Fixed-dose combination of phentermine

Drug Profile
Fixed-dose combination of
phentermine–topiramate for
the treatment of obesity
Expert Rev. Clin. Pharmacol. 6(3), 235–241 (2013)
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Keywords: diabetes mellitus • phentermine • obesity • topiramate • weight loss
The dramatic rising numbers in the prevalence
of obesity in the Western world in the last four
decades [101] have unfortunately not been followed by a concomitant increase in the development and marketing of drugs for its treatment.
On the other hand, the study and knowledge of
obesity has grown considerably, and it is now
fully recognized that it poses by itself significant risks for general human health [1,2] . The
obesity epidemic is accompanied by a significant increase in several comorbidities: Type 2
diabetes mellitus, hypertension and obstructive
sleep apnea, conditions well-known to be associated with the development of cardiovascular
disease, the leading cause of death in many
developed and developing countries [1–3] . It is
also recognized as an important risk factor for a
large number of cancers, another leading cause
of mortality worldwide [4] .
Since the approval of orlistat back in 1999,
the US FDA passed 13 years without approving new drugs for the treatment of obesity. In
addition, it withdrew sibutramine, the most
studied antiobesity drug to date, from the
market in 2010 owing to cardiovascular safety
concerns raised by adverse outcomes observed
in the SCOUT trial, which enrolled only highrisk patients [5] . Fortunately, in 2012, two new
drugs were approved in the interval of less than
1 month and, although not problem solving, it
brings great hope for health improvement in this
huge population of patients, since it is clear that
lifestyle changes alone, in general, only promote
discrete and nonsustained weight loss [6,7] .
A
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Obesity & Metabolic Syndrome
Unit, Division of Endocrinology &
Metabolism, Hospital das Clínicas,
University of São Paulo Medical School,
São Paulo, Brazil
*Author for correspondence:
[email protected]
The aim of this article is to focus on the fixed-dose combination of phentermine and topiramate,
a new antiobesity drug recently approved by the US FDA. The mechanisms of weight loss for
each drug in monotherapy is described, followed by the rationale for its use as a combination
therapy and a comprehensive review of recently published clinical trials that assessed its efficacy and safety.
rP
Bruno Halpern*,
André M Faria and
Alfredo Halpern
www.expert-reviews.com
10.1586/ECP.13.13
These two drugs are lorcaserin [8] , a selective serotonin 2C receptor agonist without the
severe cardiac adverse effects observed with the
banned drug fenfluramine, and the combination of phentermine–topiramate [9] , two medications already marketed in isolation in the USA
but that have not been studied in combination
before. This review will begin on the history and
rational for the use of combination of drugs for
the treatment of obesity and then focus specifically on the combination of phentermine–
topiramate (P–T), with its proposed mechanism
of action and a discussion of published results of
preclinical and clinical trials.
History of combination drugs & the
rational for their use
The prescription of combination drugs is routine
clinical practice in the treatment of many other
major chronic diseases such as hyper­tension,
Type 2 diabetes and asthma, and many specialists recognize it as a fairly acceptable treatment for obesity as well. The authors’ group
have recently reviewed possible advantages and
disadvantages of combination therapy for the
treatment of obesity [10] . Due to synergic and/or
additive effects, combination drugs could have
increased therapeutic efficacy and overlapping
compensatory mechanisms that lead to weight
loss plateau and potentially minimize side effects
by the use of lower doses of both medications.
Possible disadvantages include higher costs, hazardous drug interactions and dosage inflexibility
(when the combination is in the same pill).
© 2013 Expert Reviews Ltd
ISSN 1751-2433
235
Halpern, Faria & Halpern
of
4.2 kg (8.1 vs 3.9 kg) and a placebo-subtracted waist circumference
reduction of 5.1 cm (7.2 vs 2.1 cm). In total, 96% of the subjects lost
more than 5% of their initial weight and 63% lost more than 10%,
a highly impressive result. The most common adverse effects are dry
mouth and insomnia, the severity of which typically decreases with
time. Although often perceived as a drug that causes sympathetic
activation owing to its resemblance to amphetamine, in this trial
there were no significant differences in systolic and diastolic blood
pressures between the groups [22] . Data show that increases in blood
pressure and heart rate are uncommon in practice. A study at a
private weight management practice found that there is no median
blood pressure or heart rate increase with phentermine and that the
weight loss observed during the phentermine treatment is actually
associated with favorable shifts in categorical blood pressure and
can even retard progression to hypertension in an at-risk population [23] . The FDA, however, does not recommend phentermine
for people with underlying cardiovascular disease, although, as
mentioned, there are no data suggesting that the drug is harmful
in this subpopulation.
Unlike many physicians’ beliefs, despite its chemical
­resemblance to amphetamine, there is limited dependence liability with this ­medication (FDA Drug Enforcement Administration
­schedule IV) [104] . In current clinical practice in the USA, any use
of phentermine for longer than 12 weeks is considered an off-label
use, although it is widely prescribed for longer periods [21] . The
drug is unavailable in several countries, such as Brazil and some
countries in Europe.
Topiramate, a monosaccharide d-fructose derivative, is an antiepileptic and migraine prophylaxis drug that commonly results in
weight loss [24] . Its mechanisms of action are not fully understood
and are very complex, involving many pathways. It has GABAergic
activity via chloride channels, antagonizes NMDA-glutamate
receptor, blocks voltage-dependant sodium channels and also
weakly antagonizes carbonic anhydrase iso­enzymes subtypes II
and IV [20,24] . The exact mechanisms by which all these actions
promote weight loss are speculative, but clinically it has been
shown to have a great impact in reducing binge-eating episodes
and cravings, eating behaviors that affect a substantial percentage of obese individuals [25] . More recently, it has been proposed
that topiramate exerts its effects on weight by improving hypothalamic leptin and insulin signaling and action [26] . The same study
found an increase in anorexigenic peptides and improved energy
metabolism in peripheral tissues due to AMPK signaling in rodents
receiving topiramate.
A large number of placebo-randomized trials have evaluated the
efficacy and safety of topiramate as a long-term weightloss drug. A
recent meta-analysis of ten randomized trials confirmed a significant
placebo-subtracted weight loss of 5.34 kg and a sixfold increased
chance of significant weight loss (5% or 10%), although dosages
varied considerably [27] . The largest study, conducted over 60 weeks,
used dosages of 96, 192 and 256 mg, with a mean percentage weight
loss of 7.1, 9.1 and 9.7%, respectively (vs 1.7% in the placebo group)
[28] . Other advantages of topiramate include the lack of a weight plateau during the first 6-months of treatment and a favorable metabolic
profile, with reductions in insulin resistance, glucose intolerance
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During the early 1990s, the combination of phentermine and
fenfluramine was widely used in the USA, with increased efficacy
when compared with either drug in monotherapy [11] . However, as
already mentioned, fenfluramine was withdrawn from the market
in 1997 owing to an increased incidence of valvulopathy and pulmonary hypertension [12] . One postulated mechanism, although
not entirely proven, was that fenfluramine-stimulated serotonin
release associated with phentermine’s serotonin uptake inhibition
in erythrocytes and in the lung, leading to excessive circulating
serotonin levels and consequent valvulopathy, similar to what
happens in carcinoid syndrome.
Afterward, few combinations were studied in randomized
placebo-controlled trials until recently, such as sibutramine plus
orlistat, which showed disappointing results [13,14] . However, in
a questionnaire undertaken with obesity specialists in the USA,
85% of them reported prescribing combinations of drugs and
65% admitted prescribing drugs not currently approved for the
treatment of obesity [15] . It is increasingly important to bring
literature and clinical practice closer, as this survey reports great
incongruence between daily practice and evidence-based recommendations. This is not surprising, however, in view of the lack
of effective drugs in such a common disease as obesity.
In the last few years, some new combinations of drugs have
been studied, which are as follows: P–T, bupropion–naltrexone,
bupropion–zonisamide and metreleptin–pramlintide [10,16] . The
combination of bupropion–naltrexone, with an interesting mechanism of action and reasonable results on large clinical trials, was
initially approved by the FDA Advisory Committee in 2010 but
surprisingly rejected by the FDA afterward, who demanded more
safety data regarding cardiovascular effects [17] . The FDA initially
also declined approval for P–T owing to safety concerns regarding
birth defects and cardiovascular events, but a new meeting in 2012
considered the drug to be safe and effective, although large-scale
postmarketing studies of cardiovascular safety are demanded [18] .
The other two combinations are undergoing Phase III trials [102,103] .
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Drug Profile
A
Phentermine & topiramate
Phentermine is an amphetamine analogue that promotes weight loss
by acting as an appetite suppressant, which interacts at amine transporters in the central and peripheral nervous system [19,20] (Figure 1) .
Its main action is on the norepinephrine transporter, leading to a
greater release of norepinephrine in the synapsis. It also has a weak
activity on the dopamine transporter and an even weaker activity
on the serotonin transporter. The drug has been approved for the
short-term treatment of obesity since 1959 and is the most widely
prescribed antiobesity medication in the USA, even before the withdrawal of sibutramine from the market. Since it was approved a long
time before the modern regulation rules for marketing of a drug and
is a very cheap medication with no patent owner, long-term clinical
trials were never conducted. A meta-analysis of its safety, analyzing six randomized trials, has shown a modest placebo-subtracted
weight loss of 3.6 kg, with large heterogeneity between the studies,
with lengths ranging from 2 to 24 weeks [21] . More recently, a newly
developed formulation of the drug was studied in a randomized
controlled trial and resulted in a placebo-subtracted weight loss of
236
Expert Rev. Clin. Pharmacol. 6(3), (2013)
Fixed-dose combination of phentermine–topiramate for the treatment of obesity
Drug Profile
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of
and blood pressure [27] , with positive results
also observed in the Type 2 diabetic population [29] . The drug was also tested in obese
H3C
NH2
patients with binge-eating disorders, with
NH2
CH3
reduction of bingeing scores and weight loss
Phentermine
Amphetamine
[25,30] . The main disadvantage of the drug is
its adverse effect profile, which leads to significant discontinuation rates, mainly due to
Figure 1. Phentermine and amphetamine.
paresthesias, memory/concentration impairment and somnolence [28] . Nevertheless, severe adverse effects are
The trial also looked at risk factors and noted significant
rare and include nephrolithiasis, secondary to its carbonic anhydrase improvements in blood pressure, waist circumference, lipids,
­inhibition activity. This drug was never submitted for approval as ­glycemia and inflammatory biomarkers, such as C-reactive ­protein
a obesity ­monotherapy, but is c­ ommonly used ­off-label in clinical and adiponectin, in the intervention group, allowing withdrawal
practice.
of antihypertensive drugs in approximately 11% of individuals
in the lower dose and 15% in the higher dose against 5% in the
Fixed-dose combination of P–T
placebo group. In the 388 individuals with Type 2 diabetes, a
The rationale for the combination therapy of P–T comes from the greater reduction in glycated hemoglobin was observed in comgood efficacy of both drugs combined and their different profiles parison with placebo. In addition, individuals with prediabetes
of adverse effects [31] . As previously ementioned, phentermine has had greater reductions in fasting blood glucose and insulin and
sympathetic and stimulant effects, whereas topiramate has seda- fewer patients progressed to Type 2 diabetes, with a relative risk
tive properties and may also reduce blood pressure. In conjunc- of 0.78 (0.4–1.5) in the lower-dose and 0.47 (0.25–0.88) in the
tion, both drugs can have additive effects on weight, allowing higher-dose group.
smaller dosages, and opposite effects on n
­ ondesired reactions,
Only 38% of individuals withdrew from the study (43% in
thereby reducing discontinuation rates.
placebo group, 31% in P7.5/T46 and 36% in P15/T92), a low
A Phase II study was conducted with 200 individuals over drop-out rate comparing with other the weightloss trials of
24 weeks, with a very high completion rate (92% in the treat- ­bupropion–naltrexone [33] and lorcaserin [8] .
ment group vs 62% in the placebo group) and the average 8.3%
The most common side effects significantly related to the drug
placebo-subtracted weight loss warranted further trials with two were dry mouth, paresthesia (the leading cause of d
­ iscontinuation),
different dosages (phentermine 7.5 mg/topiramate 46 mg and constipation, dysgeusia, insomnia and dizziness, with a dosephentermine 15 mg/topiramate 92 mg) [32] . It should be empha- dependent pattern. Anxiety and irritability were reported by
sized that in all trials of this combination, a controlled-release approximately 4% in the intervention group versus 2% in the
formulation of topiramate not currently available was used, placebo group. Disturbance in attention was also reported in 4%
which in theory would reduce the side effect profile of this drug. of the higher-dose group against 2% in the lower dose and less
Another Phase II study encompassing 776 individuals than 1% in the placebo group. An average increase in heart rate
(the EQUATE trial) compared both dosages of the P–T com- of 1.7 beats per min was seen in the higher-dose group. However,
bination with each drug in monotherapy and placebo during this was driven by isolated one-time increases in heart rate,
28 weeks. The median weight loss was 9.2% on P–T higher accompanied by decreases in systolic and diastolic blood pressure.
dose, 8.5% on P–T lower dose, 6.4% for topiramate alone, 6.1% Nephrolithiasis was significantly more frequent in the higher-dose
for phentermine alone and 1.7% for placebo (Figure 2) [105] . Such group, with a 1% incidence (11 individuals), but there was no
encouraging results prompted subsequent Phase III trials.
difference in blurred vision between the two intervention groups
The CONQUER trial evaluated 2487 individuals during and placebo.
An extension study, SEQUEL, was designed after the completion
56 weeks with a BMI between 27 and 45 kg/m2 and at least two
of the following comorbidities: hypertension, dyslipidemia, diabe- of CONQUER to assess data of an additional 2-year ­intervention
tes or prediabetes and abdominal obesity, blindly randomized to [34] . Of the eligible 866 individuals (from the main investigational
placebo, phentermine 7.5 mg/topiramate 46 mg (P7.5/T46) and sites), 676 (71%) agreed to continue with the 52-week study and
phentermine 15 mg/topiramate 92 mg (P15/T92) [9] . The median were enrolled with the original treatment they had been iniweight loss in absolute and percentage change was 1.4 kg (1.2%), tially assigned. The results were similar to those observed at the
8.1 kg (7.8%) and 10.2 kg (9.8%), respectively. Patients who com- CONQUER trial, showing a sustained 2-year weight loss with the
pleted 1 year of treatment had a mean weight loss of 9.9 kg with the medication. Approximately 15 and 9% of individuals receiving the
lower dose and an impressive 12.9 kg with the higher dose, making higher and lower doses, respectively, lost more than 20% of initial
this combination the most potent weight loss drug ever studied in body weight, an extraordinary response in terms of medical treata Phase III trial. The percentage of individuals who achieved 5% ment of obesity. A smaller, but still highly significant, weight loss
weight loss with placebo, P7.5/T46 and P15/T92 were 21, 62 and of 10% was seen in 53.9 and 50.3% of the patients, respectively,
70%, respectively, and the percentage who achieved 10% weight compared with 11.5% in the placebo group. More than 75% of
loss were 7, 37 and 48%, respectively (Table 1) .
individuals lost more than 5% of their weight. The median weight
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237
Drug Profile
Halpern, Faria & Halpern
a substantial and significant weight loss was
shown with the higher dosage (10.9%) com0
pared with placebo (1.6%), with intermediate results observed with the lower dose
-1
(5.1%). The percentage of patients losing
-2
-1.7
5, 10 and >15% were, respectively, 66.7,
47.2 and 32.3% on P15/T92; 44.9, 18.8
-3
and 7.3% on P3.75/T23 and 17.3, 7.4 and
-4
3.4% on placebo. The secondary end point
analysis assessing cardiovascular markers
-5
pointed to similar results to those seen in the
-6
previous trials. These results suggest that the
-6.1
-6.4
drug is also effective in severely obese indi-7
viduals, independently of their risk factors.
-8
The side-effect profile was also similar with
-8.5
-9
that of the other trials, and they were more
-9.2
frequent in the higher-dose group, although
-10
mild in severity. Serious adverse effects
were similar in the three groups (2.5%).
Figure 2. EQUATE trial – weight loss percentage for P15/T92, P7.5/T46, T92, P15
There were no differences between groups
and placebo.
­regarding d
­ epressive symptom development.
P15: Phentermine 15 mg; P7.5: Phentermine 7.5 mg; T46: Topiramate 46 mg;
There
are
more completed clinical trials
T92: Topiramate 92 mg.
Data taken from [32] .
not yet published [106] . Some Phase I studies
assess pharmacokinetics of the combinaloss was 10.5% in P15/T92, 9.3% in P7.5/T46 and 2.2% in the tion in patients with renal and hepatic impairment and also in
placebo group (Table 2) . Both systolic and diastolic blood pressure association with other common used drugs such as metformin,
decreased modestly by 3–5 mmHg, with a net decrease in the sitagliptin and probenecid in healthy subjects.
number of antihypertensive drugs in the intervention group and
A Phase II trial in a diabetic population has shown comparable
a net increase in placebo. There were reductions in triglycerides weight loss to the other studies and a small, albeit significant, fall
and increases in HDL-cholesterol, as well as decreases in fasting in glycosylated hemoglobin of 1.56% compared with 1.2% with
glycemia and insulin, with a 54% reduction in new-onset d
­ iabetes placebo after 56 weeks (mean difference 95% CI: -0.69 to -0.02,
in P7.5/T46 and 76% reduction in P15/T92.
p = 0.0381). Another study enrolling patients with Type 2 diabetes
The prevalence of individual side effects and severe side effects assessed the long-term performance of the drug in an open-label
decreased during the second year of treatment, with 4.0, 2.6 and design of 72 weeks, with a mean glycosylated hemoglobin fall of
4.1% reporting serious side effects in the placebo, P7.5/T46 and 1.4% and a mean weight loss of 10.1%.
P15/T92, respectively. The pattern of side effects was not different
Studies assessing psychomotor performance are awaited and a
between the three groups.
recent trial showed positive results in obese patients suffering from
Another Phase III trial, EQUIP, assessed severely obese individ- sleep apnea/hypopnea syndrome, with a significant improvement in
uals (BMI >35 kg/m2) during 56 weeks of treatment with placebo, apnea–hypopnea index, overnight oxygen saturation and reduction
P15/T92 (the same high dose as CONQUER and SEQUEL) in blood pressure with P15/T92 when compared with placebo [36] .
and a lower dose of phentermine 3.75 mg/topiramate 23 mg
Safety profile
(P3.75/T23) [35] .
A total of 1267 individuals were enrolled, with a mean BMI of An analysis of the most common adverse effects was performed
42 kg/m2, 82% being female and a substantial participation of above. Phentermine is known for its sympathetic activation and
black patients (16–18%). Again, in the intention-to-treat analysis, is not currently recommended for individuals with established
heart disease, although there are
no published data suggesting negTable 1. CONQUER trial.
ative cardiovascular outcomes.
Mean weight >5% weight loss >10% weight loss Severe adverse effects
Regarding the combination’s
loss (%)
(% of responders) (% of responders) (% of responders)
secondary effects, it has been
Placebo 1.2
21
7
4
well demonstrated that it actually
P7.5/T46 7.8
62
37
3
reduces blood pressure in obese
patients with hypertension with a
P15/T92 9.8
70
48
5
minimal, but increased, effect on
P15: Phentermine 15 mg; P7.5: Phentermine 7.5 mg; T46: Topiramate 46 mg; T92: Topiramate 92 mg.
Data taken from [9].
heartbeat in the full-dose group.
P7.5/T46
T92
P15
Placebo
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Median weight loss (%)
P15/T92
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Expert Rev. Clin. Pharmacol. 6(3), (2013)
Fixed-dose combination of phentermine–topiramate for the treatment of obesity
Drug Profile
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of
A larger clinical trial assessing
Table 2. SEQUEL trial.
long-term cardiovascular safety
Mean weight >5% weight loss
>10% weight loss Severe adverse effects
was demanded by the FDA
loss (%)
(% of responders) (% of responders) (% of responders)
as post-approval surveillance
[18] , but its results will not be
Placebo 1.8
30
11.5
6.2
available in the next few years. P7.5/T46 9.3
75.2
50.3
5.9
Therefore, in the mean time,
P15/T92 10.5
79.3
53.9
8.1
the drug is not recommended
P15: Phentermine 15 mg; P7.5: Phentermine 7.5 mg; T46: Topiramate 46 mg; T92: Topiramate 92 mg.
for this specific population.
Data taken from [33].
Topiramate has been associated with an increased teratogenic risk when used during and imposed many difficulties toward the approval of medicapregnancy, mainly oral cleft palate and cleft lip [37] . The FDA tions for this major health problem, but the recent approval of two
demanded safety data on this issue and the FORTRESS study antiobesity medications by the FDA probably signals a change in
was completed assessing retrospective data on topiramate, which this attitude. The combination of P–T is one of them and several
concluded that although the drug was associated with a bigger well-conducted recent clinical trials have shown strongly encourprevalence of oral clefts (0.29%), this risk decreases when the aging results with a very reasonable safety and tolerability profile.
mothers stopped the medication during pregnancy (0.16%) [107] . Although a single measure or medication will not be able to entirely
The control group has an incidence of 0.07%. These data suggest solve the disease burden associated with being overweight or obese,
that women planning for pregnancy should not use the drug, and it is the hope of many specialist physicians that it will help a good
since it has been demonstrated in pharmacokinetics studies that fraction of these patients to improve their health and quality of life.
topiramate can slightly interfere with the potency of contraceptive pills, it is fundamental to advise reproductive-aged women Five-year view
to use other birth control methods and immediately discontinue Although both phentermine and topiramate have been used for
the drug in case of suspected pregnancy.
many years as monotherapy for different purposes, long-term postTopiramate, as already mentioned, inhibits carbonic anhydrase marketing data and results of other clinical trials, mainly regardand is associated with nephrolithiasis [20] . People with previous ing its cardiovascular safety profile, weight loss maintenance and
episodes of kidney stones should be informed about the risk and, efficacy in improving diabetes mellitus and other comorbidities,
although not an absolute contraindication, the decision regarding are essential for better knowledge of this combination. It is also
the treatment must be carefully weighted. Both EQUIP [35] and the authors’ hope, and that of many physicians who deal directly
CONQUER [9] showed a mean change in serum bicarbonate of or indirectly with the obesity pandemic, that new drugs being
-1.0 to -1.7 for the higher dose, -0.3 to -1.6 for the lower-dose and studied and developed, as well as combination drugs in late-stage
-0.3 to +0.5 with placebo. These changes were not progressive and development (bupropion/naltrexone, metreleptin/pramlintide
did not require intervention.
and so forth), can be approved in the next few years. With more
Topiramate is also contraindicated in people with closed-angle options to treat obesity, physicians will be able to find the best drug
glaucoma owing to the possibility of rapid sight loss [38,39] .
for each different profile of patients with regards to safety data,
adverse effects, ­comorbidities improvement and response rates.
A
Expert commentary
Despite the increasing prevalence of obesity and its related comorbidities in the Western world, along with growing knowledge on
the pathophysiology of the disease, its treatment is far from ideal,
still relying mainly on lifestyle modifications that confer a very limited efficacy on a long-term basis. Fortunately, new drugs are being
developed and combinations of existing ones are being studied.
For many years, regulatory agencies have given little importance
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
• The prevalence of obesity is growing in the Western world and very little is offered for its treatment.
• The US FDA approved two new drugs for its treatment in 2012, after a 13-year gap.
• Combination drugs for weight loss have many potential advantages but few have been well studied to date.
• Phentermine–topiramate is a combination that enhances its efficacy on weight loss and diminishes adverse reactions by combining
drugs with an opposite side-effect profile, allowing the use of lower doses than either drug in monotherapy.
• The mean weight loss and percentage of responders with this combination are the most effective of all currently available drugs studied
for obesity in randomized controlled trials. This could assist millions of patients to effectively lose weight and get healthier.
• New drugs should continue to be developed to increase our therapeutic arsenal against this chronic and potentially deadly disease.
www.expert-reviews.com
239
Halpern, Faria & Halpern
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