Phentermine is a sympathomimetic agent that functions as an appetite suppressant by
increasing the concentration of norepinephrine in the central nervous system.
Topiramate is a second-generation antiepileptic agent also approved for the treatment
of migraines, which acts as an agonist at γ-aminobutyric acid (GABAA) receptors
and as an antagonist at non-N-methyl-D-aspartic acid (NMDA) glutamate receptors.
The mechanism by which weight loss occurs with topiramate is unclear, but may be
related to a direct action on adipose tissue.
Therapy is initiated at a dose of phentermine 3.75 mg/topiramate 23 mg daily for
14 days, after which the dose is increased to phentermine 7.5 mg/topiramate 46 mg
daily. If the patient has not experienced ≥3% weight loss after 12 weeks of therapy at
the maintenance dose, the drug should either be discontinued or the dose escalated to
phentermine 15 mg/topiramate 92 mg daily. After an additional 12 weeks of therapy,
if the patient has not experienced ≥5% weight loss, the drug should be discontinued.
The efficacy of phentermine/topiramate ER has been demonstrated in two phase 3
clinical trials and one expansion trial: CONQUER, EQUIP, and SEQUEL (an
extension of the CONQUER trial).
91,92 Phentermine/topiramate ER 7.5/46 mg was
shown to produce average weight loss of 7.8% of initial body weight after 1 year and
91,93 Phentermine/topiramate ER 15/92 mg was shown to produce
average weight loss of 9.8% of initial body weight after 1 year and 10.5% after 2
91,93 Use of phentermine/topiramate ER has also been associated with
improvements in cardiometabolic parameters at the 15/92 mg dose.
taking phentermine/topiramate ER at doses ≥7.5/46 mg also showed reduced
progression to type 2 diabetes.
The most common adverse effects associated with phentermine/topiramate ER
include paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.
Topiramate has been associated with birth defects, specifically oral clefts when
taken during the first trimester, which led the FDA to approve
phentermine/topiramate ER with a risk evaluation and mitigation strategy (REMS).
This REMS is designed to inform practitioners and patients about the risk of birth
defects, the importance of contraceptive use, and the need to immediately discontinue
the drug if the patient becomes pregnant.
94 Phentermine/topiramate ER is
contraindicated in pregnancy and in patients with glaucoma, hyperthyroidism, MAOI
use within the past 14 days, and hypersensitivity to sympathomimetic amines.
Lorcaserin is FDA-approved for long-term obesity management as an adjunct to
It is a selective serotonin 2C (5-HT2C) receptor agonist. It is
thought that lorcaserin promotes feelings of satiety by activating 5-HT2C receptors in
It is available as 10 mg tablets and is dosed at 10 mg twice
daily. If the patient has not experienced ≥5% weight loss after 12 weeks of therapy at
the maintenance dose, the drug should be discontinued.
The efficacy of lorcaserin has been demonstrated in three phase 3 clinical trials:
98–100 Lorcaserin was shown to produce
average weight loss of 5.8% of initial body weight after 1 year and 7.2% after 2
98,99 Use of lorcaserin has been associated with significant improvements in
lipid profiles and glycemic parameters, including reductions in fasting plasma
The most common adverse effects associated with lorcaserin include headache,
dizziness, fatigue, nausea, dry mouth, and constipation in patients without diabetes. In
patients with diabetes, the most common adverse effects are hypoglycemia, headache,
back pain, cough, and fatigue.
In the past, nonselective serotonin agonists
(fenfluramine and dexfenfluramine) were withdrawn from the market due to adverse
cardiac events, most significantly valvulopathy.
98,101 Based on this, the FDA required
data on the rates of valvulopathy with lorcaserin; a pooled analysis of the three
previously mentioned phase 3 clinical trials found that the rates of echocardiographic
valvulopathy were similar in both the lorcaserin and placebo groups.
reported side effects include priapism, hyperprolactinemia, cognitive impairment,
hallucinations, and dissociation.
Based on the serotonergic activity of lorcaserin, it is advised to avoid it with other
serotonergic drugs such as SSRIs, SNRIs, MAOIs, and triptans.
inhibitor of CYP 2D6; caution should be used when co-administering lorcaserin with
drugs metabolized by this enzyme. The use of dextromethorphan is of particular
concern because it is metabolized by CYP 2D6 and may have serotonergic effects.
Lorcaserin is contraindicated in pregnancy.
Naltrexone/Bupropion (Contrave)
Naltrexone/bupropion is a combination drug that has been approved by the FDA for
long-term obesity management as an adjunct to lifestyle modification.
an antidepressant that inhibits dopamine and norepinephrine reuptake, has a known
side effect of weight loss when used for the treatment of depression and smoking
104 This weight loss effect is thought to be the result of appetite suppression
induced by the stimulation of pro-opiomelanocortin neurons in the hypothalamus.
Naltrexone, an opioid receptor antagonist, is believed to enhance this appetite
suppression by blocking opioid receptors on these same pro-opiomelanocortin
104 Naltrexone/bupropion is available as combination 8/90 mg tablets.
Patients initiate treatment at a dose of one tablet every morning. This dose is titrated
up over the course of 4 weeks to a dose of two tablets twice daily, for a total daily
If the patient has not experienced ≥5% weight loss after 12
weeks of therapy at the maintenance dose, the drug should be discontinued.
The efficacy of naltrexone/bupropion has been demonstrated in four 1-year,
placebo-controlled, phase 3 clinical trials: COR-I, COR-II, COR-BMOD, and CORDiabetes.
103 Naltrexone/bupropion 32/360 mg was shown to produce average weight
loss of 6.1% to 6.4% of initial body weight.
106,107 When coupled with intensive
behavior modification, patients taking naltrexone/bupropion 32/360 mg experienced
an average weight reduction of 9.3% of initial body weight.
naltrexone/bupropion has also been associated with improvements in
cardiometabolic parameters, including HbA1c reduction.
The most common adverse effects associated with naltrexone/bupropion include
nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and
103 Slight increases in blood pressure and heart rate have been seen in phase
3 clinical trials; thus, these parameters should be monitored during therapy.
Contrave has a black box warning for suicidal thoughts and behavior, although
increased rates have not been seen in phase 3 clinical trials.
inhibitor of CYP 2D6; caution should be used when co-administering
naltrexone/bupropion with drugs metabolized by this enzyme.
Naltrexone/bupropion is contraindicated in pregnancy and in patients with
uncontrolled hypertension; seizure disorders; anorexia nervosa or bulimia; sudden
discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs;
chronic use of opioids; use of MAOIs within the past 14 days; and in patients
currently taking other bupropion-containing products.
Liraglutide, marketed as Saxenda, is an injectable medication, FDA-approved for
long-term obesity management as an adjunct to lifestyle modification.
for obesity, the dose is titrated to 3 mg daily. It is also marketed under the brand
name Victoza at a dose of 1.8 mg daily for the treatment of type 2 diabetes.
Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. Activation of this
receptor acts via the central nervous system to promote feelings of satiety, thereby
If the patient has not experienced ≥4% weight loss by 16
weeks after initiating therapy, the drug should be discontinued.
The efficacy of liraglutide for weight loss has been demonstrated in three phase 3
clinical trials: SCALE Maintenance, SCALE Obesity and Pre-Diabetes, and SCALE
114–116 The results have not yet been published for the SCALE Diabetes trial.
The results of the SCALE Maintenance trial indicate that by 12 weeks, liraglutide
produces an average weight loss of 6.0% greater than placebo.
SCALE Obesity and Pre-Diabetes trial and the data released thus far for the SCALE
Diabetes trial indicate that by the end of 56 weeks of treatment, liraglutide produces
an average weight loss of 3.9% to 5.4% greater than placebo.
has also been associated with significant improvements in HbA1c, fasting plasma
The most common adverse effects associated with liraglutide include nausea,
hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite,
dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase. In order to
reduce the incidence of gastrointestinal side effects, liraglutide is initiated at a dose
of 0.6 mg daily and titrated up to the effective dose of 3 mg daily over a 5-weekperiod.
110 Liraglutide has been associated with an increased risk of medullary thyroid
carcinoma and acute pancreatitis. As a result, liraglutide is part of a REMS program
to ensure practitioners are informed of these risks.
117 Liraglutide is contraindicated in
pregnancy and in patients with hypersensitivity to liraglutide or any of its product
components, a personal or family history of medullary thyroid carcinoma, or a
personal or family history of multiple endocrine neoplasia syndrome type 2.
Several recent investigational agents have shown promise in weight loss
pharmacotherapy. In a 24-week phase IIb clinical trial, bupropion/zonisamide ER
was shown to produce weight loss of 9.9% of initial body weight, as compared to
1.7% weight loss with placebo.
118 Much like naltrexone/bupropion, this combination
drug works through a dual mechanism: Bupropion stimulates pro-opiomelanocortin
neurons in the hypothalamus, and zonisamide acts synergistically by suppressing an
appetite-stimulating neural pathway.
118 The most common adverse events were
headache, insomnia, and nausea.
Cetilistat is a lipase enzyme inhibitor, which acts similarly to orlistat, with a more
tolerable side effect profile.
In a 12-week phase II clinical trial, cetilistat
produced a mean weight loss of 4.32 kg when taken at a dose of 120 mg 3 times daily
by obese patients with diabetes.
120 The most common adverse events were mild-tomoderate GI effects.
Tesofensine, an inhibitor of noradrenalin, dopamine, and serotonin reuptake, was
initially developed to treat neurodegenerative disease and found to produce weight
loss in obese patients with Parkinson’s or Alzheimer’s disease.
evaluating this agent for weight loss in combination with caloric restriction have
shown dose-dependent reductions in weight up to 10.6% of baseline body weight
after 24 weeks of therapy. Adverse reactions associated with tesofensine included
nausea, constipation, diarrhea, insomnia, and dry mouth.
Tauroursodeoxycholic acid has also been proposed as a weight loss agent. It is
thought to induce weight loss by increasing sensitivity to leptin, a hormone that acts
57,123 However, clinical data are lacking at this time.
The most appropriate pharmacotherapeutic option for weight loss depends on
patient-specific parameters including other disease states, concomitant medication
use, adverse effects, patient preference, and cost. S.B. should avoid agents that will
exacerbate her hypertension; therefore, S.B. should not be prescribed
phentermine/topiramate and naltrexone/bupropion. Also, S.B. is currently taking
bupropion which would duplicate with naltrexone/bupropion and may cause
serotonin syndrome with lorcaserin. Orlistat and liraglutide are the only
pharmacotherapeutic options for S.B. that can be safely administered with her
hypertension and concomitant medication (bupropion). S.B. should chose the most
appropriate agent based on her personal preference including her lifestyle (many
gastrointestinal side effects and restricted fat intake and multiple daily doses with
orlistat) or the subcutaneous route of administration with the liraglutide.
is 6 kg. S.B.’s current weight is 78 kg and her BMI is down to 27.6 kg/m
2 but she is disappointed that she has
to dietary supplements? (Table 36-5)
Dietary Supplements for weight loss
Supplement Proposed Mechanism Clinical Data
Chitosan A cellulose-type Meta-analysis (14 trials) GI effects common
Caffeine Increased thermogenesis
Green tea Polyphenols and caffeine
See caffeine See caffeine See caffeine
angina, increased QTinterval, seizures, and
Glucomannan (Konjac) Fibrous polysaccharide
Hoodia Unknown, reported to be
cAMP, cyclic adenosine monophosphate; GI, gastrointestinal.
Reprinted with permission from Dunican KC, Jarvis C. Overweight and Obesity. In:
Murphy JE, Lee MW, eds. Pharmacotherapy Self-Assessment Program. 2014 Book 2
(Chronic Illnesses). Lenexa, KS: American College of Clinical Pharmacy,
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