Download Newer Weight Loss Medications: Worth the Weight

INDIANA PHARMACISTS ALLIANCE (IPA)
CONTINUING PHARMACY EDUCATION(CPE)
Newer Weight-Loss
Medications: Worth the
Weight?
Authors:
Nick Sciacca, PharmD
PGY2 Pharmacotherapy Resident
Community Health Network/Butler University
Tracy Costello, PharmD, BCPS
Assistant Professor of Pharmacy Practice
Butler University
Clinical Specialist, Family Medicine
Community Health Network
ACPE UAN: 0120-0000-14-010-H01-P
1.5 Contact Hours (.15 CEU’s)
This is a knowledge-based activity.
See end of article for CE details
Target Audience: Pharmacists
Faculty Disclosure: The faculty have no
conflicts of interest to disclose
Goal: The goal of this lesson is to review
phentermine/topiramate ER (Qsymia®) and
lorcaserin (Belviq®) and explore their potential
role in the pharmacologic management of
obesity.
Objectives: At the conclusion of this lesson,
successful participants should be able to:
1. Define the prevalence of obesity and
related comorbidities in the United
States.
2. Identify the limitations of the available
pharmacologic agents in treatment of
obesity.
3. Describe
the
pharmacology
of
phentermine/topiramate
ER
and
lorcaserin.
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4. Compare and contrast the evidence
leading to approval of the newer antiobesity medications.
5. Identify appropriate candidates for
pharmacologic management of obesity.
Background
Obesity is a condition of excess body
weight and is most commonly defined as a body
mass index (BMI) greater than 30 kg/m2. BMI
has become the preferred measurement to define
obesity because it is easy to measure and closely
correlates with morbidity and mortality from
obesity, though waist circumference may give
additional information on risk.1,2 Conditions
associated with obesity are numerous and
include type 2 diabetes, dyslipidemia,
hypertension, and coronary artery disease,
amongst others.2 Depending on age and race,
obesity is associated with a 6 to 20-year
decrease in life expectancy and is the second
leading cause of preventable death in the United
States.3,4
The most recent data from the Centers
for Disease Control and Prevention suggest that
more than one in every three adults (~36%) and
more than one in every six children (~17%)
were classified as obese between 2009 and
2010.5 The financial impact of obesity has
dramatically risen in recent years. In 1998, the
total annual cost of obesity in the U.S. was
estimated at $78.5 billion. By 2008, this cost
had increased to $147 billion annually. Obesity
now accounts for one dime of every dollar spent
on health care in the United States.
Additionally, obese beneficiaries, on average,
cost payers ~$1,400 more annually than nonobese beneficiaries.6
Current obesity treatment guidelines
recommend treating all patients with a BMI ≥ 30
kg/m2 or a BMI ≥ 27 kg/m2 with at least 1
weight-related comorbidity. Targeting a 10%
decrease in body weight over a 6 month period
is a reasonable goal. Initial treatment should
incorporate lifestyle modifications and utilize a
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combination of diet, exercise, and behavioral
therapy. However, success with lifestyle
changes alone can be challenging for many
reasons. These include a lack of patient
readiness for change, physical limitations that
restrict patient activity, and a lack of settings
that include the multidisciplinary environment
necessary for attainment of goals. If nonpharmacologic treatment fails to achieve weight
loss goals after 6 months, pharmacologic agents
could be considered as an adjunct to these
measures.2
In 2007, the Food and Drug
Administration (FDA) released a draft guidance
to assist drug manufacturers in developing
products for weight management.
Key
components of this guidance include
recommendations that clinical trials assessing
weight loss products demonstrate weight loss
and weight maintenance for at least one year and
that studies also assess effects on weight-related
comorbidities. Additionally, medications must
demonstrate either a mean change in baseline
body weight between placebo-treated groups of
≥ 5% or that the proportion of patients losing at
least 5% of their baseline body weight is ≥ 35%
and approximately double that of the placebo
group.7
Entering 2012, only two FDA-approved
weight loss medications were available in the
United States. Among these, orlistat (Xenical®,
Alli®), a gastrointestinal lipase inhibitor, was
the only drug approved for long-term use.8
Enthusiasm for the drug has been tempered, in
part due to its high rates of gastrointestinal
adverse effects, and in part due to its lack of
robustness in weight loss realized.9 The other
available agent, phentermine (Adipex-P®), a
sympathomimetic amine, is FDA-approved only
for short-term use; however, weight regain is
common upon discontinuation.10,11 Phentermine
was originally approved in 1959 and lacks the
long-term safety and efficacy data for weight
loss drugs as outlined by the FDA guidance for
industry.12 In 2012, the FDA approved two new
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medications for chronic weight management.
These agents represent the first new agents
approved by the FDA for the pharmacologic
management of obesity in 13 years.
Phentermine/Topiramate ER (Qsymia®)
Mechanism of action
Both components of Qsymia® are
believed to contribute to weight loss individually
and via different mechanisms of action.
Phentermine, an amphetamine derivative, is
thought to elicit its effects through release of
norepinephrine
and
dopamine
in
the
hypothalamus. This is theorized to decrease
appetite and subsequent food consumption.13 As
such, phentermine is often referred to as an
“anorectic” or “anorexigenic”.10
Topiramate, a monosaccharide derived
from fructose, has previously gained FDA
approval for seizure and migraine prevention.14
Although, topiramate’s precise mechanism of
action in weight loss is largely unknown,
decreased caloric intake appears to be a
significant factor. Its anorexic effects may be
due
to
effects
on
neurotransmission,
neurotransmitters, or inhibition of carbonic
anhydrase.15 Since observed weight loss cannot
fully be explained by the decrease in caloric
intake, other mechanisms such as decreased
energy efficiency and increased energy
expenditure have been proposed, though these
mechanisms have not yet been definitively
demonstrated in humans.16,17
Since multiple biochemical pathways
are implicated in food intake, satiety, and energy
homeostasis, it is thought that combining
multiple medications that target different
pathways
may
overcome
compensatory
mechanisms
that
could
evolve
with
monotherapy.18,19 Indeed, with the combination
of phentermine and topiramate, weight loss
appears to be additive, but not synergistic.20
Combining these two medications in such a way
allows for lower dosages of individual
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components to be utilized, thus lowering the
potential for adverse effects while maximizing
efficacy. This approach of combining multiple
drugs for weight loss is being utilized by many
new drugs in the pipeline.21
Evidence of efficacy
Weight Loss
Most of the efficacy data behind
phentermine/topiramate
ER
(PHEN/TPM)
comes from two separate, 56-week, Phase III
studies as well as a 1-year Phase III extension
study.17,22,23 In the first Phase III study, Effects
of Low-Dose Controlled Release, Phentermine
Plus Topiramate Combination on Weight and
Associated Comorbidities in Overweight and
Obese Adults (CONQUER), subjects were
randomized to placebo, PHEN/TPM 7.5/46 mg,
or PHEN/TPM 15/92 mg. All participants
received concomitant standardized lifestyle
counseling. Subjects in the PHEN/TPM groups
were titrated to target dose by weekly increases
of 3.75/23 mg over the initial 4 weeks.22
Interventions were nearly identical in the other
Phase
III
trial,
Controlled-Release
Phentermine/Topiramate in Severely Obese
Adults: A Randomized Controlled Trial
(EQUIP), except that patients in the low-dose
PHEN/TPM group stopped titration at the
3.75/23 mg dose instead of continuing to the
7.5/46 mg dose.17 Both studies were conducted
in patients aged 18-70 but differed slightly in
inclusion and exclusion criteria.17,22
CONQUER included subjects with a
BMI 27 – 45 kg/m2 (or any BMI with type 2
diabetes) with two or more of the following
obesity-related
comorbidities:
Stage
I
hypertension or on ≤ 2 antihypertensive
medications, triglycerides 200 – 400 mg/dL or
on ≤ 2 lipid-lowering drugs, pre-diabetes, type 2
diabetes mellitus (DM) managed with metformin
monotherapy or diet, or a waist circumference of
≥ 108 cm in men or ≥ 88 cm in women. Key
exclusion criteria included those with Stage II
hypertension and Type I DM.22 EQUIP differed
in that it included only severely obese patients
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(BMI ≥ 35 kg/m2 with no upper limit).
Additionally, EQUIP required that subjects with
comorbid hypertension be controlled (≤140/90
mmHg) on ≤ 1 antihypertensive, comorbid
hypertriglyceridemia controlled (≤ TG 200
mg/dL) on ≤ 2 lipid-lowering agents, and
subjects must demonstrate a fasting blood
glucose of ≤ 110 mg/dL.17 Key patients excluded
from both studies included those with unstable
angina, heart failure, known valvular heart
disease, thyroid disorder, or current depressive
symptoms of moderate or greater severity.
Patients suffering from a recent (within 6
months) stroke, myocardial infarction, or
coronary revascularization procedure were also
excluded. Lastly, those with a history of bariatric
surgery, kidney stones, glaucoma, bipolar
disorder, psychosis, major recurrent depression,
or suicidal behavior with ideation or intent to act
were not allowed to participate.17,22
CONQUER defined two primary
endpoints, mean percentage of body weight lost
and percentage of patients achieving at least a
5% decrease in baseline body weight. Both
doses of PHEN/TPM demonstrated efficacy over
placebo for each primary endpoint (Table 1).
EQUIP had similar primary endpoints, but also
looked at patients losing 10% and 15% of
baseline body weight. Again, both PHEN/TPM
groups lost significantly more weight than
subjects randomized to placebo (Table 1).
Subjects in the 15/92 mg group also
demonstrated significantly more weight loss
than those in the 3.75/23 mg group.
Additionally, in the 15/92 mg group, roughly
one-third of patients achieved a weight loss of ≥
15 % of baseline.22
The Two-year Sustained Weight Loss
and Metabolic Benefits with Controlled-Release
Phentermine/Topiramate
in
Obese
and
Overweight Adults (SEQUEL) was a 52-week
extension study of CONQUER in those whose
BMIs remained at least 22 kg/m2 at study
conclusion. Participants from eligible study sites
continued treatment as originally assigned
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(placebo,
PHEN/TPM
7.5/46
mg,
or
PHEN/TPM 15/92 mg) along with ongoing
lifestyle modifications. Subjects on either
PHEN/TPM dose showed significantly greater
percentage of weight lost than did subjects in the
placebo group. Additionally, greater proportions
of subjects in these groups lost ≥5% and ≥10%
when compared to placebo (Table 1). While
both doses of PHEN/TPM showed similar
effectiveness at lower BMI categories, the 15/92
mg group showed a statistically greater
percentage of weight loss compared to the
7.5/46 mg group in the most severely obese
patients (BMI 40 – 45 kg/m2).23
Secondary Endpoints
In addition to weight loss outcomes, the
Phase III studies investigated a variety of
secondary markers of cardiovascular risk. While
reductions in blood pressure were inconsistent
and did not reach statistical significance in all
PHEN/TPM groups in every study, results are
confounded by more patients in the PHEN/TPM
groups having antihypertensive medications
removed during the study period. Most subjects
treated with PHEN/TPM at treatment doses also
demonstrated significant improvements in
triglycerides (TG).
While high-density
lipoproteins (HDL) significantly improved
compared to placebo in both PHEN/TPM groups
compared to placebo in CONQUER, this
difference was only seen in the 15/92 mg groups
in the other studies. Of note, no significant
improvements were demonstrated in low-density
lipoprotein (LDL) in any PHEN/TPM group
with the exception of the 15/92 mg group in
EQUIP. Data on lipid parameters may also be
confounded by concomitant changes in lipidlowering medications. In CONQUER, treatment
with both doses of PHEN/TPM lowered HgA1c
more (-0.3%) than placebo; however, these
differences were not maintained in the extension
study.17,22,23
Safety
Adverse effects seen in greater than 5%
of study populations and more common than
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placebo are listed in Table 2. Adverse events
most commonly related to discontinuation of
PHEN/TPM in clinical trials were blurred
vision,
headache,
irritability,
dizziness,
paraesthesia,
insomnia,
depression,
and
anxiety.15
PHEN/TPM is contraindicated in
pregnancy (category X) due to the risk of oral
clefts in infants exposed to the topiramate
component during the first trimester of
pregnancy.15 This risk was thoroughly evaluated
and estimates suggest the risk of oral clefts to be
increased approximately 2-fold to 5-fold.24 Due
to this risk, all females should have a negative
pregnancy test prior to treatment and monthly
thereafter, though this is not a requirement for
the pharmacy to dispense the prescription.
Additionally, females should utilize effective
contraception during treatment. If females
become pregnant during treatment, the drug
must
be
discontinued
immediately.
Additionally, nursing mothers should not use
PHEN/TPM because both components may
present in breast milk.15 Of note, 34 pregnancies
occurred during the drug development program,
of the 19 pregnancies that were carried to fullterm, there were no major birth defects.24
Additional contraindications include glaucoma,
hyperthyroidism, or treatment with monoamine
oxidase inhibitors within the previous 14 days.15
Because the drug can cause an increase
in resting heart rate (HR), it should be used with
caution in patients with cardiovascular or
cerebrovascular disease. Heart rate should be
monitored in all patients and the drug should be
discontinued or the dosage reduced if patients
report sustained palpitations or racing
heartbeat.15 Although PHEN/TPM appears to
increase HR (0.6 – 1.6 bpm), it also appears to
lower blood pressure (systolic BP reductions of
~3 mmHg and diastolic BP reductions of ~1
mmHg). The rate-pressure product (heart rate x
systolic blood pressure), a measure believed to
represent myocardial oxygen demand, has not
been shown to differ compared to placebo. From
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the current available evidence of Phase II and III
trials, pooled rates of major adverse
cardiovascular events (MACE) do not appear to
differ between PHEN/TPM treated individuals
and placebo (RR 0.49, 95% CI 0.19-1.25).24
Other warnings and precautions of note include:
increased risk of suicidal thoughts or behavior
(discontinue if these develop), secondary angle
closure glaucoma, sleep and mood disorders,
cognitive impairment, metabolic acidosis,
elevations in serum creatinine, risk of kidney
stone formation, and hypokalemia.
FDA Approval
In July 2010, an FDA advisory panel
voted 10 to 6 against approval of PHEN/TPM
(at that time named Qnexa®) due to safety
concerns; specifically, the increased risk of oral
clefts in newborns, the elevations in heart rate,
and the lack of an adequate risk evaluation and
mitigation strategy (REMS).24 In February
2012, the FDA convened another advisory panel
to review new information from the
manufacturer. This time, however, the panel
voted 20 to 2 in favor of approving the drug. In
July 2012, the drug was officially approved by
the FDA. Along with reduced caloric intake and
increased
physical
activity,
Qsymia®
(PHEN/TPM) is indicated for weight loss in
adults with a BMI ≥ 30 kg/m2 or a BMI ≥ 27
kg/m2 with at least one weight-related
comorbidity.15 This approval was conditional,
however, on the post-approval conduction of a
controlled clinical trial investigating the drug’s
effect on major adverse cardiovascular events
(MACE).24
Phentermine/topiramate ER is classified
as a C-IV controlled substance. It should be
taken once daily in the morning to decrease the
risk of insomnia. All patients start therapy on
the lowest dose (3.75/23 mg) for 2 weeks,
followed by the 7.5/46 mg dose. This is the
maximum dosage for patients with moderate
renal (CrCl < 50 ml/min) or hepatic (Child-Pugh
score 7-9) impairment. Of note, the package
insert indicates that Cockcroft-Gault cut-offs
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were calculated using actual body weight, which
could be significantly different than the
traditional calculation in the obese population.
If the patient has not achieved at least a 3%
reduction in baseline body weight after 3 months
on this dose, the drug should either be
discontinued or the dosage increased. If the
dosage is increased, patients spend another 14
days at the 11.25 mg/69 mg dose before titrating
to the maximum dosage of 15 mg/92 mg once
daily. If the patient has not lost at least 5% of
baseline body weight after 3 months on the
maximal dose, the drug must be discontinued.
At this dosage, however, the manufacturer
recommends tapering the drug over at least a
one week span by giving one dose every other
day to prevent seizures (Figure 1).15
REMS
The FDA has required PHEN/TPM to
have a REMS in order to inform healthcare
providers and females of reproductive potential
about the teratogenicity associated with the
medication. Components of the REMS include
training for healthcare providers who prescribe
the drug, a requirement for patients to receive a
Medication Guide and a Risk of Birth Defects
with Qysmia® brochure with each drug
dispensing, and a limitation on drug availability
to “certified” pharmacies. Certified pharmacies
are prohibited from redistributing or reselling
Qysmia® to other pharmacies. Additionally, all
Qsymia® claims are required to be transmitted
through the Qsymia REMS program database.
If denied through this program, the drug cannot
be dispensed, regardless of payment method.25
Although originally only available via certain
mail-order pharmacies, the drug manufacturer
expects the drug to be available in retail
pharmacies by mid-July 2013.26
Lorcaserin (Belviq®)
Mechanism of Action
Serotonin (5-hydroxytyptamine, 5-HT)
and its related receptors have long been studied
as potential therapeutic targets for obesity.27
Enhancing the central nervous system release of
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5-HT is thought to reduce caloric intake as well
as change behaviors related to eating such as
decreased cravings for complex sugars. Weight
loss medications of the past, sibutramine,
fenfluramine, and dexfenfluramine, were
designed to target 5-HT receptors. Sibutramine
acts by inhibiting the reuptake of serotonin and
norepinephrine in the central nervous system.
Sibutramine demonstrated weight loss effects
through increased satiety and metabolism.
Unfortunately, the use of sibutramine is limited
due to toxic effects on blood pressure and
cardiovascular health, which ultimately lead to
its removal from the US, Australian, and other
markets in 2010.28, 29, 30
In comparison
fenfluramine and dexfenfluramine inhibit
serotonin reuptake and increase serotonin release
through activation of all 5-HT receptor subtypes.
Although these two medications are effective
treatment options for obesity, the non-selectivity
for 5-HT receptors leads to unwanted effects
outside the central nervous system.30 Activation
of 5-HT2B receptors by fenfluramine and
dexfenfluramine are associated with increased
risk of developing valvular heart disease and
pulmonary hypertension.27,30
These adverse
events ultimately resulted in withdrawal of
fenfluramine and dexfenfluramine from the US
market in 1997.30
Lorcaserin first demonstrated efficacy in
a 12-week phase II clinical trial of patients aged
18 to 65 with a BMI of 30 – 45 kg/m2. Patients
in the study were randomized to receive placebo,
lorcaserin 10 mg daily, lorcaserin 15 mg daily,
or lorcaserin 10 mg twice daily (BID). Patients
were excluded from the study if they had
diabetes, bariatric surgery, recent significant diet
or exercise changes, clinical significant
abnormal echocardiogram, or previous use of
fenfluramine or dexfenfluramine. Patients were
instructed to continue usual diet and exercise
habits but refrain from smoking tobacco or
drinking alcohol during the study period. The
primary end point was the change in body
weight from baseline to day 85 compared with
placebo. All dose variations of lorcaserin
demonstrated statistically significant weight loss
when compared to placebo. Additionally, the
proportion of patients who lost ≥ 5% body
weight was statistically significant in all 3
treatment arms compared to placebo (Table 3).
In this phase II trial, lorcaserin demonstrated a
dose-dependent decrease in weight with 10 mg
BID showing the largest average weight loss.
Although not all patients lost weight during the
study period, 90% of patients in the 15 mg daily
and 10 mg BID groups did demonstrate weight
loss.32
Lorcaserin is designed as a selective 5HT2C receptor agonist. Activation of the 5-HT2C
receptor, found primarily in the central nervous
system, has been associated with regulation of
energy homeostasis by decreasing food intake
and promoting satiety.31 In human subjects,
lorcaserin was found to have an 18-fold and
104-fold higher selectivity for 5-HT2c over 5HT2A and 5-HT2B respectively.27 The high
selectivity is vital to reduce potential side effects
caused by activation of the other 5-HT2
receptors subtypes, for example hallucinations,
valvular heart disease, and pulmonary
hypertension. 27,28,30
Based on the result of this phase II trial,
lorcaserin 10 mg BID was the most common
dose studied in long-term phase III trials.
Behavioral Modification and Lorcaserin for
Overweight
and
Obesity
Management
(BLOOM) was a double-blinded, placebocontrolled trial that evaluated the efficacy of
lorcaserin 10 mg BID on weight loss and the
maintenance of weight lost during one year of
treatment.
In addition to receiving either
placebo or lorcaserin, all patients received
standardized nutritional and exercise counseling
at each follow-up visit. Patients included in
BLOOM were 18 to 65 years of age and had a
BMI of 30 – 45 kg/m2 or a BMI of 27 – 45 kg/m2
with at least one of the following risk factors:
hypertension, dyslipidemia, cardiovascular
Evidence for efficacy
Weight loss
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disease, impaired glucose tolerance, or sleep
apnea. Exclusion criteria of note were patients
with diabetes, uncontrolled hypertension, or
major psychiatric disease. At the conclusion of
the 1 year study period, patients receiving
lorcaserin lost significantly more weight and
more patients lost ≥ 5% of their baseline body
weight compared to the placebo group (Table 3).
BLOOM was extended for an additional year for
patients who lost ≥ 5% of their baseline weight
in the first year. Patients were randomized to
either continue lorcaserin 10 mg BID or
switched to placebo. At the conclusion of year
2, the patients who continued to receive
lorcaserin rather than being switched to placebo
more often maintained the weight loss (67.9% vs
50.3%, p<0.001).33
A One-Year Randomized Trial of
Lorcaserin for the Weight Loss in Obese and
Overweight Adults (BLOSSOM) was published
the following year. The patients included and
excluded in BLOSSOM closely resembled those
of BLOOM and patients enrolled in the trial
were provided nutritional and exercise
counseling throughout the study period. In
contrast, BLOSSOM evaluated both lorcaserin
10 mg BID and lorcaserin 10 mg daily compared
to placebo. At the end of one year, significantly
more patients taking lorcaserin lost ≥ 5% of their
baseline body weight compared to patients
taking placebo (Table 3). Additionally, a dosedependent effect with lorcaserin was seen as
patients taking lorcaserin BID had significantly
greater weight loss compared to lorcaserin once
daily (p<0.01).34
The BLOSSOM trial
reconfirmed the effectiveness of lorcaserin with
long term use.
Although BLOOM and BLOSSOM
illustrated significant weight loss in obese and
overweight patients, neither of these trials nor
any previous phase II trials included patients
with DM.33,34
To bridge this gap, the
Randomized Placebo-Controlled Clinical Trial
of Lorcaserin for Weight Loss in Type 2
Diabetes
Mellitus
(BLOOM-DM)
was
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completed.
This one year trial compared
lorcaserin 10 mg BID and lorcaserin 10 mg daily
to placebo with primary end points of the
proportion of patients achieving ≥ 5% weight
loss from baseline, overall change in weight, and
the proportion of patients achieving ≥ 10%
weight loss from baseline. Patients aged 18 – 65
years with type 2 DM treated with metformin, a
sulfonylurea, or both; HbA1c of 7 to 10% at
baseline; and BMI of 27 – 45 kg/m2 were
eligible for inclusion. Key exclusion criteria
were use of insulin, prior bariatric surgery,
significant changes in weight or cigarette
smoking in the previous 3 months, depression or
other major psychiatric disease, malignancy
within 5 years, and pregnancy or lactation. In
this population of patients with type 2 diabetes
at the end of 1 year, lorcaserin significantly
illustrated a greater proportion of patients
achieving ≥ 5% and ≥ 10% weight loss
compared to placebo. In contrast to BLOOM
and BLOSSOM, there was not a dose-dependent
effect on weight loss seen between the 10 mg
daily and 10 mg BID doses (Table 3).35
Secondary Endpoints
In addition to weight loss outcomes, the
phase III clinical trials looked at a variety of
secondary endpoints related to cardiovascular
risk. Changes in total cholesterol (TC), lowdensity lipoprotein (LDL),
high-density
lipoprotein (HDL), and triglycerides (TGs) were
not consistent among the trials.33-35 Changes to
TC and LDL were only statistically significant
in BLOOM.33
BLOOM, BLOSSOM, and
BLOOM-DM all showed statistically significant
decreases in TGs and statistically significant
increases in HDL with a max decrease of 6
mg/dL in TGs and max increase in HDL of 5.2
mg/dL.33-35 Additionally, minor decreases in
systolic blood pressure and diastolic blood
pressure were seen in the phase III clinical trials
but with minimal or no statistical significance.
A drop in heart rate of 2 beats per minute on
average was statistically significant in BLOOM
and BLOOM-DM.33,35 Unfortunately due to the
minor changes in the cardiovascular endpoints
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and
no
specific
objective
measuring
cardiovascular events, clinical significance for
all these values could be debated.
As the focus of BLOOM-DM was
patients with diabetes mellitus, the change in
glycemic control, including changes in HbA1c
and fasting blood sugar, was an important
secondary end point for this trial. Patients
taking lorcaserin had statically significant
decreases in HbA1c and fasting blood glucose
compared to placebo after 1 year. Not all
patients reached their goals but a larger
proportion of patients reached an HbA1c goal of
≤ 7% when taking lorcaserin over placebo
(Table 4).35
Safety
Adverse effects seen in greater than 5%
of study populations are listed in Table 5.31
BLOOM-DM also reported up to 10% of
patients with diabetes mellitus experienced
symptomatic hypoglycemia.35
Due to previous safety concerns for
valvular heart disease and psychiatric disorders
with fenfluramine and dexfenfluramine, clinical
trials involving lorcaserin looked for these
adverse effects as secondary safety endpoints.
Although the incidence of these side effects was
low in clinical trials and not statistically
different from placebo groups, they are included
in the package insert for lorcaserin under the
warnings and precautions section.31,33-35 Routine
screening with an echocardiogram to assess
development of valvular heart disease is not
recommended unless the patient develops
dyspnea, edema, congestive heart failure, or new
heart murmur.31 Psychiatric concerns with the
use of lorcaserin have only been observed in
patients taking more than the recommended
daily dose of 10 mg twice daily. Patients who
experience worsening depression or suicidal
thoughts or behaviors should discontinue taking
lorcaserin.31
Additional warnings and
precautions to note include risk of serotonin
syndrome, cognitive impairment, priapism,
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decreased heart rate, and risk of hypoglycemia.31
Lorcaserin should be taken cautiously with other
serotonin-active drugs such as selective
serotonin
reuptake
inhibitors,
tricyclic
antidepressants, and monoamine oxidase
inhibitors. Also, patients should be cautious
when operating hazardous machinery or driving
an automobile until they are certain how
lorcaserin will affect them.31 Lorcaserin has not
been studied in patients taking insulin to control
diabetes mellitus and providers should be aware
that medication adjustments may be needed in
patients taking anti-diabetic medications.31
Lorcaserin is listed as a pregnancy
category X because weight loss has no benefit
during pregnancy and may result in fetal harm.31
No human studies were conducted in pregnant
women taking lorcaserin. Additionally, there is
no clinical data about the excretion of lorcaserin
in breast milk; therefore, it is not recommended
in nursing mothers at this time.31
FDA Approval
At the time of this publication,
lorcaserin is not yet available in the U.S. In
2010, lorcaserin was initially denied approval by
the FDA due to lack of sufficient data on safety
concerns in regards to tumor growth in animals
and a request for additional efficacy data in the
diabetic population.
In June 2012, with
additional material from the manufacturer, the
FDA approved lorcaserin 10 mg by mouth twice
daily for chronic weight management in adult
patients with a BMI ≥ 30 kg/m2 or with a BMI ≥
27 kg/m2 and at least one weight-related comorbid condition along with a reduced-calorie
diet and increased physical activity.36 Due to
concerns with abuse potential of lorcaserin, the
FDA recommended that lorcaserin be classified
as a controlled substance.
The Drug
Enforcement Agency has recommended
lorcaserin be classified as a schedule IV.37
Lorcaserin is expected to be available once
controlled substance scheduling is finalized.
Cost data is not currently available for
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INDIANA PHARMACISTS ALLIANCE (IPA)
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lorcaserin. No current REMS is recommended
for lorcaserin at the time of FDA-approval.
Overview of Literature Limitations
Overall, clinical trials of both agents can
be criticized for high dropout rates (~50%) and
lack of gender (~70% female) and racial (~80%
Caucasian) diversity. While PHEN/TPM was
studied concomitantly with serotonergic drugs,
lorcaserin was not – potentially eliminating
another important patient subpopulation.
Although weight loss cannot directly be
compared across clinical trials, in general,
PHEN/TPM was associated with a more
“clinically relevant” loss of weight compared to
lorcaserin. Compliance to these medications can
also be challenging. Despite lorcaserin being
dosed twice daily, it does not require patients to
follow a complex dosage titration schedule. All
trials included a relatively “healthy” obese
population, including only those with controlled
obesity-related comorbidities. Although study
results have been reported in up to two years,
long-term safety and efficacy data is still
lacking. Lastly, neither agent has shown a
reduction in cardiovascular events. Therefore,
until clinical trials examine this endpoint, weight
loss achieved from lorcaserin and PHEN/TPM
should be viewed as cosmetic only.
Conclusion
Prior to 2012, the only FDA-approved
pharmacologic treatment options for weight loss
were orlistat and phentermine. Unfortunately,
side effects and weight gain upon
discontinuation limit the utility of these
medications. With the approval of PHEN/TPM
and lorcaserin, providers have an expanded
armamentarium of drug options to help patients
combat the epidemic of obesity. Although both
agents have shown weight reduction in clinical
trials, to derive maximum benefit, diet and
exercise must be part of the standard of care.
Patients who are obese or overweight with at
least 1 weight-related comorbidity have the
potential to see the most benefit from the new
weight loss medications. However, caution
2014
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1
should be exercised when considering these
agents as both drugs lack long-term safety and
efficacy data. Additionally, no FDA-approved
weight loss drug (new or old) has ever shown a
decrease in cardiovascular death or an increase
in overall survival.
The Pharmacists Education Foundation
(PEF) is accredited by the Accreditation Council
for Pharmacy Education (ACPE) as a provider of
continuing pharmacy education. To receive
continuing pharmacy education (CPE) credit,
pharmacists MUST COMPLETE AN ONLINE
QUIZ AND EVALUATION FORM. A score of 70%
or above is required to receive CPE credit. The
link to the quiz can be accessed from the
MEMBERS page of the IPA website at
www.indianapharmacists.org. This is a free
service to IPA members in 2014. Initial release
date: 3/21/14. Expiration Date: 3/21/17
Questions: Call IPA at (317) 634-4968.
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Table 1: Primary evidence of weight loss with PHEN/TPM17,22,23
Study
Study Arms
Study
Duration
Average
weight change
from baseline
Proportion
of patients
achieving
≥5% weight
loss
21%
62%
70%
-1.2% (-1.4 kg)
CONQUER Placebo (n=994)
PHEN/TPM 7.5/46 mg
-7.8% (-8.1 kg)
(n=498)
-9.8% (-10.2
1 year
PHEN/TPM 15/92 mg
kg)
(n=995)
Placebo (n=514)
-1.55% (-1.8kg)
17.3%
EQUIP
PHEN/TPM 3.75/23 mg
-5.10% (-6.0
44.9%
(n=241)
kg)
66.7%#
1 year
PHEN/TPM 15/92 mg
-10.92% ((n=512)
12.6kg)#
Placebo (n=227)
-1.8% (-2.1 kg)
30%
SEQUEL
1 year
PHEN/TPM 7.5/46 mg
-9.3% (-9.6 kg)
75.2%
extension
(n=153)
-10.5% (79.3%
of
PHEN/TPM 15/92 mg
10.9kg)
CONQUER
(n=295)
*All comparisons to placebo are statistically significant (p < 0.0001)
#
Statistically significant difference compared to PHEN/TPM 3.75/23 mg (p < 0.0001)
Proportion of
patients
achieving ≥
10% weight
loss
7%
37%
48%
7.4%
18.8%
47.2%#
11.5%
50.3%
53.9%
Table 215
Adverse effects observed in ≥ 5% patients taking PHEN/TPM
(and more common than in placebo groups)
Constipation*
Paraesthesia*
Dry mouth*
Dysgeusia*
Dizziness*
Insomnia*
Diarrhea
Sinusitis
Nausea
Bronchitis
Fatigue
Back pain
Influenza
Urinary tract infection
Headache
Blurred vision
Upper respiratory tract infection
Nasopharyngitis
*Incidence at least 1.5x that of placebo
Table 3: Primary weight loss evidence for lorcaserin32-35
Average
Study
Study
Study Arms
weight
Duration
change from
Proportion of
patients
achieving
Proportion of
patients
achieving ≥
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baseline
Smith SR,
et al.
Placebo (n=118)
Lorcaserin 10 mg daily
(n=117)
Lorcaserin 15 mg daily
(n=118)
Lorcaserin 10 mg BID
(n=116)
Placebo (n=1499)
Lorcaserin 10 mg BID
(n=1538)
12 weeks
-0.3 kg
-1.8 kg
-2.6 kg
-3.6 kg
-2.16% (-2.2
kg)
-5.81% (-5.8
kg)
-2.8% (-2.9
BLOSSOM Placebo (n= 1541)
Lorcaserin 10 mg daily
kg)
(n=771)
-4.7% (-4.7
1 year
Lorcaserin 10 mg BID
kg)
(n=1561)
-5.8% (-5.8
kg)
-1.5% (-1.6
BLOOM- Placebo (n=248)
Lorcaserin 10 mg daily
kg)
DM
(n=95)
-5% (-5 kg)
1 year
Lorcaserin 10 mg BID
-4.5% (-4.7
(n=251)
kg)
*All comparisons to placebo are statistically significant (p < 0.001)
#
p = 0.015 compared to placebo
BLOOM
1 year +
extra
year
extension
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≥5% weight
loss
2.3%
12.8%#
31.2%
31.2%
10% weight
loss
20.3%
47.5%
7.7%
22.6%
25%
40.2%
47.2%
9.7%
17.4%
22.6%
16.1%
44.7%
37.5%
4.4%
18.1%
16.3%
N/A
Table 4: Change in glycemic control in patients with diabetes taking lorcaserin35
Placebo
Lorcaserin 10 mg
Lorcaserin 10 mg
BID
daily
HbA1c, average at 1 year
8%
8.1%
8.1%
HbA1c, change from baseline
-0.4%
-0.9% (p<0.001)
-1% (p<0.001)
Fasting blood glucose, average at 1 year
160 mg/dL 163.6 mg/dL
157.8 mg/dL
Fasting blood glucose, change from -11.9
-27.4 mg/dL
-28.4 mg/dL
baseline
mg/dL
(p<0.001)
(p<0.015)
HbA1c ≤ 7%, %
26.3%
50.4% (p<0.001)
52.2% (p<0.001)
*All p-values are related to comparisons to placebo
Table 531
Adverse effects observed in ≥ 5% patients taking lorcaserin
Nausea
Upper respiratory tract infections
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Constipation
Dry Mouth
Vomiting
Fatigue
Diarrhea
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Nasopharyngitis
Urinary tract infections
Back pain
Headache
Dizziness
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Figure 1: Dose titration schedule for PHEN/TPM15
PHEN/TPM
3.75/23 mg
daily
14 days
PHEN/TPM
7.5/46 mg
daily
3 months
3% of baseline
weight lost?
Yes
Continue
PHEN/TPM
7.5/46 mg daily
No
Titrate Off
Medication
No
5% of baseline
weight lost?
Yes
Continue
PHEN/TPM
15/92 mg daily
Yes
Discontinue
Medication
No
3 months
PHEN/TPM
15/92 mg
daily
CrCl < 50Yes
mL/min
or Child-Pugh 7-9?
14 days
PHEN/TPM
11.25/69 mg
daily
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