-
glycemia.57-63 There may be changes in the behavior of
patients and health care providers, which are reviewed by
Edelman and Pettus64 in this supplement.
HEALTH CARE REFORM ISSUES
Diabetes remains an important target for pay for perfor-
mance programs, such as the Physician Quality Reporting
System65 and the Healthcare Effectiveness Data and Infor-
mation Set.66 Traditional metrics of glucose control (eg,
achievement of HbA1c<7.0%) are now being supplemented
by the healthcare reformedriven Value-Based Purchasing
Modifier. This modifier will score clinicians in how well
they control the entire cost of care for patients with diabetes.
Patients who are admitted for uncontrolled diabetes will lead
to clinicians scoring poorly in “quality.” Clinicians who
have the highest quality scores and lowest cost will earn the
most incentive payments. Thus, increased attention on
reduction of hypoglycemic risk of patients will lead to
reduced cost, better outcomes for patients, and enhanced
payments for doctors.67
PATIENT MANAGEMENT ISSUES
Improving Self-Treatment
Improving patients’ ability to self-treat may mitigate some
of the adverse consequences of hypoglycemia. A starting
point is to assess the health literacy of patients and their
support structure/resources at home. It is essential to
Morales and Schneider Hypoglycemia
determine whether they are able to administer medications
correctly, perform self-monitoring of blood glucose, adjust
insulin doses, and know when to ask for assistance. In one
study, even after an educational program, people often
struggled to adhere to guidelines for self-treatment of
hypoglycemia.68 Therefore, it is critically important that
healthcare professionals assess patients’ need for support
during patient visits and follow-up to ensure that the required
support is provided.69 Coexisting clinical depression may
complicate, or result from, diabetes, so it is important that
clinicians screen for this condition routinely.70
Major diabetes guidelines worldwide offer recommen-
dations for dosing rescue carbohydrates (eg, 10-30 g with a
wait time of 10-15 minutes if hypoglycemia persists).
However, an Australian study in 92 adults using insulin
has suggested that the initial amount should be 20 g with a
10-minute wait for optimal treatment.71 Research in children
has shown that readily available sucrose (Skittles) can in-
crease blood glucose to the same extent as more expensive
BD Glucose tablets (Becton Dickinson and Co, Franklin
Lakes, NJ; product now discontinued), and better than
fructose (Fruit to Go). Thus, Skittles may offer a more
economic way to self-treat hypoglycemic events.72 There-
fore, the common rule of 15s (ie, 15 M&Ms, 15 Skittles,
recheck in 15 minutes) still seems sensible.
Avoiding Hypoglycemia-Associated Autonomic
Failure and Impaired Hypoglycemia Awareness
The mainstay of treatment of hypoglycemia-associated
autonomic failure is the scrupulous avoidance of hypogly-
cemia.73 A structured educational program can improve
impaired hypoglycemia awareness and patients’ self-
treatment abilities while reducing the incidence of hypo-
glycemia.74,75 After 12 months of follow-up, one program
(HyPOS) consisting of 5 weekly lessons of 90 minutes
duration each and covering key aspects of hypoglycemia in
diabetes reduced the incidence of severe episodes by
approximately half (0.1  0.2 episodes per patient-year vs
0.2  0.4 episodes per patient-year, P ¼ .04); 12.5% of
patients in the treatment group versus 26.5% of patients in
the control group experienced at least 1 severe episode.76
Selecting and Modifying Therapy to
Reduce Risk
Lifestyle approaches are the mainstay of prevention of hy-
poglycemia. These include having a well-balanced diet,
eating regular small meals, self-monitoring of blood glucose
at appropriate frequency, carrying a source of rescue car-
bohydrate such as fruit or candy at all times, and avoiding
defensive overeating to avert a hypoglycemic event. The
importance of adhering to these basic practices cannot be
overstated. However, if hypoglycemia persists despite good
adherence to best practices, then modification of therapy is
warranted. This may include revising glucose targets and
prescribing drugs or combinations of drugs that may
decrease the risk of hypoglycemia (Table 2).26 For patients
S21
with type 2 diabetes, incretin-based therapies have a low
risk of hypoglycemia, in some studies comparable to
placebo.77
The pharmacokinetic and pharmacodynamic properties
of insulin can influence the risk of hypoglycemia, and
therefore a formulation whose action closely mimics the
pancreatic insulin profile and has a constant (less variable)
glucose-lowering effect from dose to dose should be prior-
itized. Neutral protamine Hagedorn, a commonly prescribed
intermediate-acting basal insulin, has several important
drawbacks: an insufficient duration of action, a pronounced
peak in action, and, because it is a suspension, careful
shaking immediately before injection. Long-acting basal
analogues, such as insulin glargine, insulin detemir, and
insulin degludec, are formulated as solutions that do not
require resuspension and have a flatter pharmacokinetic
profile than neutral protamine Hagedorn, and may be asso-
ciated with less variability than neutral protamine Hagedorn
from injection to injection.78-80 In laboratory studies, insulin
glargine and insulin detemir have been shown to have less
variability than neutral protamine Hagedorn, and insulin
detemir and insulin degludec have been shown to have
lower variability than insulin glargine.81,82
As the result of a more physiologic profile and lower
variability compared with neutral protamine Hagedorn, the
basal analogs insulin detemir and insulin glargine are
associated with a 31% reduced risk of nocturnal hypogly-
cemia and a 27% reduced risk of severe hypoglycemia in
type 1 diabetes83 and a 54% reduction in nocturnal hypo-
glycemia and 31% reduction in symptomatic hypoglycemia
in type 2 diabetes.84 Thus, they are recommended over
neutral protamine Hagedorn in the American Association of
Clinical Endocrinologists Guidelines.85 More recently, in a
preplanned meta-analysis of pooled patient-level data from
7 randomized, controlled, phase 3a, treat-to-target trials
comparing insulin degludec with insulin glargine, both
administered once daily, there was a reduced risk of hypo-
glycemia in several patient populations (ie, type 1 diabetes,
insulin-naïve type 2 diabetes, and insulin-experienced type 2
diabetes).86 Among insulin-naïve patients with type 2 dia-
betes, rates of overall confirmed hypoglycemia (rate ratio
[RR], 0.83; 95% CI, 0.70-0.98), nocturnal confirmed hy-
poglycemia (RR, 0.64; 95% CI, 0.48-0.86), and severe hy-
poglycemia (RR, 0.14; 95% CI, 0.03-0.70) were lower for
insulin degludec versus insulin glargine. Rates of overall
confirmed hypoglycemia (RR, 0.83; 95% CI, 0.74-0.94) and
nocturnal confirmed hypoglycemia (RR, 0.68; 95% CI,
0.57-0.82) were lower in the overall type 2 diabetes popu-
lation. In patients with type 1 diabetes, the rate of nocturnal
confirmed hypoglycemia (RR, 0.75; 95% CI, 0.60-0.94) was
lower compared with insulin glargine during the mainte-
nance period.
Glycemic variability has an independent effect on risk of
hypoglycemia.87 In a study on type 2 diabetes,88 this excess
risk was essentially eliminated when the standard deviation
of glucose variability was <1.7 mmol/L (30.6 mg/dL)
irrespective of the blood glucose level and treatment
S22 The American Journal of Medicine, Vol 127, No 10A, October 2014
regimen. Another study using self-monitoring of blood
glucose data from insulin-treated patients demonstrated that
glucose fluctuations during the preceding 24 hours can
predict occurrence of 58% to 75% of severe hypoglycemic
episodes.89
Although not addressed by current guidelines, new
products consisting of insulin formulated in combination
with incretins offer the potential for an additional glucose-
lowering effect without an increased risk of hypoglycemia,
as well as to curtail the weight gain associated with insulin
intensification that might accompany using insulin alone.90
CONCLUSIONS
Hypoglycemia has many associated complications adversely
affecting patients’ longevity and is an economic burden both
for individuals and for society as a whole. It is important for
clinicians to pay close attention to hypoglycemia when
managing patients with diabetes. Implementing appropriate
glycemic targets sets the precedence for which tools will
allow patients to achieve those goals. Selecting or modi-
fying therapy to reduce hypoglycemia can take one of the
variables of diabetes management and turn it into somewhat
more of a constant, minimizing hypoglycemia risk.
ACKNOWLEDGMENTS
The authors thank Gary Patronek and Gabrielle Parker of
Watermeadow Medical for writing and editing assistance,
supported by Novo Nordisk.
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