An Overview of Hypoglycemia
Karen K. O’Brien, BS Pharm, PharmD
Assistant Professor of Pharmacy Science
Creighton University School of Pharmacy and Health Professions
Omaha, Nebraska
Alan W. Y. Chock, PharmD
Assistant Professor of Pharmacy Practice
Creighton University School of Pharmacy and Health Professions
Omaha, Nebraska
Janet L. Shea, RN, BSN, MPA
Nursing Staff
Hampden-Wilbraham Regional School District
Wilbraham, Massachusetts
6/20/2012
US Pharm. 2012;37(6):50-56.
Hypoglycemia is a low concentration of glucose in the blood, but no specific plasma
glucose level defines the condition.1 Rather, hypoglycemia is best described as a
plasma glucose concentration sufficiently low to elicit signs and/or symptoms.1 In
healthy individuals, the glycemic threshold for symptoms is 50 to 55 mg/dL, although
plasma glucose levels under 70 mg/dL signal impending hypoglycemia.2 Symptoms
can occur at higher concentrations in patients with poorly controlled diabetes, and at
lower levels in those with tight glycemic control or recent hypoglycemic exposure.2
Most hypoglycemia is iatrogenic and associated with drug-treated diabetes mellitus.1
Other causes of hypoglycemia, rare in individuals older than 10 years of age, will be
briefly discussed later.
Glucose supplies immediate energy needs and fuels metabolic functions between
meals. If it is not needed for immediate use, glucose is stored as glycogen in the liver
and muscles, or else as fat.3 Glucose is a requisite metabolic fuel for brain cells.
Because the brain can neither synthesize glucose nor store more than a few minutes’
supply in the form of glycogen, it is critically important that a steady glucose supply
be available to brain cells via the circulation.2
In healthy individuals, a finely choreographed interaction between insulin and several
counterregulatory hormones, including glucagon, epinephrine, cortisol, and growth
hormone, ensures that blood glucose concentrations are maintained within the
physiological range. This process is called glucose counterregulation. As plasma
glucose concentrations drop below physiological range, insulin secretion decreases
and ultimately ceases. Glucagon and epinephrine concentrations increase concurrently
to produce a rapid rise in plasma glucose, thus averting or swiftly correcting
hypoglycemia.2 Glucagon stimulates glycogenolysis (the breakdown of glycogen into
glucose) in the liver, as well as hepatic gluconeogenesis (the formation of glucose
from noncarbohydrate substrates). Epinephrine promotes hepatic glycogenolysis and
hepatic and renal gluconeogenesis. Cortisol and growth hormone work slowly over
hours to defend against prolonged hypoglycemia, but they play a minimal role in
reversing hypoglycemia.1
HYPOGLYCEMIA IN PATIENTS
WITH DIABETES
The goal of diabetes management is a lifetime of euglycemia without hypoglycemia.4
Hypoglycemia constitutes a significant roadblock to achieving both short-term and
long-term glycemic control, which may lead to the development of long-term
complications of diabetes.2 It is estimated that, on average, individuals with type 1
diabetes mellitus (T1DM) experience two symptomatic episodes of hypoglycemia
weekly and one severe event annually. With declining pancreatic function, the
incidence of hypoglycemia increases in type 2 diabetes mellitus (T2DM).2 The
negative effects of hypoglycemia include psychological morbidity, physical
morbidity, and mortality. In patients with diabetes, the fear of hypoglycemia exceeds
the fear of long-term complications.2
Pathophysiology
In T1DM and advanced T2DM, glucose counterregulation is compromised by the
impaired secretion of insulin, glucagon, and epinephrine, breaching three
physiological defenses against hypoglycemia. First, falling plasma glucose
concentrations fail to elicit a corresponding decrease in insulin secretion in patients
taking insulin or insulin secretagogues. With absolute or relative exogenous insulin
excess, insulin activity is dictated by the pharmacokinetic characteristics of the drug.
Second, hypoglycemia does not trigger glucagon secretion. Third, a lower plasma
glucose concentration is required to stimulate an epinephrine response.2
Hypoglycemia Unawareness
Some patients with T1DM or advanced T2DM lose the neurogenic warning
symptoms that herald impending hypoglycemia. This state, hypoglycemia
unawareness, is likely the result of repeated iatrogenic hypoglycemia episodes that
lead to impaired epinephrine response and diminished neurogenic symptoms.2 The
weakened counterregulatory response, hypoglycemia-associated autonomic failure
(HAAF), puts the patient at high risk for severe hypoglycemia. Fortunately, a 2- to 3week period of strict avoidance of hypoglycemia appears to improve the epinephrine
response and restore hypoglycemia awareness.2,3
Causes and Risk Factors
Iatrogenic hypoglycemia results from therapy that raises insulin concentrations and
lowers plasma glucose concentrations.1 Agents include insulin and insulin
secretagogues. Other diabetes drugs may cause hypoglycemia when combined with
insulin or insulin secretagogues (TABLE 1).
Conventional risk factors for iatrogenic hypoglycemia relate to relative or absolute
insulin excess (FIGURE 1). As discussed previously, HAAF is associated with a high
risk of hypoglycemia. Risk factors include an absolute deficiency of endogenous
insulin; a history of severe hypoglycemia and/or hypoglycemia unawareness, as well
as recent hypoglycemia, prior exercise, and sleep; and intensive glycemic therapy as
evidenced by lower glycosylated hemoglobin concentrations and/or lower glycemic
goals.1
Symptoms of Hypoglycemia
A reduction in blood glucose initiates an autonomic nervous system response,
resulting in neurogenic signs and symptoms (categorized as adrenergic or cholinergic)
that alert the patient to a hypoglycemic episode (TABLE 2). Each patient’s array of
symptoms is unique and may vary in magnitude over time. However, signs and
symptoms often present in diabetes are also frequently associated with other disease
states, and hypoglycemia does not necessarily elicit these signs and symptoms. Thus,
hypoglycemia is best confirmed by Whipple’s triad: symptoms consistent with
hypoglycemia, a low plasma glucose concentration, and symptom relief when the
glucose concentration is raised.4 Optimally, the presence of signs and symptoms
during mild hypoglycemia prompts the patient to ingest carbohydrates, thereby
enabling blood glucose concentrations to normalize. If the episode progresses, the
deficiency of glucose in brain cells results in neuroglycopenic symptoms. Lack of
attention to mild symptoms or compromised autonomic response signals may
preclude recognition of a hypoglycemic event. The pharmacist should counsel the
patient to be attentive to symptoms, self-monitor blood glucose (SMBG) whenever
suspicious, and treat for hypoglycemia if monitoring is not available.2
It is estimated that more than 50% of hypoglycemic episodes occur during sleep, and
the sufferer usually is unaware of them.4 An individual might assume the occurrence
of hypoglycemia if he or she awakens with bedclothes damp with sweat and is
confused, irritated, or tired, or was calling out or having nightmares during sleep.3 In
such cases, periodic 3-AM SMBG is recommended to determine whether
hypoglycemia is occurring overnight. Nighttime hypoglycemia is suspected of
causing arrhythmias that lead to unforeseen death, or dead-in-bed syndrome.1
Treatment of Mild-to-Moderate Hypoglycemia
When hypoglycemia is suspected, SMBG should be performed if a meter is available.
A reading below 70 mg/dL indicates the need for immediate consumption of 15 to 20
g of simple carbohydrates, preferably glucose.5 If testing is not possible, remember:
“When in doubt, treat.” Untreated hypoglycemia presents a greater risk than that
posed by an episode of hyperglycemia. Severe and protracted neuroglycopenia,
although rare, may lead to permanent brain damage and even death.2 Recommended
carbohydrates include 3 to 4 glucose tablets (5 g each); 1 tube of glucose gel; 4 oz.
fruit juice or soft drink (not sugar free); 8 oz. milk (low-fat preferred); 4 to 6 pieces of
hard candy (not sugar free); or 1 tbsp. sugar, honey, or corn syrup. Protein does not
impair the desired glycemic response, but fat does. Therefore, chocolate candy is not
recommended unless no other simple carbohydrate is available.
Blood glucose should be rechecked at 15-minute intervals, and treatment repeated if
glucose remains below 70 mg/dL. Once blood glucose is at or above 70 mg/dL, the
patient should eat a snack or meal to maintain euglycemia.3
Treatment of Severe Hypoglycemia
Neuroglycopenia can impair an individual to the extent that someone else must
administer treatment. If the patient can safely swallow, glucose gel, honey, jelly, or
syrup should be placed inside the cheek for absorption. If the patient is unable to
swallow or is unconscious, a glucagon injection is required to rapidly elevate the
serum glucose level.3 IV dextrose is the preferred treatment for hospitalized patients.
Once conscious, the patient should drink a carbohydrate-rich fluid, followed by a
snack once he or she is no longer nauseated. Medical supervision is indicated until the
risk of recurrent hypoglycemia has passed.2
HYPOGLYCEMIA PREVENTION
A prudent pharmacist counsels patients with diabetes on hypoglycemia avoidance
during each contact.1 Patients should follow a diabetes management plan that includes
blood glucose monitoring (with scrupulous monitoring when ill), a medication
protocol, meal and snack planning, management of activity and exercise, and
moderate alcohol ingestion.3
The patient should be reminded that diabetes medication may need to be adjusted to
respond to changes in food ingestion and physical activity. The pharmacist should
ascertain that the patient knows how to use his or her meter, and should suggest
alternative solutions if medications or meter supplies are a financial hardship.
Information on medications that are more likely to cause hypoglycemia should be
provided, and patients taking acarbose or miglitol should be cautioned that only
dextrose will raise blood glucose during a hypoglycemic episode.3 The pharmacist
should offer glucagon emergency kit training to the patient’s family members. The
patient should be reminded to carry a simple carbohydrate source—preferably glucose
tablets—at all times and to avoid the accidental consumption of sugar-free candy or
soft drinks in the treatment of hypoglycemia. The patient should be advised to
perform SMBG before driving if he or she is at risk for hypoglycemia, to test often
during long driving trips, and to refrain from driving until blood glucose is at least 70
mg/dL.3 The pharmacist must recognize that information and willingness to follow a
diabetes management plan are essential for enabling a patient to avoid hypoglycemia
and live successfully with diabetes.2
NONIATROGENIC
HYPOGLYCEMIA
Hypoglycemia can occur in those not being treated for diabetes. Organizations such as
the National Institutes of Health and the National Diabetes Information Clearinghouse
note the existence of several types of noniatrogenic hypoglycemia.
Reactive (Postprandial) Hypoglycemia
Reactive hypoglycemia occurs within 4 hours after a meal is consumed, with
diagnosis based on documentation of Whipple’s triad.1,3 Several causes have been
proposed but are unsubstantiated, including excessive release of insulin following
high sugar intake, enhanced sensitivity to the normal secretion of epinephrine and its
attendant hypoglycemic symptoms, and deficient glucagon secretion.3
Gastrointestinal surgery can cause hypoglycemia if food passes into the small
intestine too quickly, but this is uncommon. Rare hereditary enzyme deficiencies can
lead to fructose intolerance and reactive hypoglycemia.3
Fasting (Postabsorptive) Hypoglycemia
This condition may be diagnosed when the serum glucose concentration is below 50
mg/dL after overnight fasting, between meals, or following physical activity.3 Several
underlying conditions can contribute to fasting hypoglycemia, including the
consumption of medications other than those used to treat diabetes (TABLE 3).
Alcohol consumption, especially binge drinking, can cause severe or even fatal
hypoglycemia by halting gluconeogenesis and depleting hepatic glycogen.6 Critical
illnesses affecting the liver, heart, or kidneys can contribute to fasting hypoglycemia.3
Sepsis can deplete hepatic glycogen stores and impair gluconeogenesis.7 Disorders
involving renal insufficiency can decrease drug elimination and affect serum glucose
concentration.8 Starvation conditions (e.g., anorexia nervosa) can deplete glycogen
and fat stores used for energy between meals, as well as substrates used in
gluconeogenesis.
Treatment of the underlying cause will help resolve hypoglycemia. Deficiencies of
glucagon, epinephrine, cortisol, and growth hormone, which are rare, are usually
corrected by exogenous hormone supplementation.3 Such conditions are more
common in very young children than in adults. Insulinomas—rare, usually benign
pancreatic tumors that secrete excessive amounts of insulin—can cause
hypoglycemia.1,3 Surgical removal of the insulinoma is preferred, but pharmacologic
agents such as diazoxide or octreotide also may be used to lower serum insulin
concentrations.
CONCLUSION
Hypoglycemic episodes compromise wellness in all who experience them. In diabetic
patients, the risk of hypoglycemia may limit the potential for lifelong euglycemia.2,4
Pharmacists who offer education and support afford their patients the opportunity to
better understand and follow their disease-management plans and to enjoy better
health.
REFERENCES
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2. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care.
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3. National Diabetes Information Clearinghouse. Hypoglycemia.
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6, 2011.
4. American Diabetes Association. Defining and reporting hypoglycemia in diabetes:
a report from the American Diabetes Association Workgroup on Hypoglycemia.
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5. American Diabetes Association. Executive summary: standards of medical care in
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March 27, 2012.
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2012.
10. Vue MH, Setter SM. Drug-induced glucose alterations part 1: drug-induced
hypoglycemia. Diabetes Spectrum. 2011;24:171-177.
11. MedlinePlus. Drug-induced hypoglycemia.
www.nlm.nih.gov/medlineplus/ency/article/000310.htm. Accessed March 25, 2012.
12. CDC. Treatment of malaria (guidelines for clinicians).
www.cdc.gov/malaria/resources/pdf/clinicalguidance.pdf. Accessed May 1, 2012.
13. Kojak G Jr, Barry MJ Jr, Gastineau CF. Severe hypoglycemic reaction with
haloperidol: report of a case. Am J Psychiatry. 1969;126:573-576.
14. Walter RB, Hoofnagle AN, Lanum SA, Collins SJ. Acute, life-threatening
hypoglycemia associated with haloperidol in a hematopoietic stem cell transplant
recipient [letter]. Bone Marrow Transplant. 2006;37:109-110.
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