Dose escalation and side effects Phentermine/topiramate


Dose escalation and side effects
Phentermine/topiramate is prescribed for QD use.
To prevent insomnia, its known side effect, it is recommended that this medication is taken in the morning.
According to the package insert, the dose of phentermine/topiramate should be gradually escalated. After
a starting dose of 3.75/23 mg QD is administered for
2 weeks, 7.5/46 mg is administered; this dose was best
tolerated by the participants in the study. The dose
should be administered for a minimum of 3 months before a further increase to the highest dose of 15/92 mg.
Additionally, the dose is only increased if the patient
fails to achieve a total body weight loss of 3% after 3
months. If the patient tolerates the medication poorly,
a slow titration down or off (ideally over 3–5 days)
is warranted to reduce the risk of seizure; this result
was found in a study where patients with a history of
seizures abruptly discontinued topiramate intake [18]

Common side effects of phentermine/topiramate ER
include insomnia, paresthesia, dizziness, dry mouth,
dysgeusia, and constipation [38]. A fetal safety issue
also exists with this medication: it increases the risk
of oral clefts. Thus, advice on contraceptive planning
is imperative before this medication is prescribed to
women of child-bearing age.
3) Clinical efficacy
Regarding weight loss efficacy, adequate assessments
of phentermine/topiramate ER have been conducted
via long-term studies. EQUIP and CONQUER were
each one-year, randomized, double-blind, placebo-controlled studies comprising 1,267 and 2,487 participants,
respectively [41,42]. The EQUIP trial included nondiabetic patients with a BMI ≥35 kg/m2
whereas the
CONQUER study included patients with a BMI ranging from 27–45 kg/m2
and more than two obesity-related comorbid conditions. The study findings enabled the
approval of phentermine/topiramate ER by the FDA.
In the EQUIP study, the mean weight loss at 1 year for
participants in the phentermine/topiramate ER 15/92
mg group was 10.9%, compared to 1.6% in the placebo
group. Similarly, in the CONQUER trial, participants
administered the same dose of phentermine/topiramate
ER for 1 year achieved a 9.8% reduction in weight from
baseline, compared to 1.2% in the placebo group. In the
CONQUER trial, patients administered phentermine/
topiramate ER 7.5/46 mg for 1 year had a total body
weight loss of 7.8%. Notably, both studies demonstrated
an improvement in the cardiovascular risk factors. The
SEQUEL study, a 2-year extension trial, was performed
to assess the sustained weight loss of participants after
completion of the CONQUER trial [43]. The study findings reinforced previous findings that phentermine/
topiramate ER intake can result in meaningful weight
loss and significant improvements in BP, lipid profiles,
fasting glucose, fasting insulin, and WC.
4. Naltrexone/bupropion
Naltrexone/bupropion (Contrave®
) is a drug combination for the long-term management of weight loss. In
2014, this combination was approved the FDA (Mysimba®
approved by the EMA). Each component of this
medication has been used in other medical conditions
since the 1980s [18]. As there is no potential of abuse
with this medication, it is not a controlled substance.
1) Mechanism of action
As an antidepressant, bupropion is used as a smoking
cessation aide. Its anorectic mechanism of action involves the inhibition of dopamine and norepinephrine
reuptake. Naltrexone was approved for the treatment
of opioid and alcohol addiction and antagonizes an
opioid‐dependent feedback loop that limits the effects
of bupropion on the POMC neurons; hence, this drug
combination works synergistically [44].
2) Dose escalation and side effects
A slow dose escalation of naltrexone/bupropion is recommended to minimize the side effect of nausea, with
a starting dose of 8/90 mg (a single combination tablet) 

QD for 1 week (at week 2; 1 tablet BID in the morning
and evening, at week 3; 2 tablets in the morning and
1 tablet in the evening, at week two tablets BID (the
maximum dose). Typical side effects include headache,
dizziness, dry mouth, and gastrointestinal discomfort
(i.e., nausea, vomiting, constipation, or diarrhea). Although naltrexone/bupropion results in significant
weight reduction and long-term evidence to support its
efficacy exists [18], its side effects of elevation of BP
and heart rate make it challenging to prescribe to patients with significant CVD.
3) Clinical efficacy
Naltrexone/bupropion was assessed in four phase III
multicenter, long-term, double-blind placebo-controlled
trials. The COR (Contrave Obesity Research)-I (n=1,742),
COR-II (n=1,496), and COR-BMOD (Behavior MODification) (n=793) trials included patients with a BMI ≥27
, at least one weight-related comorbid condition
(i.e., hypertension [HTN]), and COR-DM (Diabetes Mellitus) [45-48]. The percent weight loss observed in CORI, COR-II, and COR-BMOD in patients administered
naltrexone/bupropion 32/360 mg for 56 weeks compared
to placebo was 6.1% vs. 1.3%, 6.4% vs. 1.2%, and 9.3%
vs. 5.1%, respectively [49]. The final study, the CORDM trial, evaluated weight loss in 505 patients with
T2DM who were either overweight or obese [48]. Here,
patients administered naltrexone/bupropion 32/360 mg
for 56 weeks vs. placebo lost 5.0% vs. 1.8%. Moreover,
their HbA1c was reduced relative to the baseline value
(0.6% vs. 0.1%) [50]. These trials revealed improvements
in high-density lipoprotein cholesterol and triglycerides
in naltrexone/bupropion-treated patients. However, improvements in WC, fasting insulin, and insulin resistance index (homeostasis model assessment of insulin
resistance, HOMA-IR) were only identified in participants in the COR-I, COR-II, and COR-BMOD studies
5. Liraglutide
Liraglutide (Saxenda®
) is an injectable glucagon-like
peptide 1 (GLP-1) derivative that was approved by the
FDA in 2014 for weight management (dose, 3.0 mg subcutaneous [SC] daily). This approval followed that of a
lower dose (1.8 mg daily [Victoza®
]) in 2010 for T2DM
management [52].
1) Mechanism of action
After meals, GLP-1 is secreted from the distal ileum,
proximal colon, and the vagal nucleus of the solitary
tract and exhibits multiple effects as an incretin hormone [53]. GLP-1 mainly regulates blood glucose by enhancing insulin secretion from the pancreatic beta-cells
and inhibits glucagon secretion in a glucose-dependent
manner. GLP-1 also induces postprandial satiety and
fullness, slows gastric emptying, and decreases appetite
and food consumption by acting on the hypothalamus,
limbic/reward system, and cortex [54]. Unlike human

liraglutide is more stable in plasma and binds
strongly to plasma proteins, thereby enabling a much
longer half-life (13 hours) than the human endogenous
GLP-1 (a few minutes) [55].
2) Dose escalation and side effects
The optimal dose of liraglutide for weight loss is 3
mg daily; however, to prevent the side effects of nausea and vomiting, treatment should be initiated with 0.6
mg QD and gradually escalated each week by 0.6 mg
up to 3 mg [38]. Previously, a meta-analysis revealed
that among all FDA-approved anti-obesity medications,
liraglutide had the highest discontinuation rate due to
its side effects (13% of patients) [56]. The most frequent
placebo-subtracted side effects were nausea (25.0%),
vomiting (12.2%), diarrhea (11.6%), constipation (11.0%),
and dyspepsia (6.4%), which were tolerated by most patients over time [57-59].

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