CANADIAN

DIABETES

ASSOCIATION

ASSOCIATION CANADIENNE DU DIABTE

Canadian
D

LE DIABTE AU CANADA
FALL 2002

VOLUME 15 No. 3

HYPOGLYCEMIA:
UNDERSTANDING THE ENEMY
Ellen L. Toth MD FRCPC, Danile Pacaud MD FRCPC

Since the publication of the

EDITORIAL
Diabetes Control
and Complications Trial (DCCT) (1) in
patients with type 1 diabetes, and the United
Kingdom Diabetes Prospective Study
(UKPDS) (2) in patients with type 2 diabetes, intensive diabetes management (IDM)
is considered the standard of care for patients
with diabetes. The DCCT demonstrated
40 to 60% reductions of significant
microvascular complications in patients on
IDM compared to the control group on conventional therapy. The UKPDS also demonstrated that intensive glycemic control is
beneficial, particularly in preventing microvascular complications. Thus, the Canadian
Diabetes Association (CDA) recommends
strict targets for glycemic control (Table 1) (3).
IDM implies frequent monitoring of
plasma glucose (PG) (4 times a day) and
careful matching of food and activity to
insulin dosing. The goal is to achieve PG as
near to normal as possible, as limited by safety and modulated by individual characteristics (e.g. pregnancy, or the presence or
absence of complications).
However, the DCCT encountered a
3-fold increase in the incidence of hypoglycemia in its intensively treated group.
Thus, hypoglycemia has the potential to
be the rate-limiting step of IDM. A metaanalysis of the occurrence of hypoglycemia
in patients with type 1 diabetes by Egger and
colleagues showed a combined odds ratio for
severe hypoglycemia in patients on IDM of
2.99the risk being inversely proportional
to normalization of HbA1c (4). In patients

with type 2 diabetes, insulin is often needed

to achieve a target HbA1c of <7%. Adding
insulin to oral agents increases the risk of
hypoglycemia, although the rates are lower
than in type 1 patients. In the UKPDS, only
30% of patients in the intensively treated
group suffered any hypoglycemia yearly over
15 years of follow-up, and only 2 to 3% per
year had severe hypoglycemia (2).
Recognizing the importance of preventing severe hypoglycemia and its long-term
complications, the CDA published guidelines
for the prevention and management of hypoglycemia (5). A summary of these guidelines
is presented in this issue, and 2 case studies are
included to illustrate the presentation of
severe hypoglycemia and demonstrate possible interventions for prevention.
Hypoglycemia is classified into the following categories:
Mild hypoglycemia: an event that the
patient can treat successfully. It is generally tolerated as the price to pay for
near-normal glycemia, the goal of IDM.
Severe hypoglycemia: an event that
requires third-party help to treat, i.e. the
patient is affected such that they cannot
completely treat or help themselves.

In This Issue
CANADIAN DIABETES
ASSOCIATION GUIDELINES
FOR THE MANAGEMENT OF
HYPOGLYCEMIA: HIGHLIGHTS
Page 3

Hypoglycemia unawareness: a distinction made with respect to hypoglycemia

in patients with type 1 diabetes regarding whether or not they have awareness
of hypoglycemic symptoms such that
they have sufficient warning and can
take preventive action. Hypoglycemia
unawareness occurs most typically in
longer-duration patients with type 1
diabetes, often with accompanying
damage of the autonomic nervous system. It can also be seen in transient situations, such as in pregnancy, or in
association with tight PG control
(HbA1c within the normal range). In
these cases, the liver and brain appear to
desensitize, but the situation is
reversible with a few weeks of hypoglycemia avoidance, i.e. setting HbA1c
targets of 6 to12 mmol/L or higher.
Strategies to minimize hypoglycemia
while providing IDM in patients with type 1
diabetes include setting individualized
glycemic and HbA1c targets, patient education
and the use of rapid-acting insulin analogues.
Whereas general recommendations for
PG targets were made in the CDAs 1998
Clinical Practice Guidelines For the
Management of Diabetes in Canada (3) (Table
1), these targets must be modified by knowledgeable practitioners in conjunction with
knowledgeable patients. Risk of hypoglycemia
is but one factor to consider. Others are the
individuals life stage, the desire for pregnancy,
the existence of early or late complications and
the availability of support systems.
Patient education must be thorough with
respect to peak actions and durations of

CANADIAN

DIABETES

insulins, diet counselling and the effects of

physical activity. This education is best provided through formal teaching programs by
Certified Diabetes Educators.
The newer rapid-acting insulins lispro
(Humalog,Eli Lilly) and aspart (NovoRapid
Novo Nordisk) yield less hypoglycemia for a
given HbA1c (6,7). Rapid-acting insulins are
used in patients with type 1 diabetes only in
IDM, in combination with a longer-acting
basal insulin (lente, NPH, ultralente). Taken
with food, rapid-acting analogues are reasonably safe. However, they can cause profound
hypoglycemia if taken with insufficient food,
or if exercise is undertaken within 2 hours of
injection. Because of their rapid action, food
cannot be delayed; PG monitoring is essential before taking them, to modify the dose
according to pre-existing PG levels, anticipated meal content and ensuing activity.
Five classes of oral agents are available to
treat patients with type 2 diabetes: sulfonylureas (glyburide, gliclazide, chlorpropamide);
biguanides (metformin); alpha glucosidase
inhibitors (acarbose); glitinides (repaglinide,
nateglinide); and thiazolidinediones (rosiglitazone, pioglitazone). Combinations of insulin
with drugs that enhance insulin action (metformin and thiazolidinediones) rather than
secretion, are preferable both for purposes of
reducing the risk of hypoglycemia and
because of optimal synergies in their mechanisms of action.
Agents most likely to cause hypoglycemia
are sulfonylureas and glitinides, as they act by
enhancing insulin secretion. The effect of
exercise on risk of postprandial hypoglycemia

ASSOCIATION

Associate Editors
Susanne Bourgh RN
BSN CDE
Victoria, British Columbia
Peggy Dunbar MEd
PDt CDE
Halifax, Nova Scotia
Danile Pacaud MD
FRCPC
Calgary, Alberta
Ellen Toth MD FRCPC
Edmonton, Alberta

ASSOCIATION CANADIENNE DU DIABTE

Table 1. Target levels of glucose control for adolescents and adults

(adapted from reference 4)
Ideal

Optimal

<0.06
3.86.1
4.47

<0.07
47
5.011

HbA1c (% of upper limit)

Fasting plasma glucose (mmol/L)
Postprandial 12 hours (mmol/L)
in patients on sulfonylureas should be considered (decrease oral agent or modify diet).
Gliclazide has been reported to produce less
hypoglycemia than other sulfonylureas in the
elderly. Both glyburide and chlorpropamide
can cause prolonged hypoglycemia in
patients who are fasting, and therefore should
be promptly discontinued in ill patients or
those needing to fast before medical tests.
Finally, patients on insulin/acarbose
combinations, in whom insulin may cause
hypoglycemia, should use a monosaccharide
(dextrose tablets) to treat hypoglycemia.
CONCLUSION
Hypoglycemia is an unwanted complication
of the treatment of patients with diabetes,
and is particularly troublesome in patients
with hypoglycemia unawareness. It should
be an important consideration during the
assessment of patients with diabetes, followed
by the setting of individualized glycemic and
HbA1c targets and proper education on its
causes and treatment. As treatments for
hyperglycemia become more effective,
understanding the enemy, hypoglycemia, and
avoiding or managing it, will become crucial
for the successful management of diabetes.

A Canadian Diabetes Association publication for Canadian physicians/

Publi par lAssociation canadienne du diabte pour les mdecins canadiens

Editor-in-Chief
Sora Ludwig MD FRCPC
Winnipeg, Manitoba

Managing Editor
Fiona Hendry
Assistant Editor
Jovita Sundaramoorthy

REFERENCES
1.

2.

3.

4.

5.

6.

7.

The Diabetes Control and Complications Trial

Research Group. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl
J Med. 1993;329:977-986.
United Kingdom Prospective Diabetes Study
Group. Intensive blood glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33).
Lancet. 1998;352:837-853.
Meltzer S, Leiter L, Daneman D, et al. 1998 clinical practice guidelines for the management of
diabetes in Canada. CMAJ.1998;159:S1-S29.
Egger M, Davey Smith G, Stettler C, Diem P.
Risk of adverse effects of intensified treatment
in insulin-dependent diabetes mellitus: a metaanalysis. Diabet Med. 1997;14:919-928.
Yale J-F, Begg I, Gerstein H, et al. 2001
Canadian Diabetes Association clinical practice
guidelines for the prevention and management
of hypoglycemia in diabetes. Can J Diabetes.
2002;26:22-35.
Heller SR, Amiel SA, Mansell P. Effect of the fast
acting insulin analog lispro on the risk of nocturnal hypoglycemia during intensified insulin therapy. Diabetes Care. 1999;22:1607-1611.
Home PD, Lindholm A, Riis A. Insulin aspart vs.
human insulin in the management of long-term
blood glucose control in Type 1 diabetes mellitus: a randomized controlled trial. Diabet Med.
2000;17:762-767.

Canadian Diabetes/le Diabte au Canada is published four times a year by the Canadian
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Copyright Canadian Diabetes Association, 2002; all rights reserved. Reproduction of this
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Research and clinical experience are continually adding to medical knowledge of diagnosis, treatments and drug therapies. When authors refer to drug therapies, indications
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CANADIAN DIABETES ASSOCIATION

GUIDELINES FOR THE MANAGEMENT
OF HYPOGLYCEMIA: HIGHLIGHTS
Jean-Franois Yale MD CSPQ
McGill Nutrition and Food Science Centre
Department of Medicine
McGill University
Montreal, Quebec, Canada
Danile Pacaud MD FRCPC
Faculty of Medicine
University of Calgary
Calgary, Alberta, Canada

INTRODUCTION
Clinical hypoglycemia is defined as a state in
which a patient with diabetes has a low plasma
glucose (PG) level, experiences autonomic
symptoms (trembling, palpitations, sweating,
anxiety) and/or neuroglycopenic symptoms
(difficulty concentrating, confusion, weakness,
dizziness, fatigue), and attains relief with the
administration of a carbohydrate.
The 2001 Canadian Diabetes Association
Clinical Practice Guidelines for the
Prevention and Management of Hypoglycemia
in Diabetes were published recently in the
Canadian Journal of Diabetes (1). They represent an expansion of the evidence-based
1998 Clinical Practice Guidelines for the
Management of Diabetes in Canada (2) since,
in those guidelines, only 7 of the 93 recommendations were related to hypoglycemia.
This article summarizes the 2001 hypoglycemia guidelines, and describes their relevance in clinical practice for primary care
physicians.The recommendations correspond
to the 1998 clinical practice guidelines (2); as
such, each recommendation is described as
being unchanged (existed in the 1998 guidelines), modified (modified from the 1998
guidelines), or new (did not exist in the 1998
guidelines).
HYPOGLYCEMIA AND ORAL
ANTIHYPERGLYCEMIC AGENTS
Drug-induced hypoglycemia is the most common cause of hypoglycemia. It is estimated

that hypoglycemia of any severity occurs

annually in 5 to 20% of patients taking oral
antihyperglycemic agents. Table 1 lists risk
factors and drugs that can potentiate the
effects of antihyperglycemic agents.
Recommendation (modified):The initial oral agent used can be an alpha-glucosidase inhibitor, a biguanide, an insulin
secretagogue (sulfonylurea or repaglinide), or a thiazolidinedione.
Recommendation (unchanged): If target glucose levels are not attainable with a
single agent, an agent or agents from other
classes may be added, until the maximum
dose of an agent of each class is reached.
The choice of drug depends on the individual patient, taking into considering a
number of factors.The biguanide metformin
should be considered first-line therapy for
obese patients with type 2 diabetes, as it is
associated with less weight gain and less
hypoglycemia than sulfonylureas. For
patients with a high risk of hypoglycemia
due to their age, lifestyle or other medical
conditions (Table 1), metformin, alpha-glucosidase inhibitors and thiazolidinediones
(TZDs) should be considered before sulfonylureas or meglitinides.
Recommendation (modified): In elderly people, sulfonylureas should be used
with caution because the risk of hypoglycemia increases exponentially with age.
Initial doses of sulfonylureas should be
half those of younger people. Gliclazide may
be preferred over glyburide, as it is associated
with a reduced frequency of hypoglycemic
events.
HYPOGLYCEMIA AND INSULIN THERAPY
Hypoglycemia is the most common adverse
effect associated with intensive insulin therapy. In the United Kingdom Prospective
Diabetes Study (UKPDS) (3), the Diabetes
Control and Complications Trial (DCCT) (4)
and the Stockholm Diabetes Intervention
Study (SDIS) (5), the number of patients

who experienced moderate to severe hypoglycemic episodes was greater in those on

intensive insulin therapy than conventional
insulin therapy.
Numerous studies have found no differences in the presentation of acute hypoglycemia induced by regular human insulin
vs. the rapid-acting insulin analogues lispro
insulin (6-9) and insulin aspart (10,11).
After the introduction of human insulin
in the 1980s, claims were made that some
patients symptomatic awareness of hypoglycemia was altered upon transfer to human
insulin. However, numerous studies have
noted no significant clinical difference in the
Table 1. Factors predisposing an
individual to antihyperglycemic
drug-induced hypoglycemia
Age
Elderly in the presence of coexisting
comorbid conditions
Impaired kidney or liver function
Adrenal insufficiency
Gastrointestinal disease
Lack of education on hypoglycemia
Lifestyle
Alcohol consumption in the absence of
sufficient energy/carbohydrate intake
Exercise
Missed or delayed meals
Medications
Salicylates (>4 g per day)
Sulfonamide antibiotics
Tricyclic antidepressants
Phenylbutazone
Warfarin
Fibrates
Monoamine oxidase inhibitors
Pentamidine
Acetaminophen
Angiotensin-converting enzyme (ACE)
inhibitors
Beta blockers

CANADIAN

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symptomatic response to (8,12) or the frequency of hypoglycemia (13,14) between

animal and human insulin.
Some studies have reported that selfmanagement behaviours, less food, more
insulin and more activity are associated with
85% of hypoglycemic episodes (15,16). For
patients managed with fixed-dose insulin
regimens, physicians should help patients
with diabetes develop individualized meal
and activity plans to minimize the risk of a
hypoglycemic episode.
Recommendation (new): All patients
currently on or starting intensive insulin
programs should be counselled about the
risks and prevention of hypoglycemia.
Patients should be encouraged to perform
frequent PG monitoring and receive appropriate instruction from their healthcare team
on how to adjust insulin dosages, diet and
physical activity in response to PG levels.
Recommendation (new): To reduce
the risk of asymptomatic nocturnal hypoglycemia, patients should:
1. Periodically monitor overnight PG
levels.
2. If the bedtime PG level is <7 mmol/L,
patients should consume a bedtime
snack with at least 15 g carbohydrate
and protein.
Recommendation (modified): A regular or rapid-acting insulin analogue, or
both, can be used before meals in intensified therapy.
Insulin lispro has been associated with
lower postprandial PG levels and lower rates
of hypoglycemia than regular insulin, and
aspart insulin has been associated with lower
rates of hypoglycemia compared to human
regular insulin. A rapid-acting insulin analogue should be tried for patients who
experience frequent hypoglycemic episodes
on regular insulin.
Recommendation (new): Substituting
a rapid-acting insulin analogue for human
regular insulin at suppertime may prevent
the delayed nighttime effect of regular
insulin and reduce the risk of nocturnal
hypoglycemia.
Administering basal insulin at bedtime
rather than at suppertime, or instituting continuous subcutaneous insulin infusion (insulin
pumps), may also reduce the risk of nocturnal
hypoglycemia.
Recommendation (new): Risk factors for severe hypoglycemia should be

ASSOCIATION

ASSOCIATION CANADIENNE DU DIABTE

Case Study 1. Hypoglycemia and type 1 diabetes

Danile Pacaud MD FRCPC
Faculty of Medicine
University of Calgary
Calgary, Alberta, Canada

PRESENTATION
Courtney, a 15-year-old female student
with type 1 diabetes, was found staring into
space and incoherent during her final math
exam. Courtneys mother, who was volunteering at school, came to her class and
found her daughter had a plasma glucose
(PG) level of 2.2 mmol/L. She gave her glucose tablets and Courtney recovered rapidly.
This was her first incidence of severe hypoglycemia since her diagnosis of diabetes 2
years ago. Courtney and her mother come
to your clinic in an anxious state.
HISTORY
Courtney manages her diabetes with
3 injections per day of intermediate-acting
(N or NPH) and rapid-acting insulin
(Regular or Toronto). Past metabolic control has been stable and acceptable for her
age. However, she complains of frequent
hypoglycemic episodes since the beginning
of soccer season 1 month ago. She has also
found that she does not have as many
symptoms of hypoglycemia as before, even
noting PG levels as low as 3.1 mmol/L
without any signs or symptoms. Courtney
and her mother were quite frightened after
this mornings episode, and wonder what
can be done to avoid another episode of
severe hypoglycemia.
Luckily, Courtney keeps a good record
of her PG levels. She had been attempting
to prevent hypoglycemia in light of her
soccer practices by decreasing her pre-dinner insulin dose by 2 units (her practices
and games are always scheduled in the early
evening, after supper). Nevertheless, she had
8 episodes of documented hypoglycemia in
the 8 days prior to her severe episode. She
may have had unrecognized episodes, especially at night (e.g. a breakfast PG level of
14.8 mmol/L, following a bedtime level of
3.1 mmol/L).
Courtneys diet has been stable, but
recently she has skipped most of her morning snacks. The majority of her lower PG
incidents were linked with increased physical activity and were therefore preventable.

Her current severe episode was probably

caused by a combination of previous frequent mild hypoglycemia, increased physical activity the previous day and decreased
food intake.
RECOMMENDATIONS
You should make the following recommendations to Courtney and her mother (1):
Switch to a rapid-acting insulin analogue. This will help decrease the
number of hypoglycemic episodes,
especially at night.
Perform nighttime PG testing on
evenings following active days, to
detect asymptomatic nocturnal hypoglycemia. (Physical activity can be associated with delayed hypoglycemia.)
Adjust insulin doses to keep PG within targets, but with a limited number
of mild hypoglycemia episodes (i.e.
1 to 2 per week).
Educate them about prevention of
hypoglycemia associated with physical activity, to help Courtney avoid
some of her low PG readings. Her
rapid-acting insulin may be decreased
by up to 50% if physical activity is
planned in the near future (in the
next 2 hours for insulin analogues
such as lispro or aspart, and 4 hours
for regular insulin). For unplanned
physical activity, extra carbohydrate
should be taken before and during
the course of longer activity.
Finally, either her bedtime snack
should be increased or her bedtime
insulin reduced on nights following
active days. This may help reduce
the incidence of delayed nocturnal
hypoglycemia.
FOLLOW-UP
Three months later, Courtney returns for
follow-up. She was able to apply your recommendations, especially about preventing
hypoglycemia. Since having only about
2 PG readings per week <4 mmol/L, she is
now able to feel and recognize symptoms of
hypoglycemia with each episode. She has
not had any more moderate or severe hypoglycemic episodes. Courtney is now considering intensifying her diabetes management
Continued on page 5

CANADIAN

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ASSOCIATION

identified in people with type 1 diabetes

so that appropriate strategies can be used
to prevent hypoglycemia.
Risk factors include a history of previous
severe hypoglycemic events, a greater reduction in HbA1c , recurrent previous hypoglycemic reactions and young (preschool) age.
Recommendation (new): During insulin therapy of type 1 diabetes, the frequency of mild hypoglycemic episodes
should be minimized, particularly in those
at high risk, in an attempt to reduce the
development of hypoglycemia unawareness.
Recommendation (new): In individuals with hypoglycemia unawareness, strategies should be implemented to reduce the
risk of hypoglycemia and hypoglycemia
unawareness, and to increase physiologic
counterregulatory responses to hypoglycemia.
Such strategies include increased frequency of PG monitoring, an increase in PG
targets and multiple insulin injections with
increased PG targets.
LONG-TERM COMPLICATIONS OF
SEVERE HYPOGLYCEMIA
Potential long-term complications of severe
hypoglycemia include mild intellectual
impairment and, in rare cases, permanent
neurologic sequelae such as hemiparesis and
pontine dysfunction.
In adults, findings of the consequences of
repeated severe hypoglycemia on intellectual
performance are inconsistent between retrospective and prospective studies. However,
the DCCT study reports no adverse association between intensive diabetes management
and cognitive function (4).
In childhood, no studies have resolved
definitively the issue of long-term effects
of hypoglycemia on cognitive function.
However, the available information is more
suggestive of increased risks of cognitive
impairment in the presence of repeated
hypoglycemia (17,18).
Recommendation (modified): The
metabolic goals and therapeutic strategies
for adolescents >12 years of age are the
same as those for adults.
The target HbA1c for prepubertal children is 120 to 140% of the upper limit of
normal, with targets for glucose and HbA1c
graduated according to the childs age.
Extreme caution is required to avoid hypoglycemia in children 5 years of age, because

ASSOCIATION CANADIENNE DU DIABTE

of the permanent cognitive deficit that may

occur in this age group.
TREATMENT OF HYPOGLYCEMIA
The goals of hypoglycemia treatment are to
detect and treat low PG levels promptly by
employing an intervention that provides the
fastest rise in PG to a safe level, thereby
removing the risk of injury, and to relieve
symptoms quickly while avoiding overtreatment (and resulting rebound hyperglycemia
and weight gain).
There are 7 recommendations concerning the treatment of hypoglycemia:
Recommendation (new): Mild to moderate hypoglycemia should be treated with
the oral ingestion of 15 g of carbohydrate,
preferably as glucose or sucrose tablets or
solution, or hydrolyzed polysaccharide.
Hydrolized polysaccharides are not readily available in Canada. Glucose or sucrose, in
tablet form or in solution, should therefore be
the first choice.In smaller children, a dose of
10 g of glucose may be used initially.
Recommendation (new): Severe hypoglycemia in a conscious person should be
Case Study 1continued from page 4
with multiple daily injections or use of a
continuous subcutaneous insulin infusion
pump. However, she is concerned that this
may result in another episode of severe
hypoglycemia.Although intensified diabetes
management was found to increase the rates
of severe hypoglycemia in both adults and
adolescents in the Diabetes Control and
Complication Trial (2,3), several studies have
shown no association with intensified diabetes management and severe hypoglycemia
in children and adolescents (4-7). This is
likely due to better patient education.
Interestingly, the key to improving
metabolic control while avoiding frequent
mild hypoglycemia and increased risk of
severe hypoglycemia is increased frequency
of monitoring, plus education on insulin
adjustment, physical activity and food
intake.You can therefore reassure Courtney
that she can safely intensify her diabetes
management with the help of her diabetes
education team.
REFERENCES
1.

Yale J-F, Begg I, Gerstein H, et al. 2001

Canadian Diabetes Association clinical practice
guidelines for the prevention and management

treated with the oral ingestion of 20 g of

carbohydrate, preferably as glucose tablets
or equivalent.
Recommendation (new): Severe hypoglycemia in an unconscious person in the
home situation should be treated with
1 mg glucagon subcutaneously or intramuscularly. Children 5 years of age
should be treated with 0.5 mg glucagon.
Caregivers or support personnel should
call for Emergency Services and the episode
should be discussed with the healthcare team
as soon as possible. Hospitalization is probably not required once consciousness and the
ability to ingest food have been restored.
Recommendation (new): For severe
hypoglycemia with unconsciousness, IV
glucose, 10 to 25 g (20 to 50 cc of D50W),
should be given over 1 to 3 minutes.
This should be considered standard treatment by medical or paramedical personnel,
despite problems with intravenous access and
the risk of phlebitis.
Recommendation (new): In hospitalized patients, a PRN order for glucagon
should be considered for any patient at

2.

3.

4.

5.

6.

7.

of hypoglycemia in diabetes. Can J Diabetes.

2002;26:22-35.
Diabetes Control and Complications Trial
Research Group. The effect of intensive treatment on the development and progression of
long-term complications in insulin-dependent
diabetes mellitus. N Engl J Med. 1993;
329:977-986.
The Diabetes Control and Complications Trial
Research Group. Effect of intensive diabetes
treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes
mellitus: Diabetes Control and Complications
Trial. J Pediatr. 1994;125:177-188.
Nordfeldt S, Ludvigsson J. Severe hypoglycemia in children with IDDM. A prospective
population study, 1992-1994. Diabetes Care.
1997;20:497-503.
Bognetti E, Calori G, Meschi F, et al.
Prevalence and correlations of early microvascular complications in young type I diabetic
patients: role of puberty. J Pediatr Endocrinol
Metab. 1997;156:587-592.
Dammacco F, Torelli C, Frezza E, et al.
Problems of hypoglycemia arising in children
and adolescents with insulin-dependent diabetes mellitus. The Diabetes Study Group of
The Italian Society of Pediatric Endocrinology
& Diabetes. J Pediatr Endocrinol Metab.
1998;11(suppl 1):167-176.
Ludvigsson J, Nordfeldt S. Hypoglycaemia
during intensified insulin therapy of children
and adolescents. J Pediatr Endocrinol Metab.
1998;11(suppl 1):159-166.

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risk for severe hypoglycemia when IV

access is not readily available.
Recommendation (new): To prevent
repeated hypoglycemia, the patient
should have a snack or meal in addition
to fast-acting treatment, once the hypoglycemia has been reversed.
A snack (including 15 g of carbohydrate
and a protein source) is recommended if a
meal is >1 hour away.
Recommendation (new): All patients
currently on or starting therapy with
insulin or insulin secretagogues should be
counselled about the recognition and prevention of drug-induced hypoglycemia.
REFERENCES
1.

2.

3.

4.

5.

6.

7.

8.

Yale J-F, Begg I, Gerstein H, et al. 2001

Canadian Diabetes Association clinical practice
guidelines for the prevention and management
of hypoglycemia in diabetes. Can J Diabetes.
2002;25:22-35.
Meltzer S, Leiter L, Daneman D, et al. 1998
clinical practice guidelines for the management
of diabetes in Canada. CMAJ. 1998;159(suppl
8):S1-S29.
United Kingdom Prospective Diabetes Study
Group. Effect of intensive blood-glucose control
with metformin on complications in overweight
patients with type 2 diabetes (UKPDS 34).
Lancet. 1998;352:854-865.
The Diabetes Control and Complications Trial
Research Group. Hypoglycemia in the Diabetes
Control and Complications Trial. Diabetes.
1997;46:271-286.
Reichard P, Pihl M, Rosenqvist U, Sule J.
Complications in IDDM are caused by elevated
blood glucose level: the Stockholm Diabetes
Intervention Study (SDIS) at 10-year follow up.
Diabetologia. 1996;39:1483-1488.
McCrimmon RJ, Frier BM. Symptomatic and
physiological responses to hypoglycemia
induced by human soluble insulin and the analogue lispro human insulin. Diabet Med.
1997;14:929-936.
Torlone E, Fanelli C, Rambotti AM, et al.
Pharmacokinetics, pharmacodynamics and glucose counterregulation following subcutaneous
injection of the monomeric insulin analogue
[Lys (B28), Pro (B29)] in IDDM. Diabetologia.
1994;37:713-720.
Jacobs MA, Salobir B, Popp-Snijders C, et al.
Counter-regulatory hormone responses and
symptoms during hypoglycaemia induced by
porcine, human regular insulin, and Lys(B28),
Pro(B29) human insulin analogue (insulin
Lispro) in healthy male volunteers. Diabet Med.
1997;14:248-257.

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ASSOCIATION CANADIENNE DU DIABTE

Case Study 2. Hypoglycemia and type 2 diabetes

Ellen L. Toth MD FRCPC
Division of Endocrinology
Department of Medicine
University of Alberta
Edmonton, Alberta, Canada

PRESENTATION
Joseph Dorochuk lay in a hospital bed, surrounded by intravenous (IV) poles and
encased in casts. Bruises and scars were visible between the dressings. He was 70 years
of age, and hailed from a small Alberta town.
Mr. Dorochuk, I asked, what happened?
He explained that his truck had run into
a parked van. He then described how he
had been having trouble with dizziness for
weeks, and had also had trouble focussing
and concentrating. It was particularly bad
when he had to negotiate the towns single
traffic light. He would stop there, not
knowing whether to proceed.
How long have you had diabetes?
I asked.
Only a few months, he replied. He
had presented with symptoms, and his primary care physicians had prescribed glyburide 5 mg BID and sent him on his way.
But Mr. Dorochuk knew a little bit about
9.

Tsui E, Chiasson JL, Tildesley H, et al. The use

of lispro insulin in subcutaneous insulin
pumps: counterregulatory hormone responses.
Diabetologia. 1996;39(suppl 1):A223.
10. Ewing FM, Frier BM. Comparison of the physiological and symptomatic responses to hypoglycemia induced by human soluble insulin and
the insulin analogue aspart in patients with type
1 diabetes. Diabet Med. 1998;15(suppl 2):S34.
11. Frier BM, Lindholm A, Ewing FM, Hylleberg B.
No difference in hypoglycaemic symptom
threshold for insulin aspart and human insulin
in type 1 diabetic patients. Diabetologia.
1999;42(suppl 1):A237.
12. MacLeod KM, Gold AE, Frier BM. A comparative
study of responses to acute hypoglycemia
induced by human and porcine insulins in
patients with type 1 diabetes. Diabet Med.
1996;13:346-357.
13. MacLeod KM, Gold AE, Frier BM. Frequency,
severity and symptomatology of hypoglycemia: a
comparative trial of human and porcine insulins
in type 1 diabetic patients. Diabet Med.
1995;12:134-141.

managing diabetes, since his mother had

also had the disease and had followed a strict
diet. He started dieting as well, and lost
about 30 pounds. He also continued taking
his glyburide faithfully. His doctor was
pleased at his 3-month follow-up visit, and
his plasma glucose (PG) level was normal
on random testing.
When we checked his HbA1c level, it was
also normal, only 3 months after diagnosis.
WHAT DOES THIS CASE TEACH US?
Overtreatment with oral agents is
possible.
Management of type 2 diabetes
should always begin with diet and
education.
Unless a patient is severely symptomatic, addition of oral hypoglycemic
agents should occur only after 1 to 3
months of lifestyle modification.
Glyburide is not an ideal agent for the
elderly.
Had Mr. Dorochuk received adequate
instruction on self-monitoring and hypoglycemia, the accident might have been prevented. Thankfully, there was no loss of life
and Mr. Dorochuk managed his diabetes
well with diet alone for many years to come.
14. Colagiuri S, Miller JJ, Petocz P. Double-blind
crossover comparison of human and porcine
insulins in patients reporting lack of hypoglycemia
awareness. Lancet. 1992;339:1432-1435.
15. Clarke WL, Cox DJ, Gonder-Frederick LA, et al.
The relationship between nonroutine use of
insulin, food and exercise and the occurrence
of hypoglycaemia in adults with IDDM and varying degrees of hypoglycemic awareness and
metabolic control. Diabetes Educ. 1997;
23:55-58.
16. Fritsche A, Stumvoll M, Renn W, Schmulling
RM. Diabetes teaching program improves
glycemic control and preserves perception of
hypoglycemia. Diabetes Res Clin Pract.
1998;40:129-135.
17. Rovet JF, Ehrlich RM. The effect of hypoglycemia seizures on cognitive function in children with diabetes: a 7-year prospective study.
J Pediatr. 1999;134:503-506.
18. Rovet J, Alvarez M. Attentional functioning in
children and adolescents with IDDM. Diabetes
Care. 1997;5:803-810.

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Suite de la page 8

lincidence de lhypoglycmie chez les

patients atteints de diabte de type 1, effectue par Egger et ses collaborateurs, a montr
que le risque relatif dhypoglycmie grave
chez les patients recevant un traitement
intensif tait de 2,99 le risque tant
inversement proportionnel la normalisation de lHbA1c (4). Chez les patients atteints
de diabte de type 2, linsuline est souvent
ncessaire pour atteindre lHbA1c vise de <
7 %. Lajout dinsuline aux agents oraux
accrot le risque dhypoglycmie, mais son
incidence est moindre que chez les patients
atteints de diabte de type 1.Au cours de ltude UKPDS, seulement 30 % des patients
recevant le traitement intensif ont eu une
hypoglycmie annuelle lors des les 15 ans du
suivi et seulement de 2 3 % ont prsent
une hypoglycmie grave par anne (2).
Lhypoglycmie est classe comme suit (5) :
Hypoglycmie lgre : incident que le
patient peut traiter lui-mme. On laccepte habituellement comme le prix
payer pour obtenir une glycmie quasi
normale, ce qui est le but du traitement
intensif du diabte.
Hypoglycmie grave : incident qui
exige lintervention dune autre personne, cest--dire que le patient est
suffisamment affect pour ne pas se
traiter efficacement lui-mme.
Hypoglycmie insouponne : une distinction que lon fait au sujet de lhypoglycmie chez les patients atteints de
diabte de type 1 est sils ressentent ou
non les symptmes dhypoglycmie de
faon appliquer temps les mesures
ncessaires pour la prvenir. Les hypoglycmies insouponnes se produisent
typiquement chez les patients qui
prsentent un diabte de type 1 de
longue date et souvent, des lsions du
systme nerveux autonome et dautres
complications. Elles surviennent aussi
dans des situations temporaires, telle la
grossesse, ou en association une
matrise rigoureuse de la glycmie
(lHbA1c est dans les limites de la normale). Dans ces cas, il semble que le foie
et le cerveau soient dsensibiliss,
mais la situation est rversible si on
vite les hypoglycmies pendant
quelques semaines, en visant une
HbA1c entre 6 et 12 mmol/L ou plus.
Les stratgies visant rduire au minimum le nombre dhypoglycmies tout en

Tableau 1. Objectifs glycmiques chez les adolescents et les adultes

(adaptation de la rfrence 4)
Valeur idale

Valeur optimale

HbA1c (% de la limite suprieure)

Glycmie jeun (mmol/L)
Glycmie post-prandiale, 1 2 h (mmol/L)

< 0,06
3,8 6,1
4,4 7

< 0,07
47
5,0 11

administrant un traitement intensif aux

patients atteints de diabte de type 1 comprennent ltablissement dobjectifs personnaliss pour la glycmie et lHbA1c,
lducation des patients et ladministration
danalogues de linsuline action rapide.
Dans ses Lignes directrices de pratique
clinique 1998 (3) (tableau 1), lACD fait des
recommandations gnrales au sujet des
objectifs glycmiques, mais ces objectifs
doivent tre adapts par des praticiens bien
renseigns en collaboration avec des patients
bien informs. Le risque dhypoglycmie
nest quun des facteurs considrer. Dautres
facteurs tels le stade de la vie, le dsir dune
grossesse, lexistence de complications aux
stades prcoce ou avanc du diabte et la
disponibilit de groupes de soutien.
Les patients doivent tre bien renseigns
sur la dure daction et le moment de leffet
maximal des insulines, sur support dimentaire et les effets de lactivit physique. Les
cours orientes et donns par des ducateurs
agrs en diabte sont la meilleure faon dduquer les patients.
Les insulines lispro (Humalog, Eli Lilly)
et aspart (NovoRapid, Novo Nordisk)
action rapide rcentes produisent moins
dhypoglycmies pour un taux donn
dHbA1c (6,7). Les insulines action rapide
sont utilises seulement pour le traitement
intensif des patients atteints de diabte de
type 1, en association une insuline de base
action prolonge (lente, NPH, ultralente).
Lorsque pris avec de la nourriture, les analogues action rapide sont assez srs, mais ils
peuvent causer une hypoglycmie profonde
sils sont pris avec une quantit insuffisante de
nourriture ou si le patient fait de lexercice
moins de 2 heures aprs une injection. En raison de laction rapide des analogues,
le patient ne doit jamais tarder manger. Il
doit absolument vrifier sa glycmie avant
linjection afin dadapter la dose la glycmie,
au repas prvu et lactivit qui suivra.
Il existe cinq classes dagents oraux pour
le traitement du diabte de type 2 : les

sulfonylures (glyburide/glibenclamide, gliclazide, chlorpropamide), les biguanides (metformine),les inhibiteurs de lalpha glucosinide,
natglinide) et les thiazolidindiones (rosiglitazone, pioglitazone). Lassociation de linsuline
des mdicaments qui augmentent son action
plutt que sa scrtion (metformine et thiazolidindiones) est prfrable tant pour
rduire le risque dhypoglycmie que pour
obtenir des synergies optimales des mcanismes daction.
Les agents les plus susceptibles de causer
une hypoglycmie sont les sulfonylures et
les glitinides, car ils augmentent la scrtion
dinsuline. Il faut considrer leffet de lexercice sur le risque dhypoglycmie post-prandiale chez les patients qui prennent une
sulfonylure (rduire la dose de lagent oral
ou modifier lalimentation). On a constatr
que le gliclazide produisait moins dhypoglycmies que les autres sulfonylures chez les
personnes ges. Comme le glyburide/
glibenclamide et le chlorpropamide peuvent
causer une hypoglycmie prolonge chez les
patients jeun, leur administration doit tre
interrompue sans tarder chez les patients
malades ou chez ceux qui doivent tre jeun
en raison dexamens mdicaux.
Enfin, les patients qui reoivent une association dinsuline et dacarbose, chez qui linsuline peut causer une hypoglycmie, doivent
prendre un monosaccharide (comprims de
dextrose) pour traiter lhypoglycmie.
CONCLUSION
Lhypoglycmie est une complication du
traitement du diabte posant un problme
particulier lorsquelle est insouponne. Plus
les traitements de lhyperglycmie deviendront efficaces, plus il sera essentiel de connatre lennemi quest lhypoglycmie. Ainsi,
il sera alors plus facile de lviter et de la
traiter.
RFERENCES (voir page 2)

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Canadian
D

LE DIABTE AU CANADA

VOLUME 15 No 3

AUTUMNE 2002

LHYPOGLYCMIE : POUR
MIEUX CONNATRE LENNEMI
Ellen L. Toth, M.D., FRCPC, et Danile Pacaud, M.D., FRCPC

Depuis la publication
des rsultats de ltude
RSUM
DCCT (1) (Diabetes
Control and Complications Trial), mene
auprs de patients atteints de diabte de type
1, et de ltude UKPDS2 (United Kingdom
Prospective Diabetes Study), faite auprs de
patients atteints de diabte de type 2, le
traitement intensif du diabte est maintenant
considr la norme chez les patients atteints
de diabte. Au cours de ltude DCCT, on a
observ une baisse de 40 60 % de la
frquence des complications microvasculaires

significatives chez les patients qui recevaient

un traitement intensif du diabte par rapport
au groupe tmoin, qui lui recevait le traitement classique. Ltude UKPDS a galement
dmontr quune matrise rigoureuse de la
glycmie est bnfique, surtout pour prvenir
les complications microvasculaires. Ainsi,
lAssociation canadienne du diabte (ACD)
recommande des objectifs rigoureux pour un
meilleur quilibre de la glycmie (tableau 1) (3).
Le traitement intensif du diabte exige
des dosages frquents de la glycmie ( 4 fois
par jour) et un bon quilibre entre lapport

alimentaire, les activits physiques et les doses

dinsuline. Le but est lobtention dune glycmie aussi prs que possible de la normale
sans quil y ait de danger pour les patients
tout en tenant compte de circonstances particulires (ex. grossesse ou prsence ou
absence de complications).
Toutefois, au cours de ltude DCCT,
lincidence de lhypoglycmie a t trois fois
plus leve chez les patients recevant le
traitement intensif. Ainsi, lhypoglycmie
peut tre le facteur limitant du traitement
intensif du diabte. Une mta-analyse de
Suite la page 7

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