large retrospective matched cohort study over the obesity

 randomized controlled trial (RCT) that evaluated the
effect of orlistat in 3,305 patients, orlistat was found
to cause a total body weight loss of 2.4% after 4 years.
More importantly, it significantly lowered the risk
of type 2 diabetes mellitus (T2DM), compared to placebo (6.2% vs. 9.0%), over 4 years [21]. Orlistat also
improved blood pressure (BP), insulin sensitivity, and
lipid profiles owing to its primary action of decreasing intestinal fat absorption. However, in this study,
91% of participants administered orlistat experienced
at least one gastrointestinal event and 8% withdrew
from the study due to adverse events. Further, there
are concerns regarding the potential risk of colorectal
cancer due to the presence of excess fat in the colon.
In animal models, orlistat was associated with clusters
of apoptosis-resistant, neoplastic, premalignant colonic
lesions [22].

 However, a large retrospective matched
cohort study (n=33,625 on orlistat; 160,374 on placebo)
showed no evidence of an increased risk of colorectal
cancer after the initiation of orlistat [23]. Meanwhile, a
significant decrease in the absorption of vitamins A, D,
E, and K was observed in participants administered orlistat [21]. To prevent possible deficiencies in fat-soluble
vitamins (such as vitamin D), a supplement can be recommended.
2. Lorcaserin
Lorcaserin (Belviq®
and Belviq XR®
) is a selective
agonist of the 5-hydroxytryptamine (5-HT) 2C receptors
and a Drug Enforcement Administration (DEA) schedule IV-controlled medication. In 2016, its extended released (XR) form (once daily [QD] 20 mg of lorcaserin)
was approved by the FDA following twice-daily (BID)
10 mg of lorcaserin in 2012. However, on February 13,
2020, the FDA requested that the drug manufacturer
voluntarily withdraw lorcaserin from the US market
because it was determined that potential risk of cancer associated lorcaserin outweighs the benefits [24]. It
was an update to the FDA Drug Safety Communication: Safety clinical trial shows possible increased risk
of cancer with weight-loss medicine Belviq, Belviq XR
(lorcaserin) issued on January 14, 2020 [25]. This withdrawal came after the FDA’s reviewing data from the
Cardiovascular and Metabolic Effects of Lorcaserin
in Overweight and Obese Patients – Thrombolysis in
Myocardial Infarction 61 (CAMELLIA-TIMI 61) clinical
trial to evaluate the risk of CVD problems [26]. It was
a randomized, double-blind, placebo-controlled, multicenter, parallel group trial conducted between January
2014 and June 2018 in the US, Canada, Mexico, the
Bahamas, Europe, South America, Australia, and New
Zealand. The study population consisted of 12,000 men
and women who were overweight or obese. Patients
were required to have either established CVD, or to
be at least 50 years old for men or 55 years for women
with T2DM plus at least one additional cardiovascular
risk factor. Eligible patients were assigned randomly to
either lorcaserin 10 mg BID or placebo. Approximately
96% of patients completed the study, and 62% who
completed remained on treatment at the end of study.
The median follow-up time was 3 years and 3 months.
The primary safety analysis showed no meaningful
difference between lorcaserin and placebo in the risk
of major adverse cardiovascular events, demonstrating noninferiority. However, it was found that more
patients taking lorcaserin (n=462; 7.7%) were diagnosed
with cancer compared to those taking a placebo, which
is an inactive treatment (n=423; 7.1%). A range of cancer types was reported, with several different types of
cancers occurring more frequently in the lorcaserin
group, including pancreatic, colorectal, and lung.

was no apparent difference in the incidence of cancer
over the initial months of treatment, but the imbalance increased with longer duration on lorcaserin.
On the other hand, lorcaserin has failed to gain approval from the European Medical Agency (EMA) due
to preclinical data that revealed the potential of breast
cancer development and concerns regarding psychiatric
issues—the aggravation of depression, suicidal ideation,
and psychosis and valvulopathy. Moreover, phase III
studies to determine the difference in adverse event incidence between groups were deemed underpowered [27].
1) Mechanism of action
Lorcaserin decreases food intake by increasing satiety through its serotonin anorectic effect by stimulating the proopiomelanocortin (POMC) receptors in the
arcuate nucleus of the hypothalamus [28]. At least 14
serotonin receptor subtypes that modulate different
physiological functions, ranging from hallucinations to
muscle contraction, exist [29]. The side effects caused
by non-specific serotonin agonists (i.e., fenfluramine
and dexfenfluramine) are due to the stimulation of
the peripheral serotonin 2B receptor. Fenfluramine is
a predominant 5-

HT2b receptor agonist that is believed
to cause adverse CVD effects by stimulating mitotic
activity and subsequent cell overgrowth within the
valve leaflets [30]. Owing to its high selectivity for
5-HT2c receptor (15-fold and 100-fold selectivity over the
5-HT2A and 5-HT2B receptors, respectively), lorcaserin
can suppress appetite and hunger without triggering
pulmonary hypertension or valvular heart defects [31].
Many studies suggest that lorcaserin has multiple psychological effects—reducing craving and impulsivity
and elevating satiety), which contribute to weight loss.

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