Diabetes Mellitus

10/24/2019 Diabetes Mellitus
Diabetes Mellitus
Terra Arnason, MD, PhD, FRCPC

Kerry Mansell, BSP, PharmD, CDE
Introduction
Diabetes mellitus is a chronic metabolic disturbance characterized by fasting and/or postprandial
hyperglycemia. Rather than a single disease entity, diabetes mellitus is a heterogeneous syndrome
that is caused by an absolute or relative lack of insulin, resistance to the action of insulin, or both.
Dysglycemia is a term that describes abnormal blood glucose levels without a definite threshold. The
term reflects current evidence that minor degrees of blood glucose abnormalities, even those that do
not meet the diagnostic threshold for diabetes mellitus, are still associated with increased
cardiovascular risk.[1]
Long-term diabetes mellitus may lead to complications that involve the small blood vessels
(microangiopathy), large blood vessels (macroangiopathy) and nerves (neuropathy) of multiple organs
and systems. Because diabetes is associated with significant dysfunction of numerous metabolic
pathways, clinicians must pay close attention to factors such as hypertension and dyslipidemia in
addition to blood glucose. Heart disease is the most common cause of death in patients with
diabetes.[2]
Classification
diabetes mellitus (T1DM) is due to autoimmune beta cell destruction resulting in an absolute
deficiency of insulin. T1DM usually presents with acute metabolic symptoms of relatively short
duration in a child, adolescent or young adult. If untreated, ketoacidosis may occur. Although onset of
T1DM is not common after 30 years of age, some older individuals with type 2 diabetes mellitus may
develop markers of autoimmunity and progress quickly to an insulin-dependent state. In North
America, T1DM accounts for 5–10% of all patients with diabetes.
diabetes mellitus (T2DM) manifests primarily as insulin resistance along with some degree of
insulin deficiency. Over time, insulin deficiency worsens, resulting in more prominent hyperglycemia.
T2DM is commonly discovered incidentally, or is diagnosed in adults who are often obese and have
nonspecific symptoms. T2DM makes up 90% of all cases of diabetes mellitus and the prevalence is
rising rapidly, particularly in certain ethnic groups, both in Canada and worldwide. It is also being
diagnosed more frequently and earlier in obese children and adolescents.
diabetes is defined as onset or recognition of glucose intolerance in pregnancy.
Other specific causes of diabetes mellitus include the monogenetic syndromes such as maturity-onset
diabetes of the young (MODY), or are a result of pancreatic diseases (Type 3c), infectious agents,
drugs, pancreatic surgery or other diseases leading to carbohydrate intolerance. Drugs that can
perturb blood glucose levels and interfere with glycemic control in patients with diabetes are
presented in Table 1.
Table 1: Examples of Drugs That Can Cause Dysglycemia[a]

Beta-blockers, e.g., atenolol, metoprolol, propranolol
Corticosteroids, e.g., prednisone
Diazoxide
HMG-CoA Reductase Inhibitors (statins)
Immunosuppressive agents, e.g., sirolimus, tacrolimus, temsirolimus
Interferon alfa
Isoniazid
Niacin
Pasireotide
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Pentamidine
Protease inhibitors, e.g., amprenavir, atazanavir, darunavir, fosamprenavir, indinavir,
lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir
Second-generation antipsychotic agents, e.g., clozapine, olanzapine, paliperidone,
quetiapine, risperidone
Thiazide or loop diuretics, e.g., chlorthalidone, furosemide, hydrochlorothiazide
[a]
Medication-induced dysglycemia should not preclude the use of these medications if clinically indicated.
Goals of Therapy
Control symptoms
Establish and maintain glycemic control while avoiding hypoglycemia
Prevent or minimize the risk of acute and chronic complications
Achieve optimal control of associated risk factors such as hypertension, obesity and
dyslipidemia
Investigations
Diabetes mellitus may present in a variety of settings:
asymptomatic; incidental discovery through routine laboratory screening (see Figure 1)
nonspecific signs and symptoms such as fatigue, lassitude, weight changes
presence of diabetic macrovascular or microvascular complications including neuropathy,
kidney disease, erectile dysfunction, vision changes
acute metabolic symptoms such as polyuria, polydipsia, weight loss
diabetic ketoacidosis
The diagnosis of diabetes in Canada is established by:[3]
a random plasma glucose ≥11.1 mmol/L (random is defined as any time of day without
regard to the interval since the last meal)
a fasting plasma glucose (FPG) ≥7 mmol/L (fasting is defined as no caloric intake for ≥8
hours)
a plasma glucose level ≥11.1 mmol/L 2 hours after a 75 g oral glucose load (oral glucose
tolerance test [OGTT])
an HbA1c ≥6.5% (in adults) using a standardized, validated assay, in the absence of
conditions that affect the accuracy of the HbA1c (not to be used for suspected T1DM)[4]
In the absence of clinical symptoms of hyperglycemia, confirm the diagnosis with a repeat test
performed on another day;[3] with the exception of a random plasma glucose, the same test should be
used to confirm the initial result.
Screening
Screening for T1DM is not recommended in individuals with normal glucose levels. While the
autoantibodies thought to contribute to the destruction of the pancreatic beta-cells can be detected
prior to disease, their presence does not guarantee that diabetes will occur. Although research
continues, there are no interventions proven to prevent or delay the onset of T1DM.
Diabetes Canada recommends screening for T2DM every 3 years in individuals over 40 years of
age, or those determined to be high risk using a validated tool such as CANRISK, by testing either
fasting plasma glucose (FPG) or HbA1c.[5][6] Earlier and more frequent testing should be
considered in individuals at a higher risk (see Table 2).[7]
[5]
Table 2: Risk Factors for Diabetes Mellitus
Age ≥40 years
First-degree relative with T2DM
Member of high-risk population, e.g., Indigenous, Hispanic, South Asian, Asian,
African, low socioeconomic status
History of prediabetes e.g., IFG, IGT, HbA1c 6–6.4%
History of gestational diabetes mellitus
History of delivery of a macrosomic infant
Presence of end-organ damage associated with diabetes, e.g., cardiovascular,
microvascular
Presence of vascular risk factors:
abdominal obesity[a]
HDL cholesterol <1 mmol/L in males or <1.3 in females[a]
hypertension[a]
being overweight[a]
triglycerides ≥1.7 mmol/L[a]
smoking
Presence of associated diseases:
acanthosis nigricans[a]
cystic fibrosis
history of pancreatitis
HIV infection
hyperuricemia/gout
non-alcoholic steatohepatitis
obstructive sleep apnea
polycystic ovary syndrome[a]
psychiatric disorders, e.g., bipolar disorder, depression, schizophrenia
[a] Associated with insulin resistance.
Abbreviations: HIV = human immunodeficiency virus; IFG = impaired fasting glucose: 6.1–6.9
mmol/L; IGT = impaired glucose tolerance: OGTT result of 7.8–11 mmol/L; T2DM = type 2 diabetes
mellitus
Type 1 and Type 2 Diabetes Mellitus
Therapeutic Choices
Insulin must be initiated in patients with T1DM at the time of diagnosis and should be considered in
those with T2DM who present with marked hyperglycemia and HbA1c ≥1.5% above their target
(typically >8.5%). In newly diagnosed T2DM patients with HbA1c <1.5% above their target, lifestyle
modifications alone may be appropriate as a first step. However, if glycemic goals are not reached
within 3 months, pharmacotherapy should be initiated.[8]
Nonpharmacologic Choices
Nonpharmacologic therapy plays a pivotal role in the treatment of both type 1 and type 2 diabetes.
The use of a flow chart may be helpful to ensure interventions are not overlooked (see
www.diabetes.ca for an example).
is vital in making patients full participants in the diabetes health-

care delivery team and ensuring that they can effectively and safely manage their disease. A
well-structured educational program should include:
a basic understanding of diabetes
the role of diet, exercise and medications
how and when to self-monitor blood glucose and why it is necessary
the management of sick days
recognition and treatment of hypoglycemia
knowledge of the major side effects of medications and possible medication
adjustments in response to changes in diet and activity
care of the feet
awareness of risk of heart disease and importance of risk-factor control, including body
weight
Individualized . Provide counselling by a registered dietitian and
include information on nutrients from all the basic food groups. If they are overweight, reduce
total caloric consumption in patients with T2DM to decrease weight and improve metabolic
control. For patients on insulin, tailor the distribution of food intake into meals and snacks
according to the individual's preference, lifestyle and medications. In patients with T1DM,
carbohydrate intake and insulin dose must be linked. Options include advising patients to fix
carbohydrate consumption or count the amount of carbohydrate ingested and adjust the
insulin dose accordingly.
(SMBG) is an essential component of normalizing blood
glucose for the majority of patients with diabetes mellitus. It allows appropriate recognition of
low blood glucose levels and provides immediate feedback about the effects of therapy.
For patients treated with insulin, SMBG is especially important. In these patients,
individualize self-monitoring strategies and take both pre- and postprandial
measurements. A minimum of 3 blood sugar measurements per day should be
performed for those on basal-bolus insulin regimens.[9]
For those who are being managed on oral antihyperglycemics or lifestyle alone, the
benefits and optimal timing and frequency of SMBG has not yet been established. The
frequency and duration of blood glucose monitoring in patients on oral therapy must be
individualized and should be based on factors such as type of oral antihyperglycemic
agent, risk of hypoglycemia, presence of concurrent illness, as well as the need to
evaluate the effectiveness of new medications or dosage changes. For example, in
stable patients receiving metformin alone who are at low risk of hypoglycemia and are
meeting their glycemic targets, SMBG may not be necessary. For medications that carry
a higher risk of hypoglycemia (e.g., glyburide, insulin), or in patients with risk factors for
hypoglycemia (e.g., advanced age, renal dysfunction, multiple comorbidities,
hypoglycemia unawareness), SMBG is useful to ensure safety.
Capillary blood glucose testing has been the usual technique used for SMBG. Other devices
are available that measure the glucose concentration in interstitial fluid to provide continuous
glucose monitoring (CGM) or flash glucose monitoring (FGM).[9] These technologies
represent alternatives to the traditional SMBG for some people, particularly those who may
have labile glucose levels or require frequent SMBG.
will improve cardiovascular function, enhance insulin sensitivity, and lower
blood pressure and lipid levels. Physical activity also helps improve glycemic control in
people with T2DM. Patients engaging in physical activity more vigorous than walking should
undergo a thorough physical examination to ensure safety prior to commencing the exercise
program. Encourage aerobic exercise totalling ≥150 minutes per week along with resistance
training at least twice a week.[10] It is imperative to educate patients treated with insulin
about the effect of exercise on blood glucose and how to adjust the insulin dosage
accordingly. Predictable intensity and duration allow individuals to understand how blood
glucose levels will change immediately following the exercise. Typically, blood glucose levels
will decrease after moderate-intensity exercise but may increase after intense activity (likely
a stress response). Teach patients how to time their meals and/or regulate food consumption
to ensure the safety of the prescribed exercise regimen.
including directed histories and physical examinations are intended to
detect comorbidities and complications; assessments should include:
blood pressure measurements at all appropriate visits[11]
foot examinations annually; refer patients at high risk of foot ulceration or amputation
and those with existing ulcers to a health-care provider trained in foot-care
management[12]
HbA1c measurements every 3 months for patients who have not achieved target values;
testing every 6 months may be acceptable in stable patients who consistently meet
glycemic targets[9]
assessment of the accuracy of blood glucose meters by comparing blood glucose
readings from the glucose meter and a simultaneous phlebotomy draw at least once per
year; reading should be within 15%[9]
serum creatinine and random urine albumin-creatinine ratio once a year to screen for
chronic kidney disease[13]
lipid profile (either fasting or non-fasting) at the time of diagnosis and then annually if
results are normal initially;[14] more frequent testing (every 3–6 months) should occur if
treatment is initiated[15]
referral to a specialist (ophthalmologist or optometrist) for an eye examination using
dilated fundoscopy or wide-angle stereoscopic retinal photography at the time of
diagnosis in patients with T2DM, and 5 years after diagnosis in patients with T1DM ≥15
years; repeat annually in T1DM and every 1–2 years in T2DM if initially normal[16]
reinforcing skills learned in education and dietary counselling
patients with diabetes to reduce the risk of complications and hospitalization. In
adults, annual influenza immunization and a one-time pneumococcal vaccination is
recommended. A 2nd pneumococcal vaccination is recommended for patients over 65 years
of age who received their original immunization >5 years earlier at <65 years of age.[17]
Pharmacologic Choices
Type 1 Diabetes
Insulin may be administered by syringe, pen or continuous subcutaneous insulin infusion

(CSII or insulin pump). Although insulins from animal sources are still marketed in Canada,
most patients use human insulin and insulin analogues since these agents cause less antibody
generation and related adverse reactions (e.g., hypersensitivity, insulin resistance). Human
insulins are produced by recombinant DNA technology and have an amino acid sequence
identical to endogenous human insulin. Insulin analogues are slightly modified human insulin
molecules (see Table 7). The rapid-acting insulin analogues (RAIAs) insulin aspart, insulin
glulisine and insulin lispro allow for more flexibility to control postprandial glucose because
of their faster onset of action compared with short-acting insulins. A concentrated 200 units/mL
version of insulin lispro is available, reducing the volume needed to be injected, which is useful
in those requiring large doses with each meal (>50 units). In January 2017, Health Canada
approved faster-acting insulin aspart, which provides a more rapid onset of action.[18] This
product may be administered up to 2 minutes prior to a meal and, if necessary, up to 20
minutes after starting the meal.
The long-acting insulin analogues (LAIAs) insulin detemir and insulin glargine appear to
produce more predictable effects than intermediate-acting human insulin (NPH) and are
associated with fewer episodes of hypoglycemia, particularly nocturnal hypoglycemia.[19] In a
meta-analysis, patients with T1DM who used LAIAs for a year had significantly fewer episodes
of nocturnal hypoglycemia compared to using NPH (NNT = 20 to prevent 1 episode).[20] Insulin
glargine is available in different formulations, including a concentrated 300 units/mL product.
This concentrated formulation appears to have a longer duration of action, has no peak effect
and further reduces hypoglycemia compared to glargine 100 units/mL.[21] Insulin degludec is
a long-acting basal insulin available in 100 units/mL and 200 units/mL strengths. Insulin
degludec has a long duration of action of approximately 42 hours.[22] Compared with insulin
glargine 100 units/mL, it was shown to be as effective in controlling glucose, with a 26%
relative risk reduction in nocturnal hypoglycemia.[23]
Insulin Regimens
Although an in-depth discussion about the different types of insulin regimens is beyond the
scope of this chapter, the Diabetes Control and Complications Trial (DCCT) showed that
intensive treatment regimens control blood glucose more effectively than conventional
regimens and reduce the risk of long-term diabetic microvascular complications
(retinopathy, nephropathy, neuropathy).[24] Follow-up data from the trial demonstrate a
long-term benefit of intensive therapy on the risk of cardiovascular events and mortality.[25]
Newly diagnosed patients and those with poor glycemic control on conventional regimens
should be offered the option of intensive diabetes management consisting of multiple-dose
insulin (MDI) regimens (see Table 3). It is essential to assess each patient to determine
whether an intensive regimen is a suitable option. Less intensive regimens may be a better
choice in the frail elderly, unmotivated patients or those who lack awareness of severe
hypoglycemia. In clinical practice, RAIA in combination with LAIA is preferred over regular
insulin in order to minimize risk of hypoglycemia and improve HbA1c and postprandial
glucose levels.[26][27]
Most lean patients with T1DM require approximately 0.5 units of insulin per kilogram of
body mass. In the first few months following a T1DM diagnosis, patients may experience
periods where the requirement for insulin is decreased or transiently eliminated. This
phenomenon is known as the honeymoon phase. Initiate insulin therapy judiciously in order
to minimize the risk of hypoglycemia and adjust the dose every 2–3 days according to
blood glucose results. Regular home monitoring allows patients to adjust the dose of insulin
in response to abnormal blood glucose levels, effects of diet and exercise, and changing
blood glucose patterns. Optimal blood glucose control is achieved by matching the timing
of insulin injections with caloric intake: regular insulin is given approximately 30 minutes
before meals and RAIAs should ideally be administered 0–15 minutes prior to starting a
meal.
The use of insulin pumps and regimens involving multiple doses of RAIA (vs. regular
human insulin) improves the stability of postprandial glucose levels and may also diminish
the frequency and severity of hypoglycemia, especially early nocturnal hypoglycemia. In
addition, insulin pumps can achieve a tighter and more reproducible degree of glycemic
control, particularly in those with a high initial HbA1c, but at a significantly increased
expense for the patient.
Table 3: Insulin Regimens in Type 1 and Type 2 Diabetes Mellitus

Rapid- or Short-Acting Intermediate- or Long- Comments
(Bolus) Acting (Basal)
Intensive: Basal-Bolus (Multiple-Dose Insulin Regimens)
Insulin aspart, glulisine or Insulin degludec, detemir, Recommended in

lispro before each meal glargine 100 units/mL or all T1DM when not
Alternatively regular glargine 300 units/mL once using an insulin
human insulin may be daily at supper bedtime pump, and in some
used (preferred); may use detemir T2DM.
or glargine 100 units/mL twice Requires glucose
daily in 2 equal doses monitoring and
Alternatively NPH once dosing calculations
twice daily may be used with each meal.
Intensive: Continuous Subcutaneous Insulin Infusion (Insulin Pump)
Rapid- or Short-Acting Intermediate- or Long- Comments

(Bolus) Acting (Basal)
Rapid-acting insulin None Expensive and
delivered by an electronic frequent testing
infusion set: insulin aspart required.
or lispro recommended; Carbohydrate
basal and boluses counting and
delivered according to insulin-correction
programmable settings ratios required for
dosing.
DKA may occur
quickly after
discontinuation,
tubing block or
pump failure.
Basal Insulin Only
None Insulin degludec, detemir, Use in T2DM only.

glargine 100 units/mL or Variable initiation
glargine 300 units/mL once strategies,
daily preferred; NPH can be including starting
used as an alternative with 5–10 units at
bedtime and
titrating to a fasting
blood glucose <7
mmol/L.
Basal-Plus (for patients desiring fewer injections)
Insulin aspart, glulisine or Insulin degludec, detemir, Use in T2DM only.

lispro before the single glargine 100 units/mL or Could substitute a
largest daily meal glargine 300 units/mL once premixed insulin
Alternatively regular daily. Alternatively, if NPH product given twice
human insulin may be preferred, administer with daily.
used breakfast supper
Titrate to a fasting
blood glucose
<7 mmol/L and to 2
hr postprandial
blood glucose <10
mmol/L.
Abbreviations: BG = blood glucose; DKA = diabetic ketoacidosis; NPH = neutral protamine

Hagedorn (isophane) insulin
Adverse Effects of Insulin Therapy
is the most common adverse effect of insulin therapy and occurs more
frequently in patients aiming for tight control of blood glucose.
Good glycemic control will always come with the risk of hypoglycemia.
Hypoglycemia is most commonly the result of either a missed meal or an
unusual amount of exercise. Frequent hypoglycemic events may lead to reduced
autonomic symptoms ( ). Teach patients to account
for diet and physical activity when planning insulin treatment regimens.
hypoglycemia is manifested by autonomic symptoms:
sweating, tremors, tachycardia, hunger, nausea and a general sensation of
weakness. It can easily be treated with an oral source of sugar. Fifteen grams of
glucose (e.g., 3/4 cup of juice or regular soft drink, 6 Life Savers) will usually
raise the blood glucose approximately 2 mmol/L within 20 minutes.
hypoglycemia requires assistance in its recognition and/or treatment.
Neuroglycopenic symptoms such as confusion, altered behaviour, difficulty
speaking and disorientation can progress to seizures and coma, and prevent the
patient from appropriately treating the hypoglycemic episode. If the patient is
conscious, an oral glucose preparation consisting of 20 grams of carbohydrate
should be used, preferably as glucose tablets or equivalent. Glucose gel is not a
preferred treatment option. It must be swallowed for significant effect, and the
blood glucose response is very slow.
In patients with no IV access, 1 mg of glucagon IM or SC
temporarily increases blood glucose, allowing for the intake of oral carbohydrate.
Glucagon is effective in malnourished patients or in alcohol-induced
hypoglycemia. If IV access is available, the treatment of choice is 20–50 mL of
50% dextrose IV over 1–3 minutes.
Assess specifically for and use strategies to recover
awareness, such as relaxing glycemic targets for up to 3 months and increasing
patient self-monitoring of BG.[28][29]
(lipohypertrophy) is most often the result of frequent use of
the same injection site. This results in low or unpredictable absorption of insulin from
that site, and in some cases, disfigurement. All patients should be educated about the
need to rotate injection sites in a systematic fashion.
, such as urticaria, angioedema, rashes and local erythema, are rare
with human insulin. If they do occur, switching to a different insulin manufacturer may
help.
Immune-mediated due to the production of anti-insulin antibodies is
also rare with human insulin. Patients who have developed immune-mediated
resistance to animal insulins should be switched to human insulin. Reduce the dose
substantially at the initiation of the switch. Concentrated regular insulin, 500 units/mL,
may be useful in the treatment of patients requiring very large doses of insulin.
Concern was raised about a possible association between and the use
of insulin glargine.[30] However, a focused look at breast cancer incidence with the
use of any type of insulin, including glargine, did not reveal increased rates of cancer.
[31]
Type 2 Diabetes Mellitus
Initial management of patients with T2DM generally depends on the HbA1c, as described
below:[8]
In patients with an HbA1c less than 1.5% above their personalized target, initiate
nonpharmacologic therapy alone (e.g., diet and exercise); however, medications must be
initiated without delay if glycemic targets are not met within 3 months. Upon starting
medication in these patients, monotherapy with metformin is the drug of choice unless
contraindicated; however, initial treatment may include a combination of oral agents and/or
insulin if the patient is exhibiting hyperglycemic symptoms or if it is unreasonable to expect
excellent control with this approach. The patient populations in whom metformin use is
contraindicated or cautioned will be discussed in further detail below.
In patients with an HbA1c more than 1.5% above their personalized target, medication should
be initiated immediately (along with diet and exercise). In these patients, combination therapy
(preferably metformin combined with another drug) with medications from different classes
may be required. In addition to oral medications, bedtime insulin can be considered as an
appropriate 2nd agent at this point. Also a MDI regimen may be appropriate in patients who
exhibit extremely high glucose levels at presentation, or for those who are very symptomatic.
In all patients who have been started on antihyperglycemic agents, aim to reach the desired
HbA1c target within 3–6 months through dosage titration or addition of other agents (see
Figure 2, Table 8). Typically, the higher the baseline HbA1c, the greater the reduction in HbA1c
that can be achieved with treatment.[32] After metformin, the drug chosen as the second-line
agent should be individualized, taking into consideration presence of clinical cardiovascular
disease, kidney function, hypoglycemia and weight concerns, cost, and insurance coverage,
amongst others.
Vascular protection is a significant goal in the management of diabetes (see Targets for
Control). In 2008 the FDA began requiring cardiovascular safety trials as part of the approval
process for new medications for T2DM. None of the cardiovascular outcome trials initiated
since 2008 have demonstrated an increase in cardiovascular events, and some trials found a
reduction in CV events. Currently there are more trials testing cardiovascular endpoints for
other agents ongoing. Diabetes Canada recommends that the results of cardiovascular safety
trials be considered when selecting medications for the treatment of T2DM.[8]
Biguanides
Metformin is generally considered the first choice for patients with a new and
uncomplicated diagnosis of T2DM. It decreases hepatic glucose production and may lower
glucose absorption and enhance insulin-mediated glucose uptake. It is not associated with
weight gain, it lowers HbA1c by approximately 1–1.5% and the risk of hypoglycemia is low
when it is used as monotherapy. However, it can potentiate the hypoglycemic effects of
insulin and sulfonylureas. Although the use of metformin has traditionally been discouraged
due to the perceived risk of lactic acidosis in patients with heart failure, renal or hepatic
disease, or hypoxemic states, a Cochrane review of 347 studies comparing over 70 000
subjects found no increase in the rate of lactic acidosis among patients receiving metformin
compared with controls receiving other antihyperglycemic agents.[33] Metformin is thought
to improve CV risk,[8] is considered safe to use in stable heart failure and liver disease, and
reduced doses can be used with creatinine clearance >30 mL/min. Metformin is also
routinely held preoperatively and when imaging-contrast agents are being given due to the
possibility of acute renal failure, which may increase the risk of lactic acidosis.
Alpha-glucosidase Inhibitors
Acarbose and miglitol (not available in Canada) inhibit intestinal alpha-glucosidases,

resulting in delayed digestion of starches and disaccharides and reduced postprandial
glucose levels. They do not significantly inhibit intestinal lactase. Acarbose does not cause
hypoglycemia but can increase the risk of hypoglycemia when combined with insulin or
insulin secretagogues, and causes significant GI effects. In addition, it requires TID dosing
(before meals) and lowers HbA1c by ≤1%. Because the digestion of sucrose is impaired by
acarbose, hypoglycemia in patients taking acarbose should be treated with glucose rather
than sucrose. It is not known whether acarbose alters CV risk. This class is generally not
used as first-line therapy or monotherapy in newly diagnosed individuals.
Dipeptidyl Peptidase-4 Inhibitors
Endogenous glucagon-like peptide-1 (GLP-1) is rapidly degraded by the enzyme dipeptidyl

peptidase-4 (DPP-4) to an inactive state. DPP-4 inhibitors (alogliptin, linagliptin,
saxagliptin and sitagliptin) increase the availability of GLP-1 as well as other potentially
active peptides involved in glucose homeostasis.[34] Overall, they lower HbA1c by ≤1% and
are well tolerated medications with low risk of hypoglycemia. Although the SAVOR-TIMI
trial showed an increase in hospitalization for heart failure with saxagliptin,[35] this has not
been noted with other medications in this class. Typically, these agents are added as
second- or third-line agents when BG is still uncontrolled with metformin. Trials have shown
that these drugs do not increase CV risk.[8]
Glucagon-Like Peptide-1 Agonists
Glucagon-like peptide-1 agonists mimic the actions of GLP-1, an endogenous “incretin”

hormone. GLP-1 is secreted in response to food ingestion by endocrine cells found in the
gastrointestinal tract.[36] Once released into the circulation, GLP-1 increases insulin
secretion, suppresses glucagon secretion during the postprandial period, slows gastric
emptying and increases satiety,[34] resulting in better control of glucose levels. When GLP-
1 agonists are administered subcutaneously, they increase GLP-1 action by approximately
5-fold.[37] They lower HbA1c to a greater extent than DPP-4 inhibitors, but cause more
nausea upon initiation of therapy and can cause vomiting as well. Semaglutide has been
associated with an increased rate (3%) of diabetic retinopathy complications compared to
placebo (1.8%).[38] Dulaglutide and semaglutide are given SC once weekly. Liraglutide is
given SC once daily without regard to meals, and lixisenatide is given SC once daily within
1 hour of a meal. Exenatide is marketed in 2 formulations. The solution is administered by
SC injection twice daily prior to meals, while the injectable suspension is administered by
SC injection once weekly without regard to meals.
Lixisenatide and the extended-release formulation of exenatide have a neutral effect on CV

risk.[8] In the LEADER trial, patients with T2DM known to have CV disease were
randomized to liraglutide or placebo and followed for a mean of 3.5 years.[39] The primary
outcome of death from CV causes, nonfatal MI or nonfatal stroke occurred in 13% of the
liraglutide group versus 14.9% of the placebo group (hazard ratio [HR] 0.87, 95% CI 0.78–
0.97). In SUSTAIN-6 patients with T2DM and established CV disease were randomized to
semaglutide or placebo and followed for a mean of 2.1 years. This trial used the same
primary outcome. Events occurred in 6.6% of the semaglutide group vs. 8.9% with placebo
(HR 0.74, 95% CI 0.58–0.95).[40]
Insulin Secretagogues: Sulfonylureas
The sulfonylureas (SUs) chlorpropamide, gliclazide, glimepiride, glyburide and

tolbutamide stimulate both basal and meal-stimulated insulin release. HbA1c can be
lowered by 1–1.5%. Significant differences exist between agents in regard to effectiveness,
hypoglycemia risk, postprandial correction of glucose and weight gain. First-generation
SUs (chlorpropamide, tolbutamide) are typically not used due to their pharmacokinetic
profile and higher affinity for drug interactions. Glyburide is an inexpensive second-
generation SU. Compared with other agents in this group, glyburide is associated with a
greater risk of hypoglycemia,[41] especially in elderly patients or those with renal
impairment. Though more common with glyburide, hypoglycemia and weight gain can
occur with any of these agents to varying degrees. Glyburide is included in the BEERS list
of medications considered potentially inappropriate for use in the elderly.[42] SUs are
considered useful as either add-on therapy, or less often as monotherapy when metformin
is contraindicated. The CV safety of SUs is uncertain.[8]
Insulin Secretagogues: Meglitinides
Repaglinide and nateglinide (not available in Canada) promote insulin release, but their
actions are much shorter compared with SUs. Meglitinides need to be taken just prior to
meals to reduce postprandial glucose elevations and should be omitted if the meal is
missed. Repaglinide is expected to lower HbA1c to a similar extent as SUs and it is also
considered to confer a lower risk of hypoglycemia in the context of missed meals (patients
who skip meals could omit the associated repaglinide dose). FPG usually drops after about
1 month of regular use.[43] It has been theorized that the greater effect on postprandial
glucose compared with SUs would translate into a more favourable effect on cardiovascular
outcomes; however, this benefit has not been established.[41]
Sodium-Glucose Cotransporter 2 Inhibitors
The newest class of antihyperglycemics are the sodium-glucose cotransporter 2 (SGLT2)

inhibitors (canagliflozin, dapagliflozin, empagliflozin and ertugliflozin). These drugs
prevent glucose reabsorption in the kidneys, leading to increased excretion of urinary
glucose and a lowering of blood glucose.[44] Some weight loss is associated with SGLT2
inhibitors, and their glucose-lowering ability is similar to that of other antihyperglycemic
agents.[45][46] There is a small decrease in blood pressure, which may be a benefit in
many, and a low risk of hypoglycemia. Side effects of note with this class of medications
include mycotic genital infections, volume depletion–related adverse effects, urinary tract
infections and some reports of diabetic ketoacidosis. Canagliflozin has been associated
with an increased risk of lower extremity amputations and risk of fracture.[8] Currently, it is
recommended that SGLT2 inhibitors not be used in those with reduced glomerular filtration
rate. Clinical trials have shown lower rates of kidney disease progression when compared
to placebo,[47][48] and research is ongoing into whether these agents may help preserve
renal function.[49][50]
The CV safety of empagliflozin was tested in EMPA-REG OUTCOME.[47] Patients with

T2DM and evidence of CV disease were randomized to empagliflozin 10 mg, 25 mg or
placebo once daily. The primary composite outcome was death from CV causes, nonfatal
MI or nonfatal stroke. After a mean of 2.6 years, the endpoint occurred in 10.5% with
empagliflozin and 12.1% with placebo (HR 0.86, 95% CI 0.74–0.99). The CANVAS
program investigated the safety of canagliflozin.[48] High-risk patients with T2DM were
followed for a mean of 3.6 years. A similar primary composite outcome was used, and was
found lower in the canagliflozin group than with placebo (26.9 vs. 31.5 participants per
1000 patient years [HR 0.86, 95% CI 0.75–0.97]). DECLARE-TIMI 58 tested the CV safety
of dapaglifozin.[51] A total of 17,160 patients with T2DM who had, or who were at risk for
CV disease were randomized to dapagliflozin 10mg daily or placebo and followed for a
median of 4.2 years. The rate of major adverse cardiovascular events was not significantly
different with dapagliflozin (8.8% vs. 9.4% with placebo), but the rate of CV death or
hospitalization for heart failure was 4.9% with dapagliflozin and 5.8% with placebo (HR
0.83, 95% CI 0.73-0.95).
Thiazolidinediones (TZDs)
Pioglitazone and rosiglitazone are agonists at peroxisome proliferator-activated receptor

gamma (PPARG) receptors located on the cell nucleus. These medications influence gene
expression in the cell leading to enhanced insulin sensitivity and lower levels of blood
glucose and circulating insulin. The precise mechanism underlying these effects remains
unclear.[52] The TZDs also exhibit increased peripheral glucose uptake, enhanced fat cell
sensitivity to insulin and decreased hepatic glucose output. The risk of hypoglycemia with
TZDs is very low when taken as monotherapy; however, they may enhance the
hypoglycemic effects of insulin and SUs. The mean decrease in HbA1c is 1–1.5%.
Individual TZDs may differ in their effects on serum lipids.[53] Both agents are associated
with weight gain due to increased subcutaneous fat deposition, fluid retention and edema,
which is likely the cause of the increased incidence of heart failure in patients receiving
TZDs.[52][54] Other reported adverse effects include worsening macular edema[55] and an
increased risk of fractures, particularly of the hip and wrist.[56][57]
The cardiovascular safety of thiazolidinediones is in question. Some analyses have

reported an increase in the risk of ischemic events such as MI in patients receiving
rosiglitazone,[58][59] while other research suggests that rosiglitazone confers a protective
effect from ischemic events.[60] Studies of pioglitazone have more consistently lacked any
signal of increased risk of ischemic events.[60] To ensure that the risks and benefits of this
medication have been clearly communicated, Health Canada requires that physicians
counsel patients and obtain their written consent for all new and renewed rosiglitazone
prescriptions. The FDA has removed its prescribing restrictions for rosiglitazone-containing
products (Avandia, Avandamet, Avandaryl, generics) after a re-evaluation of the RECORD
trial did not show an increased risk of MI.[61]
Concerns have emerged about the increased risk of bladder cancer with pioglitazone.[62]
This TZD is now contraindicated in patients with active or previous bladder cancer. Various
countries have suspended the sale of both TZDs due to cardiovascular or bladder cancer
concerns.
Insulin Regimens for Type 2 Diabetes Mellitus
Due to the progressive nature of T2DM, noninsulin antihyperglycemic agents gradually lose
their effectiveness over time. Insulin remains an important option for patients because of its
powerful effects on lowering HbA1c. Insulin does not alter CV risk.[8] Although it is
appropriate to consider insulin initiation at any point in the management of T2DM, it is
commonly reserved for the following situations:
Maximum tolerated dose of noninsulin antihyperglycemic agents yet HbA1c still not at
target
End-organ damage (e.g., kidney failure), making use of some antihyperglycemics
inappropriate
At initial diagnosis when HbA1c ≥1.5% above the individualized target
With metabolic decompensation
In pregnancy and in women planning pregnancy
The use of insulin is often delayed because of the perceived complexity of self-injections.
Also, insulin is associated with weight gain and carries a risk of hypoglycemia; thus, self-
monitoring is critical to its safe and effective use. Insulin is eventually required, either alone
or in combination with other agents.[8] Many patients with T2DM require high doses of
insulin (≥1 unit/kg) to overcome their significant insulin resistance. There are several
commonly used insulin regimens (see Table 3):
Generally, insulin is added to existing antihyperglycemic therapy when targets are not
being met after a 3‑month trial. Daily bedtime injection of basal insulin is prescribed at
a dose of 0.1–0.2 units/kg of LAIA or NPH insulin.[8][63] Alternatively, an empiric dose
of 5–10 units of LAIA (glargine or detemir) or intermediate (NPH) may be initially
chosen depending on whether the patient is lean or obese. Subsequently, the dose is
adjusted to achieve a fasting glucose <7 mmol/L. Some clinicians will choose to adjust
insulin by 2 units every 3 days, whereas others may choose to increase basal insulin
by 1 unit every night until the fasting blood glucose (FBG) target is achieved. Other
agents may need to be reduced once glycemic control is achieved; metformin is often
continued because it has proven to lower insulin requirements, ameliorate weight gain
and reduce the risk of hypoglycemia.[64]
If glycemic targets are not being met with bedtime insulin in combination with a
daytime antihyperglycemic regimen, an intensified insulin regimen can be initiated
with the introduction of mealtime insulin(s) depending upon blood glucose patterns.
Generally, oral antihyperglycemic medications are discontinued when mealtime insulin
injections are added with the exception of metformin, which can help minimize weight
gain and reduce the amount of insulin required.
If glycemic values are extremely high upon initial presentation, then intensive insulin
therapy may be started immediately, rather than introducing oral agents. To initiate
insulin, start with 40% of the total daily dose (0.5 units/kg total insulin units divided
over the 24-hour day) administered as a basal insulin (NPH or LAIA) and 20% of the
daily dose administered before meals 3 times daily (regular or RAIA). The dose is
then adjusted to achieve glycemic targets; fasting and pre-meal glucose <7 mmol and
2-hour postprandial glucose <10 mmol in most cases.
Insulin may be administered in twice-daily injections of a premixed insulin with two-
thirds of the daily dose (0.5 units/kg) administered in the morning before breakfast and
the remaining one-third of the daily dose administered before the evening meal
(usually 30/70 [30% regular, 70% basal mix] in the morning and evening). These
regimens provide convenience at the expense of flexibility and the ability to correct for
abnormal results. However, this approach is a reasonable alternative for patients with
diabetes who have little variation in exercise or food intake from day to day, require
home care for insulin injections, or do not have the cognitive ability or visual acuity to
adjust insulin doses. In order to achieve glycemic targets with this regimen, both the
dose and type of mixture may need to be modified.
Targets for Control
The 2018 Diabetes Canada clinical practice guidelines emphasize that glycemic targets should be
individualized based on patient-specific factors (see Table 4). The target of HbA1c ≤7% for most
patients with T1DM and T2DM is based on strong evidence supporting the relationship between
tight glucose control and a reduction in microvascular and neuropathic complications.[65] In
contrast, it remains unclear if macrovascular (ischemic) events are influenced by tight glucose
control.[68][69][70] A more aggressive HbA1c of ≤6.5% may be targeted in patients with T2DM if the
benefits are thought to outweigh the risk of hypoglycemia. Conversely, a higher HbA1c of up to
8.5% may be more appropriate if the risk of hypoglycemia outweighs the benefits of tight control,
e.g., in frail elderly patients, those with limited life expectancy or patients with a history of recurrent
severe hypoglycemia.[65]
[65][66][67]
Table 4: Recommended Targets for Blood Glucose Control
FPG/Preprandial
Age Diabetes HbA1c Glucose 2-h PPG
(years) Type (%) (mmol/L) (mmol/L)
T2 ≤6.5[a]
4–7 5–10
>18 T1,T2 ≤7 4–5.5 if goal HbA1c 5–8 if goal HbA1c not
not reached reached
T1, T2 7.1–8.5[b]
T1 ≤7.5 4–8[c] 5–10

≤18
T2 ≤7 No recommendation No recommendation
[a]
Consider HbA1c ≤6.5% in some T2DM patients to reduce risk of nephropathy and retinopathy.
[b]
HbA1c 7.1–8% may be considered for functionally dependent patients. Consider HbA1c 7.1–8.5%
where there is a history of recurrent, severe hypoglycemia, limited life expectancy, or in the frail elderly
with or without dementia.
[c]
Consider preprandial targets of 6–10 mmol/L as well as higher HbA1c targets in children and
adolescents who have had severe or excessive hypoglycemia or have hypoglycemia unawareness
Abbreviations: HbA1c = glycosylated hemoglobin; FPG = fasting plasma glucose; PPG = postprandial
plasma glucose; T1 = type 1 diabetes mellitus; T2 = type 2 diabetes mellitus
is a critical component of the management strategy for patients with diabetes.

It is important to target all associated risk factors in addition to achieving glycemic control.[71] It
has been shown that a coordinated, multifactorial intervention involving behaviour modification
and pharmacologic therapy targeting hyperglycemia, hypertension, dyslipidemia, body weight,
microalbuminuria and platelet activation can significantly reduce the risk of major cardiovascular
and microvascular outcomes.[72] See Diabetes Mellitus-Chronic Complications for further
discussion of managing CV risk.
Choices during Pregnancy and Breastfeeding

Carbohydrate intolerance during pregnancy can occur in patients with diabetes prior to pregnancy
and in those who develop diabetes during pregnancy.
Diabetes and Pregnancy
Both type 1 and type 2 diabetes mellitus can occur in women of childbearing age, while
(GDM) is a condition that develops during pregnancy, primarily due to
insulin resistance that results from the high levels of gestational hormones.[73] Regardless of the
specific diagnosis type, the existence of diabetes in pregnancy significantly increases the risk of
negative outcomes in both the mother and fetus/infant.[74] Pre-existing diabetes (type 1 or 2)
increases the risk of miscarriage, perinatal mortality, fetal macrosomia and congenital
malformations, the latter being due to hyperglycemia in the first weeks of gestation.[75] Similarly,
GDM increases the risk of fetal hyperinsulinemia, heavier birth weight, higher rates of cesarean
deliveries and neonatal hypoglycemia.[73] Children born to mothers with diabetes and mothers
with a history of GDM also appear to have an increased risk of developing diabetes in the future.
[76]
When diabetes is pre-existing, pre-pregnancy counselling is essential and good glucose control
should be achieved even before conception.[73] Although the benefits of treating women with pre-
existing diabetes have been clearly demonstrated,[73] the benefits of treating GDM are less clear.
[77][78]
Diabetes treatments confer a risk of hypoglycemia and some may exhibit teratogenic
effects; thus, careful monitoring and therapeutic selection is required. Fortunately, hypoglycemia
may not pose substantial risks to the developing fetus,[75] but instances of diabetic ketoacidosis
are very dangerous and can occur in cases such as unrecognized failure of an insulin pump.
Pre-pregnancy Planning
Counsel women of childbearing age with diabetes about the need to plan and prepare for any
pregnancy in order to minimize the risks to the fetus and the mother. In the months preceding
conception, women should undertake the following risk-reduction activities:[73]
Begin folic acid supplementation at least 3 months prior to conception. The initial dose
should be 1 mg daily and is continued until at least 12 weeks’ gestation.
Undergo an eye exam because pregnancy can accelerate retinopathy resulting from poor
glycemic control. A baseline exam should occur prior to conception and subsequent
exams should be scheduled periodically during the pregnancy and for 1 year postpartum.
Continue insulin, metformin or glyburide if already taking; switch to an insulin regimen
from other non-insulin antihyperglycemic agents. Aim to achieve an HbA1c level of ≤7%
(≤6.5% if safely achievable).
Undergo screening for cardiovascular disease (or risk factors) and chronic kidney disease
(CKD). Clinicians should be especially vigilant about CKD and hypertension prior to and
throughout pregnancy, given the risk of an additive effect with pregnancy.
Discontinue any teratogenic medications such as ACE inhibitors, angiotensin receptor
blockers or statins. The fast-acting insulin analogues lispro and aspart are safe in
pregnancy and may provide a decreased risk of hypoglycemia compared with regular
insulin.[79][80][81] In women with pre-existing diabetes, NPH insulin or LAIA (detemir and
glargine) can be used throughout pregnancy.[82][83]
Management during Pregnancy
All pregnant women should be screened for GDM. There is controversy over the most
appropriate approach to screening. See Figure 3 for the approach preferred by Diabetes
Canada. Referral to a specialized clinic for the management of diabetes in pregnancy, if
available, is recommended. Initiate nonpharmacologic therapy (strict diet and exercise) in
women who are newly diagnosed with GDM.[73] Continue nonpharmacologic therapy and start
multiple daily injections of RAIA or regular insulin if fasting and postprandial targets have not
been met within 2 weeks of adjusting these lifestyle measures.[84][85] In women with GDM who
cannot take insulin, it may be reasonable to consider glyburide or metformin, recognizing
that use of either agent is off-label.[78][86]
In women with diabetes who successfully become pregnant, strict glycemic control is
recommended, along with frequent self-monitoring of blood glucose. Both pre- and
postprandial testing is suggested in order to facilitate the achievement of both targets outlined
in Table 5. Aim to achieve an HbA1c level of ≤6.5% (≤6.1% if safely achievable). In addition,
ketone testing (urine or blood) may be considered to ensure that the diet is adequate to
prevent starvation ketosis. To reduce the risk of preeclampsia, women with pre-existing
diabetes should start ASA 81 mg daily at 12–16 weeks’ gestation. Consider the use of an
insulin pump or CGM to improve glycemic control in those with T1DM.
[73]
Table 5: Recommended Glycemic Targets during Pregnancy
FPG/Preprandial 1-Hour Postprandial 2-Hour Postprandial
Glucose (mmol/L) Glucose (mmol/L) Glucose (mmol/L)
<5.3 <7.8 <6.7
Abbreviations: FPG = fasting plasma glucose
Diabetes and Breastfeeding
Mothers with diabetes are encouraged to breastfeed to reduce the risk of childhood obesity.[73]
Although insulin is transferred into breast milk, it poses little risk to the infant because the
hormone is degraded in the gastrointestinal tract before reaching the systemic circulation.[86] As a
result, breastfeeding mothers receiving insulin do not need to alter their regimen unless it is in
response to their personal glycemic levels. Frequent monitoring of blood glucose is extremely
important after delivery because insulin requirements may change quickly, and the increased
caloric output during breastfeeding theoretically puts the mother at increased risk of hypoglycemia.
Management during Breastfeeding
After delivery, most women will remain in hospital for at least 24 hours. During this time,
glycemic monitoring should be performed frequently to assess for changes in blood glucose
levels. In many cases of GDM, hyperglycemia will resolve completely during this time and
antihyperglycemic medications may be discontinued altogether. In addition, all postpartum
women with GDM should have their glycemic status assessed by their primary care provider
sometime in the months following delivery. All patients diagnosed with GDM should have a 75
g OGTT between 6 weeks and 6 months following delivery to detect persistent hyperglycemia.
In women who require ongoing antihyperglycemic medication, insulin remains the first choice
for reasons stated above. However, both glyburide and metformin have also been used in
breastfeeding women with T2DM. Limited data suggest glyburide does not pass into breast
milk and metformin appears to have little penetration.[86] Although these agents can be
considered for use in breastfeeding mothers, long-term studies have not been done to rule out
any unanticipated adverse effects.
A discussion of general principles on the use of medications in these special populations can
be found in Drug Use during Pregnancy and Drug Use during Breastfeeding. Other specialized
reference sources are also provided in these appendices.
Therapeutic Tips
Assess all patients every 3–6 months. Study their home monitoring records (if available) and
note the occurrence, frequency and trends of hypoglycemia. Hypoglycemia should be addressed
before hyperglycemia to ensure patient safety in the short term.
Review home blood glucose records, looking for predictable glucose trends that can be
improved upon. Whether glucose readings are printed out, tabulated in a logbook or in the
glucometer memory, they must be brought to follow-up appointments, reviewed and discussed.
Inadequate control of diabetes is frequently related to poor adherence to diet and/or
medications. Chronic infections can also negatively impact glucose control.
The use of snacks may be important in some patients who use insulin and experience glycemic
variability between meals; this could consist of a small amount of carbohydrate and protein. Not
everyone will require a snack between meals.
Monitor blood sugar, blood pressure, serum lipids, and body weight, and for the presence of
complications. Foot examination is an integral part of such monitoring (see Nonpharmacologic
Choices).
Encourage all patients at risk of hypoglycemia to wear a MedicAlert ID bracelet or the
equivalent.
.....
Preventing Type 2 Diabetes Mellitus
Risk Factors and Strategies

The prevalence of T2DM has been rising for decades and is expected to afflict 5 million Canadians by
the year 2025.[87] As a result, many studies have focused on preventative strategies aimed at
individuals who exhibit risk factors for the development of this disease. Although family history,
sedentary lifestyle, obesity and poor diet are risk factors for T2DM, individuals with slightly elevated
blood glucose levels are likely at the greatest short-term risk of reaching the diagnostic threshold.
Individuals who exhibit elevated blood glucose concentrations (yet below the threshold for diabetes)
can be described as having (FPG 6.1–6.9 mmol/L),
(plasma glucose of 7.8–11 mmol/L 2 hours after a 75 g oral glucose load) or both.
Generally, individuals exhibiting slight elevations in blood glucose concentrations have been insulin-
resistant for years, but glucose levels were likely maintained by increased insulin secretion.
Frequently, insulin resistance is accompanied by other metabolic disruptions that are probably linked
by 1 or more common biologic pathways. Clustering of metabolic risk factors such as central obesity,
hypertension, dyslipidemia, insulin resistance and glucose abnormalities is termed
. It confers a significant short-term risk of overt diabetes and a long-term risk of
cardiovascular disease.[88]
Several large studies have examined nonpharmacologic (diet, exercise, weight loss) and
pharmacologic strategies aimed at preventing the onset of T2DM in high-risk individuals.
The Finnish Diabetes Prevention Study (DPS)[89] and the Diabetes Prevention Program (DPP)[90]
showed that along with a supervised of moderate intensity (about
150 min/wk) significantly reduced the relative risk of progression from prediabetes to diabetes by 58%
at 4 years. In the DPS, diabetes was diagnosed in 11% of those randomized to lifestyle intervention
versus 23% in the control group. In the DPP study, diabetes developed in 4.8%, 7.8% and 11% of
those randomized to lifestyle intervention, metformin and placebo respectively. The weight loss
associated with lifestyle interventions was about 5–6% of initial body weight in these studies.
Interestingly, the benefits of the lifestyle changes persisted long after these trials were completed.[91]
[92] These findings prove the success of lifestyle interventions and the significance for all people at
high-risk of developing diabetes.
Other studies have evaluated the impact of pharmacologic interventions on the incidence of T2DM. It
has been shown that metformin,[90][92] acarbose,[93] TZDs,[94][95][96][97] and orlistat[98] can also
reduce the incidence of T2DM in at-risk patients. In 1 study, rosiglitazone significantly reduced the
risk of progression to diabetes from 26% to 11.6% over 3 years compared with placebo, a similar
benefit to that reported in the lifestyle intervention trials above. The benefit was offset to some extent
by a significantly higher incidence of heart failure relative to placebo (0.5% vs. 0.1%).[94] In contrast,
ramipril did not prevent the progression from prediabetes to diabetes in this same study.[99]
There are no known safe and effective measures to prevent T1DM, although recent advances in
immunomodulatory therapies have reached human trials. Time and controlled trials are still needed to
review and assess the efficacy and safety of these interventions.[100]
.....
Diabetic Ketoacidosis
Assessment and Management

Diabetic ketoacidosis is a potentially fatal complication of severe insulin deficiency seen in T1DM that
presents as metabolic decompensation. It is characterized by variable hyperglycemia, volume
depletion, acidosis, depressed levels of consciousness and detectable ketones in the urine or blood.
[101]Upon presentation, patients are depleted in sodium, potassium, chloride and water. Despite body-
wide potassium depletion, serum potassium is frequently elevated at the time of presentation due to
lack of insulin and an inability of potassium to efficiently enter cells. Pre-renal failure may be present
secondary to severe dehydration. Hyperglycemia, as well as high triglycerides and free fatty acids,
may result in pseudohyponatremia, or falsely low sodium measurements.
Diabetic ketoacidosis is found most often in T1DM and may be seen at 1st presentation in newly
diagnosed patients, or when patients are nonadherent to insulin therapy. It is also often associated
with the onset of a severe or stressful illness (e.g., severe infection), surgery, trauma, MI or the use of
SGLT2 inhibitors in patients who were previously stable. Patients with diabetic ketoacidosis are
generally hospitalized. A detailed patient care flow sheet is published in the 2018 Diabetes Canada
clinical practice guidelines and is available online[101] (www.guidelines.diabetes.ca). Management of
diabetic ketoacidosis is outlined in Table 6.
Table 6: Management of Diabetic Ketoacidosis (DKA)

Fluids: Patients are always significantly volume depleted. Give IV NS 500 mL for 4 h, then
250 mL for 4 h (faster if in shock), then individualize. Good urinary output is reassuring that
volume is being replaced.
Potassium: Potassium chloride is the preparation of choice. Do not give unless urine is
being produced; may need to wait for IV fluids to improve volume status. If serum K+ is <3.3
mmol/L, add K+ 40 mmol/L of fluid; if 3.3–5.5 mmol/L, add K+ 20 mmol/L; if >5.5 mmol/L, do
not add K+, but monitor hourly. Rehydration and insulin will drive K+ levels down.
Insulin: Do not give insulin if K+ is <3.3 mmol/L, as insulin will drive K+ into cells and drop
levels further. Once K+ >3.3 mmol/L, insulin can be infused at 0.1 units/kg/h using a 2nd IV
line. One protocol is as follows: mix 25 units R insulin in 250 mL NS and adjust rate to drop
glucose to <14 mmol/L. Continue IV insulin until the anion gap resolves and patient eating
without nausea. stop or hold insulin in DKA. Rather, if the glucose drops below 14
mmol/L, continue the insulin infusion but also switch the saline IV to D5½NS and adjust the
IV rate to maintain glucose between 12 and 14 mmol/L. When anion gap closed and patient
eating, overlap IV insulin with SC insulin by 2 h before stopping IV. DKA can rapidly reoccur if
waiting for SC insulin to peak.
Bicarbonate: Not first-line therapy and infrequently used. Consider giving 1 ampoule (50
mmol) of sodium bicarbonate in 200 mL D5W over 1 h if acidosis is severe and ICU is being
considered (e.g., pH <7, lowered LOC).
Laboratory tests: Latest recommendations include bedside testing for beta-hydroxybutyrate,

a ketone that is not detected with standard ketone testing.[102][103] Initial CBC, glucose,
electrolytes, urea, creatinine and ABG. Request blood or urine cultures to look for infection as
indicated. Radiology looking for infection/trigger as indicated. Repeat electrolyte and glucose
hourly; ABG only if severe acidosis persists. Capillary glucose (with bedside glucometer)
hourly for trends, but require repeated blood draws for confirmation.
Supportive care: Keep the patient warm and rested. Insert an NG tube if vomiting and a
urinary catheter if anuric (urinary retention may be significant).
Pitfalls:
• Children with DKA are at higher risk of cerebral edema due to treatment of DKA with
associated sodium, pH and glucose shifts. It is essential that a specialized team and
monitored setting be used in pediatric cases. A diagnosis of DKA does not initially require
detection of ketones. Routine detection of ketones may require both urine and blood testing
over time.
• For urinary ketones, Ketostix strips detect acetoacetate but not hydroxybutyrate; beware of
false negatives. Acetone smell may be absent, undetected or unrecognized by some. Where
available, use rapid beta-hydroxybutyrate testing.
• Temperature may be low initially—absence of fever does not rule out infection.
• Leukocytosis is usually present and does not necessarily mean infection.
• Low serum sodium may be due to pseudohyponatremia from high glucose or TG.
• High serum potassium is caused by acidosis and may be seen in spite of severe total body
potassium depletion.
• Dehydration may mask a respiratory infection; reassess after rehydration and stabilization.
• Severe abdominal pain or signs of an acute abdomen need to be reassessed after
stabilization—they often disappear.
• A premature switch to SC insulin and/or discharge results in high recurrence and
readmission rates.
Abbreviations: ABG = arterial blood gases; CBC = complete blood count; D5½NS = dextrose 5% with ½
normal saline; D5W = dextrose 5%; DKA = diabetic ketoacidosis; ICU = intensive care unit; K+
= potassium; LOC = level of consciousness; NG = nasogastric; NS = normal saline; R = regular; TG
= triglycerides
.....
Algorithms
[a]
Figure 1: Screening and Diagnosis of Diabetes Mellitus
[a]
If both FPG and HbA1c are available but discordant, use the test that appears furthest to the right
side of the algorithm.
[b]
Consider 75 g OGTT if ≥1 risk factors.
[c]
Consider 75 g OGTT.
[d]
Prediabetes = IFG or HbA1c 6–6.4%.
[e]
In the presence of symptoms of hyperglycemia, a single test result in the diabetes range is sufficient
to make the diagnosis of diabetes. In the absence of symptoms of hyperglycemia, if a single laboratory
test result is in the diabetes range, a repeat confirmatory laboratory test (FPG, HbA1c, 2hPG in a 75 g
OGTT) must be done on another day. It is preferable that the same test be repeated (in a timely
fashion) for confirmation, but a random PG in the diabetes range in an asymptomatic individual should
be confirmed with an alternative test. If results of two different tests are available and both are above
the diagnostic cut points, the diagnosis of diabetes is confirmed.
Abbreviations: 2hPG = 2-hour plasma glucose; FPG = fasting plasma glucose; HbA1c = glycosylated
hemoglobin; IFG = impaired fasting glucose; OGTT = oral glucose tolerance test; PG = plasma glucose
Adapted from Ekoé JM, Goldenberg R, Katz P. Diabetes Canada 2018 clinical practice guidelines for the prevention and
management of diabetes in Canada: Screening for diabetes in adults. 2018;42(Suppl 1):S16-9, Copyright
(2018), with permission from Elsevier. Journal homepage: journals.elsevier.com/canadian-journal-of-diabetes.
[8]
Figure 2: Stepwise Approach to Type 2 Diabetes
[a]
Reinforce the need to continue lifestyle interventions at every opportunity.
[b]
See Table 4 for suggested HbA1c target.
[c]
Drug regimens should be adjusted in a timely fashion so as to achieve the target HbA1c level within
3–6 months.
Abbreviations: CV = cardiovascular; HbA1c = glycosylated hemoglobin
[a]
Figure 3: Diabetes Canada Preferred Strategy for Diagnosis of Gestational Diabetes
[a]
In view of the controversies about diagnostic tests, other accepted methods may be used.
Abbreviations: 1hPG = 1-hour plasma glucose; 2hPG = 2-hour plasma glucose; FPG = fasting plasma
glucose; GDM = gestational diabetes mellitus; OGTT = oral glucose tolerance test; PG = plasma glucose
Reproduced from Feig DS, Berger H, Donovan D et al. Diabetes Canada 2018 clinical practice guidelines for the prevention and
management of diabetes in Canada: Diabetes and pregnancy. 2018;42(Suppl 1):S255-82, Copyright (2018),
with permission from Elsevier. Journal homepage: journals.elsevier.com/canadian-journal-of-diabetes.
Drug Tables
Table 7: Insulin and Analogues[a]
Drug/Cost[b] Onset Peak Duration Comments
Drug Class: Rapid-Acting Insulin Analogues
10–15 min 60–90 min 4–5 h Appearance: clear.

NovoRapid,
Fiasp
$$$

Apidra
$$$

Humalog Caution—Humalog products
available in non-standard
$$$ concentrations.
Drug Class: Short-Acting Insulin
30–60 min 2–4 h 5–8 h Appearance: clear.

Entuzity, Caution—Entuzity products
Humulin R, available in non-standard
Novolin ge concentrations.
Toronto
$$
30 min 2–4 h 5–7 h Appearance: clear. Used only if

Hypurin human insulin or analogues not
Regular tolerated.
$$$$$/10 mL
vial
Drug Class: Intermediate-Acting Insulin
1–2 h 5–8 h 14–18 h Appearance: cloudy.

Humulin N,
Novolin ge NPH
$$
1–3 h 6–12 h 24–28 h Appearance: cloudy. Used only

if human insulin or analogues
Hypurin NPH not tolerated.
$$$$$/10 mL
vial
Drug/Cost[b] Onset Peak Duration Comments
Drug Class: Long-Acting Insulin Analogues
1h Flat, no 42 h Appearance: clear

discernible Do not mix with other insulins.
Tresiba peak Do not inject IM or IV.
$$$$$ Caution—Tresiba products
available in non-standard
concentrations.
1.5 h Flat, no 6–24 h Appearance: clear.

Levemir discernible Do not mix with other insulins.
peak At low doses, duration of action
$$$$$
is shorter and may require BID
administration to maintain
fasting glucose targets.
1.5 h Flat, no 24 h Appearance: clear.

Lantus, discernible Do not mix with other insulins.
Basaglar, peak Do not inject IM or IV.
Toujeo
Caution—Toujeo products
$$$$ available in non-standard
concentrations.
Drug Class: Mixed (Regular/NPH) Human Insulin
Combination Appearance: cloudy.

of individual
Humulin 30/70, components
Novolin ge
30/70, 40/60,
50/50
$$
Drug Class: Mixed Insulin Analogues
10–15 min Not Not Appearance: cloudy.

available available
Humalog
Mix25,
Humalog Mix50
$$$
10–15 min 60–90 min 15–18 h Appearance: cloudy.
NovoMix 30
$$$
[a]
Insulin products are shown in order of onset of action, with the very rapid-acting insulin analogues at the
top. Mixed insulin products are grouped at the end of the table.
[b]
Cost of 5 × 3 mL cartridges unless otherwise specified; includes drug cost only.
Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ $100–125
Table 8: Antihyperglycemic Agents
Drug[a]/Cost[b] Dosage Adverse Drug Comments

Effects Interactions

Drug Class: Alpha-glucosidase Inhibitors
50–100 mg TID PO Flatulence, Potentiates other No weight gain;

Glucobay with each meal; diarrhea, antihyperglycemic not absorbed;
start low and go abdominal pain, agents; may contraindicated
$ slow cramps, nausea. reduce metformin in irritable
bioavailability. bowel
syndrome,
inflammatory
bowel disease.
Use glucose to
treat
hypoglycemia.
Drug Class: Biguanides
500–2500 mg/day Nausea, Alcohol No weight gain.

Glucophage, Glumetza, PO divided BID; diarrhea, potentiates Contraindicated
generics start low and go abdominal hypoglycemic in hepatic
slow to minimize discomfort, effect. impairment,
$ gastrointestinal side anorexia, severe renal
effects; little metallic taste, impairment,
additional benefit lactic acidosis if previous lactic
above 1500 mg/day hepatic or renal acidosis.
disease.
Drug Class: Dipeptidyl Peptidase-4 Inhibitors (DPP4Is)
25 mg once daily Nasopharyngitis, Does not inhibit Avoid in

Nesina PO hypersensitivity cytochrome P450 patients with
reactions, isozymes. Low heart failure.
$$$ pancreatitis potential for drug May be taken
(rare). interactions. with or without
food.
5 mg once daily PO Nasopharyngitis, Clearance of Avoid in

Trajenta hypersensitivity linagliptin is patients with
reactions, enhanced by heart failure.
$$$ pancreatitis strong CYP3A4 May be taken
(rare). inducers, e.g., with or without
rifampin. food.
5 mg once daily PO Nasopharyngitis, Clearance of Avoid in

Onglyza hypersensitivity saxagliptin is patients with
reactions, reduced by strong heart failure.
$$$ pancreatitis CYP3A4/5 May be taken
(rare). inhibitors, e.g., with or without
imidazole food.
antifungals,
macrolides.
Clearance of
saxagliptin is
enhanced by
strong CYP3A4/5
inducers, e.g.,
rifampin.

100 mg once daily Nasopharyngitis, Does not inhibit Avoid in
Januvia PO hypersensitivity cytochrome P450 patients with
reactions, isozymes. Low heart failure.
$$$$ pancreatitis potential for drug May be taken
(rare). interactions. with or without
food.
Drug Class: Glucagon-Like Peptide-1 (GLP-1) Agonists
Initial: 0.75 mg Nausea, May reduce rate Causes weight

Trulicity weekly SC vomiting, of absorption of loss.
Typically increased diarrhea, some oral Caution in
$215 to 1.5 mg weekly injection site medications. patients with
SC thereafter reactions, acute heart rhythm
pancreatitis disturbances
(rare). and severe
renal
impairment.
Contraindicated
in pregnancy
and those with
personal or
family history of
medullary
thyroid
carcinoma or
multiple
endocrine
neoplasia
syndrome type
2.
Solution: 5 mcg BID Nausea, May reduce rate Causes weight

Byetta, Bydureon SC increased to vomiting, of absorption of loss.
10 mcg BID SC diarrhea, some oral Caution in
$$$$$ after 1 month if injection site medications. patients with
required reactions, acute heart rhythm
Suspension: 2 mg pancreatitis disturbances
weekly SC (rare). and severe
renal
impairment.
Contraindicated
in pregnancy
and those with
personal or
family history of
medullary
thyroid
carcinoma or
multiple
endocrine
neoplasia
syndrome type
2.

Initial: 0.6 mg once Nausea, May reduce rate Causes weight
Victoza daily SC vomiting, of absorption of loss.
Increase to 1.2–1.8 diarrhea, some oral Caution in
$$$$$ injection site medications. patients with
mg once daily SC
reactions, acute heart rhythm
pancreatitis disturbances
(rare). and severe
renal
impairment.
Contraindicated
in pregnancy
and those with
personal or
family history of
medullary
thyroid
carcinoma or
multiple
endocrine
neoplasia
syndrome type
2.

Adlyxine once daily SC for vomiting, of absorption of loss.
14 days diarrhea, some oral Caution in
$$$$$ Increase to 0.02 mg injection site medications. patients with
once daily SC on reactions, acute heart rhythm
day 15 pancreatitis disturbances
(rare). and severe
renal
impairment.
Contraindicated
in pregnancy
and those with
personal or
family history of
medullary
thyroid
carcinoma or
multiple
endocrine
neoplasia
syndrome type
2.

Ozempic weekly SC for 4 vomiting, of absorption of loss.
weeks diarrhea, some oral Caution in
$215 injection site medications. patients with
Increase to 0.5 mg
weekly SC from wk reactions, acute heart rhythm
5 onward pancreatitis disturbances
May increase to 1 (rare). and severe
mg weekly SC after renal
a further 4 wk impairment.
Contraindicated
in pregnancy
and those with
personal or
family history of
medullary
thyroid
carcinoma or
multiple
endocrine
neoplasia
syndrome type
2.
Drug Class: Insulin Secretagogues, sulfonylureas
40–320 mg/day PO; Prolonged Hypoglycemic Contraindicated

Diamicron, generics administer in 2 hypoglycemia; effect potentiated in type 1
divided doses if weight gain. by salicylates, diabetes,
$ daily dose ≥160 mg sulfonamides and pregnancy.
monoamine
oxidase inhibitors;
beta-blockers
may mask
hypoglycemic
symptoms.
30–120 mg once Prolonged Hypoglycemic Contraindicated

Diamicron MR, daily PO hypoglycemia; effect potentiated in type 1
generics weight gain. by salicylates, diabetes,
sulfonamides and pregnancy.
$ monoamine
oxidase inhibitors;
beta-blockers
may mask
hypoglycemic
symptoms.
1–4 mg once daily Prolonged Hypoglycemic Contraindicated

Amaryl, generics PO hypoglycemia; effect potentiated in type 1
weight gain. by salicylates, diabetes,
$ sulfonamides and pregnancy.
monoamine
oxidase inhibitors;
beta-blockers
may mask
hypoglycemic
symptoms.

2.5–20 mg/day PO; Weight gain; Hypoglycemic Contraindicated
Diabeta, generics administer in 2 prolonged effect potentiated in type 1
divided doses if hypoglycemia. by salicylates, diabetes.
$ daily dose >10 mg Risk of sulfonamides and
hypoglycemia monoamine
may be greater oxidase inhibitors;
compared with beta-blockers
gliclazide and may mask
glimepiride, hypoglycemic
especially in symptoms.
elderly or
patients with
renal
impairment.
Drug Class: Insulin Secretagogues, meglitinides
0.5–4 mg PO Hypoglycemia, Clearance of Contraindicated

GlucoNorm, Apo- 0–30 min before especially if repaglinide is in type 1
Repaglinide, other meals meal not taken; reduced by strong diabetes,
generics weight gain. CYP3A4 pregnancy.
inhibitors, e.g.,
$ imidazole
antifungals,
macrolides,
protease
inhibitors.
Clearance of
repaglinide is
enhanced by
strong CYP3A4
inducers, e.g.,
rifampin,
carbamazepine.
Strong inhibitors
of CYP2C8 have
the potential to
reduce
metabolism of
repaglinide, e.g.,
atazanavir,
ritonavir.
Enhanced and
prolonged
hypoglycemia
occurs when
taken with
gemfibrozil (avoid
combined use).
Drug Class: Sodium-Glucose Cotransporter 2 Inhibitors

100–300 mg once Increased risk of Strong enzyme Less effective
Invokana daily PO genitourinary inducers, e.g., in moderate
infections; rifampin, and ineffective
$$$ reduced phenytoin, in severe renal
intravascular carbamazepine, impairment.
volume resulting will reduce
in hypotension; plasma levels.
hyperkalemia. Loop diuretics
increase risk of
hypotension.
5–10 mg once daily Increased risk of Loop diuretics Less effective

Forxiga PO genitourinary increase risk of in moderate
infections; hypotension. and ineffective
$$$ reduced in severe renal
intravascular impairment.
volume resulting
in hypotension;
hyperkalemia.
10–25 mg once Increased risk of Loop diuretics Less effective

Jardiance daily PO genitourinary increase risk of in moderate
$$$ reduced in severe renal
volume resulting
in hypotension;
hyperkalemia.
5–15 mg once daily Increased risk of Loop diuretics Less effective

Steglatro PO genitourinary increase risk of in moderate
reduced in severe renal
volume resulting
in hypotension;
hyperkalemia.
Drug Class: Thiazolidinediones (TZDs)
15–45 mg once Weight gain, Potentiates the Avoid in

Actos, generics daily PO fluid retention, effect of other patients with
hemodilution; antihyperglycemic heart failure.
$$$ worsening heart agents. Effects on CV
failure; macular Gemfibrozil outcomes being
degeneration; inhibits evaluated.
increased risk of metabolism and Ovulation
fractures and increases plasma resumes in
possibly bladder levels. previously
cancer. anovulatory
women, e.g.,
polycystic
ovarian
syndrome;
increased risk
of pregnancy if
adequate
contraception
not used.

4–8 mg daily PO in Weight gain, Potentiates the Avoid in
Avandia 1–2 doses fluid retention, effect of other patients with
hemodilution; antihyperglycemic heart failure.
$$$$ worsening heart agents. Effects on CV
failure; macular Gemfibrozil outcomes being
degeneration; inhibits evaluated.
increased risk of metabolism and Ovulation
fractures and increases plasma resumes in
possibly bladder levels. previously
cancer. anovulatory
women, e.g.,
polycystic
ovarian
syndrome;
increased risk
of pregnancy if
adequate
contraception
not used.
Patient consent
required.
Drug Class: Dipeptidyl Peptidase-4 Inhibitor/Biguanide Combinations
If on metformin Nasopharyngitis, Does not inhibit Avoid in

Kazano monotherapy: hypersensitivity cytochrome P450 patients with
continue metformin reactions, isozymes. Low heart failure.
$$$ dose, add alogliptin pancreatitis potential for drug May be taken
12.5 mg BID PO (rare). interactions. with or without
If on both agents Nausea, Alcohol food.
already: continue diarrhea, potentiates Contraindicated
current doses, but abdominal hypoglycemic in hepatic
divide alogliptin BID discomfort, effect. impairment,
anorexia, severe renal
Maximum: 12.5 metallic taste,
mg/1000 mg BID impairment,
lactic acidosis if previous lactic
hepatic or renal acidosis.
disease.
If on metformin Nasopharyngitis, Clearance of Avoid in

Jentadueto monotherapy: hypersensitivity linagliptin is patients with
continue metformin reactions, enhanced by heart failure.
$$$ dose, add linagliptin pancreatitis strong CYP3A4 May be taken
2.5 mg BID PO (rare). inducers, e.g., with or without
If on both agents Nausea, rifampin. food.
already: continue diarrhea, Alcohol Contraindicated
current doses abdominal potentiates in hepatic
discomfort, hypoglycemic impairment,
Maximum: 2.5 anorexia,
mg/1000 mg BID effect. severe renal
metallic taste, impairment,
disease.

If on metformin Nasopharyngitis, Clearance of Avoid in
Komboglyze monotherapy: hypersensitivity saxagliptin is patients with
continue metformin reactions, reduced by strong heart failure.
$$$ dose, add pancreatitis CYP3A4/5 May be taken
saxagliptin 2.5 mg (rare). inhibitors, e.g., with or without
BID PO Nausea, imidazole food.
If on both agents diarrhea, antifungals, Contraindicated
already: continue abdominal macrolides. in hepatic
current doses discomfort, Clearance of impairment,
anorexia, saxagliptin is severe renal
Maximum: 2.5 metallic taste, enhanced by
mg/1000 mg BID impairment,
lactic acidosis if strong CYP3A4/5 previous lactic
hepatic or renal inducers, e.g., acidosis.
disease. rifampin.
Alcohol
potentiates
hypoglycemic
effect.
If on metformin Nasopharyngitis, Does not inhibit Avoid in

Janumet monotherapy: hypersensitivity cytochrome P450 patients with
continue metformin reactions, isozymes. Low heart failure.
$$$$ dose, add sitagliptin pancreatitis potential for drug May be taken
50 mg BID PO (rare). interactions. with or without
If on both agents Nausea, Alcohol food.
already: continue diarrhea, potentiates Contraindicated
current doses abdominal hypoglycemic in hepatic
discomfort, effect. impairment,
Maximum: 50 anorexia,
mg/1000 mg BID severe renal
disease.
50/500 mg, 50/1000 Nasopharyngitis, Does not inhibit Avoid in

Janumet XR mg or 100/1000 mg hypersensitivity cytochrome P450 patients with
once daily PO reactions, isozymes. Low heart failure.
$$$$ Maximum: 100 pancreatitis potential for drug May be taken
mg/2000 mg once (rare). interactions. with or without
daily Nausea, Alcohol food.
diarrhea, potentiates Contraindicated
abdominal hypoglycemic in hepatic
discomfort, effect. impairment,
anorexia, severe renal
disease.
Drug Class: Sodium-Glucose Cotransporter 2 Inhibitor/Biguanide Combinations

If on metformin Increased risk of Strong enzyme Less effective
monotherapy: genitourinary inducers, e.g., in moderate
Invokamet continue metformin infections; rifampin, and ineffective
dose, add reduced phenytoin, in severe renal
$$$$ canagliflozin 50 mg intravascular carbamazepine, impairment.
BID PO volume resulting will reduce Contraindicated
If on both agents in hypotension; plasma levels. in hepatic
already: continue hyperkalemia. Loop diuretics impairment,
current doses Nausea, increase risk of severe renal
diarrhea, hypotension. impairment,
Maximum: 150 abdominal Alcohol previous lactic
mg/1000 mg BID discomfort, potentiates acidosis.
anorexia, hypoglycemic
metallic taste, effect.
lactic acidosis if
hepatic or renal
disease.
Use nearest Increased risk of Loop diuretics Less effective

strength genitourinary increase risk of in moderate
Xigduo combination to infections; hypotension. and ineffective
existing doses of reduced Alcohol in severe renal
$$$ separate intravascular potentiates impairment.
ingredients; either volume resulting hypoglycemic Contraindicated
10 mg/850 mg or in hypotension; effect. in hepatic
10 mg/1000 mg BID hyperkalemia. impairment,
PO Nausea, severe renal
diarrhea, impairment,
abdominal previous lactic
discomfort, acidosis.
anorexia,
metallic taste,
lactic acidosis if
hepatic or renal
disease.
If on metformin Increased risk of Loop diuretics Less effective

monotherapy: genitourinary increase risk of in moderate
Synjardy continue metformin infections; hypotension. and ineffective
dose, add reduced Alcohol in severe renal
$$$ empagliflozin 5 mg intravascular potentiates impairment.
BID PO volume resulting hypoglycemic Contraindicated
If on both agents in hypotension; effect. in hepatic
already: continue hyperkalemia. impairment,
current doses Nausea, severe renal
Maximum: 12.5 abdominal previous lactic
mg/1000 mg BID discomfort, acidosis.
anorexia,
metallic taste,
lactic acidosis if
hepatic or renal
disease.

If on metformin Increased risk of Loop diuretics Less effective
monotherapy: genitourinary increase risk of in moderate
Segluromet continue metformin infections; hypotension. and ineffective
dose, add reduced Alcohol in severe renal
ertugliflozin 2.5 mg intravascular potentiates impairment.
BID PO volume resulting hypoglycemic Contraindicated
If on both agents in hypotension; effect. in hepatic
already: continue hyperkalemia. impairment,
current doses Nausea, severe renal
Maximum: 7.5 abdominal previous lactic
mg/1000 mg BID discomfort, acidosis.
anorexia,
metallic taste,
lactic acidosis if
hepatic or renal
disease.
Drug Class: Sodium-Glucose Cotransporter 2 Inhibitor/Dipeptidyl Peptidase-4 Inhibitor

Combinations
10/5 mg or 25/5 mg Increased risk of Loop diuretics Less effective

once daily PO genitourinary increase risk of in moderate
Glyxambi infections; hypotension. and ineffective
reduced Clearance of in severe renal
$$$$$ intravascular linagliptin is impairment.
volume resulting enhanced by Avoid in
in hypotension; strong CYP3A4 patients with
hyperkalemia. inducers, e.g., heart failure.
Nasopharyngitis, rifampin. May be taken
hypersensitivity with or without
reactions, food.
pancreatitis
(rare).
5/100 mg or 15/100 Increased risk of Loop diuretics Less effective

Steglujan mg once daily PO genitourinary increase risk of in moderate
$$$$ reduced Does not inhibit in severe renal
intravascular cytochrome P450 impairment.
volume resulting isozymes. Low Avoid in
in hypotension; potential for drug patients with
hyperkalemia. interactions. heart failure.
Nasopharyngitis, May be taken
hypersensitivity with or without
reactions, food.
pancreatitis
(rare).
Drug Class: Long-Acting Insulin Analogue/Glucagon-Like Peptide-1 (GLP-1) Agonist Combinations

Initial: Hypoglycemia Increased risk of Not for use in
16 units/0.58 mg Nausea, hypokalemia with type 1 diabetes.
Xultophy once daily SC vomiting, potassium- Caution in
Titrate dose up or diarrhea, lowering drugs patients with
$325/5 × 3 mL injection site May reduce rate heart rhythm
down by 2 units
cartridges reactions, acute of absorption of disturbances
every 3–4 days
according to blood pancreatitis some oral and severe
glucose results (rare). medications. renal
impairment.
Maximum:
50 units/1.8 mg Contraindicated
once daily SC in pregnancy
and those with
personal or
family history of
medullary
thyroid
carcinoma or
multiple
endocrine
neoplasia
syndrome type
2.
If on <30 units Hypoglycemia Increased risk of Not for use in

insulin/day, initial Nausea, hypokalemia with type 1 diabetes.
Soliqua dose: vomiting, potassium- Caution in
15 units/5 mcg diarrhea, lowering drugs patients with
$205/5 × 3 mL once daily SC injection site May reduce rate heart rhythm
cartridges If on 30–60 units reactions, acute of absorption of disturbances
insulin/day, initial pancreatitis some oral and severe
dose: 30 units/10 (rare). medications. renal
mcg once daily SC impairment.
Titrate dose up or Contraindicated
down by 2–4 units in pregnancy
every wk according and those with
to blood glucose personal or
results family history of
medullary
Maximum: thyroid
60 units/20 mcg carcinoma or
once daily SC multiple
endocrine
neoplasia
syndrome type
2.
[a]
Combination therapy: always use agents from different classes; combinations can be used as initial
therapy if hyperglycemia is not expected to be controlled by a single agent.
[b] Cost of 30-day supply unless otherwise specified; includes drug cost only.
Dosage adjustment may be required in renal impairment; see Dosage Adjustment in Renal Impairment.
Legend: $ < $30 $$ $30–60 $$$ $60–90 $$$$ $90–120 $$$$$ $120–150
Suggested Readings
Davies MJ, D'Alessio DA, Fradkin J et al. Management of hyperglycemia in type 2 diabetes, 2018. A
consensus report by the American Diabetes Association (ADA) and the European Association for the
Study of Diabetes (EASD). 2018 Oct 4. [Epub ahead of print].
Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 clinical
practice guidelines for the prevention and management of diabetes in Canada.
2018;42(Suppl 1):S1-S325. Available from: guidelines.diabetes.ca/.
Roglic G, Norris SL. Medicines for treatment intensification in type 2 diabetes and type of insulin in
type 1 and type 2 diabetes in low-resource settings: synopsis of the World Health Organization
guidelines on second- and third-line medicines and type of insulin for the control of blood glucose
levels in nonpregnant adults with diabetes mellitus. 2018;169(6):394-7.
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Diabetes Mellitus

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Diabetes Mellitus

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10/24/2019 Diabetes Mellitus

Terra Arnason, MD, PhD, FRCPC

diabetes is defined as onset or recognition of glucose intolerance in pregnancy.

Table 1: Examples of Drugs That Can Cause Dysglycemia[a]

[a] Associated with insulin resistance.

Type 1 and Type 2 Diabetes Mellitus

is vital in making patients full participants in the diabetes health-

Insulin may be administered by syringe, pen or continuous subcutaneous insulin infusion

Table 3: Insulin Regimens in Type 1 and Type 2 Diabetes Mellitus

Insulin aspart, glulisine or Insulin degludec, detemir, Recommended in

Intensive: Continuous Subcutaneous Insulin Infusion (Insulin Pump)

Rapid- or Short-Acting Intermediate- or Long- Comments

Basal Insulin Only

None Insulin degludec, detemir, Use in T2DM only.

Basal-Plus (for patients desiring fewer injections)

Insulin aspart, glulisine or Insulin degludec, detemir, Use in T2DM only.

Abbreviations: BG = blood glucose; DKA = diabetic ketoacidosis; NPH = neutral protamine

Adverse Effects of Insulin Therapy

Type 2 Diabetes Mellitus

Acarbose and miglitol (not available in Canada) inhibit intestinal alpha-glucosidases,

Dipeptidyl Peptidase-4 Inhibitors

Endogenous glucagon-like peptide-1 (GLP-1) is rapidly degraded by the enzyme dipeptidyl

Glucagon-Like Peptide-1 Agonists

Glucagon-like peptide-1 agonists mimic the actions of GLP-1, an endogenous “incretin”

Lixisenatide and the extended-release formulation of exenatide have a neutral effect on CV

Insulin Secretagogues: Sulfonylureas

The sulfonylureas (SUs) chlorpropamide, gliclazide, glimepiride, glyburide and

Insulin Secretagogues: Meglitinides

Sodium-Glucose Cotransporter 2 Inhibitors

The newest class of antihyperglycemics are the sodium-glucose cotransporter 2 (SGLT2)

The CV safety of empagliflozin was tested in EMPA-REG OUTCOME.[47] Patients with

Pioglitazone and rosiglitazone are agonists at peroxisome proliferator-activated receptor

The cardiovascular safety of thiazolidinediones is in question. Some analyses have

Insulin Regimens for Type 2 Diabetes Mellitus

Targets for Control

T1 ≤7.5 4–8[c] 5–10

is a critical component of the management strategy for patients with diabetes.

Choices during Pregnancy and Breastfeeding

Diabetes and Pregnancy

Management during Pregnancy

Abbreviations: FPG = fasting plasma glucose

Diabetes and Breastfeeding

Management during Breastfeeding

Preventing Type 2 Diabetes Mellitus

Risk Factors and Strategies

Assessment and Management

Table 6: Management of Diabetic Ketoacidosis (DKA)

Laboratory tests: Latest recommendations include bedside testing for beta-hydroxybutyrate,

Abbreviations: CV = cardiovascular; HbA1c = glycosylated hemoglobin

Drug Class: Rapid-Acting Insulin Analogues

10–15 min 60–90 min 4–5 h Appearance: clear.

10–15 min 60–90 min 4–5 h Appearance: clear.

10–15 min 60–90 min 4–5 h Appearance: clear.

Drug Class: Short-Acting Insulin

30–60 min 2–4 h 5–8 h Appearance: clear.

30 min 2–4 h 5–7 h Appearance: clear. Used only if

Drug Class: Intermediate-Acting Insulin

1–2 h 5–8 h 14–18 h Appearance: cloudy.

1–3 h 6–12 h 24–28 h Appearance: cloudy. Used only

Drug/Cost[b] Onset Peak Duration Comments

Drug Class: Long-Acting Insulin Analogues

1h Flat, no 42 h Appearance: clear

1.5 h Flat, no 6–24 h Appearance: clear.

1.5 h Flat, no 24 h Appearance: clear.