US Pharm. 2013;38(4):48-52.
ABSTRACT: Obesity is linked to health conditions including
diabetes, hypertension, dyslipidemia, and cancer. Chronic drug therapy
for obesity has been limited by cardiovascular (CV) and/or
gastrointestinal adverse events (AEs), but two recently approved
drugs—lorcaserin (Belviq) and phentermine and topiramate
extended-release (Qsymia)—may prove helpful for achieving weight loss in
obese patients. Lorcaserin is the first approved serotonin (5-HT)2C
receptor agonist. The phentermine and topiramate extended-release
combination is thought to work by suppressing appetite, reducing caloric
intake and energetic efficiency, and increasing energy expenditure. The
drugs’ efficacy cannot be compared directly at present, and it remains
to be seen whether these agents are associated with an increased risk of
Current National Health and Nutrition Examination Survey data on
obesity prevalence indicate that, in the period from 2009 to 2010, more
than one-third of adults and almost 17% of children and adolescents were
obese.1 The Healthy People 2010 goals of 15% obesity among
adults and 5% obesity among children were not met, and the threat of
obesity-related health conditions continues to rise.1
Obesity-related health conditions include type 2 diabetes (T2DM),
hypertension, dyslipidemia, coronary heart disease (CHD), stroke,
gallbladder disease, osteoarthritis, sleep apnea and respiratory
problems, and certain types of cancer (endometrial, breast, prostate,
FACTORS INVOLVED IN OBESITY
The pathophysiology of obesity is complex and multifactorial,
involving physiological, genetic, and behavioral components. A certain
amount of stored fat is required for survival during times of
malnutrition or starvation. However, as weight increases, excess
adipocytes release surplus free fatty acids, leading to lipotoxicity,
insulin-receptor dysfunction, and hyperglycemia. In particular, white
adipose tissue releases prefatty acids and adipokines, which are
lipotoxic and inflammatory. The diverse effects of inflammatory
adipokines include hyperglycemia, endothelial dysfunction, atheroma
formation, plaque, and thrombosis. These injurious inflammatory
secretagogues are countered by anti-inflammatory hormones such as
adiponectin, visfatin, and acylation-stimulating protein.3
The influence of another factor—the obesogenic environment—on weight has yet to be fully understood. The obesogenic environment
is “the sum of influences that the surroundings, opportunities, or
conditions of life have on promoting obesity in individuals or
populations.”4 Multiple factors, including the built
environment (physical design, land-use patterns, transportation systems)
and the food and nutrition environments (food access, advertising,
marketing), must be addressed in order to truly make progress in the
areas of obesity prevention and intervention.4
An initial recommended loss of 10% of body weight during the first 6
months of a weight-loss regimen reduces many obesity-related health
risks.2 The current (1998) obesity guidelines from the
National Institutes of Health (NIH) include an Expert Panel’s Treatment
Algorithm, which gives a step-by-step approach to managing weight loss
in obese patients. Major components of this strategy include dietary
therapy, increased physical activity, and behavior therapy. After 6
months of attempted lifestyle changes, pharmacotherapy may be considered
as an adjunct in patients with a BMI ≥30 kg/m2 and no concomitant risk factors. Pharmacotherapy also may be considered in patients with a BMI ≥27 kg/m2 and an obesity-related risk factor or disease such as hypertension, dyslipidemia, CHD, T2DM, or sleep apnea.2
An update of the NIH obesity guidelines is in development, but it is
unclear whether this resource will provide guidance on the use of the
newer agents discussed in this article.
PHARMACOTHERAPY FOR OBESITY
Prior to the recent approvals of lorcaserin (Belviq, Eisai Inc.) and
phentermine and topiramate extended-release (Qsymia, Vivus
Pharmaceuticals), the only pharmacotherapeutic agent for long-term use
was orlistat (approved in 1999). Orlistat is available both OTC (Alli)
and by prescription (Xenical), but hepatotoxicity, as well as
undesirable gastrointestinal adverse events (AEs)—oily spotting,
abdominal pain/discomfort, flatus with discharge—in patients not
following a low-fat diet, may limit use.5 Sibutramine
(Meridia) was approved in 1997, but later was removed from the U.S.
market based on concerns about cardiovascular (CV) safety raised by the
Sibutramine Cardiovascular Outcomes Trial, which demonstrated a 16%
increase in the risk of serious CV AEs. These serious AEs included
nonfatal heart attack, nonfatal stroke, need for resuscitation once the
heart stopped, and death in a group of patients given sibutramine versus
a placebo group.6 Furthermore, the removal of the
weight-loss drugs fenfluramine and dexfenfluramine in 1997 based on
evidence that they were linked to heart-valve damage serves as a
reminder that weight-loss drugs may prove efficacious, but are by no
means without risks.7
The FDA has stipulated criteria for the development of new
weight-loss medications. Clinical trials of weight-loss drugs must meet
the following 1-year benchmarks in order for the drug to be considered
effective: 1) The difference in mean weight loss between the
active-product and placebo groups is at least 5 percentage points, with a
statistically significant difference; and 2) the proportion of subjects
in the active-product group who lose 5% or more of baseline body weight
is at least 35% and approximately double the proportion in the placebo
group, with a statistically significant difference between groups.8
RECENTLY APPROVED TREATMENTS: BELVIQ AND QSYMIA
See TABLE 1 for a comparison of these agents.
Lorcaserin, the first serotonin (5-HT)2C receptor agonist,
was approved by the FDA on June 27, 2012, following an earlier
rejection based on results of a preclinical study indicating that the
drug may cause breast tumor in rats.7 Approved for chronic
weight management, lorcaserin is thought to “decrease food consumption
and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus.”9 Human 5-HT2C receptors are distributed in areas of the brain that are associated with regulation of food intake, and 5-HT2C
receptor knockout mice become hyperphagic, demonstrating partial leptin
resistance, increased adiposity, insulin resistance, and glucose
intolerance.10 The selectivity of lorcaserin for the 5-HT2C–receptor subtype is critical for obesity treatments, since activity at 5-HT2A and 5-HT2B may be associated with perceptual disturbances and valvular heart disease, respectively.11
Previously approved nonselective serotonergic agonists (fenfluramine
and dexfenfluramine) validated serotonin receptors as pharmacologic
targets for weight loss, but these agents were linked to
serotonin-associated valvulopathy thought to result from agonism of 5-HT2B receptors expressed on cardiac valvular interstitial cells.12
Lorcaserin has the potential to bind at the 5-HT2A
receptor, which has been associated with perceptual disturbances. In
preclinical data, evidence of lorcaserin binding to this receptor is not
strong, but a small proportion of patients who received
supratherapeutic doses reported altered perception, abnormal dreams,
sedation, or feelings of euphoria. Because of the novel mechanism of
action and sporadic reports of AEs possibly associated with abuse
potential, a study compared a single oral dose of lorcaserin (20, 40,
and 60 mg) with zolpidem (15 and 30 mg), ketamine (100 mg), and placebo.
This crossover study of recreational polydrug users found that
subjective effects of lorcaserin 20 mg were similar to those of placebo,
and supratherapeutic doses were associated with levels of dislike
compared with placebo, zolpidem, and ketamine.11 Although
this study demonstrated that lorcaserin does not appear to have
behavior-modifying effects or significant abuse potential, two studies
of abuse-related behavior in rats led the FDA to recommend that
lorcaserin be classified as a Schedule IV controlled substance (CIV).13
Lorcaserin is indicated for chronic weight management in conjunction
with a reduced-calorie diet and increased physical activity in patients
with either an initial BMI ≥30 kg/m2 (obese) or an initial BMI ≥27 kg/m2
(overweight) and at least one weight-related comorbid condition such as
hypertension, dyslipidemia, or T2DM. Lorcaserin is dosed at 10 mg twice
daily, and common AEs include nausea, constipation, and upper
The phentermine and topiramate extended-release combination was
approved by the FDA on July 17, 2012, almost 2 years following a
previous rejection based on concerns over the drug’s potential to cause
birth defects and the ways to mitigate these risks, as well as evidence
that the heart-rate elevation associated with the combination might
increase the risk of major CV AEs.14 The manufacturer’s
proposed name for this product was Qnexa, which was disallowed by the
FDA because of its strong similarity to other drug names.15
Phentermine and topiramate extended-release has the same indication
as lorcaserin, i.e., for patients with either an initial BMI of ≥30 kg/m2 (obese) or an initial BMI of ≥27 kg/m2
(overweight) and at least one weight-related comorbid condition (e.g.,
hypertension, dyslipidemia, or T2DM), in conjunction with a
reduced-calorie diet and increased physical activity.16
Phentermine as a single agent was previously approved as short-term (a
few weeks) adjunctive therapy to a comprehensive weight-management
program in obese patients with an initial BMI ≥30 kg/m2 or BMI ≥27 kg/m2
with the presence of other risk factors. Phentermine is believed to
suppress appetite by stimulating increased hypothalamic release of
norepinephrine, but it has no detectable impact on serotonin. Animal
studies suggest that the weight-loss effects associated with topiramate
may result from reduced caloric intake, decreased energetic efficiency,
and increased energy expenditure.17
Qsymia dosing, which requires upward titration, is initiated at 3.75
mg/23 mg daily for 14 days, then increased to 7.5 mg/46 mg daily. The
patient should be evaluated after 12 weeks of taking the 7.5-mg/46-mg
dosage. If the patient has not lost at least 3% of baseline body weight,
Qsymia should be discontinued or the dosage should be escalated to
11.25 mg/69 mg for 14 days, followed by Qsymia 15 mg/92 mg. Weight loss
should be reevaluated after an additional 12 weeks, and if the patient
has not lost at least 5% of baseline body weight, Qsymia should be
discontinued. Discontinuation should occur gradually (taking a dose
every other day for 1 week prior to stopping treatment altogether) in
order to avoid precipitating a seizure.16 The stepwise dosing
regimen for Qsymia is significantly more complex than the regimen for
Belviq, which involves simple twice-daily dosing.
Patient counseling should include the recommendation that Qsymia be
dosed in the morning to avoid insomnia. This medication is scheduled as
CIV based on the abuse potential of the phentermine component
(recreational use or unhealthy weight loss). As with all sympathomimetic
amines, it is necessary to monitor patients taking Qsymia for
hypertension and tachycardia. In addition, since a fetus exposed to
topiramate may experience teratogenic effects such as oral clefts,
Qsymia is available only through a limited program under the Risk
Evaluation and Mitigation Strategy. This program includes prescriber
training, pharmacy certification, and a patient medication guide that
details important safety information.16
Both Belviq and Qsymia were tested in placebo-controlled trials of
different designs, but they have not been evaluated in a head-to-head
clinical trial. Thus, it is not possible to directly compare the
efficacy of these two medications.
A double-blind clinical trial that led to the approval of Belviq
utilized primary outcomes of weight loss at 1 year and maintenance of
weight loss at 2 years. Results showed that 45.7% of lorcaserin patients
had lost at least 5% body weight at 1 year, compared with 20.3% of
placebo patients. Of lorcaserin patients who lost more than 5% body
weight during year 1, the loss was maintained during year 2 in 67.9%,
versus in 50.3% of placebo patients. In addition, the rate of cardiac
valvulopathy did not increase in the lorcaserin group.12
The clinical trial resulting in Qsymia approval involved men and women with class II (BMI 35-39.9 kg/m2) or class III obesity (BMI >40 kg/m2)
who took phentermine and topiramate extended-release for 56 weeks and
had primary outcomes of percentage of weight loss and proportion of
patients achieving 5% weight loss. Patients taking the combination drug
showed a dose-dependent mean change from baseline of –5.1 kg (3.75 mg/23
mg dosage) or –10.9 kg (15 mg/92 mg dosage) weight loss versus placebo
patients (–1.6 kg weight loss). In addition, 45% of patients taking 3.75
mg/23 mg and 67% of patients taking 15 mg/92 mg lost at least 5% body
weight versus 17% of placebo patients.17
The obesity pandemic is not merely a cosmetic issue, but a disease in
itself that greatly increases the risk of other serious medical
conditions, including diabetes, heart disease, and depression. The
history of market withdrawals and CV AEs of obesity drugs may make
practitioners hesitate to prescribe these drugs because of questions
about the risk-to-benefit ratio. The FDA is requiring postmarketing
studies of both new drugs, including a long-term CV-outcomes trial to
assess the risk of major cardiac AEs such as heart attack and stroke.9,16
While it is exciting that the FDA has approved new obesity drugs for
the first time in 13 years, the ultimate place of Belviq and Qsymia in
weight-loss therapy has not been determined.
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Accessed September 18, 2012.
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