Expert Review of Cardiovascular Therapy

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Phentermine, topiramate and their combination

for the treatment of adiposopathy (‘sick fat’) and
metabolic disease

Harold Bays

To cite this article: Harold Bays (2010) Phentermine, topiramate and their combination for the
treatment of adiposopathy (‘sick fat’) and metabolic disease, Expert Review of Cardiovascular
Therapy, 8:12, 1777-1801, DOI: 10.1586/erc.10.125

To link to this article: https://doi.org/10.1586/erc.10.125

Published online: 10 Jan 2014.

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Phentermine, topiramate and

their combination for the
treatment of adiposopathy
(‘sick fat’) and metabolic disease
Expert Rev. Cardiovasc. Ther. 8(12), 1777–1801 (2010)

Harold Bays
L-MARC Research Center, 3288 Illinois
Avenue, Louisville, KY 40213, USA
hbaysmd@aol.com
Positive caloric balance often causes pathologic adipocyte and adipose tissue anatomical and
functional changes (termed adiposopathy or ‘sick fat’), which may lead to pathogenic adipocyte
and adipose tissue responses and metabolic disease. Fat weight loss may improve adiposopathy,
and thus improve metabolic disease in overweight patients. Unfortunately, the efficacy of
non-surgical weight loss therapies is often limited due to redundant physiological systems
that help ‘protect’ against starvation and/or negative caloric balance. One strategy to overcome
these limitations is to combine weight loss drug therapies having complementary mechanisms
of action, thereby affecting more than one physiologic process influencing body fat
accumulation. Phentermine is a noradrenergic sympathomimetic amine approved for short-
term treatment of obesity. Topiramate is a sulfamate-substituted monosaccharide derivative
of the naturally occurring sugar monosaccharide d -fructose approved as a treatment for
migraine headaches and seizure disorders. Although known to facilitate weight loss since its
approval, topiramate monotherapy does not have a regulatory indication as an anti-obesity
agent. Phentermine HCl/topiramate controlled-release (PHEN/TPM CR) is a combination agent
containing immediate-release phentermine and controlled-release topiramate. Clinical trials
involving thousands of patients demonstrate PHEN/TPM CR to be effective in improving the
weight of patients, and also effective in improving adiposopathy-associated metabolic diseases.
This review examines the pathophysiology of adiposopathy as a contributor to metabolic
disease, the data supporting phentermine monotherapy, topiramate monotherapy and their
combination as anti-obesity and anti-adiposopathy agents, and the preliminary evidence
supporting PHEN/TPM CR as a generally well-tolerated and effective agent to improve
metabolic disease.

Keywords : adiposity • adiposopathy • blood pressure • cholesterol • diabetes mellitus • dyslipidemia

• hypertension • lipids • obesity • phentermine • PHEN/TPM CR • Qnexa® • topiramate • VI-0521

Clinical overview fat-mass-related complications; however, adipos-

Adiposity promotes the most common metabolic
diseases encountered in clinical medicine [1] .
Many of these metabolic diseases are major ath-
erosclerotic coronary heart disease (CHD) risk
factors (e.g., diabetes mellitus, high blood pres-
sure [BP] and dyslipidemia) [2,3] . The association
between increased adiposity, metabolic disease
and CHD risk is not absolute [4] . In some indi-
viduals, adiposity may elicit limited pathogenic
adipose tissue endocrine and immune responses,
which are made even less pathogenic if other body
organs are able to mitigate these pathogenic adi-
pose tissue responses. Such patients may develop
ity-induced metabolic diseases may be avoided or
delayed [5] . Conversely, even modest fat weight
gain among genetically or environmentally sus-
ceptible patients may incite pathogenic adipose
tissue endocrine and immune responses that
lead to metabolic disease [6] . Thus, adiposity is
most likely to ‘cause’ metabolic disease when fat
weight gain results in pathogenic adipose tissue
endocrine and immune adipose tissue responses
in patients having other body organs (e.g., liver,
muscle, brain etc.) with inadequate potential to
prevent the pathologic metabolic consequences
of ­dysfunctional adipose tissue [2] .

www.expert-reviews.com 10.1586/ERC.10.125 © Harold Bays MD ISSN 1477-9072 1777

 Review Bays
Adipose tissue as a pathogenic organ
Clinicians often apply the suffix ‘pathos’ to describe diseased
organs, such as cardiomyopathy, myopathy, encephalopathy,
ophthalmo­pathy, retinopathy, enteropathy, nephropathy, neuropa-
thy and dermopathy. ‘Adiposopathy’ is a term applied to reflect
anatomic abnormalities of adipocytes and adipose tissue that arises
from fat weight gain, and that results in pathogenic endocrine
and immune adipose tissue responses adversely affecting meta-
bolic health. In lay terms, ‘adiposopathy’ can be ­characterized as
­representing ‘sick fat’, which is an endocrine ‘disease’ [7] .
Adipogenesis
The degree to which adiposity is manifest as adiposopathy largely
depends on the effects of a positive caloric balance on adipo-
genesis. During positive caloric balance, adipocytes normally
undergo increased recruitment, proliferation and differentiation;
during a negative caloric balance, adipocytes shrink in size and/or
may undergo apoptosis [8–13] . If, during positive caloric balance,
increased adipogenesis provides adequate, added adipose tissue
functionality, then patients may avoid adverse metabolic conse-
quences associated with adiposity. Conversely, if adipogenesis is
impaired, then inadequate recruitment, proliferation and/or dif-
ferentiation may cause adipocytes and adipose tissue to become
dysfunctional, pathogenic, and contributory to metabolic disease.
Specifically, if during positive caloric balance the recruitment
and proliferation of new fat cells is impaired, then existing fat
cells may become excessively enlarged. For decades, data sup-
port excessive adipocyte hypertrophy as being associated with
adipocyte and adipose tissue dysfunction, which contributes to
metabolic disease [6,14–16] .
Fat depots
The pathogenic potential of adipose tissue is not solely due to how
calories are stored (adipocyte hypertrophy vs hyperplasia), but also
due to where fat is stored [6] . Visceral or intraperitoneal (omental,
mesenteric and umbilical), extraperitoneal (­peripancreatic and
perirenal) and intrapelvic (gonadal/epididymal and urogenital)
adipose tissues reportedly have higher metabolic activity compared
with subcutaneous, peripheral adipose tissue (truncal, gluteo­
femoral, mammary and inguinal) [6,17] . Due to differences in loca-
tion and function, overweight patients with a disproportionate
increase in visceral adiposity may have an increased risk of devel-
oping metabolic diseases [5,18–23] . Conversely, some overweight
individuals who have relatively unimpaired adipogenesis predomi-
nantly in peripheral subcutaneous adipose tissue may avoid clini-
cally meaningful adverse adipose tissue pathogenic responses, and
thus remain metabolically healthy [6,18,24–27] .
Although visceral adipose tissue accumulation is most often
associated with metabolic disease [28] , other fat depots also have
pathogenic potential [6,19] . Adipose tissue has the potential for
pathogenic responses from virtually all fat depots, such as sig-
nificant immunologic abnormalities involving pericardial, peri-
muscular, perivascular, orbital and paraosseal adipose tissue [29] .
During positive caloric balance, impaired adipogenesis in sub-
cutaneous adipose tissue may lead to increased storage of fat in
1778
other depots, resulting in visceral adipose tissue accumulation and
visceral adipocyte hypertrophy, which is particularly pathogenic.
Furthermore, an increase in adipocyte size and adipose tissue
accumulation in the subcutaneous abdominal region is most often
associated with an increased, not decreased, risk of metabolic
disease [6,22,30] .
Free fatty acids
Circulating free fatty acid levels are determined by many factors,
such as:
• Whether the patient is in a fasting (postabsorptive) state;
• The degree to which other body organs (e.g., muscle and liver)
metabolize free fatty acids;
• The degree to which adipose tissue stores free fatty acids
as triglycerides.
If adipocytes and/or adipose tissue are impaired in their ability
to adequately store free fatty acids, then the resultant increase in
circulating free fatty acids may contribute to metabolic disease.
Because it is the largest fat depot (making up ≥80% of body fat),
subcutaneous adipose tissue produces the majority of the free fatty
acids, possibly including the majority of free fatty acids in the
portal system [19,31] . Nonetheless, an increase in visceral adipocyte
hypertrophy and/or visceral adipose tissue often increases free
fatty acid delivery to the liver through its portal drainage, which
may promote hepatic ‘lipotoxicity’. The increased, lipotoxic free
fatty acid delivery to the liver increases the risk of ­hepatic-mediated
insulin resistance and dyslipidemia [32,33] .
In addition to its contribution to the portal system, subcutane-
ous adipose tissue contributes to most of the systemic circulating
free fatty acids [32,33] , which are potentially lipotoxic to the muscle
and pancreas, thus decreasing insulin sensitivity in muscle and
possibly decreasing insulin secretion from the pancreas [34–36] .
In summary, while visceral adipose tissue accumulation is most
associated with metabolic disease, both visceral and subcutaneous
adipose tissue have pathogenic potential [19] .
Adipose tissue as an active endocrine & immune organ
Anatomically, excessive adipocyte hypertrophy (due to excessive
fat content) adversely affects intracellular organelles, as evidenced
by increased markers of intracellular endoplasmic reticulum stress
and mitochondrial dysfunction [37,38] . This supports the concept
of ‘sick fat’ [2,7] , wherein adiposity lead to pathologic adipocyte
and adipose tissue anatomic changes, which leads to pathogenic
adipose tissue endocrine and immune responses, which then
­contribute to metabolic disease.
Adipose tissue is an active endocrine organ whose disruption
can contribute to metabolic disease [6,7,37,39–42] . Adipose tissue is
also an active immune organ whose disruption can contribute to
metabolic disease [6,29,37,43–48] . Biopsy of the periumbilical sub-
cutaneous (abdominal) region supports adiposity as increasing
adipose tissue macrophage content and/or increasing markers of
macrophage activation, representing potential pathogenic adipose
tissue immune responses [49] . Pathogenic alterations in adipose
Expert Rev. Cardiovasc. Ther. 8(12), (2010)
 Phentermine, topiramate & their combination for treatment of adiposopathy & metabolic disease
tissue endocrine and immune factors associated with adiposopa-
thy contribute to metabolic disease, while improvements in adi-
pose tissue endocrine and immune factors may improve metabolic
disease [6,23,25,50] .
Interaction or ‘cross-talk’ with other body tissues
Adiposopathy alone does not cause metabolic disease. It is the
interaction or ‘cross-talk’ with other body organs that substan-
tially determines whether pathogenic adipocyte and adipose tissue
endocrine and immune responses ultimately ‘cause’ metabolic
disease [2] . Many non-adipose tissue body organs modulate the
pathogenic endocrine and immune responses from adipose tis-
sue during positive caloric balance [2] . One of the best described
pathogenic responses of dysfunctional adipose tissue (‘sick fat’) is
the increased net release, and thus increased circulating levels, of
free fatty acids. Normally, after meals, circulating free fatty acids
are substantially reduced (suppressed), due to increased insulin
secretion that stimulates free fatty acid storage in adipose tissue
and other body tissues. As insulin levels decrease in the hours
after initial release, free fatty acid levels gradually rise [51] . If,
during positive caloric balance, fat weight gain results in exces-
sive adipocyte hypertrophy and adipose tissue dysfunction, then
this may result in insulin resistance and impaired storage of free
fatty acids within adipocytes. The disruptive imbalance between
lipolysis and lipogenesis in adipose tissue increases both fasting
and postprandial circulating free fatty acids, relative to those
without insulin resistance [52] . If the liver is limited (‘inflexible’)
in its ability to metabolize the increased delivery of free fatty acids,
then intrahepatic lipid deposition (often reflected by ‘fatty liver’)
may promote hepatic insulin resistance and dyslipidemia [53] .
Conversely, if the liver is ‘hyperflexible’, in its ability to manage
the pathogenic responses of adipose tissue through genetic pre-
disposition, or through the use of therapeutic agents (e.g., per-
oxisome proliferator-activated receptor [PPAR]-g agonists), then
the adverse metabolic disease consequences of increased free fatty
acids may be averted [2,52,54] .
Similarly, some patients have an inherent or acquired impair-
ment in the ability to metabolize intramuscular fat [53] . A lack
of ‘flexibility’ on the part of skeletal muscle may result in an
inability to metabolize the adiposopathic increased free fatty
delivery from the circulation. If so, then this may result in ectopic
free fatty acid storage in muscle and the accumulation of ‘toxic’
intramyocellular lipids such as diacylglycerol, fatty acyl CoA and
ceramides [2] . This ‘lipotoxicity’ promotes insulin resistance in
muscle [55–57] .
Therapeutically, hypocaloric nutritional intervention would
not be expected to affect the inherent ‘flexibility’ for muscle to
metabolize free fatty acids. However, such intervention would be
expected to improve adipose tissue function, improve free fatty
acid storage in adipose tissue, reduce circulating free fatty acids,
reduce lipid delivery to skeletal muscle, and thus reduce lipid
deposition in skeletal muscle. As a result, reduced fatty acid deliv-
ery and reduced lipid deposition in skeletal muscle may improve its
insulin sensitivity [57] . Similarly, some patients may have familial
or genetic limitations in their ability to secrete insulin. The disease
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Review
of Type 2 diabetes mellitus is often revealed when adiposity results
in pathogenic adipose tissue endocrine and immune responses,
including an increased release of free fatty acids. This exacerbates
genetic limitations of the pancreas, potentially resulting in an even
further impairment in insulin secretion [58,59] . In addition, adipose
tissue is also known to have substantial inter­actions and cross-
talk with other body organs, such as the immune system, heart
and vasculature, brain, endocrine glands, intestine, kidneys, and
other body organs, all with potential physiologic and pathologic
metabolic consequences [2] .
Adiposopathy
The goal of treating adiposity is to improve patient health. If the
patient has fat mass-related morbidities, then fat weight loss may
improve such conditions [60] . If the patient has adiposopathy-
induced metabolic disease (e.g., Type 2 diabetes mellitus, high
BP and/or dyslipidemia), then fat weight loss interventions may
reduce adipocyte hypertrophy, reduce visceral adiposity, improve
adipocyte and adipose tissue pathogenic endocrine and immune
responses, and thereby improve metabolic disease (Table 1) [50,54] .
However, reducing body fat is not the only way to improve
adipose tissue function. Adding adipocyte or adipose tissue func-
tionality is another approach. PPAR-g agonists may improve
metabolic diseases normally associated with an increase in body
fat (Type 2 diabetes mellitus and dyslipidemia) by increasing adi-
pogenesis (recruitment, proliferation and differentiation of new
adipocytes) [25,52] . PPAR-g agonists illustrate how adding (func-
tional) adipose tissue may be an effective treatment for metabolic
diseases otherwise associated with adiposity and adiposopathy.
Conversely, not all weight loss interventions improve metabolic
disease. Antiretroviral therapy for HIV is sometimes associated
with ‘HIV lipodystrophy’, wherein weight loss is manifest by a
disproportionate loss of subcutaneous adipose tissue relative to
visceral adipose tissue. These HIV drug therapies may promote
insulin resistance and dyslipidemia [61] , and illustrate how even
weight loss can be associated with pathogenic adipocyte and
­adipose tissue dysfunction resulting in metabolic disease.
Currently, bariatric surgery appears to be the most effective
intervention to reduce adiposity and adiposopathy through
improvement in adipose tissue function and perhaps other
mechanisms [50] . Perhaps the most cost-effective treatment for
adiposity and adiposopathy in the individual, willing patient is
appropriate nutrition and increased physical activity (Table 1) [2] .
However, a challenge for the clinician and patient is that public
health weight loss nutritional and physical activity initiatives, as
well as commercial nutritional weight loss plans, have met with
limited success in both individuals and populations [62] . Other
weight loss therapeutic options include anti-obesity drug therapies
(Table 1) [54] . Targeting weight loss is medically justified because
even just a 5% weight loss in overweight patients may improve
pathogenic adipose tissue responses [63] . Thus, while many over-
weight patients may want (and sometimes expect) therapeutic
interventions that result in weight loss of up to 100 lbs or more [7] ,
demonstrable and significant metabolic benefits can be achieved
with ‘only’ a 5–10% reduction in body weight [64,65] .
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Table 1. Examples of treatments for adiposopathy (‘sick fat’) and their effects upon illustrative and
selected adipose tissue factors that may contribute to metabolic disease.
Intervention May affect glucose metabolism, BP and May affect glucose May affect BP May affect lipid
lipid metabolism metabolism metabolism
Visceral Free Leptin Adiponectin TNF-a Renin– Androgens Estrogens
adipose fatty angiotensin–
tissue† acids aldosterone
enzymes
Weight loss interventions
Appropriate ↓ ↓ ↓ ↑ ↓ ↓ ↓ (women) ↓ /- (men)
nutrition ↑ (men)
and physical
activity
Orlistat ↓ ↓ ↓ ↑ ↓ ? ↓ (women) ?
Sibutramine ↓ ↓ ↓ ↑/- ? ? ↓ (women) ?
Cannabinoid ↓ ↓ ↓ ↑ ↓ ? ? ?
receptor
antagonists
Lorcaserin ↓ ? ? ? ? ? ? ?
Phentermine ↓ [105] ? ? ? ? ? ? ?
Topiramate ↓ [119] ↓ [172] ↓ /- ↑­[119] - [119] ? ? ?
[119,130]

Phentermine/ ↓ ? ? ? ? ? ? ?
topiramate
combination
Laparoscopic ↓ ? ↓ ↑ ↓ ↓ ? ?
adjustable gastric
banding
Gastric bypass ↓ ↓‡ ↓ ­↑ ↓ ↓ ↑ (men) ↓ (men)
Diabetes mellitus therapies §

PPAR-g agonists¶ ↓ /- ↓ ↓ /- ­↑ ↓ - ↓ ↓ /- (men)

(pioglitazone,
rosiglitazone)
Metformin ↓ ↓ ↓ ­↑ - ↓ ↓ (women) ?
Sulfonylurea ­↑ ↓ ↑/- ­↑ ­↑/-/↓ ? ? ?
Insulin ­↑/- ↓ ­↑ ↓ ↓ /- ­↑ ↓ /- (women) ?
Glucagon-like ↓ ↓ ↓ /- ↑/- - ? ↓ ?
peptide-1
(GLP-1) #
†
Visceral adiposity may be approximated by measurements of waist circumference.
‡
Acutely (e.g., 1 month), free fatty acids may be increased during rapid weight loss.
§
Not all of the listed metabolic effects of anti-diabetes mellitus therapies are adipocyte or adipose tissue mediated.
¶
PPAR-g agents may: (1) increase adipose tissue proliferation and differentiation, (2) favorably alter the visceral-to-subcutaneous adipose tissue deposition ratio,
(3) reduce hepatic fat deposition, and (4) improve other aspects of adipose tissue function [3,23,53]. While some of the weight gain associated with PPAR-g agents is
due to fluid retention, much of the weight gain observed with these agents used to treat metabolic diseases traditionally associated with fat weight gain are
(paradoxically?) due to promoting increased amounts of functional adipose tissue.
#
Not all of the listed metabolic effects described with GLP-1 have yet been proven to occur with GLP-1 agonists.
↑: Increased; ↓: Decreased; ?: Unreported; -: Neutral effect; PPAR-g: Peroxisome proliferator-activated receptor-g.
Data taken from [2,3,23,171].

Weight loss challenges One potential physiologic impediment may be related to adi-
Unfortunately, despite available therapeutic options, genetic, pogenesis. Physiologically, during fat weight loss, a reduction in
physiologic, environmental and behavioral factors impede adipogenic markers does not necessarily reflect adipocyte dys-
­effective management of the unabated obesity epidemic [201] . function [23,50] . Instead, it is physiologically appropriate that

1780 Expert Rev. Cardiovasc. Ther. 8(12), (2010)

 Phentermine, topiramate & their combination for treatment of adiposopathy & metabolic disease
adipogenic processes diminish when the need for additional
adipocytes and adipose tissue is diminished, as occurs during
active weight loss. However, the potential for adipogenesis may
be increased, as evidenced by enhanced preadipocyte adipogenic
and anti-apoptotic protein expression [66,67] . An increase in adipo-
genic potential may be a contributing physiologic cause for the
increased potential for all-too-common fat regain among those
who lose body fat.
Another important factor contributing to the lack of persistence
with weight loss is that the human body is not very efficient in
self-regulating against excessive energy storage. Conversely, the
human body is often entirely too efficient in self-regulating against
too little available energy through multiple redundant mechanisms
intended to prevent starvation. It appears that conserving energy
during a negative caloric balance represents a more urgent priority
for survival than expending energy during positive caloric bal-
ance. While this may be advantageous in environments of food
scarcity and when high physical activity is necessary for survival,
it is potentially disadvantageous when food and ­transportation
conveniences are readily available.
The major components of total daily energy expenditure
include resting energy expenditure, non-resting energy expen-
diture (e.g., physical activity and exercise) and the thermal effect
of food [68] . Data suggest that having a low resting metabolic rate
(i.e., having low resting energy expenditure) is not a major ‘cause’
of obesity in most patients, despite the common belief other-
wise [69] . Instead, resting energy expenditure is largely dependent
upon the BMI. While individual variabilities exist, formulae that
include BMI (and age), such as the Harris–Benedict equation,
yield reasonable mean resting energy expenditure predictions
for normal and obese individuals [70] . Thus, in those without
secondary causes of adiposity, patients with higher BMI have
higher resting energy expenditure, while patients with lower BMI
have lower resting energy expenditure. During dynamic weight
loss (negative caloric balance), the resting metabolic rate often
decreases below what is appropriate for BMI, and may [71] or
may not [72] return to what is appropriate for BMI shortly upon
stabilization of body weight and a return to energy balance. Non-
resting energy expenditure may also decrease during weight loss
due to improved ­skeletal muscle work efficiency [73] . Whatever
degree of conservation of energy occurs during dynamic weight
loss, diminished total energy expenditure limits fat weight
reduction during times of negative caloric balance, which is a
limitation perhaps mitigated by engaging in routine physical
exercise [74] .
An example of a neuroendocrine mechanism that helps account
for this conservation involves leptin. Leptin is an adipocyte-released
cytokine whose blood levels increase with adipocyte size and num-
ber. In obese patients with leptin deficiency, leptin administration
reduces food intake and can result in dramatic weight loss [75,76] .
However, most evidence suggests leptin approximates its maximum
physiological effects at the high end of normal physiologic levels [5] .
Thus, in those without leptin deficiency, the supraphysiologic levels
of leptin found with obesity in humans do not effectively counter-
act persistent or worsening obesity. However, during weight loss,
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Review
leptin levels decrease and low leptin levels can significantly favor
positive caloric balance through increased appetite, among other
possible mechanisms (Figure 1) [77] . Increased physical activity, such
as through increased physical exercise, may enhance leptin sensitiv-
ity [78] , reduce the so-called ‘leptin resistance’ [79] , and better allow
for improved longer term weight loss maintenance [25] . Thus, in
addition to improving cardiovascular health [80] , preserving lean
body mass [81,82] and potentially improving metabolic parameters
during weight loss [83] , increased physical activity, such as through
routine physical exercise, may also favorably affect leptin activ-
ity. This represents yet another potential justification for recom-
mending increased physical activity, along with appropriate nutri-
tion, towards the goal of maximizing chances of successful and
­persistent weight loss.
Physiological barriers such as these help to account for the fre-
quent failure of nonsurgical weight loss interventions and a high
rate of fat regain among overweight patients who have lost weight.
Although not always effective [84] , a pharmaceutical approach to
overcome these multiple barriers is through combining weight
loss drug therapies having complementary mechanisms of action,
thereby potentially affecting more than one physiologic process [23] .
Several combination anti-obesity strategies are in development [3] .
An example of one such complementary approach is the combined
use of phentermine and topiramate. The remainder of this review
will focus on how both these agents, alone and in combination,
reduce body weight, improve adipocyte and adipose tissue function
(as described previously), and improve metabolic disease.
Phentermine
Indication & history
Phentermine is an approved anti-obesity agent indicated as an
adjunct to appropriate nutrition and physical exercise for short-
term (up to 12 weeks) treatment of obesity. Significantly due to
its generic status, phentermine is the most commonly prescribed
prescription appetite suppressant [3] . Phentermine resin was first
approved by the US FDA in 1959 [85] . Phentermine resin formu-
lations allow for a slower gastrointestinal release after ingestion.
Administration of phentermine resin often begins with a 15 mg
dose, titrated to 30 mg per day if needed.
In the 1970s, phentermine hydrochloride (HCl) was developed,
with (depending upon the manufacturer) doses ranging from 8
to 37.5 mg, which is generally equivalent to 6.4–30 mg of phen-
termine resin. The phentermine HCl salt easily dissociates in the
GI tract, resulting in immediate-release of phentermine drug;
phentermine HCl is absorbed from the GI tract approximately
three-times faster than phentermine resin [86] . Theoretically,
immediate-release phentermine HCl has a more intense appetite-
suppressant effect compared with phentermine resin, but for a
shorter duration of time.
Mechanism of action
Anti-obesity therapies promote weight loss generally through
decreased gastrointestinal absorption of energy (e.g., orlistat [3]
and some bariatric surgeries [50]), increased energy expenditure
and/or decreased energy (caloric) intake. Thyroid hormone is
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Paraventricular hypothalamus
(↑ Catabolism)
↑ TRH
CNS factors ↑ CRH
↓ CB1R
↑ Noradrenaline (?)†
↑ Dopamine
Arcuate nucleus of hypothalamus
↑ Serotonin
Ventromedial hypothalamus
↑ Leptin ↑ POMC (↑ α-MSH)/CART
↑ Insulin (catabolic, anorexigenic neuron arm) (↑ Catabolism)
↑ Adiponectin (?)‡ ↑ MC4R/MC3R
↑ Glucose§ ↓ NPY and AgRP ↑ BDNF
↑ PYY 3–31 (anabolic, orexigenic neuron arm) ↓ CB1R
↑ VIP
↓ Ghrelin
↑ GLP-1 Lateral hypothalamus
(↓ Anabolism)
↓ MCH
↓ OREXIN
↓ CB1R

Figure 1. Simplified relationship between selected CNS factors† on anorexigenic and orexigenic effectors within
the hypothalamus. CNS factors may increase anorexigenic POMC (which is cleaved to form melanocortins such as MSH) and CART
expression, and decrease orexigenic expression of NPY and AgRP. Alterations in these appetitive effectors contribute to ‘second-order’
signaling through arcuate nucleus neuron projection to other hypothalamic regions. The net result is increased anorexigenic and
increased catabolic effects, with decreased orexigenic and decreased anabolic effects. This figure is greatly simplified, and does not show
all the interconnected signaling pathways between these CNS factors.
†
The reported effects of these CNS factors on POMC and NPY are not always consistent in the literature, with more research needed to
confirm these effects.
‡
While CNS adiponectin may have anorexigenic effects [175] , adiponectin may not cross the blood–brain barrier [176] , so the physiological
importance of adiponectin on the CNS is unclear [140] .
§
Meant to reflect the fed versus non-fed state as reflected by relative physiologic increases or decreases in glucose levels. While the
signaling may be glucose mediated, this is not necessarily meant to represent pathologic hyperglycemia.
AgRP: Agouti-related peptide; BDNF: Brain-derived neurotrophic factor; CART: Cocaine amphetamine-regulated transcript;
CB1R: Cannabinoid 1 receptor; CRH: Corticotropin-releasing hormone; GLP-1: Glucagon-like peptide-1; MC3R: Melanocortin 3 receptor;
MC4R: Melanocortin 4 receptor; MCH: Melanin-concentrating hormone; MSH: Melanocyte-stimulating hormone; NPY: Neuropeptide Y;
POMC: Pro-opiomelanocortin; PYY 3–31: Peptide YY; TRH: Thyroid-releasing hormone; VIP: Vasoactive intestinal peptide.
Data taken from [23,173,174].

a classic example of an orally administered agent that increases
energy expenditure through its CNS and systemic effects [87–90] .
As perhaps the first anti-obesity agent, thyroid hormone was
used as early as 1893 to induce weight loss [87] . However, exces-
sive use of thyroid hormone has toxic effects upon the CNS and
multiple other body organs. Dextrothyroxine was one of the five
treatment groups evaluated in the Coronary Drug Project. The
thyroid treatment arm in this study was stopped due to excessive
mortality [91] . Toxicity due to excessive thyroid hormone is why
the product information has a black warning against the use of
thyroid hormone for weight loss [87] .
Similarly, amphetamines were used as early as 1938 as weight
loss treatments [92] . The mechanism of action of amphetamines
includes an increase in CNS dopamine and norepinephrine (both
catecholamines), and serotonin (an indolamine) activity. Clinical
trials in humans suggest sympathomimetic agents increase energy
expenditure [93,94] . In animals, amphetamines are reported to
increase energy expenditure [95] , such as through increasing ther-
mogenesis [96] . Other animal data suggest that while amphet-
amines may increase locomotor activity, they may suppress the
overall resting metabolic rate [97] . Although one might suppose
that amphetamines (like other stimulants) increase the metabolic
rate, the reported human data are remarkably scarce regarding
the effect of amphetamines on energy expenditure. One study
suggested that dextroamphetamine or methylphenidate treatment
of children with attention-deficit hyperactivity disorder tended to
increase the resting metabolic rate but decrease physical activity,
resulting in an overall decrease in energy expenditure. Thus, at
least at doses typically prescribed for weight loss in obese patients,
the long-term effects of amphetamines on total energy expenditure
are unclear. What does seem to be clear is that administration of
these monoamine neurotransmitters reduces appetite, as would be
expected through their decreases in neuropeptide Y [98] , increases
in pro-opiomelanocortin [99] and increases the anorexigenic pep-
tide located in the hypothalamus, termed ‘cocaine and amphet-
amine-regulated transcript’ (CART) [100] , among other potential
effects (Figure 1) . As with thyroid hormone, amphetamines have
potential toxic CNS and other adverse systemic effects, including
an increase in BP, tachycardia and euphoria. Amphetamines also
have a high potential for abuse and addiction [87] .

1782 Expert Rev. Cardiovasc. Ther. 8(12), (2010)

 Phentermine, topiramate & their combination for treatment of adiposopathy & metabolic disease
In the USA, the authority to prescribe certain controlled sub-
stances is defined by Drug Enforcement Agency (DEA) schedul-
ing. Schedule I controlled substances include drugs with a high
potential for abuse and with no accepted medical use, such as
heroin, peyote and others. Most physicians do not have a medi-
cal need to apply for the special permission required to prescribe
Schedule I drugs. DEA Schedule II drugs include those with a
high potential for abuse, but which have medical use. Common
examples include cocaine (for topical use), methadone, morphine
and amphetamines. Therapeutic forms of amphetamines include
amphetamine, dextroamphetamine and methamphetamine.
Depending upon the preparation, amphetamines have an indi-
cated use to treat attention-deficit disorder and narcolepsy. Some
amphetamines continue to have a regulatory indication to treat
obesity, although they are rarely used for this purpose. Instead,
the product information for amphetamines usually has a black
box warning regarding the high potential for abuse, and risk of
sudden death and serious cardiovascular events.
Phentermine is commonly described as a noradrenergic and
possibly dopaminergic [101] sympathomimetic amine, although
some question whether phentermine causes clinically meaning-
ful release of dopamine from central neurons, at least relative to
amphetamine [102] . Phentermine is chemically related to amphet-
amine, but does not have its addictive potential. Phentermine
is listed as a Schedule IV drug (along with other drugs such as
barbiturates, benzodiazepines and librium) because it has a low
potential for abuse, and because it has a medical use for short-term
treatment of obesity. Figure 1 describes first- and second-order hypo-
thalamic signaling, which may be influenced by increased CNS
noradrenergic activity [103] , as might be promoted by phentermine.
While phentermine increases sympathetic activity (which reduces
appetite), little evidence suggests that its weight loss effects are
substantially due to increasing resting energy expenditure [104] .
Adverse experiences
Phentermine is contraindicated where sympathomimetic drug
administration may pose a significant risk, such as in patients with
unstable cardiovascular disease, moderate-to-severe high BP, hyper-
thyroidism and unstable cardiac dysrhythmias. Phentermine is not
recommended in patients treated with monoamine oxidase inhibi-
tors or in patients with a history of drug abuse (including excessive
alcohol consumption). Phentermine should be used with caution
in patients concurrently treated with other agents that affect the
CNS agents, such as agents that increase adrenergic responses
(i.e., decongestants). Phentermine’s side effects include palpitations,
tachycardia, increase in BP, tremor, diaphoresis, over­stimulation,
anxiety, irritability, restlessness, dizziness, insomnia, euphoria,
dysphoria, headache, dryness of the mouth and ­gastrointestinal
complaints (i.e., diarrhea and constipation) [3] .
Phentermine, adiposopathy & metabolic disease
Although phentermine is among the oldest approved anti-obesity
agents, it has among the least data with respect to its effects upon
adiposopathy. Limited to no published data exist on phenter-
mine monotherapy effects upon adipogenesis, free fatty acids and
www.expert-reviews.com
Review
important adipose tissue endocrine and immune factors (Table 1) .
Shorter term data suggest that the weight loss associated with
phentermine may have some favorable lipid effects [105] , with vari-
able effects regarding BP [105,106] . However, published data on
the long-term (≥1 year) effects of phentermine monotherapy on
metabolic disease are lacking.
Topiramate
Indication & history
Topiramate is a sulfamate-substituted monosaccharide derivative
of the naturally occurring sugar monosaccharide d-fructose. It
was originally developed as a treatment for Type 2 diabetes mel-
litus [60,107] . Despite promising early animal data, the direct anti-
hyperglycemic effects of topiramate (independent of weight loss)
were not confirmed in humans [108] . However, some authors con-
tinue to believe topiramate has insulin secretagogue and ­insulin
sensitization potential [109] .
Topiramate has undergone evaluation and development at least
since 1979. Topiramate was approved in the USA as a marketed
pharmaceutical in 1996 [110] . Topiramate has a US regulatory
indication for prophylaxis of migraine headaches and treatment of
seizure disorders. Most applicable to this review is that while topi-
ramate does not have a regulatory indication for weight loss [111] ,
some clinicians have used topiramate ‘off label’ for the purpose
of weight reduction. This is because early on, even at the time of
approval, the treatment emergent ‘adverse’ experiences described
in its development reportedly included: “mild, dose-related weight
loss was associated with topiramate therapy” [112] . Since approval,
clinical trial data have supported topiramate as having weight
loss effects [113–119] .
An illustrative study was a placebo-controlled, 6-month clini-
cal trial of topiramate (not controlled-release) in obese subjects
starting with 16 mg once a day, which was increased to 16 mg
twice a day, and then increased weekly by 16 mg twice a day
until reaching the target dose of 64, 96, 192 or 384 mg per
day [116] . Mean weight loss from baseline for placebo was -2.6%.
At the respective doses of topiramate, weight loss was -5.0, -4.8
and -6.3%. This suggested that most of the weight loss with
topiramate occurred at the lower topiramate doses. A total of
21% of topiramate subjects withdrew because of adverse experi-
ences (compared with 11% of placebo-administered patients).
According to the authors: “The most frequent adverse events were
related to the central or peripheral nervous system, including pares-
thesia, somnolence, and difficulty with memory, concentration, and
attention. Most events were dose-related, occurred early in treatment,
and usually resolved ­spontaneously” [116] .
Another study evaluated the long-term effects of topiramate
(again, not controlled-release) in obese subjects participating in
a nonpharmacologic weight-loss program [114] . Topiramate pro-
duced significant weight loss of -7.0, -9.1 and -9.7% at respective
doses of 96, 192 and 246 mg per day, compared with a loss of
-1.7% in the placebo group. As before, most of the weight loss was
achieved at the lower topiramate doses. Importantly, topiramate
significantly improved BP, glucose and insulin levels. Regarding
safety and tolerability, the authors stated: “The most common
1783
 Review Bays
adverse events more frequently observed in topiramate-treated sub-
jects occurred mostly during the titration phase and were related to
the central or peripheral nervous system and included paresthesia,
difficulty with concentration/attention, depression, difficulty with
memory, language problems, nervousness, and psychomotor slowing.”
The study was stopped early because the study sponsor elected
to: “develop a new controlled-release formulation with the potential
to enhance tolerability and simplify dosing” [114] . However, this
controlled-release monotherapy development program was later
abandoned, presumably because of a lack of consistent benefits
and sufficient efficacy, balanced against the adverse experiences
found with higher topiramate monotherapy doses thought to be
required to obtain an approvable weight-loss indication [60] .
Mechanism of action
Topiramate is a ‘neurostabilizer’ [107] . Signaling from CNS neu-
ron to neuron is propagated by action potentials, which result
from ion (i.e., sodium and potassium) flux across voltage-gated
ion channels in neuron cell walls. Seizures occur when excessive
firing disrupts the normal neural signaling flow from postsyn-
aptic depolarization, to action potential generation, to neuro­
transmitter release [120] . Although not yet definitively proven,
topiramate may reduce seizure activity by modifying excitatory
voltage-activated sodium and calcium channels, antagonizing
a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid ­kainate
(AMPA/KA) receptors, and enhancing g-aminobutyric acid
(GABA) ­receptor-mediated inhibitory currents [121] .
Similarly, although yet to be proven, topiramate has several
potential mechanisms accounting for weight loss. As it is a
CNS-acting drug, topiramate may have CNS effects that alter
caloric balance. Topiramate’s antagonism of AMPA/KA recep-
tors may reduce compulsive or addictive food cravings [122] ,
which is supported by topiramate’s effectiveness in improving
binge eating disorder [123] and effectiveness in reducing other
addictive behaviors [124] . Topiramate’s activation of GABA recep-
tors may decrease night-time and deprivation-induced feeding
[125] . Decrease feeding during caloric deprivation would favor
persistence of weight loss. While animal studies suggest topira-
mate may increase levels of neuropeptide Y (NPY) in the hypo-
thalamus (an effect that would seem to promote positive caloric
balance [126,127]), topiramate may also increase levels of hypo-
thalamic corticotropic-releasing hormone, which may be cata-
bolic (Figure 1) [128] . Topiramate may also increase hypothalamic
galanin, with unclear body weight implications [128,129] . While
some studies suggest leptin levels decrease with topiramate-
induced weight reduction [119] , other reports suggest leptin levels
may either not significantly decrease, or only modestly decrease
with topiramate-induced weight loss, which is another effect that
may favor persistence of weight loss [130] . Anorexia is commonly
reported with topiramate; however, topiramate may not reduce
objective measures of appetite during weight loss [131] . A lack of
increased hunger and appetite during weight loss may reflect a
cumulative effect of the anorectic effects of topiramate, balanced
against the orexigenic effect of topiramate-­promoted fat loss or
related energy deficit through other mechanisms [131] . Again,
1784
this would favor persistence of weight loss. Regarding energy
expenditure, topiramate may decrease energy storage and usage
efficiency, and thus increase energy expenditure [132] . Topiramate
may increase thermogenesis [133] .
Applicable to adipocyte function, topiramate (as well as related
sulfamates) may inhibit adipocyte mitochondrial carbonic anhy-
drase isozyme V [134] , inhibiting carbonic anhydrase-mediated
lipogenesis [135,136] . Topiramate is also associated with decreased
lipoprotein lipase activity in white adipose tissue, which would
limit free fatty acid substrate for lipogenesis [137] . Conversely,
topira­mate may increase lipoprotein lipase activity in brown adi-
pose tissue, which may represent increased thermogenesis and
increase lipoprotein lipase activity in skeletal muscle, further sup-
porting the potential for substrate oxidation [137] . Another effect on
the level of the adipocyte is that topiramate may increase adiponec-
tin levels [138] , which favorably affects many peripheral physiologic
processes relevant to metabolic disease [139] . While the clinical
significance is unclear, increased circulatory adiponectin may have
CNS effects regarding energy balance [140] .
Finally, clinical trials support topiramate as altering taste, which
could conceivably affect caloric intake [141] , and topiramate is a
carbonic anhydrase inhibitor, which may have anorexigenic effects
(see later). Overall, topiramate has multiple potential mechanisms
that could promote both weight loss, and ­persistence of weight loss.
Adverse experiences
Many of the adverse experiences reported with topiramate
are dose-related [112] . As with some other sulfa-based drugs
(e.g., acetazolamide, hydrochlorothiazide and cotrimoxazole)
topiramate can cause acute myopia, sudden onset of blurring of
vision, redness of the sclera, photophobia and discomfort of the
eyes resulting from secondary angle-closure glaucoma [142,143] .
Angle-closure glaucoma occurs when the aqueous humor pro-
duced in the anterior chamber (the space between the iris/lens
and cornea) by ciliary processes is unable to be drained through
the trabecular meshwork due to closure of the angle between
the iris and the cornea. The increased intraocular pressure may
adversely affect various portions of the eye, such as the cornea,
sclera, iris, lens and optic nerve. This potential adverse experience
usually occurs within hours to weeks after topiramate initiation.
Treatment involves stopping the topiramate [144] . The increased
risk of secondary angle-closure glaucoma with topiramate is in
contrast to primary angle-closure glaucoma, wherein treatment
may include procedures such as iridoplasty or medications such
as acetazolamide [145] . Acetazolamide may improve glaucoma by
inhibiting carbonic anhydrase isozymes in the ciliary processes of
the eye, reducing bicarbonate and aqueous humor secretion, and
thus reducing the elevated intraocular pressure [146] . This is some-
what paradoxical, given that topiramate, like acetazolamide, is an
inhibitor of carbonic anhydrase, and suggests that the secondary
angle-closure glaucoma with topiramate is not related to its inhibi-
tion of carbonic anhydrase. Finally, the commonality of carbonic
anydrase inhibitors helps explain why both acetazolamide and topi-
ramate may be effective in treating conditions such as ­idiopathic
intracranial hypertension [147] .
Expert Rev. Cardiovasc. Ther. 8(12), (2010)
 Phentermine, topiramate & their combination for treatment of adiposopathy & metabolic disease
However, while topiramate-associated glaucoma may not be
related to mild inhibition of carbonic anhydrase, other adverse
experiences may be related to this effect. Carbonic anhydrase is a
ubiquitous family of metalloenzymes that catalyze carbon dioxide
and water to bicarbonate and protons. In human metabolism,
nutrients (e.g., carbohydrates, protein and fats) are metabolized
by body tissues to generate sources of energy (e.g., adenosine
tri­phosphate), water and carbon dioxide. Carbonic anhydrase
enzymes help transport carbon dioxide by converting tissue car-
bon dioxide to bicarbonate, which is then carried by red blood
cells to the lungs, where pulmonary carbonic anhydrase converts
the bicarbonate back to carbon dioxide, which then undergoes
respiratory exchange for oxygen. The types of topiramate adverse
experiences most likely due to carbonic anhydrase inhibition
include metabolic acidosis [148] , increased risk of kidney stones [149]
and oligohidrosis (that generally reverses after stopping topira-
mate), which may contribute to hyperthermia (mostly described
in children) [150] . Other adverse experiences that may be related to
carbonic anhydrase inhibition include an increase in paresthesias,
which is among the most common adverse experiences associ-
ated with topiramate, as with other carbonic anhydrase inhibi-
tors [151] . Additional adverse experiences sometimes associated with
topira­mate as well as other carbonic anhydrase inhibitors include
anorexia, fatigue, somnolence and depression [152] .
Special mention should be made of the potential CNS adverse
experience of topiramate, which, as noted before, include difficulty
with concentration, difficulty with memory and depression [117] .
These potential adverse experiences are important with any drug
affecting the CNS, and particularly important with regards to
anti-obesity drug development. Rimonabant is a cannabinoid
receptor 1 (CB1) antagonist that underwent extensive, if not com-
prehensive, clinical trial evaluation. Rimonabant was not only
effective in generating weight loss, but also improved adiposopathy
and many metabolic diseases, such as dyslipidemia and Type 2
diabetes mellitus [153] . However, rimonabant never obtained US
regulatory approval because the FDA was more concerned about
the potential for CNS adverse experiences than it was impressed by
the numerous and significant improvements in metabolic disease
– suggesting that the current criteria for anti-obesity drug develop-
ment may need to be re-evaluated [154] . Paramount in the termina-
tion of rimonabant and several other CB1 antagonist development
­programs was a modest increase in depression and anxiety [155] .
Because topiramate is a CNS-acting drug, and is being consid-
ered as a component of an anti-obesity agent, an understanding
of its CNS effects becomes paramount. Publication of potential
suicidality associated with topiramate is basically limited to case
reports [156] . Because the frequency of suicide with individual
anticonvulsants was not sufficient for proper statistical analyses,
in 2008 the FDA mandated a warning labeling for many anti-
convulsant medications regarding the increased risk of suicidal
thoughts and behaviors, which included labeling applicable to
topiramate. A subsequent cohort study of a large database includ-
ing 297,620 new episodes of treatment with an anticonvulsant
agent identified 26 completed suicides, 801 attempted suicides and
41 violent deaths. This ana­lysis was not designed to determine if
www.expert-reviews.com
Review
the anticonvulsants caused, or contributed, to suicides, or if these
findings were simply incidental to the use of the anticonvulsants.
Topiramate was chosen as the reference drug in this study. This
exploratory analysis suggested that gabapentin, lamotrigine, oxcar-
bazepine and tiagabine were associated with an increased risk of
suicidal acts or violent deaths compared with topiramate [157] . This
might be interpreted as suggesting topiramate had the least poten-
tial to cause suicides as compared with the other approved and
commonly prescribed anticonvulsant therapies. Finally, it is note-
worthy that this study evaluated topiramate (not ­controlled-release)
at doses typically used for anticonvulsant therapy.
Topiramate, adiposopathy & metabolic disease
Although topiramate does not have an indication for weight loss,
it is interesting that topiramate appears to have more published
data than phentermine (which does have an indication for weight
loss) with respect to parameters associated with adiposopathy.
While the effects upon adipogenesis are unknown, the medical
literature does report data suggesting that topiramate has effects
upon adipose tissue factors that would generally be considered
favorable in preventing, or improving, metabolic disease (Table 1) .
Phentermine & topiramate
controlled-release combination
Rationale & history
Common themes in the development of pharmacologic thera-
pies for metabolic diseases (e.g., obesity, diabetes mellitus,
­hyper­tension and dyslipidemia) include:
• Drug treatment is intended to be an adjunct to appropriate
nutrition, increased physical activity and other favorable
­lifestyle interventions;
• Monotherapy of any single therapeutic agent is often ­insufficient
to achieve desired treatment goals;
• Compared with either agent alone, combining different thera-
peutic agents with complementary mechanisms of action may
have greater efficacy at lower doses of each;
• Compared with either agent alone, lower doses of the constitu-
ent drug therapies may improve upon the intolerances and
­toxicities associated with higher doses.
The phentermine and topiramate controlled-release (PHEN/
TPM CR; VI-0521; Qnexa®, Vivus, Inc., CA, USA ) development
program was consistent with this approach. PHEN/TPM CR
clinical trials were designed to evaluate the efficacy and safety of
the combined use of lower doses of two different drugs with dif-
fering mechanisms of action for the purpose of weight reduction
(e.g., reducing appetite and increasing satiety) over a 24-h period.
By utilizing a more-than-one treatment target approach, the hope
was to counteract redundant physiologic mechanisms that often
limit fat weight loss and frequently promote fat weight regain in
overweight patients.
The PHEN/TPM CR development program involved a once-
a-day, co-formulated combination single capsule of phenter-
mine HCl (which is readily dissolved and absorbed in the GI
1785
 Table 2. Preliminary data of Phase III clinical trials of the once-a-day phentermine/topiramate controlled-release combination agent.

1786
Clinical Patients Treatments Duration Patients Percent weight loss (ITT) Patients with Metabolic effects Ref.
trial completing ≥5% weight compared with placebo
Review

the study (%; ITT)

(%)
EQUATE n = 756 Placebo 4-week 66% of Placebo = -1.7% Placebo = 16% PHEN/TPM CR mid and full [160,
Bays

(OB-301) BMI = 30–45 kg/m2 Phentermine titration total study Phentermine HCl 7.5 mg = PHEN/TPM CR dose significantly reduced 161,
Mean BMI = HCl 7.5 mg followed population -5.5% mid dose = HbA1c by 0.10 and 0.11%, 207,
36.3 kg/m2 Phentermine by completed Phentermine HCl 15 mg = -6.1% 62%** respectively*** (baseline 215]
Women = 79% HCl 15 mg 24 weeks the study on Topiramate CR 46 mg = -5.1% PHEN/TPM CR full HbA1c = 5.42 and 5.48%,
African–American = Topiramate CR 46 mg of study drug Topiramate CR 92 mg = -6.6% dose = 66%** respectively)
19% Topiramate CR 92 mg treatment PHEN/TPM CR mid dose = (other values not
Diabetes mellitus = PHEN/TPM CR mid = total of -8.5%* reported)
0% dose 28 weeks PHEN/TPM CR full dose =
PHEN/TPM CR full dose -9.2%*
EQUIP BMI >35 kg/m2 Placebo (n = 514) 4-week Placebo = Placebo = -2% Placebo = 17% PHEN/TPM CR low dose [205,
(OB-302) Mean BMI = PHEN/TPM CR low titration 47% PHEN/TPM CR low dose = PHEN/TPM CR significantly reduced waist 216]
42 kg/m2 dose (n = 241) followed PHEN/ -5%*** low dose = circumference, systolic BP
Women = 83% PHEN/TPM CR full dose by TPM CR low PHEN/TPM CR full dose = 45%*** and total cholesterol;
FBG <110 mg/dl (n = 512) 52 weeks dose = -11%*** PHEN/TPM CR full PHEN/TPM CR full dose
TG ≤200 mg/dl of 57%*** dose = 67%*** significantly reduced waist
BP ≤140/90 mmHg treatment PHEN/ circumference, systolic BP,
(patients could be = total of TPM CR full diastolic BP, TG, total
on medication for 56 weeks dose = cholesterol and LDL-C, and
TG and BP) 59%*** increased HDL-C
CONQUER BMI = 27–45 kg/m2 Placebo (n = 994) 4-week Placebo = Placebo = -2% Placebo = 21% PHEN/TPM CR mid dose [162,
(OB-303) Mean BMI = 37% PHEN/TPM CR mid titration 57% PHEN/TPM CR low dose = PHEN/TPM CR significantly reduced waist 205,
Women = 70% dose (n = 498) followed PHEN/ -8%*** low dose = circumference, systolic BP, 216]
Two or more of the PHEN/TPM CR full dose by TPM CR mid PHEN/TPM CR full dose = 62%*** TG and total cholesterol, and
following (n = 995) 52 weeks dose = -10%*** PHEN/TPM CR full increased HDL-C levels;
comorbidities: high of 69%*** dose = 70%*** PHEN/TPM CR full dose
BP, high TG, treatment PHEN/ significantly reduced waist
hyperglycemia, = total of TPM CR full circumference, systolic BP,
increased waist 56 weeks dose = diastolic BP, TG, total
circumference, 64%*** cholesterol and LDL-C, and
Type 2 diabetes increased HDL-C levels
mellitus = 16%
‘Low dose’ = phentermine 3.75 mg/topiramate 23 mg per day. ‘Mid dose’ = phentermine 7.5 mg/topiramate 46 mg per day. ‘Full dose’ = phentermine 15 mg/topiramate 92 mg per day.
*p < 0.001 PHEN/TPM CR versus phentermine and topiramate monotherapies.
**p < 0.001 PHEN/TPM CR versus placebo.
***p < 0.0001 PHEN/TPM CR versus placebo.
BMI: Body mass index; BP: Blood pressure; CONQUER: A Phase III Randomized, Double-Blind, Placebo-controlled, Multicenter Study to Determine the Safety and Efficacy of VI-0521 in the Treatment of Obesity in
Adults with Obesity-related Co-morbid Conditions [217]; EQUATE: A Phase III Randomized, Double-Blind, Parallel-Design Study Comparing Multiple Doses of VI-0521 to Placebo and their Single-Agent Phentermine
and Topiramate Constituents for the Treatment of Obesity in Adults [217]; EQUIP: A Phase III Randomized, Double-Blind, Placebo-controlled Multicenter Study to Determine the Safety and Efficacy of VI-0521 in the
Treatment of Obesity in an Adult Population with BMI ≥35 kg/m2 [217]; FBG: Fasting blood glucose; HbA1c: Hemoglobin A1c; HDL-C: High-density lipoprotein cholesterol; ITT: Intent-to-treat population defined as
randomized patients with at least one dose of therapy and one post randomization assessment; LDL-C: Low-density lipoprotein cholesterol; PHEN/TPM CR: Phentermine HCl and topiramate controlled-release;
TG: Triglyceride.

Expert Rev. Cardiovasc. Ther. 8(12), (2010)

 Phentermine, topiramate & their combination for treatment of adiposopathy & metabolic disease Review

Table 3. Percent of adverse experiences occurring in over 5% of study participants (regardless of causality)
with PHEN/TPM CR during the EQUIP (n = 1264) and CONQUER (n = 2485) trials.
Adverse experience PHEN/TPM CR EQUIP study PHEN/TPM CR CONQUER study
Placebo (%) Low dose (%) Full dose (%) Placebo (%) Mid dose (%) Full dose (%)
Dry mouth 3.7 6.7 17.0 2.4 13.5 20.8
Tingling 1.9 4.2 18.8 2.0 13.7 20.5
Constipation 6.8 7.9 14.1 5.9 15.1 17.4
Upper respiratory 10.9 15.8 12.3 12.9 12.2 13.4
infection
Altered taste 1.0 1.3 8.4 1.1 7.4 10.4
Insomnia 4.9 5.0 7.8 4.7 5.8 10.3
Headache 10.1 10.4 11.9 9.1 7.0 10.2
Dizziness 4.1 2.9 5.7 3.1 7.2 10.0
Common cold 7.2 12.5 9.0 8.7 10.6 9.9
Sinus infection 5.5 7.5 7.2 6.7 6.8 8.6
Back pain 5.1 5.4 5.5 4.9 5.6 7.2
Nausea 4.7 5.8 7.2 4.2 3.6 6.8
Blurred vision 3.1 6.3 4.5 3.6 4.0 6.0
Bronchitis 4.3 6.7 5.5 4.3 4.4 5.2
Diarrhea 4.5 5.0 4.7 4.8 6.4 5.8
Urinary tract infection 3.5 3.3 4.7 3.7 5.2 5.4
Cough 3.5 3.3 5.1 3.0 3.8 4.8
Influenza 4.7 7.5 5.1 4.3 4.6 3.5
‘Low dose’ = phentermine 3.75 mg/topiramate 23 mg per day. ‘Mid dose’ = phentermine 7.5 mg/topiramate 46 mg per day. ‘Full dose’ = phentermine
15 mg/topiramate 92 mg per day.
CONQUER: A Phase III Randomized, Double-Blind, Placebo-controlled, Multicenter Study to Determine the Safety and Efficacy of VI-0521 in the Treatment of Obesity
in Adults with Obesity-related Co-morbid Conditions [217]; EQUIP: A Phase III Randomized, Double-Blind, Placebo-controlled Multicenter Study to Determine the
Safety and Efficacy of VI-0521 in the Treatment of Obesity in an Adult Population with BMI ≥35 kg/m2 [217]; PHEN/TPM CR: Phentermine HCl and topiramate
controlled-release.
Preliminary data taken from [205].

tract to provide therapeutic effects early in the day), added to
controlled-release topiramate (to provide persistent therapeu-
tic weight loss effects throughout the day). As noted before,
the maximum approved dose of phentermine monotherapy, as
found with the slower release resin formulation, is 30 mg per day,
which is roughly equivalent to 37.5 mg of the immediate-release
phentermine HCl. The maximum approved dose of topiramate
monotherapy is 400 mg per day. In its development program,
PHEN/TPM CR evaluated three combination doses. ‘Low
dose’ was defined as phentermine HCl 3.75 mg/topiramate CR
23 mg; ‘mid dose’ was phentermine HCl 7.5 mg/topiramate CR
46 mg; and ‘full dose’ was phentermine HCl 15 mg/topiramate
CR 92 mg. Thus, across the dose ranges, the PHEN/TPM CR
combination agent contained 40% or less of the maximum
approved dose of phentermine HCl (maximum dose phentermine
HCl monotherapy = 37.5 mg per day), and less than 25% of the
maximum approved dose of topiramate (maximum topiramate
monotherapy dose = 400 mg per day). Finally, the clinical trial
development program utilized a titration dosing schedule for
the first 4 weeks.
A full discussion of the results of the clinical trials in the
PHEN/TPM CR development program awaits peer-reviewed
published data. However, much of the PHEN/TPM CR clinical
trial data were presented as poster and podium abstracts at major
scientific meetings. The study sponsor also issued press releases
supplementing the scientifically presented data. Study sponsor
press releases are generally good at reporting basic study details
(as described herein), at least in part due to security regulations
and requirements [158] . However, press releases may be incomplete
regarding nuanced study limitations that may be more fully vet-
ted through peer review during the publication process [158] . The
same might be said about scientific abstracts. With these caveats
in mind, Table 2 summarizes preliminary disclosed data regarding
some of the sentinel Phase III clinical trials of the PHEN/TPM CR
combination agent.
Mechanism of action
The mechanism of action of PHEN/TPM CR would be expected
to reflect the mechanism of action of the individual components
previously described.

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 Review Bays

Adverse experiences discontinuation rate due to adverse experiences associated

Table 3 lists adverse experiences (regardless of cause) that occurred
in over 5% of study participants in the two largest trials to date.
Dry mouth and paresthesias (‘tingling’) occurred in approximately
20% of PHEN/TPM CR full-dose-administered subjects, with
other adverse experiences occurring in less than 20% of study par-
ticipants (e.g., constipation, altered taste, insomnia, headache, diz-
ziness, nausea and blurred vision). However, from a persistence-of-
use standpoint, it is often not the quantity or frequency of adverse
experiences associated with a pharmaceutical, but rather the quality
(degree) or severity of adverse experiences that is most clinically rel-
evant. Many commonly prescribed drugs have a high frequency of
adverse experiences that are not severe enough to negate their clini-
cal utilization. The product information (PI) of amoxicillin/clavu-
lanate potassium [202] describes a 9% frequency of diarrhea/loose
stools, with a warning of: “serious and occasionally fatal hypersensitivity
(anaphylactic) reactions” in patients treated with penicillin. The PI
of ibuprofen [203] describes a 4–16% frequency of gastrointestinal
complaints with a warning that: “serious gastrointestinal toxicity such
as bleeding, ulceration and perforation can occur at any time, with or
without warning symptoms.” The PI of metformin [204] describes a
53% frequency of diarrhea, 26% frequency of nausea/vomiting, 12%
frequency of flatulence and a warning of potential lactic acidosis that:
“when it occurs, it is fatal in approximately 50% of cases.” The point
is that simply having associated adverse experiences is not enough
to prevent the clinical use of a drug. Instead, the degree of severity
should be considered when determining the clinical importance of
the adverse experiences associated with a pharmaceutical treatment.
Table 4 provides data that somewhat reflect the severity of
these adverse experiences through representing the percent of
adverse experiences resulting in study discontinuation. The
with placebo was 9%, while the discontinuation rate due to
PHEN/TPM CR low, mid and full dose was 12, 12 and 18%,
respectively, with no particular adverse experience being an out-
lier causing disproportionate study discontinuation. Despite
the modest increase in discontinuations due to adverse experi-
ences in the PHEN/TPM CR group, it is interesting that Table 2
and Table 4 report a higher study completion rate in those in the
PHEN/TPM CR group compared with the placebo group, par-
ticularly with the mid-to-full PHEN/TPM CR dose. This sug-
gests that overall, more in the placebo group discontinued from the
trials than the PHEN/TPM CR groups, due to reasons other than
adverse experiences. One might speculate that the higher comple-
tion rate in the PHEN/TPM CR group might, at least in part, be
due to the greater weight loss efficacy of PHEN/TPM CR over pla-
cebo, resulting in a greater inclination to remain in the studies. It is
also possible that a topiramate-­induced reduction in food-addictive
behavior (as previously discussed) may have enhanced adherence
and completion of study protocols. Finally, CNS stimulant medica-
tions may improve retention of previously required information,
facilitate memory consolidation and conceivably have motivational
effects that might affect clinical trial completion. However, previ-
ously published data that might support such effects typically did
not include phentermine, are inconsistent and mostly studied in
patients with attention-deficit hyperactivity disorder. Furthermore,
while CNS stimulants might conceivably have the aforementioned
effects, the evidence does not always support stimulants as being
cognitive ‘enhancers’ [159] .
One of the main challenges of anti-obesity drug develop-
ment, particularly from a regulatory perspective, is the effect of
CNS-acting anti-obesity agents upon adverse experiences such

Table 4. Discontinuations due to adverse experiences in the EQUIP and CONQUER studies.
Parameter Placebo PHEN/TPM CR low dose PHEN/TPM CR mid dose PHEN/TPM CR full dose
Subjects (n) 1508 241 498 1507
Study completion (%) 53 57 69 62
Total discontinuations due to 9 12 12 18
AEs (%)
Blurred vision (%) 0.5 2.1 0.8 0.7
Headache (%) 0.7 1.7 0.2 0.9
Insomnia (%) 0.4 0.0 0.4 1.7
Depression (%) 0.2 0.0 0.8 1.4
Tingling (%) 0.0 0.4 1.0 1.2
Irritability (%) 0.1 0.8 0.8 1.2
Anxiety (%) 0.3 0.0 0.2 1.1
Dizziness (%) 0.2 0.4 1.2 0.8
‘Low dose’ = phentermine 3.75 mg/topiramate 23 mg per day. ‘Mid dose’ = phentermine 7.5 mg/topiramate 46 mg per day. ‘Full dose’ = phentermine
15 mg/topiramate 92 mg per day.
AE: Adverse experience; CONQUER: A Phase III Randomized, Double-Blind, Placebo-controlled, Multicenter Study to Determine the Safety and Efficacy of VI-0521 in
the Treatment of Obesity in Adults with Obesity-related Co-morbid Conditions [217]; EQUIP: A Phase III Randomized, Double-Blind, Placebo-controlled Multicenter
Study to Determine the Safety and Efficacy of VI-0521 in the Treatment of Obesity in an Adult Population with BMI ≥35 kg/m2 [217]; PHEN/TPM CR: Phentermine HCl
and topiramate controlled-release.
Preliminary data taken from [205].

1788 Expert Rev. Cardiovasc. Ther. 8(12), (2010)

 Phentermine, topiramate & their combination for treatment of adiposopathy & metabolic disease
as ­anxiety and depression. As opposed to several other develop-
ment programs, study subjects in some of the PHEN/TPM CR
trials were permitted to have mild depression, as long as their
antidepressant therapy was stable prior to study entry. Preliminary
reports suggest that PHEN/TPM CR does not significantly
increase moderate or severe depression as measured by depres-
sion scales such as the Patient Health Questionnaire (PHQ) – 9.
Other scales, such as the Columbia Suicide Severity Rating Scale
reportedly demonstrated no increase in suicidality [205] .
PHEN/TPM CR, adiposopathy & metabolic disease
Table 1lists the effects of PHEN/TPM CR upon adipocyte and/or
adipose tissue factors thought to contribute to metabolic disease.
Most have yet to be evaluated or reported. Table 2 describes the weight
loss and improvement in metabolic diseases of PHEN/TPM CR in
three sentinel clinical trials.
The 6-month EQUATE trial evaluated 756 generally
healthy obese subjects with a BMI between 30 and 45 kg/m2.
PHEN/TPM CR mid- and full-dose combination therapies sig-
nificantly reduced body weight over the same doses of phenter-
mine and topiramate monotherapies [160] . Diabetes mellitus was
an exclusion criterion. Nonetheless, a subset analysis demonstrated
that both mid- and full-dose PHEN/TPM CR reduced hemoglo-
bin A1c (HbA1c) [6,161,206] . The most common adverse experiences
for placebo, PHEN/TPM CR mid dose and PHEN/TPM CR full
dose, respectively, were tingling (3, 16 and 23%), dry mouth (0,
13 and 18%), headache (13, 15 and 16%) and constipation (8, 7
and 15%) [207] .
The 1-year EQUIP study evaluated 1267 generally healthy obese
subjects with a BMI of 35 kg/m2 or more. PHEN/TPM CR low
and full dose significantly reduced body weight compared with
placebo. Despite having minimal or drug-controlled metabolic
abnormalities at baseline, PHEN/TPM CR low dose signifi-
cantly reduced systolic BP and total cholesterol. PHEN/TPM CR
full dose significantly reduced systolic BP, reduced diastolic BP,
reduced triglycerides (TGs), reduced total cholesterol, reduced
LDL cholesterol (LDL-C), and increased HDL (HDL-C) lev-
els [205] . The significant reduction in total body weight, the
reduction in waist circumference, and the significant improve-
ment in metabolic parameters compared with placebo supported
PHEN/TPM CR as being effective in treating adiposopathy and
its adverse ­metabolic consequences.
The 1-year CONQUER trial included 2487 obese patients
with a BMI of 27 kg/m 2 or more and common metabolic
comorbidities associated with adiposopathy. This study dem-
onstrated that PHEN/TPM CR significantly reduced body
weight, and reduced waist circumference (an anatomical mani-
festation of adiposo­pathy) compared with placebo. In addition,
PHEN/TPM CR mid dose significantly reduced BP, TG and
total cholesterol, and increased HDL-C levels. PHEN/TPM CR
full dose significantly reduced systolic BP, reduced diastolic BP,
reduced TG, reduced total cholesterol, reduced LDL-C and
increased HDL-C levels. Among the subset of patients with
Type 2 diabetes mellitus upon study entry, both the mid- and
full-dose PHEN/TPM CR significantly reduced HbA1c, fasting
www.expert-reviews.com
Review
glucose, insulin levels (after an oral glucose tolerance test), and
the homeostatic model assessment of insulin resistance [162,205] .
Among the subset of patients with high BP at study entry, both
the mid- and full-dose PHEN/TPM CR significantly reduced
systolic BP. Among the subset of patients with hypertriglyceri-
demia at study entry, both mid- and high-dose PHEN/TPM CR
significantly reduced TG levels [205] .
A trial not listed in Table 2 was a 56-week, randomized, double-
blind, placebo-controlled trial of PHEN/TPM CR full dose in
130 obese subjects (BMI 27–45 kg/m2) with drug-naive Type 2
diabetes mellitus, or Type 2 diabetes mellitus treated with oral
antihyper­glycemic drugs [163,208] . Patients with stable depression
were eligible, as were those treated with selective serotonin reuptake
inhibitors (SSRIs) or serotonin/norepinephrine reuptake inhibitors
(SNRIs). Baseline mean age was 50 years, 90 were women, 40 were
men, and over 90% of subjects completed the trial. PHEN/TPM CR
produced a 9.4% reduction in body weight (vs a reduction of 2.7%
with placebo), and a reduction in HbA1c of 1.6% (vs reduction
of 1.1% with placebo). The high degree of HbA1c reduction with
placebo was due to the increase in anti-diabetes mellitus therapies
utilized in the placebo group during the trial versus a net decrease
in anti-diabetes mellitus therapies utilized in the PHEN/TPM CR
group. In addition to improvements in fasting and postprandial
glucose levels, PHEN/TPM CR also resulted in a decrease in waist
­circumference, BP and ­triglyceride levels.
Taken in totality, these studies support PHEN/TPM CR as
not only effective in improving the weight of patients, but also
effective in improving the metabolic health of patients.
Conclusion
The PHEN/TPM CR development program involved the com-
bined use of two pharmaceuticals known to have weight loss
properties and complementary mechanisms of action. Its com-
ponents were at doses lower than approved for their monotherapy
treatment indications. This helps account for why the reported
adverse experiences with PHEN/TPM CR were not severe enough
to result in substantial discontinuance of drug therapy. In fact,
the PHEN/TPM CR had higher persistence of use than the
placebo group. Most importantly, PHEN/TPM CR improved
adiposo­pathy, as evidenced by the significant loss of body weight,
reduction in waist circumference and improvement in multiple
metabolic parameters. This all supports PHEN/TPM CR as not
only improving the weight of patients, but also improving the
health of patients.
Expert commentary & five-year view
In early to mid-2010, only two anti-obesity drugs were
approved for long-term use in the USA (i.e., orlistat and sibutra-
mine). In early 2010, sibutramine was no longer approved in
Europex [3,23,164] , leaving only orlistat. Obesity is the greatest
epidemic in human existence, based upon the number of lives
affected [23] . Thus far, regulatory agencies have determined that
the risks of all but one or two anti-obesity drug therapies exceed
their potential benefits in treating adiposity, adiposopathy and
­metabolic disease.
1789
 Review Bays
The history of anti-obesity drug development has often been
‘challenging’ at best, and disastrous at worst [23,87] . Adverse safety
experiences with previous anti-obesity drugs may have tempered,
and perhaps even jaded regulatory enthusiasm for approving
future anti-obesity agents [87] . Hopefully, a ‘new age’ in anti-
obesity drug development will result from the increased recogni-
tion of adipose tissue being far more than simply an inert storage
organ. Adipose tissue is an active endocrine and immune organ
whose dysfunction promotes the most common metabolic diseases
encountered in clinical practice (e.g., diabetes mellitus, high BP
and dyslipidemia) [5] . As such, the next 5–10 years may represent
a renaissance in what was known in the 1940s to 1970s, which is
that adipocytes [14,15] and adipose tissue [28] are potentially patho-
genic. In other words, recognizing adipocyte hypertrophy and
visceral adiposity as contributing, or in fact ‘causing’, metabolic
disease is not a novel concept [6] . It is certainly not novel to clini-
cians who, in the day-to-day management of patients, frequently
observe onset or worsening of glucose, BP and lipid levels in their
patients who gain body fat.
Towards the goal of ‘rediscovering’ the pathogenic metabolic
potential of adipose tissue in human disease, the terms ‘adiposo­
pathy’ and ‘sick fat’ as scientific and clinical terms, respec-
tively, may afford advantages over older, less meaningful terms.
‘Obesity’, ‘metabolic syndrome’ and ‘ectopic fat’ are examples of
terms that may soon become obsolete, or at least acquire different
meanings than intended today. For example, if it is to continue to
describe a ‘disease’ at all, the term ‘obesity’ may eventually refer
to body-mass pathology alone [23] . The potential of adipose tissue
to contribute to metabolic disease is better assessed based upon
its pathogenic endocrine and immunological responses, relative
to a simple measurement of body weight [17] . Likewise, the term
‘metabolic syndrome’ remains problematic for many reasons;
most of all because it was never intended to represent or describe
a unified pathophysiologic process [1,165] . Broken down to its basic
components, ‘metabolic syndrome’ is nothing more than a collec-
tion of common metabolic abnormalities that tend to cluster and
which are CHD risk factors [6] . The National Education Program,
Adult Treatment Panel III includes increased waist circumference
as one of the five components of defining ‘metabolic syndrome’.
The International Diabetes Federation goes further in recogniz-
ing the pathogenic importance of pathogenic adipose tissue by
requiring increased waist circumference as being present to meet
the definition of the ‘metabolic syndrome’, which must then be
accompanied by other metabolic abnormalities. These defini-
tions provide implicit recognition of the pathogenic potential of
adipose tissue with respect to promoting metabolic abnormalities
and increasing CHD risk. Thus, one might argue that the term
‘metabolic syndrome’ might best be replaced by a term that bet-
ter describes the underlying cause of the clustering of common
atherosclerotic risk factors. ‘Adiposopathy’ is such a term [1,2] .
A third term that may be destined for evolution or dissolu-
tion is ‘ectopic fat’. Adipose tissue has biologic and physiologic
importance, such as by providing heat insulation, mechanical
cushion, endocrine functions, immune functions and storage
of energy. Thus, the presence of adipose tissue is important for
1790
metabolic health; the absence of body fat is pathologic [6] . Ectopic
fat describes the situation wherein existing adipose tissue is no
longer able to efficiently store excess energy. Fats (free fatty acids,
triglycerides, etc.) are inappropriately transported and stored in
body organs, increasing the risk of metabolic disease. Some of
this excessive energy may be stored through a pathologic transfer
of free fatty acids to non-adipose tissue organs (e.g., the liver and
muscle), which contributes to metabolic disease [6] . However,
most excessive energy is stored in various adipose tissue depots.
This results in the sometimes curious characterization of addi-
tional adipose tissue (such as increased visceral adipose tissue) as
representing ‘ectopic fat’ [166] . In fact, any excessive fat in any loca-
tion is considered by some as representing ‘ectopic fat’. However, if
all excessive fat storage is ‘ectopic’, then this raises the question as
to the clinical utility of this term. One could argue that ‘adipos-
ity’ is a term sufficient in describing excessive body fat, and the
term ‘adiposopathy’ is more precise in describing when excessive
body fat is pathogenic in causing or promoting adverse metabolic
consequences leading to metabolic disease.
As the pathogenic potential of adipose tissue becomes more
widely acknowledged, specific diagnostic criteria will need to be
developed for adiposopathy or ‘sick fat’ [1] . Once this process is
complete, then perhaps regulatory agencies would be more open
to establishing treatment indications to improve adiposopathy
(a true disease) [167] , and thus free themselves from approval pro-
cesses whose only definitive metrics are focused on reductions
in body weight [168,209] . In other words, the current FDA guid-
ance for industry has comments such as how: “excessive body fat
increases the risk of death and major comorbidities such as Type 2
diabetes, hypertension, dyslipidemia, cardiovascular disease, osteo-
arthritis of the knee, sleep apnea and some cancers” [209] , suggest-
ing a belief that adiposity is merely associated with, rather than
potentially causative of, fat-mass complications and metabolic
disease. Furthermore, although current guidance does stress the
importance of improvement in metabolic disease, the degree by
which weight loss agents safely improve the weight of patients
remains the focus, as opposed to the degree by which these agents
improve the metabolic health of patients.
This brings us to PHEN/TPM CR. Phentermine is an anti-
obesity drug indicated for short-term treatment of obesity. It is an
approved pharmaceutical that has been in clinical use for approxi-
mately 50 years, and is the most widely prescribed anti-obesity
agent. Phentermine has no reported adverse drug inter­actions
when used with topiramate, and has no product information state-
ments warning against its use with topiramate. Topiramate is an
anti-seizure drug and migraine headache prophylactic drug. It is
an approved pharmaceutical that has been in development since
the 1970s and in clinical use for over a decade. It is among the most
commonly prescribed anticonvulsant therapies. Topiramate has no
reported adverse drug interactions when used with phentermine,
and has no product information statements warning against its use
with phentermine. Data in this review support PHEN/TPM CR
as being no less safe or no less tolerated than what would be
expected from the individual components. This might be antici-
pated given that the PHEN/TPM CR combination agent includes
Expert Rev. Cardiovasc. Ther. 8(12), (2010)
 Phentermine, topiramate & their combination for treatment of adiposopathy & metabolic disease
topiramate in a controlled-release formulation (although this has
yet to be proven to afford benefits over non-controlled-released
formulations), and utilizes doses of phentermine and topiramate
that are a fraction of their respective maximum approved doses.
The safety dataset will be substantially enhanced by the results of
the long-term OB-305 extension study (SEQUEL), due sometime
in latter 2010 or early 2011. If clinicians accept PHEN/TPM CR
as being as safe as the individual components, then fundamental
decisions will have to be made regarding the clinical importance
of adiposity and adiposopathy.
Clinicians may question whether the weight loss with
PHEN/TPM CR is sufficient to improve fat-mass diseases. The
OB-204 study reported a significant improvement in sleep apnea
with PHEN/TPM CR, which would seem to be a significant ben-
efit in reducing fat mass [210] . Clinicians may also question whether
the statistically significant weight loss with PHEN/TPM CR
represents clinically meaningful weight loss. Insight as to what
may be ‘clinically meaningful’ might be derived from regulatory
agency guidance. The FDA ‘Guidance for Industry: Developing
Products for Weight Management’ [209] has suggested regulatory
metrics for approval of weight loss drugs and therapeutic biologics
(termed ‘products’). According to the FDA, Phase I and II trials
should characterize the pharmacokinetics and dose response of the
product, over a range of doses and across a broad range of BMI
(e.g., BMI ≥30 kg/m2 ; or ≥27 kg/m2 if with comorbidities) to
determine no-effect, maximally tolerated doses and efficacy of all
doses relative to placebo. The duration should be long enough to
capture the product’s maximal or near-maximal weight loss effects.
Primary end points should be mean absolute or percent change
in body weight in the active versus placebo group, as well as the
proportion of each treatment group with a weight loss of 5% or
more of baseline weight. Other end points should include evalua-
tions of weight-related comorbidities. The EQUATE study (Table 2)
supports PHEN/TPM CR as fulfilling many of these criteria.
Phase III trials should be randomized, double-blind, placebo-
controlled 1-year studies in patients with a BMI of 30 kg/m2 or
more, or 27 kg/m2 or more if with comorbidities such as Type 2
diabetes mellitus, hypertension, dyslipidemia, sleep apnea and car-
diovascular disease (with some having a BMI >40 kg/m2), and with
representation from demographic, ethnic and racial groups having a
high prevalence of obesity. The concomitant lifestyle modification
program: “should strike an appropriate balance between effectiveness
and simplicity.” A reasonable safety set would include 3000 subjects
randomized to active drug and no fewer than 1500 randomized
to comparator placebo. Recommended primary end points would
be mean difference in percent loss of baseline body weight (active
treatment vs placebo) and categorical (proportional) ana­lysis of
study participants who lost at least 5% of baseline body weight
(active treatment vs placebo). Secondary end points should include
changes in fasting glucose, insulin and HbA1c levels, BP, pulse and
lipid levels. Waist circumference should also be measured; however,
while acceptable as a surrogate in clinical practice, waist circum­
ference is not considered an acceptable surrogate for visceral fat in
the context of a clinical trial. More direct measures for visceral adi-
posity would include dual energy x-ray absorptiometry composition
www.expert-reviews.com
Review
analysis, which is also important to ensure that the weight loss is
primarily fat and not loss of lean body mass. Concomitant meta-
bolic drug therapies should be assessed by protocol-defined algo-
rithms to determine their initiation, withdrawal, increase in dose
and decrease in dose during the course of the trials. ‘Effectiveness’
of a weight loss product is achieved if after 1 year of treatment, one
of the two following benchmarks are met:
• The difference in mean weight loss between the active product
and placebo-treated groups is at least 5%, and the difference is
statistically significant;
• The proportion of subjects who lose 5% of baseline body weight
or more in the active product group is at least 35%, is approx-
imately double the proportion in the placebo-­treated group,
and the difference between groups is statistically significant.
Although overweight and obese study participants are expected
to receive standard of care for metabolic comorbidities, and
although no specific criteria are given, glycemic, BP and lipid
measurements are expected to improve as would be anticipated
with the degree of weight loss.
Other guidance recommendations are specific for individual
weight loss agents. Weight management products that act upon the
CNS should include an assessment of neuropsychiatric function
through validated scales, as well as potentially additional studies
to evaluate abuse liability. Weight management products that are
therapeutic proteins should undergo assessment of immuno­genic
potential for 6–12 months. Combination weight management
products should first have data comparing the combination prod-
uct to its individual components of sufficient duration to capture
their respective maximal or near-maximal weight effects. The
combination weight management product should have greater
weight loss efficacy compared with its individual components,
with weight loss twice the individual components being preferred.
Special guidance is made regarding the evaluation of overweight
and obese patients with Type 2 diabetes mellitus. Weight loss with
bariatric surgery can substantially improve many metabolic param-
eters. Its favorable effects upon Type 2 diabetes mellitus are partic-
ularly noteworthy, with remission of Type 2 diabetes mellitus being
as high as 80% [50] . Conversely, several prior anti-obesity drug
trials have often resulted in a less than robust response in weight
loss and in improving diabetes mellitus, possibly because dramatic
weight loss may be required to significantly improve fat function
(particularly in older patients). This suggests that the degree of
success of weight-loss interventions in improving diabetes mellitus
may be dependent upon the age of the patient, the pathology of
the diabetes mellitus, the duration of the diabetes mellitus, and
the degree of potential improvement in the functionality of adipo-
cytes and adipose tissue [17] , as well as other body organs. In their
guidance, the FDA reflected this viewpoint by stating: “compared
with nondiabetic patients, overweight and obese patients with Type 2
diabetes often respond less favorably to weight-management products.”
In consideration of all the above, Table 2 supports PHEN/TPM CR
as meeting many of the FDA weight loss guidance criteria. Table 2
also supports PHEN/TPM CR as providing clinically meaning-
ful improvements in metabolic diseases such as diabetes mellitus,
1791
 Review Bays

hypertension and dyslipidemia. PHEN/TPM CR does not appear
to significantly adversely increase depression, as assessed by com-
mon neuropsychiatric scales [205] . Finally, as noted before, in a
trial of overweight or obese patients with Type 2 diabetes mellitus,
PHEN/TPM CR produced a robust 9.4% reduction in body weight
(vs a reduction of 2.7% with placebo), and a substantial reduction
in HbA1c of 1.6% (vs reduction of 1.1% with placebo) [163,208] .
The high degree of HbA1c reduction with placebo was at least
partially due to an increase in anti-diabetes mellitus therapies. The
even greater HbA1c reduction with PHEN/TPM CR was despite
a net decrease in anti-diabetes mellitus therapies. It is unclear that
these data suggest PHEN/TPM CR as having unique weight loss
and/or antiglycemic properties that make it superior to other anti-
obesity drug therapies in patients with Type 2 diabetes mellitus.
To prove this, head-to-head controlled clinical trials would need
to be performed. However, it is interesting to revisit the fact that
topiramate was originally developed as an agent to treat Type 2
diabetes mellitus [60,107–109] .

Box 1. US FDA: 2008 guidance for evaluating cardiovascular risk associated with new anti-diabetes
mellitus drug therapies.
“To establish the safety of a new antidiabetic therapy to treat Type 2 diabetes, sponsors should demonstrate that the therapy will not
result in an unacceptable increase in cardiovascular risk. To ensure that a new therapy does not increase cardiovascular risk to an
unacceptable extent, the development program for a new Type 2 antidiabetic therapy should include the following.

For new clinical studies in the planning stage:

• Sponsors should establish an independent cardiovascular end points committee to prospectively adjudicate, in a blinded fashion,
cardiovascular events during all Phase II and Phase III trials. These events should include cardiovascular mortality, myocardial infarction,
and stroke, and can include hospitalization for acute coronary syndrome, urgent revascularization procedures and possibly other
end points.
• Sponsors should ensure that Phase II and Phase III clinical trials are appropriately designed and conducted so that a meta-analysis can
be performed at the time of completion of these studies that appropriately accounts for important study design features and patient or
study level covariates. To obtain sufficient end points to allow a meaningful estimate of risk, the Phase II and Phase III programs should
include patients at higher risk of cardiovascular events, such as patients with relatively advanced disease, elderly patients and patients
with some degree of renal impairment. Because these types of patients are likely to be treated with the antidiabetic agent, if approved,
this population is more appropriate than a younger and healthier population for assessment of other aspects of the test drug’s safety.
• Sponsors also should provide a protocol describing the statistical methods for the proposed meta-analysis, including the end points
that will be assessed. At this time, we believe it would be reasonable to include in a meta-analysis all placebo-controlled trials, add-on
trials (i.e., drug versus placebo, each added to standard therapy), and active-controlled trials, and to preserve the study level
randomized comparison but include, when possible in the meta-analysis, important identifiers of study differences or other factors
(e.g., dose, duration of exposure, add-on drugs). It is likely that the controlled trials will need to last more than the typical 3–6 months
duration to obtain enough events and to provide data on longer-term cardiovascular risk (e.g., minimum 2 years) for these chronically
used therapies.
• Sponsors should perform a meta-analysis of the important cardiovascular events across Phase II and Phase III controlled clinical trials
and explore similarities and/or differences in subgroups (e.g., age, sex, race), if possible.

For completed studies, before submission of the new drug application (NDA)/biologics license application (BLA):
• Sponsors should compare the incidence of important cardiovascular events occurring with the investigational agent to the incidence of
the same types of events occurring with the control group to show that the upper bound of the two-sided 95 percent confidence
interval for the estimated risk ratio is less than 1.8. This can be accomplished in several ways. The integrated analysis (meta-analysis) of
the Phase II and Phase III clinical trials described above can be used. Or, if the data from all the studies that are part of the meta-
analysis will not by itself be able to show that the upper bound of the two-sided 95 percent confidence interval for the estimated risk
ratio is less than 1.8, then an additional single, large safety trial should be conducted that alone, or added to other trials, would be able
to satisfy this upper bound before NDA/BLA submission. Regardless of the method used, sponsors should consider the entire range of
possible increased risk consistent with the confidence interval and the point estimate of the risk increase. For example, it would not be
reassuring to find a point estimate of 1.5 (a nominally significant increase), even if the 95 percent upper bound was less than 1.8.
• If the premarketing application contains clinical data that show that the upper bound of the two-sided 95 percent confidence interval
for the estimated increased risk (i.e., risk ratio) is between 1.3 and 1.8, and the overall risk-benefit ana­lysis supports approval, a
postmarketing trial generally will be necessary to definitively show that the upper bound of the two-sided 95 percent confidence
interval for the estimated risk ratio is less than 1.3. This can be achieved by conducting a single trial that is adequately powered or by
combining the results from a premarketing safety trial with a similarly designed postmarketing safety trial. This clinical trial will be a
required postmarketing safety trial.
• If the premarketing application contains clinical data that show that the upper bound of the two-sided 95 percent confidence interval
for the estimated increased risk (i.e., risk ratio) is less than 1.3 and the overall risk-benefit ana­lysis supports approval, a postmarketing
cardiovascular trial generally may not be necessary.
• The report of this meta-analysis should contain sufficient detail for all the analyses; conventional graphical plots for meta-analysis
finding by study, subgroup, and overall risk ratio; and all the ana­lysis data sets that would allow a verification of the findings.”
Data taken from [214].

1792 Expert Rev. Cardiovasc. Ther. 8(12), (2010)

 Phentermine, topiramate & their combination for treatment of adiposopathy & metabolic disease Review

Clinical importance of treatment

Treatment of adiposity, adiposopathy and

Prophylaxis of migraine headache with topiramate: metabolic disease with PHEN/TPM CR‡:
– Topiramate dose = 100 mg per day† – Topiramate mid/full dose = 46/92 mg per day§
– Topiramate not controlled release¶ – Topiramate controlled release¶

Expert Rev. Cardiovasc. Ther. © Future Science Group (2010)

Figure 2. Relative importance of prophylactically treating migraine headaches versus treating adiposity, adiposopathy and
metabolic disease.
†
Topiramate doses may be as low as 50 mg per day for prophylaxis of migraine headaches, and as high as 400 mg per day for treatment
of seizure disorders.
‡
Both phentermine and topiramate are approved drugs. Neither phentermine nor topiramate have product information that warns
of potential adverse experiences with their combined use.
§
The ‘low dose’ PHEN/TPM CR evaluated in clinical trials contained 23 mg of topiramate CR.
¶
It is yet to be proven that controlled-release topiramate affords additional efficacy or safety advantages over
non-controlled-release formulations.
PHEN/TPM CR: Phentermine HCl and topiramate controlled‑release.

Having met efficacy criteria, the main issue regarding the regu-
latory approval of PHEN/TPM CR would seem to be (not sur-
prisingly) matters of safety [211] . On 15 July 2010, a FDA advisory
committee issued a mixed decision of 10 to 6 against endorsing
PHEN/TPM CR as an approved pharmaceutical at that time.
Reports suggested that: “the FDA and most panel members did not
question the effectiveness of ” PHEN/TPM CR; “several panel mem-
bers said they could just as easily have voted the other way.” However,
the main potential safety concerns noted were an increase in heart
rate (“…in the 1-year cohort, small mean increases in heart rate were
observed in the QNEXA treatment groups [0.6–1.6 beats per minute
at the top dose] compared with placebo treatment groups…”) [211] ,
possible birth defects, impaired memory and concentration,
metabolic acidosis with kidney stones and psychiatric problems
(e.g., depression and suicidal ideations) [212] .
All of these potential adverse experiences were discussed previ-
ously in this review, except for the potential for birth defects.
The pregnancy risks of pharmaceuticals are often characterized
by the FDA according to categories. The safest are pregnancy
categories A (e.g., thyroid medication at replacement doses) and
B (e.g., amoxi­cillin). The least safe are pregnancy categories D
(e.g., tetracycline) and X (e.g., statins). Phentermine and topi-
ramate are both pregnancy category C [211] , which means that
animal reproduction studies have shown an adverse effect on
the fetus, but no adequate and well-controlled studies exist in
humans, and the potential benefits may warrant use of the drug
in pregnant women despite potential risks.
Regarding issues that may have influenced the split deci-
sion, some reports suggest that the FDA’s advisory commit-
tee’s decision was inf luenced by the controversy (just days
before) involving matters of another FDA advisory committee’s
deliberation regarding an otherwise unrelated anti-diabetes
mellitus drug [212] . With regard to the FDA’s initial reaction
to the decision:
“Eric Colman, deputy director of the FDA’s Division of
Metabolism and Endocrinology Products, noted that the agency’s
current draft guidelines only call for one year of safety data. He
told reporters after the meeting that based on the outcome of
Thursday’s committee and the upcoming panels for lorcaserin and
Contrave, the FDA likely will update that guidance before releas-
ing a final version of the document. Colman said he was ‘surprised’
by the outcome of Thursday’s vote. ‘I’ve learned that you never
know what is going to happen, what they are going to say, how they
are going to vote,’ he told reporters. But Colman said he thought
there was ‘a little bit of hesitancy’ from those who voted against
approval, adding that those panelists ‘were not strongly against
the drug, but had lingering concerns that were enough to vote no.’
While the FDA is requiring makers of Type II diabetes drugs to
conduct cardiovascular outcomes trials, Colman noted that the
agency has yet to mandate the same for weight loss drugs. ‘We’ve
had those conversations,’ he said. ‘But the discussion hasn’t evolved
to the point to where we are making it formal,’ Colman said,
noting the panel’s concerns about increased heart rates in Vivus’
studies of Qnexa” [213] .

www.expert-reviews.com 1793
 Review Bays
The reference to the regulatory requirements of cardiovascular
outcomes pertains to the FDA guidance on the development of
diabetes mellitus drug therapies, as issued in December 2008 (Box 1)
[214] . It is therefore possible that similar regulatory recommendations
may soon apply to anti-obesity drug development, with the potential
requirement of a planned or partially enrolled cardiovascular disease
outcome study upon approval. Alternatively or additionally, longer
term clinical trials might be required (longer than 1 year) to assess
the safety risks associated with chronic anti-obesity therapy.
In addition to legitimate matters of safety, unique obstacles
may exist to anti-obesity drug development. These impediments
may include bias against pharmaceutical therapies for obesity,
especially among those who believe obesity is mainly a behavioral
problem that should only be managed through appropriate nutri-
tion and lifestyle changes. But while true that adiposity often has a
strong behavioral component, medical science has not historically
withheld drug development or medical care on the basis that a
disease or condition is substantially due to a lack of medically
favorable personal behavior [7] . As importantly, the resistance to
anti-obesity drug development may also reflect medical and social
biases against the obese, which have existed for centuries [169] , and
manifest by a sense that treating adiposity is not as important as
treating other diseases. In other words, perfectly valid clinical
reasons exist why medical science currently has only one or two
drugs available to treat the world’s greatest epidemic [87] . But it is
also reasonable to question the apparent belief among many that
unless a weight-loss pharmaceutical has virtually no risk, then
the benefits of weight loss are not sufficient to warrant approval.
It is disturbing that adiposity and adiposopathy are on the brink
of representing the first epidemics in history that medical science
has implicitly decided are untreatable by pharmaceutical therapy.
As such, a most fundamental question facing researchers, regu-
latory agencies and clinicians is that relative to other diseases, how
important is treating adiposity, adiposopathy and affiliated meta-
bolic diseases (e.g., Type 2 diabetes mellitus, hypertension and
dyslipidemia)? Through their prescribing habits, clinicians have
already decided that the risk:benefit ratio of the 100 mg dose of
topiramate (not controlled-release) is acceptable for prophylaxis of
migraine headaches [170] . Do clinicians likewise agree that PHEN/
TPM CR (which incorporates, at most, 92 mg of topiramate in
a controlled-release formulation) is acceptable for treatment of
adiposity, adiposopathy and metabolic disease? Is preventing
migraine headaches of greater or less clinical importance than
improving the numerous metabolic abnormalities associated with
adiposity and adiposopathy? (Figure 2) . If clinicians ultimately agree
that the pathologies of adiposity and adiposopathy are equally as
worthy of treatment as preventing migraine headaches, then based
upon available evidence, PHEN/TPM CR appears to not only
improve the weight of patients, but also appears to improve the
metabolic health of patients. This meets the evolving, suggested
criteria for weight loss drug development, which states: “An emerg-
ing concept is that the development of anti-obesity agents must not
only reduce fat mass (adiposity) but must also correct fat dysfunction
­(adiposopathy)” [60] .
1794
Update
Following the online publication of this manuscript on 16 August
2010, the following updates have occurred:
• In October 2010, sibutramine (Meridia) was withdrawn from
the US market due to its potential to increase the risk for cardio­
vascular events. This left only one drug, orlistat, approved for
long-term treatment of obesity (see the section of this manu-
script entitled ‘Expert commentary & five-year view, for more
information).
• After the decision of the US FDA advisory panel (described in
this manuscript), the FDA issued a Complete Response Letter
to the manufacturer of phentermine HCl/topiramate control-
led-release (PHEN/TPM CR), wherein additional data was
requested [218] , including:
−− Clinical: the FDA requested a comprehensive assessment of
PHEN/TPM CR’s teratogenic potential, cardiovascular
implications of the associated increase in heart rate, and data
from the already completed SEQUEL study (OB-305) (see
the section of this manuscript entitled ‘Expert commentary
& five-year view’ for more information);
−− Labeling: the FDA reserved the right to comment further
on proposed labeling;
−− Risk Evaluation and Mitigation Strategy (REMS): the FDA
requested a further discussion of a previously submitted
REMS plan to better determine the long-term health out-
comes of PHEN/TPM CR;
−− Safety update: the FDA requested a safety update of any new
adverse experiences;
−− Drug scheduling: the FDA stated that if approved, PHEN/
TPM CR would be a Schedule IV drug due to the phenter-
mine component (see the section of this manuscript entitled
‘Phentermine’ for more information).
Financial & competing interests disclosure
Harold Bays has served as a Clinical Investigator for (and has received
research grants from) pharmaceutical companies such as Abbott, Aegerion,
Akros, Amarin, Amgen, Amylin, Alteon, Arena, Arete, AstraZeneca,
Aventis, Bayer, Boehringer, Bristol-Myers Squibb, Cargill, Ciba Geigy,
Daiichi Sankyo, Eli Lilly, Esperion, Essentialis, Fujisawa, GelTex,
Genentech, GlaxoSmithKline, Hoechst Roussel, Hoffman LaRoche, Home
Access, InterMune, Intekrin, Ironwood Pharmaceuticals, ISIS, Johnson &
Johnson, KOS, Kowa, Kyorin, Lederle, Marion Merrell Dow, Merck,
Merck Schering Plough, Metabolex, Microbia, Miles, Neuromed, Nicox,
Novartis, NovoNordisk, Obecure, Orexigen, Parke Davis, Pfizer, Pliva,
Posen, Purdue, Reliant, Roche, Rorer, Regeneron, Sandoz, Sanofi, Sciele,
Searle, Shionogi, Schering Plough, SmithKline Beecham, Surface Logix,
Takeda, TAP, UpJohn, Upsher Smith, Warner Lambert, Vivus and Wyeth-
Ayerst. Harold Bays has served as a consultant, speaker and/or advisor to
and for pharmaceutical companies such as Abbott, Amarin, Arena,
AstraZeneca, Aventis, Bayer, Bristol-Myers Squibb, Cerenis, Daiichi
Expert Rev. Cardiovasc. Ther. 8(12), (2010)
 Phentermine, topiramate & their combination for treatment of adiposopathy & metabolic disease Review

Sankyo, DSM Nutritional Products, Inc., Essentialis Therapeutics,
GlaxoSmithKline, Ironwood Pharmaceuticals, Johnson & Johnson, KOS,
Merck, Merck Schering Plough, Metabasis Therapeutics, Microbia,
Novartis, Nicox, Ortho-McNeil, Parke Davis, Perenis Therapeutics,
Pfizer, Reliant, Roche, Sandoz, Sanofi Aventis, Schering Plough,
SmithKline Beecham, Surface Logix, Takeda, UpJohn, Vivus and Warner
Lambert. The author has no other relevant affiliations or financial involve-
ment with any organization or entity with a financial interest in or finan-
cial conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No funding or writing assistance was utilized in the production of
this manuscript.

Key issues
• Adipose tissue is an active endocrine and immune organ.
• An increase in fat storage in adipocytes can result in pathologic anatomical, mechanistic, endocrinologic and immunologic adipose
tissue responses that may contribute to metabolic disease.
• Adiposopathy (‘sick fat’) is defined as pathogenic adipose tissue anatomical changes that often occur with positive caloric balance,
particularly among those who are environmentally or genetically predisposed, which results in pathological endocrine and immune
responses that are important contributors to metabolic disease.
• Phentermine is a noradrenergic sympathomimetic amine approved for short-term treatment of obesity.
• Topiramate is a sulfamate-substituted monosaccharide derivative of the naturally occurring sugar monosaccharide d-fructose approved
as treatment for migraine headaches and seizure disorders, which also has weight loss effects.
• Phentermine HCl/topiramate controlled-release is a combination agent containing immediate-release phentermine and
controlled-release topiramate that may not only improve the weight of patients, but may also improve adiposopathy-associated
metabolic diseases.

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