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
kg/m2
, 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
[51].
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
GLP-1, 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].
3) Clinical efficacy
Liraglutide was approved base on the results of
three main RCTs; The SCALE Obesity and Prediabetes, the SCALE Diabetes and the SCALE Maintenance
[58,60,61]. In the SCALE Obesity and Prediabetes, obese
participants (n=2,487), including 61.2% of the prediabetic cohort, received liraglutide 3 mg QD or placebo.
After 56 weeks, a weight loss of 8.0% was achieved in
the liraglutide group (vs. 2.6% of placebo) and 63.2%
and 33.1% of the participants in the liraglutide group
achieved ≥5% and ≥10% weight reduction, respectively
[58] (vs. 27.1% and 10.6% in the placebo group, respectively).
Moreover, cardiovascular indicators, including BP and lipid profiles, were better improved in the
treatment group. Particularly, HbA1c (-0.30%±0.28%)
and fasting glucose levels (-7.1±0.8 mg/dL) were significantly reduced in subjects administered liraglutide 3.0
mg compared to placebo. The SCALE Diabetes assigned
overweight or obese patients with T2DM (n=846) to
receive liraglutide 3 mg QD or 1.8 mg QD or placebo
for 56 weeks and reported a decrease in the weight of
the patients (6.0%, 4.7%, and 2.0%, respectively) [58].
Early achievement of weight loss ≥4% with liraglutide
3 mg (at 16 weeks) was associated with greater weight
reduction at the study’s termination [62]. Compared to
the 1.8 mg SC daily group, the liraglutide 3.0 mg SC
daily group had a greater improvement in the T2DM
Young Jin Tak and Sang Yeoup Lee: An Updated Review on Anti-Obesity Drugs
www.wjmh.org 215
measures, including HbA1c, fasting plasma glucose,
HOMA-IR, and number of hypoglycemic agents. The
SCALE Maintenance aimed to evaluate weight maintenance in non-diabetic participants who underwent
a ≥4-week run-in with a low-calorie diet. Subjects who
lost ≥5% of their body weight (n=422) were randomized
to receive liraglutide 3.0 mg SC daily or placebo for 56
weeks. The liraglutide 3.0 mg SC daily group achieved
an additional weight loss of 6.2% (0.2%, placebo) [61].
One of the main benefits of liraglutide, besides weight
loss, is its favorable effects on CVD outcomes in obese
patients with T2DM.
Despite initial considerations of the risk of acute
pancreatitis, long-term trials suggest that the risk
of this disease does not significantly increase with
liraglutide [63,64]. Particularly, biomarkers of acute
pancreatitis—
amylase and mainly lipase—increase
in a non-dose dependent manner during treatment
with GLP-1 receptor analogs. However, their increase
was not accompanied by symptoms; moreover, when
monitored, acute pancreatitis could not be predicted
[65]. Based on rodent studies that demonstrated the
proliferative effect of liraglutide on thyroid C-cells,
contraindications for liraglutide include patients with
(or a family history of) medullary thyroid carcinoma
or type 2 multiple endocrine neoplasia [27]. In rodents
administered incretin-based medications, pancreatic,
intestinal, and breast neoplasms were found to develop
more frequently; however, these results were not found
in human studies [66-68]. A phase IIIb RCT reported
no difference in calcitonin levels and medullary thyroid carcinoma rates between liraglutide (≤1.8 mg) and
placebo during a follow-up of 3.5–5 years [69]. Additionally, the total risk of malignant and benign neoplasms,
including pancreatic cancer, was not found to increase
in the liraglutide vs. placebo group [63,64,70].
However,
these results should be interpreted cautiously and an
intensive post-marketing surveillance of liraglutide
should be performed as the studies were not designed
to assess cancer risk and the incidence of medullary
thyroid carcinoma was too low for detection in the trials. As no concern regarding neuropsychiatric safety
was reported, this medication can serve as a good option for obese patients with mental disorders [71] if
they can afford this costly medication (liraglutide 3.0
mg) and agree to a daily injection.
