As obesity occurs via multifactorial pathways, a
single drug might exhibit limited efficacy. Thus, a
high dose might be required, which often causes unacceptable side effects. Combination therapy comprising
multiple anti-obesity drugs with complementary modes
of action is warranted to broaden the target energy
regulatory systems via actions on distinct mechanisms,
which could maximize the effect on weight management while maintaining safety and tolerability [72]. To
date, however, there has been no approved combination
agent for obesity management, besides phentermine/
topiramate and naltrexone/bupropion. Other co-administered medications have been investigated to elucidate
their long-term efficacy and adverse events [15,16].

combinations primarily focus on both controlling hunger/appetite/satiety and inhibiting peripheral calorie
absorption (i.e., phentermine/sodium glucose co-transporter 2 [SGLT-2] inhibitor, a GLP-1 agonist/other gut
hormones, or an SGLT-2 inhibitor). SGLT-2 inhibitors,
such as dapagliflozin, empagliflozin, and canagliflozin,
block glucose reabsorption from the renal tubules and
result in glycosuria. Therefore, they are primarily
used by diabetic patients for blood sugar control [73].
Interestingly, these drugs are effective, to some extent,
in individuals without diabetes [74]. Theoretically, the
amount of glucose loss in urine is approximately 75
g/d (300 kcal energy deficit). Resultantly, 7–8 kg of
weight loss owing to these medications can be expected
in patients with diabetes over 6–12 months. However,
in previous clinical studies with diabetic patients, only
2–3 kg weight loss was achieved with such agents; this
was attributed to compensatory hyperphagia/increased
appetite [75]. Thus, combining an appetite suppressor,
such as phentermine, with a SGLT-2 inhibitor can
serve as a good option for weight management. In a recent clinical trial that examined canagliflozin in combination with phentermine, additional weight loss was
achieved (6.9%, canagliflozin 300 mg+phentermine 15
mg vs. 1.3%, canagliflozin 300 mg vs. 3.5%, phentermine
15 mg) [76]. Similarly, SGLT-2 inhibitors combined with
a GLP-1 agonist caused a greater weight reduction
than individual administration of each agent [77].
Despite the marked availability, anti-obesity drugs
are reported to be underused by healthcare providers
[3,78]. Only 2% of obese adults who are eligible for obesity pharmacotherapy receive prescriptions for these
agents from their doctor [79]. As a highly stigmatized
disease, there remains a misconception that obesity is
mainly due to a lack of willpower and representative of
laziness; thus, these patients are considered undeserving of proper treatment with medications or surgery
[80]. The high cost of these medications also prevents
adequate prescription for long periods. Weight loss is
extremely challenging to achieve and sustain, and longterm management of obesity often requires adjunctive
pharmacological interventions. 

Today, practitioners
have access to several FDA-approved options. Moreover, as there is growing evidence that these drugs can
delay the onset of obesity-related complications and
improve metabolic and cardiovascular parameters, they
should be considered in a timely manner.
The decision to initiate drug therapy in an obese individual should be made after the risks and benefits
are considered. Importantly, health providers should
determine the risk-benefit profile of a given anti-obesity
drug on a patient-by-patient basis. Further, the treatment goals should be clear. Patient preferences based
on tolerability markedly affect adherence and can
cause poor adherence or discontinuation, thereby negating the treatment effects [13,14]. At every visit, physicians should discuss the adverse events that accompany
a given drug and evaluate the drug’s effect on weight
loss. The goal of treatment with anti-obesity drugs in
obese individuals should be long-term maintenance of
weight reduction and improvement in overall health.
In most clinical trials that evaluated pharmacologic
interventions for more than 12 months, a weight loss
of 4% to 8% was typical [56]; however, this is rather
disappointing considering the high prices of these
drugs. Therefore, upon initiation of an anti-obesity
medication, health providers must communicate several important messages to their patients. First, not every drug will produce effective results in patients and
individual responses will vary widely. Second, when
the maximal therapeutic effect of a drug is achieved, a
plateau will be reached. Lastly, when drug therapy is
discontinued, weight regain is normally expected.
Treatment response to most of these drugs should be
evaluated at around 12 weeks using the maintenance
dose. A trial period of 3 to 4 months is essential for
predicting whether a patient might achieve a clinically
significant weight loss at 1 year (classified as responders or non-responders); this is supported by data that
early weight loss with any medical intervention is a
good indicator of long-term outcomes [62,81-83]. Recently
approved anti-obesity drugs have “stopping rules” that
are suggested by the FDA and EMA to help clinicians
identify patients that might achieve a weight reduction
>5% within 1 year.

 Stopping rules can avoid unnecessary exposure and enhance the risk–benefit ratio [27].
If <5% weight loss is achieved after 12 weeks of treatment with a full dose (<4% weight loss at 16 weeks for
liraglutide), the medication should be discontinued and
other drugs should be considered. However, it can be
difficult for practitioners to determine whether to continue the use of a given anti-obesity drug at the twelfth
week, if the full dose has not been administered. Additionally, stopping rules are based on the results of the
trials that conducted combined interventions involving
an anti-obesity drug and intensive lifestyle modifications not medication only. Thus, the decision regarding
the further continuation of a given medication should
be made according to its effectiveness at reducing
weight when diet, exercise, and behavioral modifications are adopted. Without a low-calorie diet and an
increase in physical activity, the application of a medication alone could lead to failure to achieve weight reduction of 5% even after 12 weeks of treatment

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