Hypoglycemia_2014 Morales n Doron

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Hypoglycemia*

Javier Morales, MD,a

Doron Schneiderb

aAdvanced 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 insufciency, older age, and history of hypoglycemia-associated autonomic failure. Reported

rates of hypoglycemia vary considerably among studies because of differences in study design, de nitions

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 patientsquality 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.

2014 The Authors. Published by 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-

nicant concern of primary care practitioners and patients

when it comes to initiating or intensifying antihyper-

glycemic therapy.1 Hypoglycemia can be dened in several

ways: by plasma glucose values (biochemical denition), by

symptoms (type and severity), andby time of day in which

it occurs (daytime or nocturnal).2 The literature is incon-

sistent in describing biochemical hypoglycemia, and these

denitions may vary in clinical trials in inpatient versus

outpatient settings; thus, an American Diabetes Associa-

tion (ADA) workgroup has proposed 5 classications

(Table 1).2 As Seaquist et al2 have noted, the ADA standard

of70 mg/dL (3.9 mmol/L) is an alert value, intended to

provide a margin of error for the limited accuracy of glucosemonitoring devices at lower glucose levels. Because this

value is above the threshold for symptoms, it allows suf-

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 denition

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

*This is an open access article under the CC BY-NC-SA license ( http://

creativecommons.org/licenses/by-nc-sa/3.0/).Funding: The publication of this manuscript was funded by Novo

Nordisk Inc.

Conict 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: [email protected]

0002-9343/$ -see front matter 2014 The Authors. Published by Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.amjmed.2014.07.004
http://creativecommons.org/licenses/by-nc-sa/3.0/http://creativecommons.org/licenses/by-nc-sa/3.0/mailto:[email protected]://dx.doi.org/10.1016/j.amjmed.2014.07.004http://dx.doi.org/10.1016/j.amjmed.2014.07.004mailto:[email protected]://creativecommons.org/licenses/by-nc-sa/3.0/http://creativecommons.org/licenses/by-nc-sa/3.0/http://crossmark.crossref.org/dialog/?doi=10.1016/j.amjmed.2014.07.004&domain=pdf


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the absence of symptoms, a lower level (eg, 63 mg/dL

[3.5 mmol/L]) should be used for biochemical denition.3

With respect to symptomatic denitions, 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 difculty, odd behavior, incoordi-

nation).4,5 Unfortunately, the symptoms experienced are

inconsistent between individuals, which complicates our ef-

forts in identifying hypoglycemiaand in counseling patients

who experience these symptoms.6 Furthermore, symptoms

are not pathognomonic and can occur while a person is

biochemically normoglycemic (pseudo-hypoglycemia) or

when normalizing glucose levels in those patients with pro-

longed hyperglycemia.7 Assessing the frequency of nocturnal

hypoglycemia is challenging because of inconsistencies in

dening the beginning and end of the nocturnal period in

various studies. Furthermore, continuous glucose monitoringstudies conrm that many episodes of hypoglycemia are

not detected by patients with type 1 diabetes8 and type 2

diabetes.9

FREQUENCY OF HYPOGLYCEMIAData from population-based studies conrm 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 eventsper 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

exclude people with a high risk of severe hypoglycemia or

hypoglycemia unawareness. If treated to a very tight glucose

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 iscritical that these patients be identied and case managed

more proactively.

RISK FACTORS/BEHAVIORS PREDISPOSINGTO HYPOGLYCEMIAAntidiabetic therapies, individually and used in combina-

tion, vary substantially in their risk of hypoglycemia.13-16 In

one meta-analysis of intensication 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 identied numerous patient-level predictors

of hypoglycemia. In type 1 diabetes, these include a history

of hypoglycemia (P .006) and co-prescribing of any oral

drug (P .048), whereas in insulin-treated type 2 diabetes,

predictors included a history of hypoglycemia(P < .0001)

and duration of insulin treatment (P .014).10 In a study of

patients intensifying therapy because of insufcient control

on 1 or 2 oral medications, after adjustment for confounding

variables, the following factors were signicant predictors:

prior anamnestic (remembered) hypoglycemia (odds ratio

[OR], 4.05; 95% condence 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 mildepisodes reported.17

Table 1 Denitions of Hypoglycemia2

Severe Hypoglycemia

Documented

Symptomatic

Hypoglycemia

Asymptomatic

(Documented)

Hypoglycemia

Probable Symptomatic

Hypoglycemia Pseudo-hypoglycemia

Requires assistance of

a third party and is

ameliorated bynormalization of

plasma glucose

Typical symptoms

accompanied by

measured plasmaglucose 70 mg/dL

Measured plasma

glucose 70 mg/dL

but withouttypical symptoms

Typical symptoms responding

to self-treatment but not

conrmed by biochemicaldocumentation but

presumably caused by

plasma glucose 70 mg/dL

Typical symptoms but with

a measured plasma glucose

greater than but approaching70 mg/dL

S18 The American Journal of Medicine, Vol 127, No 10A, October 2014


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SUBGROUPS AT RISK

Patients with Renal InsufciencyPatients with diabetes who have chronic kidney disease

have a higher frequency of hypoglycemia than people withdiabetes 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

(glomerularltration rate


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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 yearscompared 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 Modied-Release Controlled Evaluation trial

[ADVANCE]), the mortality rate among those reportingsevere hypoglycemia was 19.5%, compared with 9% for

those without severe hypoglycemia, and all-cause mortality

risk remainedincreased 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 signicant 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 Classication of Diseases 9th Revisione

codedhypoglycemic 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 inammatory 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 studylooking 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 .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 thedevelopment 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 signicant burdens to the healthcaresystem, for both emergency services43-45 and increased use

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 otherstudies comparing patients

with and without hypoglycemia.48-50 Furthermore, patients

may incur out-of-pocket costs for managing hypoglycemicevents.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 functioningata 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 ConsequencesNumerous 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 ISSUESDiabetes remains an important target for pay for perfor-

mance programs, such as the Physician Quality Reporting

System65 andthe Healthcare Effectiveness Data and Infor-

mation Set.66 Traditional metrics of glucose control (eg,

achievement of HbA1c


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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 requiredsupport 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 amountshould 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, FranklinLakes, 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 AutonomicFailure and Impaired Hypoglycemia AwarenessThe 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 .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 toReduce RiskLifestyle 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 modication of therapy is

warranted. This may include revising glucose targets and

prescribing drugs or combinations of drugs that maydecrease the risk of hypoglycemia (Table 2).26 For patients

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 inuence the risk of hypoglycemia, and

therefore a formulation whose action closely mimics the

pancreatic insulin prole 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 insufcient 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 atter pharmacokinetic

prole than neutral protamine Hagedorn, and may be asso-

ciated with less variabilitythanneutral protamine Hagedorn

from injection to injection.78-80 In laboratory studies, insulin

glargine and insulin detemir have been shown to have lessvariability 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 prole 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 ofClinical 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-nave type 2 diabetes, and insulin-experienced type 2

diabetes).86 Among insulin-nave patients with type 2 dia-

betes, rates of overall conrmed hypoglycemia (rate ratio

[RR], 0.83; 95% CI, 0.70-0.98), nocturnal conrmed 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 forinsulin degludec versus insulin glargine. Rates of overall

conrmed hypoglycemia (RR, 0.83; 95% CI, 0.74-0.94) and

nocturnal conrmed 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

conrmed 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


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regimen. Another study using self-monitoring of blood

glucose data from insulin-treated patients demonstrated that

glucose uctuations 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 insul in

intensication that might accompany using insulin alone.90

CONCLUSIONSHypoglycemia has many associated complications adversely

affecting patientslongevity 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 willallow 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.

ACKNOWLEDGMENTSThe authors thank Gary Patronek and Gabrielle Parker of

Watermeadow Medical for writing and editing assistance,

supported by Novo Nordisk.

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