Anti-Obesity Medications: An Update for Canadian
Physicians
Renuca Modi, MD, CCFP
1,2,3
, Rameez Kabani, MD
4
, Jerry T. Dang, MD
5
, Sarah Chapelsky, MSc, MD
1,6
, Arya M. Sharma, MD, FRCPC
6,7
1
Diplomate of the American Board of Obesity Medicine;
2
Department of Family Medicine, University of Alberta, Edmonton, AB, Canada;
3
Edmonton Adult Bariatric Specialty Clinic, Royal Alexandra Hospital, Edmonton, AB, Canada;
4
Division of General Internal Medicine,
Department of Medicine, University of Calgary, Calgary, AB, Canada;
5
Division of General Surgery, Department of Surgery, University
of Alberta, Edmonton, AB, Canada;
6
EABSC, Royal Alexandra Hospital, Edmonton, AB, Canada;
7
Division of Endocrinology and
Metabolism, Department of Medicine, University of Alberta, Edmonton, AB, Canada
Corresponding Author: Renuca Modi: renuca@ualberta.ca
Submitted: 22 September 2019; Accepted: 17 December 2019; Published: 18 November 2020.
DOI: http://dx.doi.org/10.22374/cjgim.v15i4.394
ABSTRACT
Objective
To review for Canadian physicians the latest pharmacological options for obesity management.
Quality of Evidence
A literature search was conducted in PubMed with no time restriction. Canadian and international
guidelines referenced. National and international statistics databases quoted for epidemiological
data. Levels of evidence range from I to III. 
Main Message
As a chronic progressive disease affecting over 7.2 million Canadians, obesity requires early
identification and treatment by primary care practitioners. Three anti-obesity medications are
approved for use in Canada under the tradenames Xenical®, Saxenda®, and Contrave® which help
bridge the gap between non-pharmacological and surgical options for the treatment of obesity.
Family physicians are front-line members of the obesity management team and should remain
updated on the pharmacological options for weight management.
Conclusion
Anti-obesity medications lead to greater average weight loss when combined with behavior
modifications and provide individuals with excess weight a sustainable option for obesity
management.
RESUME
Objectif
Examiner, à l’intention des médecins canadiens, les dernières options pharmacologiques pour
la gestion de lobésité.
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Introduction
Obesity is a complex, progressive chronic disease with serious
health consequences. In Canada, obesity rates in adults have
increased by 18% since 2009; more than 7.2 million Canadian
adults have obesity.
1
This growing epidemic has led multiple
health organizations, including the Canadian Medical Association
and Obesity Canada, to recognize obesity as a chronic disease
requiring enhanced research, treatment, and prevention efforts.
2
As a leading cause of type 2 diabetes, hypertension, cardiovascular
disease, stroke, osteoarthritis, sleep apnea, and a wide range of
cancers, the early identification and treatment of obesity should
be a top priority among healthcare professionals.
3
Beyond its
effects on physical health, obesity also has a significant impact
on mental health, social well-being, and economic success due
to the widespread weight bias and the negative stigma associated
with this chronic illness.
4,5
Behavioral modification alone has
proven inadequate in addressing the obesity epidemic, generally
resulting in little more than 3–5% sustainable weight loss (in
spite of greater weight loss in the short term).
6
Although bariatric
surgery is the most effective treatment for long-term weight
management, only 1 of 183 eligible Canadians can access this
treatment annually (with wide disparities between provinces).
7
Thus, there remains a significant gap between nonpharmacological
and surgical obesity management.
The aim of this review was to inform physicians of the recently
approved pharmacological options for weight management
including their mode of action, efficacy, and safety profiles.
Quality of Evidence
A PubMed literature search was conducted with no time
restriction using search terms such as obesity, weight loss,
treatment, medication, clinical trial, and review. This yielded
over 100 relevant articles, of which 20 were reviewed in detail.
Canadian and international guidelines on the treatment of
obesity were also reviewed. In addition, a supplemental search
of references from selected articles and associated reference lists
was performed. National and international statistics databases
were reviewed for relevant epidemiological data. Finally, expert
opinions of Canadian obesity medicine physicians shared at the
6th Canadian Obesity Summit (Ottawa, Ontario, 2019) were
included to provide a current and relevant overview of obesity
treatment in Canada.
Main Message
Recent history of obesity medications in Canada
In 2010, the serotonin–norepinephrine reuptake inhibitor,
sibutramine (Meridia), was voluntarily withdrawn from the
Canadian market after a randomized controlled trial (RCT) showed
that excess nonfatal cardiovascular events were associated with
this medication in individuals at a high risk for cardiovascular
disease.
8
This left the gastric and pancreatic lipase inhibitor,
orlistat (Xenical®), as the only obesity medication available in
Canada. Given its mechanism of action, orlistat has several
undesirable side effects including fatty stools, oily spotting, fecal
urgency, and flatus with discharge that can occur in 16 to 40%
Qualité des preuves
Une recherche documentaire a été effectuée dans PubMed sans restriction de temps. Les lignes
directrices canadiennes et internationales sont référencées. Bases de données statistiques nationales
et internationales citées pour les données épidémiologiques. Les niveaux de preuve vont de I à III.
Message principal
En tant que maladie chronique progressive touchant plus de 7,2 millions de Canadiens, lobésité
nécessite un dépistage et un traitement précoces par les praticiens de soins primaires. Trois
médicaments contre l’obésité sont approuvés au Canada sous les noms commerciaux Xenical®,
Saxenda® et Contrave®, qui aident à combler le fossé entre les options non pharmacologiques
et chirurgicales pour le traitement de lobésité. Les médecins de famille sont des membres de
première ligne de léquipe de gestion de lobésité et doivent se tenir au courant des options
pharmacologiques pour la gestion du poids.
Conclusion
Les médicaments contre lobésité entraînent une perte de poids moyenne plus importante lorsqu’ils
sont associés à des modifications du comportement et offrent aux personnes en surpoids une
option durable pour la gestion de lobésité.
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of the patients.
9
While these side effects can be mitigated by
the consumption of a low-fat diet, in real-world use more than
95% of the patients discontinue treatment within the first year.
10
In 2015, the Canadian Task Force on Preventative Healthcare
recommended against the routine use of orlistat, mainly due to
concerns about adverse events.
In 2015, liraglutide (Saxenda®), a glucagon-like peptide-1
(GLP-1) receptor agonist already approved at a lower dose (1.8
mg) for type 2 diabetes mellitus, was approved at a higher dose
(3.0 mg) for the long-term treatment of obesity. Subsequently,
in 2018, a sustained-release combination of naltrexone and
bupropion (NB) (Contrave®) was also approved by Health
Canada for long-term obesity treatment. Used individually, NB
had already been available for more than 30 years. Naltrexone
monotherapy is indicated for the treatment of alcohol and/or
opioid dependence.
11
Bupropion, a norepinephrine–dopamine
reuptake inhibitor, is used extensively in primary care to treat
mood disorders.
12
It is also a nicotinic receptor antagonist, and
in this context, it is prescribed as a smoking cessation aide.
13
These novel anti-obesity medications specifically target
homeostatic and hedonic mechanisms of food intake. Compared
to orlistat, these agents result in greater weight loss, and their
gastrointestinal side effects are generally transient. Cardiovascular
safety data are more robust than with the previous anti-obesity
drugs. Liraglutide reduces major cardiac events in patients with
type 2 diabetes with high-risk cardiac profiles.
14
A large, double-
blind cardiovascular safety trial with naltrexone–bupropion was
discontinued after results of a scheduled interim analysis, showing
possible cardiovascular benefits, became widely known.
15
As
such, these novel agents have the potential to transform obesity
care in Canada by addressing the need for treatment options
that bridge the gap between behavioral and surgical treatments.
Understanding the role of the brain in energy balance
Centrally, the hypothalamus is responsible for regulating
homeostatic eating behaviors that involve hunger and satiety.
Two central nervous system (CNS) pathways regulate energy
intake; the orexigenic pathway leads to an increase in food
intake, while the anorexigenic pathway leads to a reduction in
food intake. Peripheral hormones, including ghrelin released by
the stomach, GLP-1 and PYY from the distal gut, insulin from
pancreatic beta-cells, and leptin from adipose tissue, cross the
blood–brain barrier and regulate food consumption by signaling
to these CNS pathways.
The mesolimbic reward system (dopaminergic region of the
brain) is responsible for regulating hedonic mechanisms of food
intake such as eating for pleasure or in response to cravings. It
appears that there are overlapping neurobiological circuits in
patients with obesity and those struggling with drug addiction
wherein both food and drugs have powerful reinforcing effects
moderated by abrupt dopamine surges in the reward centers of the
brain.
16
Progressively, subjects with obesity are conditioned to eat
more as the release of dopamine in eating becomes habituated.
17
The newer anti-obesity medications act by stimulating the
hypothalamic anorexigenic pathway, inhibiting the hypothalamic
orexigenic pathway, and/or altering the mesolimbic reward system.
By altering the physiological drivers for increased energy intake,
these medications complement and help sustain the behavioral
efforts of patients with obesity by inhibiting pathways that limit
weight loss and promote weight regain.
Modes of action
Liraglutide has 97% homology to the endogenous GLP-1 secreted
by L-cells in the distal gut. It reduces food intake by stimulating
the anorexigenic pathway in the hypothalamus and concurrently
inhibiting the orexigenic pathway. In addition, liraglutide delays
gastric emptying via autonomic inhibition of vagal activity.
Overall, there is a decrease in frequency and quantity of food
consumption leading to a caloric deficit.
18
NB works centrally and synergistically to facilitate weight loss.
In the hypothalamus, NB stimulates the anorexigenic pathway
leading to reduced hunger and food intake. In the mesolimbic
region, NB alters reward eating patterns, improving control over
eating behaviors and cravings.
19
Efficacy of anti-obesity medications
Liraglutide 3.0 mg
The Satiety and Clinical Adiposity Liraglutide Effect (SCALE)
Trials included four Phase 3 RCTs. Study subjects were required to
have a body mass index (BMI) ≥ 27 kg/m
2
with comorbidities or a
BMI ≥ 30 kg/m
2
. Each trial involved randomization to liraglutide
or placebo along with standardized lifestyle recommendations
including a calorie reduced diet and increased physical activity.
20–23
Weight loss outcomes are summarized for both the intention to
treat analysis group (Table 1) and the completers (Table 2). As
expected, the completers experienced more favorable weight-
loss effects.
SCALE maintenance randomized 422 non-diabetic study
subjects 1:1 to liraglutide 3.0 mg or placebo over 56 weeks
following a low-calorie diet phase requiring participants to lose
at least 5% of their body weight.
20
Mean weight loss during the
run-in was 6%. In the liraglutide arm, 81.4% of the study subjects
(vs 48.9% in the placebo group) maintained a ≥5% weight loss
achieved in the run-in period. Scale prediabetes randomized
3731 nondiabetic subjects 2:1 to liraglutide 3.0 or placebo over
56 weeks. Primary endpoints at 1 year were: (i) change in body
weight; (ii) proportion of study subjects losing ≥5% baseline
body weight; and (iii) the proportion of study subjects losing
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>10% baseline body weight.
21
Scale diabetes included 846 type 2
diabetic subjects randomized 2:1:1 to liraglutide 3.0 mg, liraglutide
1.8 mg, or placebo over 56 weeks. Primary endpoints were
identical to Scale prediabetes.
22
Scale sleep apnea randomized
in a 1:1 ratio—359 adults with obesity with untreated moderate
(apnea–hypopnea index [AHI] 15.0–29.9 events/hour) or
severe (AHI ≥ 30 events/hour) obstructive sleep apnea (OSA)
to liraglutide 3.0 mg or placebo for a 32-week period.
23
At week
32, the liraglutide group had a greater reduction in mean AHI
compared with placebo (12.2 vs 6.1 events/hour).
Naltrexone–Bupropion
The Contrave® Obesity Research Program (COR) consisted of
four 56-week Phase 3 RCTs. All study subjects had body mass
indices of 27–45 kg/m
2
and were provided with comprehensive
lifestyle recommendations including calorie-reduced diets and
increased physical activity. Primary endpoints were percentage
change in body weight and proportion of study subjects able to
lose ≥ 5% baseline body weight.
24–27
COR-1 randomized 1742 study subjects in a 1:1:1 ratio
to naltrexone SR 32 mg plus bupropion SR 360 mg (hereafter
NB32), naltrexone SR 16 mg plus bupropion 360 mg (NB16), or
placebo.
24
COR-2 randomized 1496 study subjects in a 2:1 ratio
to NB32 or Placebo. The co-primary endpoints were assessed at
28-weeks and re-evaluated at 56 weeks.
25
COR-BMOD included
793 participants, randomized in a 3:1 ratio to NB32 or placebo.
26
This study included an intense 56-week behavior modification
program that included high-level activity (360 min per week),
calorie-reduced nutrition prescriptions, and 28 group therapy
sessions led by dieticians, psychologists, and exercise specialists.
COR-Diabetes included 505 type 2 diabetics, randomized in a
2:1 ratio to NB32 or placebo.
27
Weight loss outcomes are summarized for both the intention
to treat analysis group (Table 3) and the completers (Table 4).
Table 1. Liraglutide: weight loss outcomes for the intention to treat analysis group
Phase 3
Clinical trial
% weight change ≥5%* >10%**
Liraglutide Placebo Liraglutide Placebo Liraglutide Placebo
Scale 1: Maintenance
56 weeks
6.2 0.2 50.5 21.8 26.1 6.3
Scale 2: Prediabetes
56 weeks
8.0 2.6 63.2 27.1 33.1 10.6
Scale 3: Diabetes
56 weeks
6.0 2.0 54.3 21.4 25.2 6.7
Scale 4: Apnea
32 weeks
5.7 1.6 46.3 18.5 23.4 1.7
Data from Scale 1–4 Clinical Trials.
20–23
*Proportion (%) of study subjects that lost at least 5% randomization weight. **Proportion (%) of study subjects losing more
than 10% randomization weight.
Table 2. Liraglutide: weight loss outcomes for the completers
Phase 3
Clinical trial
% weight change ≥5%* >10%**
Liraglutide Placebo Liraglutide Placebo Liraglutide Placebo
Scale 1: Maintenance
56 weeks
6.7 0.1 52.7 22.7 26.1 6.3
Scale 2: Prediabetes
56 weeks
9.2 3.5 72.8 35.7 40.9 14.9
Scale 3: Diabetes
56 weeks
6.6 2.5 58.7 20.7 27.4 7.8
Scale 4: Apnea
32 weeks
5.7 1.6 46.3 18.5 23.4 1.7
Data from Scale 1–4 Clinical Trials.
20–23
*Proportion (%) of study subjects that lost at least 5% randomization weight. **Proportion (%) of study subjects losing more
than 10% randomization weight.
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Overall, study subjects treated with naltrexone–bupropion
experienced statistically greater weight loss outcomes compared
to placebo.
Citing the high-quality evidence of the SCALE and COR
clinical trials, as well as other clinical trials of anti-obesity
medications not approved by Health Canada, existing clinical
practice guidelines
28
strongly recommend incorporating anti-
obesity medications into the care of patients with obesity. A
similar recommendation is expected in a forthcoming update
to the adult clinical practice guidelines for obesity management,
which is being prepared by Obesity Canada and the Canadian
Association of Bariatric Physicians and Surgeons.
Comparison with orlistat
A network meta-analysis of 28 randomized clinical trials of at
least 1-year duration showed that placebo-subtracted weight
loss with liraglutide or NB is approximately twice that achieved
with orlistat (liraglutide 5.3 kg, NB 5 kg, orlistat 2.6 kg).
29
More
patients achieve clinically significant weight loss with these
newer medications (Table 5).
Table 3. Naloxone–Bupropion: weight loss outcomes for the intention to treat analysis group
Phase 3
Clinical trial
% weight change ≥5%* >10%**
NB32 Placebo NB32 Placebo NB32 Placebo
COR1
56 weeks 5.4 1.3 42 17 21 7
COR 2
28 weeks
56 weeks
5.9
6.4
2.0
1.6
48.9
47.9
17.1
16.9
23.9
39.4
7.4
7.9
COR 3: BMOD
56 weeks 8.1 4.9 57 43 36 18
COR 4: Diabetes
56 weeks 3.7 1.7 35 21 15 5
Adapted from Contrave® Product Monograph,
19
COR 1–4,
24–27
, and Bausch Health/Orexigen; data on file. *Proportion (%) of study subjects that lost at least
5% randomization weight. **Proportion (%) of study subjects losing more than 10% randomization weight.
Table 4. Naloxone–Bupropion: weight loss outcomes for the completers
Phase 3
Clinical trial
% weight change ≥5%* >10%**
NB32 Placebo NB32 Placebo NB32 Placebo
COR1
56 weeks 8.1 1.8 61.9 23.1 34.5 10.7
COR 2
28 weeks
56 weeks
7.8
8.2
2.4
1.4
68.8
64.9
22.3
21.7
35.7
39.4
9.4
7.9
COR 3: BMOD
56 weeks 11.5 7.3 80.4 60.4 55.2 30.2
COR 4: Diabetes
56 weeks 5.9 2.2 53.1 24.0 26.3 8.0
Adapted from Contrave® Product Monograph,
19
COR 1–4,
24–27
and Bausch Health/Orexigen; data on file. *Proportion (%) of study subjects that lost at least
5% randomization weight. **Proportion (%) of study subjects losing more than 10% randomization weight.
Table 5. Percentage of patients achieving clinically significant weight loss at
1 year
>5%
weight loss
>10%
weight loss
Placebo 23% 9%
Liraglutide 63% 34%
Naltrexone–bupropion 55% 30%
Orlistat 44% 20%
Data adapted from Khera et al.
29
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Obesity medications in clinical practice
Indications
The indications for anti-obesity medications are based on BMI
criteria and the presence of weight-related co-morbidities (Box
1). We also consider obesity medications for patients below these
BMI cut-offs who may have already lost weight through behavior
change, particularly if long-term weight-loss maintenance is a
concern. We recommend prioritizing obesity medications for
patients with severe comorbidity (e.g., idiopathic intracranial
hypertension), a history of weight cycling, and those who are
actively gaining weight.
Anti-obesity pharmacotherapy should be used as an adjunct
to behavioral modification; these interventions are mutually
reinforcing. Anti-obesity medications that decrease appetite
encourage adherence to a hypocaloric diet; the additional weight
loss achieved with medication may reduce barriers to physical
activity. When obesity medication is prescribed in the absence
of behavior change, less weight loss is achieved, and patient
satisfaction is lower.
30
More intensive behavioral programs result in greater weight
loss; likewise, when combined with pharmacotherapy, more
intensive behavioral programs result in greater weight loss. In
clinical trials, the standardized lifestyle intervention is easily
adaptable to general practice. Subjects are advised to reduce
their food intake by 500 kilocalories below their estimated daily
requirement, which can be calculated using the Mifflin-St Jeor
equation, and participate in aerobic exercise for 150 min weekly.
Self-monitoring is also recommended; patients are advised to
weigh themselves regularly and maintain a food record. Lifestyle
counseling generally occurs every 1–3 months.
Side effects
Gastrointestinal symptoms are common with liraglutide and
NB. To mitigate these side effects, dose escalation over a 4-week
period is recommended. Gastrointestinal side effects tend to be
mild to moderate in nature and self-limited (Box 2).
Choice of agent
Initial selection of a weight loss medication is guided by
contraindications, co-morbidities, and patient preference.
Contraindications for liraglutide are the same as other drugs in
GLP-1 agonist class (Box 3). Contraindications for naltrexone–
bupropion relate to opioid use and conditions that increase the
risk of seizure.
We prescribe liraglutide preferentially in patients with diabetes.
We typically recommend NB for patients with unmanaged
depression, a history of binge drinking, or prior success with
smoking cessation using bupropion. Patient preference also plays
a role; while many patients prefer an oral to a subcutaneous
medication, others highly value single day dosing.
Box 2. Summary of dosing schedules
Orlistat (Xenical®)
120 mg TID with meals
Liraglutide 3.0 (Saxenda®)
0.6 mg SC daily × 1 week
1.2 mg SC daily × 1 week
1.8 mg SC daily × 1 week
2.4 mg SC daily × 1 week
3.0 mg SC daily
Naltrexone SR/Bupropion SR (Contrave®)
1 tab QD × 1 week
1 tab BID × 1 week
2 tabs QAM + 1 tab QPM × 1 week
2 tabs BID
Data sourced from Xenical
®
, Saxenda
®
, and Contrave
®
Product Monographs.
18,19,30
Box 1. Indications for anti-obesity agents
BMI ≥ 27 kg/m
2
+ risk factors, OR
BMI ≥ 30 kg/m
2
Adjunct to lifestyle modifications; consider if patient has not
lost 0.5 kg (1lb) per week by 3–6 months after lifestyle changes
Data adapted from Lau et al.
6
Box 3. Contraindications
Orlistat (Xenical®)
Chronic malabsorption states
Cholestasis
Liraglutide (Saxenda®)
Personal or family history of medullary thyroid carcinoma
(MTC)
Patients with multiple endocrine neoplasia syndrome type
2
Pregnancy or breastfeeding
Naltrexone SR/Bupropion SR (Contrave®)
uncontrolled hypertension
Seizure disorder or a history of seizures
Use of other bupropion-containing drugs
Current or prior diagnosis of bulimia or anorexia
Chronic opioid or opiate agonist or partial agonist use
Acute opiate withdrawal
Abrupt discontinuation of alcohol, benzodiazepines, or
other sedatives, and antiepileptic drugs
Concomitant administration of MAOIs
Concomitant administration of the antipsychotic
thioridazine
Pregnancy and breastfeeding
Severe hepatic impairment
End-stage renal disease
Data sourced from Xenical®, Saxenda®, and Contrave®Product Monographs.18,19,31
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Currently, we are unable to predict which weight loss
medication will result in the greatest weight loss for a given
individual. If one medication is poorly tolerated or ineffective,
another should be trialed. When indicated, obesity medications
can be used simultaneously if the expected clinical outcome is
to further reduce daily caloric consumption—however, both an
increased risk for adverse effects as well as cost-effectiveness
must be considered.
Follow-up
We suggest patient assessment monthly for the first 3 months
of medication use, and every 3 months thereafter.
31
Patients
initiated on liraglutide should be monitored for gastrointestinal
side effects and injection site reactions. Patients started on NB
should be monitored for gastrointestinal side effects, worsening
hypertension, tachycardia, anxiety, suicidal ideation, and
worsening headaches. Recommended baseline and follow-up
investigations are the same as for patients undergoing an isolated
behavior intervention.
6
After 12 weeks at the target dose, an
anti-obesity medication should be discontinued if 5% weight loss
has not been achieved. Cross-over trials of obesity medications
consistently show accelerated weight regain when medication is
stopped.
20–23
As such, anti-obesity medications, as medications
for any other chronic disease (e.g., hypertension, type 2 diabetes,
etc.), should be continued indefinitely when they are effective
and well-tolerated.
Conclusion
Obesity treatment has historically been a frustrating aspect of
medical practice for primary care practitioners; the long-term
outcomes of behavioral therapy are disappointing, bariatric
surgery is scarcely available, and medications have been
poorly effective. The newest anti-obesity medications target
the neurohormonal regulation of appetite, addressing a key
mechanism in the pathophysiology of obesity. These medications
allow physicians to deliver more effective obesity therapy to a
greater number of patients.
Conflicts of Interest
Authors R.M., S.C., and A.S. have received speaker and consulting
honorarium from Novo Nordisk and Bausch Health. Authors
R.K and J.D have no conflict of interest to disclose.
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