ArticlePDF Available

Pharmacotherapy for obesity: A quantitative analysis of four decades of published randomized clinical trials

Authors:

Abstract and Figures

This article provides the first comprehensive meta-analysis of randomized clinical trials of medications for obesity. Based on stringent inclusionary criteria, a total of 108 studies were included in the final database. Outcomes are presented for comparisons of single and combination drugs to placebo and for comparisons of medications to one another. Overall, the medications studied produced medium effect sizes. Four drugs produced large effect sizes (ie d>0.80; amphetamine, benzphetamine, fenfluramine and sibutramine). The placebo-subtracted weight losses for single drugs vs placebo included in the meta-analysis never exceeded 4.0 kg. No drug, or class of drugs, demonstrated clear superiority as an obesity medication. Effects of methodological factors are also presented along with suggestions for future research.
Content may be subject to copyright.
PAPER
Pharmacotherapy for obesity: a quantitative analysis
of four decades of published randomized clinical trials
CK Haddock
1
*, WSC Poston
1
, PL Dill
1
, JP Foreyt
2
and M Ericsson
3
1
University of Missouri-Kansas City and Mid America Heart Institute, St Luke’s Hospital, Kansas City, Missouri, USA;
2
Baylor
College of Medicine, USA; and
3
University of Umea
˚
, Sweden and University of Missouri-Kansas City, Missouri, USA
AIM: This article provides the first comprehensive meta-analysis of randomized clinical trials of medications for obesity.
METHOD: Based on stringent inclusionary criteria, a total of 108 studies were included in the final database. Outcomes are
presented for comparisons of single and combination drugs to placebo and for comparisons of medications to one another.
RESULT: Overall, the medications studied produced medium effect sizes. Four drugs produced large effect sizes (ie
d
> 0.80;
amphetamine, benzphetamine, fenfluramine and sibutramine). The placebo-subtracted weight losses for single drugs
vs
placebo included in the meta-analysis never exceeded 4.0 kg. No drug, or class of drugs, demonstrated clear superiority as
an obesity medication. Effects of methodological factors are also presented along with suggestions for future research.
International Journal of Obesity
(2002) 26, 262 273. DOI: 10.1038=sj=ijo=0801889
Keywords: pharmacotherapy; meta-analysis; clinical trials
Introduction
No comprehensive meta-analytic studies of obesity pharma-
cotherapy have been published to date, but three meta-
analyses have been published on single drugs. Lijesen et al
1
meta-analyzed eight controlled and 16 uncontrolled trials of
human chorionic gonadotropin and concluded that it was
not effective for the treatment of obesity. Four placebo-
controlled, double-blind studies of sibutramine efficacy for
reducing visceral fat were meta-analyzed by Van Gaal et al,
2
who concluded that it was effective in reducing waist cir-
cumference and visceral fat when compared to placebo.
Greenway
3
examined phenylpropanolamine (PPA) trials
since 1973, including trials that were reviewed by previous
investigators
4,5
and concluded that the average weight loss
in excess of placebo (kg=week) at the end of studies had
decreased since 1985.
Two multi-drug reviews that have been cited as meta-
analytic confirmation of obesity pharmacotherapy’s efficacy
6
were authored by Goldstein and Potvin
7
and the National
Task Force on the Prevention and Treatment of Obesity.
8
Goldstein and Potvin
7
conducted a detailed review of 20
long-term (ie those lasting 6 months or longer) phenter-
mine, mazindol, fenfluramine, dexfenfluramine and fluox-
etine studies from 1967 to 1993. While they presented a
comprehensive review of clinical trials on these drugs and
concluded that extended treatment was beneficial for those
patients unable to lose weight without pharmacotherapy,
they did not provide a quantitative synthesis of these drugs’
efficacy. The National Task Force on the Prevention and
Treatment of Obesity
8
also provided a comprehensive
review of the safety and efficacy of FDA-approved and
selected non-approved anti-obesity medications, ie (bold
drugs are those that were identified as FDA-approved)
amphetamine=dexamphetamine, benzphetamine hydro-
chloride, dexfenfluramine, diethylpropion, fenfluramine,
fluoxetine, mazindol, methamphetamine hydrochloride,
phendimetrazine tartrate, phentermine (hydrochloride
and resin), phenlypropanolamine, the combination of
phentermine fenfluramine, sibutramine and sertraline, but
they also did not quantitively synthesize outcomes of the
drug therapies. The Task Force reviewed English-language
trials that evaluated drug safety and efficacy that lasted for a
minimum of 24 weeks and concluded that pharmacotherapy
for obesity, when combined with appropriate behavioral
approaches, helped many obese patients lose weight or
maintain their weight loss.
8
*Correspondence: CK Haddock, Health Research Group, University of
Missouri-Kansas City, 4825 Troost, Room 124, Kansas City, MO 64110,
USA.
E-mail: haddockc@umkc.edu
Received 5 January 2001; revised 14 August 2001;
accepted 1 October 2001
International Journal of Obesity (2002) 26, 262–273
ß 2002 Nature Publishing Group All rights reserved 0307–0565/02 $25.00
www.nature.com/ijo
The purpose of this study is to provide a comprehensive
meta-analytic review of anti-obesity agents, both prescrip-
tion and over-the-counter (OTC), and drugs that are=were
FDA-approved and are=were used off-label for obesity.
8
The
specic aims are to evaluate the clinical efcacy of obesity
medications and determine whether methodological factors
(eg length of treatment, year of publication) are system-
atically related to treatment outcome. In addition, based
on the results of this meta-analysis, suggestions for future
research are discussed.
Methods
Literature search
Inclusion criteria. For this meta-analysis, we evaluated
only anti-obesity agents that are=were FDA-approved for
the treatment of obesity, both prescription and OTC, and
drugs that are FDA-approved and are used off-label for
obesity (see Table 1). We compiled this list by examining
those that were highlighted by the National Task Force on
the Prevention and Treatment of Obesity
8
as being currently
approved for the treatment of obesity in the United States,
those that were used off-label, and including recently
approved drugs that were not reviewed by the Task Force.
8
In addition, we based our selection of drugs on extensive
consultation with several experts in the eld of obesity
research.
We retained fenuramine and dexfenuramine in the
review because they were widely studied and used in clinical
settings even though they were removed from the market in
1997. We did not include experimental obesity agents such
as acarbose, beta-adrenoreceptor agonist (BRL 26830A), bro-
mocriptine, buspar, cimetidine, uvoxamine, human chor-
ionic gonadotropin, human growth hormone, leptin,
naloxone=naltrexone or synthyroid. We also did not include
dietary supplements, which are dened by the Dietary Sup-
plement Health and Education Act of 1994
9
as products
intended to supplement the diet that contain one or more
of the following ingredients: (1) a vitamin; (2) a mineral; (3)
a herb or other botanical; (4) an amino acid; (5) a dietary
substance for use to supplement the diet by increasing the
total dietary intake; or (6) a concentrate, metabolite, consti-
tuent, extract, or combination of any of the previously
described ingredients. Examples of substances in this cate-
gory include 5-hydroxytryptophan (5-HTP), ma huang (ephe-
drine), guarana (caffeine), chitosan, chromium (picolinate
and nicotinate), dehydroepiandrosterone (DHEA), garcinia
cambogia=hydroxycitric acid, pyruvate and St Johns Wort
(hypericin).
Studies which met the following stringent criteria were
included in the review: (1) the data were contained in
published reports in peer-reviewed journals; (2) only
human studies were included; (3) an English version of the
study was available; (4) a direct comparison between an
obesity drug therapy designed to produce weight loss and
another treatment modality or a control group of obese
individuals was provided; (5) participants were assigned
randomly to treatment groups and the randomization
scheme was not broken during assignment (ie some partici-
pants assigned randomly, some haphazardly); (6) groups
were distinguishable on relevant parameters (eg drug type,
use of lifestyle intervention); (7) the study provided suf-
cient outcome data to compute an effect size based on
weight loss (see effect size denition below); (8) the study
Table 1 Anti-obesity agents
Generic name Example trade name DEA schedule Number of studies
a
Years of publications (range)
Amphetamine (dexamphetamine)
b
Biphetamine II 6 1969 1974
Benzocaine Slim Mint, Trocaine OTC 1 1999
Benzphetamine
b
Didrex III 3 1960 1987
Dexfenuramine
b,c
Redux IV 18 1989 1998
Diethylpropion
b
Tenuate, Tenuate Dospan IV 13 1965 1983
Fenuramine
b,c
Pondimin IV 15 1966 1992
Fluoxetine
d
Prozac None 11 1987 1995
Mazindol
b
Sanorex, Mazanor IV 28 1969 1982
Methamphetamine
b
Desoxyn II 1 1960
Orlistat
e
Xenical None 6 1995 1999
Phendimetrazine
b
Bontril, Plegine, Prelu-2, X-Trozine III
f
f
Phentermine (HCL and resin)
b
Adipex-P, Fastin, Oby trim, Ionamin IV 9 1969 1992
Phenylpropanolamine (PPA)
b
Dexatrim, Acutrim OTC 9 1975 1999
Sertraline
d
Zoloft None
f
f
Sibutramine
e
Meridia IV 5 1991 1998
Note
: FDA, Food and Drug Administration; DEA, Drug Enforcement Agency; OTC, over the counter.
a
Number of studies in our database that address each drug. Because some studies address more than one drug, the sum of these numbers is greater
than the total number of studies included in the database.
b
Drugs highlighted by the National Task Force on the Prevention and Treatment of Obesity (1996).
c
Removed from the market in 1997.
d
FDA-approved drugs that have been used off-label for obesity.
e
Approved by the FDA after the 1996 report by the National Task Force on the Prevention and Treatment of Obesity.
f
No studies of these drugs met our inclusionary criteria.
Obesity medication meta-analysis
CK Haddock
et al
263
International Journal of Obesity
was published on or before December 1999 (to provide a
point to begin coding and data analysis). Unfortunately, we
were not able to code a large number of studies that address
drug treatments for obesity. Uncodable studies typically did
not present data in a manner where group outcomes could
be precisely distinguished (eg cross-over studies where data
were only presented at the conclusion of the study) or did
not present sufcient data to compute an effect size (typi-
cally these studies presented no data on outcome variability
nor information where outcome variance could be esti-
mated). Finally, there were some studies where drugs were
used for weight maintenance following obesity treatment,
but were not used as part of a primary treatment to produce
weight loss.
10 12
We located a small number of maintenance
articles and, although codeable, they were not included in
the analyses.
Studies were located by computer searches of databases
(eg Medline, PsychInfo), reviewing tables of content=
reference sections of journals, abstracts, previous reviews,
past empirical studies, relevant book chapters, and recent
issues of journals which regularly publish obesity research
(eg American Journal of Clinical Nutrition, International Journal
of Obesity and Related Metabolic Disorders, Journal of the Amer-
ican Medical Association, Journal of Consulting and Clinical
Psychology; and Obesity Research). In addition, a number of
individuals who regularly publish in the obesity literature
were asked to provide personal lists of obesity studies that
address pharmacotherapy. Based on inclusionary criteria and
the search procedures, a total of 108 randomized clinical
trials (published in 103 articles) were located. The character-
istics of these studies are outlined in the results section
below.
Coding of studies
A Pharmacotherapy for Obesity: a Meta-Analysis of Control Trials
Coding Manual containing the operational denitions of the
variables used in this review was developed (available via
email in MS Word for Windows format upon request from
the rst author). Reliability of coding was maintained by
providing intensive training of the project assistants, includ-
ing approximately 20 h of didactic and coding practice. Each
coder was required to reach perfect agreement with sample
studies coded by the principal investigator (CKH) prior to
coding other studies. Finally, another project research assis-
tant independently veried all coding. Because the majority
of codes used in this review required little judgement (eg
average weight of subjects, drug name), consistent coding
was easily achieved. When parameters varied during the
course of a study (eg drug dose), an average of that parameter
was coded for the meta-analysis.
Coding and combining effect sizes
The standardized mean difference, d, based on change scores
(reduction in weight), used as the measure of effect size in
this review, is dened as:
d
i
¼
DXt
i
D Xc
i
DXs
i
where DX
t
i
is the mean weight loss in the treatment group
of the ith study, DX
c
i
is the mean of the control or
alternative treatment in the ith study, and DX
s
i
is the
pooled standard deviation of change for the two groups.
When sufficient data were not reported to directly com-
pute d, standard alternative methods of deriving the
effect size were used if possible.
13
This effect size controls
for both placebo effects and lifestyle treatments in esti-
mating the effect of the drugs. Because effect sizes based
on change scores tend to be large compared to those
based on post-test mean differences,
14
direct comparisons
to reviews using effect sizes based on post-test scores
should be avoided.
The statistical procedures for combining effect sizes in this
review weight each study by an inverse function of its sample
variance as the sampling variance becomes small, the
weight becomes large (Shadish and Haddock,
15
formula
18 7). When a single study provided more than one rele-
vant effect size for an analysis, all within-study effect sizes
were aggregated to avoid statistical dependency. Consistent
with conventions in meta-analysis, results described only as
insignicant where adequate data were not presented to
compute an effect size were conservatively coded as zero.
Hedgescorrection for small sample bias (Hedges,
16
Formula
4) was applied to all effect sizes.
In addition to providing d as a measure of effect size, raw
differences between treatment group weight losses are also
provided for each study. Although meta-analytic methods
have been developed for statistically combining raw data in
their original metric, many studies did not provide sufcient
data on the variance of weight changes with which to
compute appropriate weights.
15
Thus, these unweighted
raw differences between treatment groups are provided for
descriptive purposes only and should be interpreted with
caution.
Statistical analyses
Standard statistical procedures for meta-analysis were used
for data analysis.
17,18
Outcomes were considered a post-test if
they (1) occurred at the end of an intact treatment package,
(2) were the only outcome provided by the authors, or (3)
were designated as a post-test by the study authors. For many
studies, coding follow-up or long-term (ie after the initial
post-test outcomes) effect sizes proved challenging.
Although several studies continued to monitor the weights
of patients past initial or post-test assessments of drug
effects, many signicantly altered the original study design
and thus precluded our ability to present directly interpre-
table treatment effect sizes. Thus, these studies essentially
present a new research trial based on previously treated
patients. Only clinical trials that maintained the basic
structure of their research design and allowed for clean
Obesity medication meta-analysis
CK Haddock
et al
264
International Journal of Obesity
examination of long-term treatment effects were coded as
follow-ups.
Results
Characteristics of studies
Appendix 1 contains a complete list of studies included in
the meta-analysis. Of the 108 clinical trials included, 102
were primarily concerned with pharmacologically induced
weight loss. In the remaining six studies weight loss was a
secondary outcome, with factors such as macronutrient
intake serving as the primary endpoint of concern. However,
these six studies used medication designed to promote
weight loss and reported sufcient data to be included in
the meta-analysis. Publication dates of the studies ranged
from 1960 to 1999, with 9.3% in the 1960s, 42.6% in the
1970s, 12.0% in the 1980s and 36.1% published in the 1990s.
Average age of the subjects included in the clinical trials was
40.7 y, although actual ages ranged from 5 y (Stewart et al,
94
Appendix 1) to 77.0 y.
Single drug vs placebo: post-treatment outcomes
Table 2 presents design characteristics of studies providing
drug placebo comparisons. Weeks of treatment varied
greatly by drug, with more recently introduced medications
employing longer treatment periods (eg PPA and benzphe-
tamine with an average of 7.4 and 8.9 weeks, respectively,
and sibutramine and orlistat averaging 14.5 and 47.5 weeks
of treatment). The majority of patients were female, with the
proportion of females ranging from 57.6 to 88.5%. Consis-
tent with published guidelines, most studies used some form
of lifestyle management program even though these guide-
lines were published long after many studies were in print.
19
This partially reects the multidisciplinary nature of obesity
treatment and the recognition that successful drug interven-
tions must address eating and activity behaviors in obese
patients.
With the exception of benzocaine, patients receiving drug
therapy, whether or not it was combined with lifestyle
modication, experienced greater average weight loss than
patients in the placebo groups. Unweighted weight loss
differences ranged from 7 0.80 to 3.82 kg, with most drugs
demonstrating modest weight losses relative to placebo. It is
interesting to note that ve drugs (benzocaine, dexfenur-
amine, diethylpropion hydrochloride, fenuramine and
mazindol) had studies in which no weight loss or weight
gain occurred relative to the placebo groups, as noted by the
negative values in the drug-placebo value ranges.
Figure 1 presents the effect sizes and 95% condence
intervals for drug placebo comparisons. Condence inter-
vals for the effect sizes are presented only for those drugs
with three or more studies in the meta-analysis database.
These results represent the post-test outcome of studies
without consideration of possible design differences such
as study length, drug dose etc. Outcomes suggest that the
Table 2 Single drug
vs
placebo: post-treatment outcomes
Weeks Number at post-test Female (%) Percentage
Drug number of any Dosage=day using lifestyle kg lost with kg lost Drug 7
of studies) treatment Drug Placebo Drug Placebo (mg) treatment drug with placebo placebo (kg)
Amphetamine (2) 16 (16 16) 23 (14 32) 21 (12 30) 78.8 (71.9 85.7) 77.7 (63.6 91.7) 15 (15 15) 50 5.2 (4.5 5.9) 2.5 (2.4 2.6) 2.7 (2.1 3.3)
Benzocaine (1) 14 7 10 100 100 96 100 0.80 1.60 7 0.80
Benzphetamine (3) 8.9 (1.6 17) 21 (12 33) 22 (13 32) 58.3 (0 95) 57.6 (0 86.9) 123.3 (100 150) 66.7 4.03 (1.6 7.3) 0.73 ( 7 1.3 2.0) 3.3 (1.7 5.3)
Dexfenuramine (14) 30.0 (4 56) 46.6 (5 295) 44.1 (5 268) 83.0 (52.9 100) 80.7 (41.2 100) 37.4 (30 130) 92.9 8.9 (3.7 21.3) 5.1 ( 7 0.4 11.3) 3.82 ( 7 0.20 10.0)
Diethylpropion
hydrochloride (9)
17.6 (6 52) 21.2 (5 32) 18 (4 29) 88.5 (70 100) 88.3 (70 100) 75 (75 75) 100 6.5 (1.9 13.1) 3.5 ( 7 0.4 10.5) 3.00 ( 7 1.6 11.5)
Fenuramine (14) 9.7 (4 18) 20 (5 58) 21.2 (6 68) 71.5 (11.1 100) 72.1 (9.1 100) 80.1 (39 120) 64.3 5.06 (2.5 11.6) 2.41 (1.2 3.2) 2.41 ( 7 0.10 5.0)
Fluoxetine (11) 27.5 (6.0 60) 55.2 (7 138) 55.7 (9 136) 64.1 (0 100) 64.4 (0 100) 57.4 (32.5 60) 81.8 4.10 (1.4 9.3) 0.78 ( 7 1.5 2.4) 3.3 (0.20 7.4)
Mazindol (22) 11.0 (2 20) 23.5 (8 50) 17.7 (8 30) 84.4 (59.4 100) 84.9 (63.6 100) 2.4 (1 3) 84.1 5.8 (2.2 10.1) 3.03 (0.4 9.3) 2.7 ( 7 0.10 7.3)
Orlistat (6) 47.5 (16 76) 236.9 (46.7 657) 164.5 (46 340) 72.2 (51.2 83.7) 73.6 (46.5 88.3) 302.9 (190 360) 100 7.1 (4.0 10.3) 5.02 (3.0 6.1) 2.08 (0.30 4.2)
Phentermine (6)
(hydrochloride
and resin)
13.2 (2 24) 32 (15 76) 29.4 (12 74) 86.5 (70.6 100) 85.0 (72.2 100) 27.5 (15 30) 83.3 6.3 (3.6 8.8) 2.8 (1.5 5.2) 3.6 (0.6 6.0)
Phenylpropanol-
amine (PPA) (7)
7.4 (2 14) 23.5 (8 36) 22.4 (10 36) 88.2 (76.5 100) 83.1 (56.3 100) 72.4 (57 75) 85.7 3.03 (0.90 6.1) 1.9 (0.60 4.3) 0.89 (0.30 2.0)
Sibutramine (4) 14.5 (8 26) 27.3 (15 52) 26.8 (15 49) 85.8 (70.2 100) 86.0 (70 100) 14.0 (10.0 20.0) 100 5.3 (4.0 7.3) 1.8 (0.8 3.3) 3.5 (2.4 5.1)
Note
: unless otherwise indicated, numbers in parentheses are the range of the distribution of values. Aggregate data based on studies that presented necessary information. Weeks of treatment are based on
any treatment, because studies rarely presented data separately for those weeks involving medication use. An asterisk (*) indicates unweighted effect sizes (computed for drugs with less than three studies).
Drugs not included in this table did not have studies that met the study inclusionary criteria that also provided sufcient data to compute drug placebo effect sizes. Data presented for kg lost for drug
conditions, placebo conditions, and drug minus placebo are unweighted. Negative numbers for kg changes indicate weight gain.
Obesity medication meta-analysis
CK Haddock
et al
265
International Journal of Obesity
various drugs generally produced comparable weight losses.
However, it could be argued that amphetamine, benzpheta-
mine, fenuramine and sibutramine produced the largest
mean effect sizes among the drugs studied, each of which
were in the large range of effect size magnitude (ie > 0.80) as
is typically dened in meta-analysis.
20
Furthermore, fenur-
amine and sibutramine produced signicantly better weight
losses (based on the effect size 95% condence intervals)
than ve of the other drugs studied, ie benzocaine, dexfen-
uramine, uoxetine, mazindol and orlistat. Nevertheless,
both drugs overlapped with amphetamine, benzphetamine,
diethylpropion, phentermine and PPA, suggesting that there
were no statistically signicant differences between these
drugs effect sizes.
Effect of length of treatment
Not surprisingly, there was a strong correlation between the
year of publication of a study and the length of the studys
treatment (r ¼ 0.436, P < 0.001) among studies providing
single drug vs placebo outcomes. However, there was no
overall relationship between treatment length and effect
size (r ¼ 0.016, P ¼ 0.875), suggesting that many drugs may
have their greatest impact on weight early in treatment.
Seven drugs were judged to have a sufcient number of
studies and variance in treatment length to be examined in
within-drug analyses (ie dexfenuramine, diethylpropion
hydrochloride, fenuramine, mazindol, orlistat, phenter-
mine and PPA). Given the small number of studies within
each drug type, the fact that each effect size is based on a
group of patients rather than a single subjects outcome and,
because a correlation coefcient represents an effect size,
21
it
was a priori decided that a correlation coefcient of 0.30
would be judged to be a potentially important indicator of
association. However, traditional inferential tests also are
reported. The correlations between effect size and treatment
length and publication year are presented in Table 3.
There were no signicant associations between effect size
and treatment length for any of the seven drugs examined,
although the magnitude of the correlation for phentermine
was large, suggesting that treatment length did inuence
phentermines effect size. Table 3 also presents correlations
between the amount of weight (kg) lost in both treatment
and placebo groups for the seven drugs. Overall, longer
treatment was associated with greater weight loss in both
drug and placebo groups. Treatment length and amount of
weight loss (kg) were signicantly correlated only for dexfen-
uramine (both drug and placebo) and the placebo groups in
diethylpropion hydrochloride studies. Patients receiving
diethylpropion hydrochloride or orlistat (or those participat-
ing in diethylpropion hydrochloride or orlistat study placebo
groups) also demonstrated greater weight loss with increased
treatment time, but the correlations were not statistically
signicant. Patients receiving placebo in both fenuramine
and mazindol studies experienced less weight loss with
increasing treatment time. Thus, with a few exceptions,
increasing treatment length was associated with greater
weight loss among patients receiving drug or placebo.
Figure 1 Effect sizes and 95% condence intervals of drug placebo comparisons.
Note
: high=low lines were not constructed for amphetamine and
benzocaine due to insufcient studies ( < 3). Horizontal line at an effect size of zero represents no treatment effect.
Obesity medication meta-analysis
CK Haddock
et al
266
International Journal of Obesity
Effect of publication year
Overall, there was no relationship between year of publica-
tion and effect size, suggesting that the placebo-controlled
outcomes of drug studies are not changing over time
(r ¼ 0.055, P ¼ 0.592). Most of the seven selected drugs
demonstrated no or positive, but statistically insignicant,
relationships between publication year and effect size except
for dexfenuramine. The correlation between dexfenura-
mines effect size and year of publication was strong and
negative, suggesting that effect size in dexfenuramine stu-
dies decreased over time. This was also demonstrated in the
negative correlation between publication year and the
amount of weight (kg) lost in patients taking dexfenura-
mine, suggesting that later dexfenuramine studies that met
our inclusion criteria demonstrated less weight loss than
earlier studies. While the same trend was noted in patients
receiving placebos in dexfenuramine studies, the correla-
tion was not statistically signicant.
Single drug vs placebo: follow-up outcomes
Nineteen studies provided data where (1) the research design
remained intact and (2) data were presented for a follow-up
assessment period after the formal study was complete.
Lengths of the follow-ups ranged from 1 to 136 weeks
(mean ¼ 17.3; median 6.0). The relationship between
length of follow-up and effect size was not signicant
(P ¼ 0.066), although the magnitude of the correlation was
moderate (r ¼ 7 0.430). Table 4 presents follow-up effect
sizes from these randomized clinical trials.
All studies discontinued drug treatment during the
follow-up period. In addition, most studies did not provide
booster sessions during this time. Thus, the follow-up peri-
ods for the majority of studies examined represent post-
treatment observation periods without any extension of
the treatments, not reecting the current long-term treat-
ment paradigm in obesity management. With the exception
of amphetamine and mazindol, all drugs with follow-up
Table 3 Relationships among treatment length and year of publication on post-treatment single drug
vs
placebo outcomes
Length of treatment Year of publication
Drug Effect size
kg lost in
drug group
kg lost in
placebo group Effect size
kg lost in
drug group
kg lost in
placebo group
All studies 0.016 (0.875) 0.430 ( < 0.001) 0.395 ( < 0.001) 0.055 (0.592) 0.182 (0.080) 0.165 (0.115)
Dexfenuramine 7 0.080 (0.787) 0.578 ( 7 0.030) 0.613 (0.020) 7 0.576 (0.031) 7 0.543 (0.036) 7 0.367 (0.179)
Diethylpropion hydrochloride 7 0.084 (0.830) 0.555 (0.121) 0.797 (0.010) 0.385 (0.306) 0.049 (0.900) 7 0.303 (0.427)
Fenuramine 7 0.057 (0.846) 7 0.066 (0.838) 7 0.366 (0.242) 0.216 (0.459) 0.442 (0.151) 0.253 (0.427)
Mazindol 0.254 (0.254) 7 0.139 (0.547) 7 0.408 (0.066) 7 0.093 (0.680) 7 0.061 (0.793) 0.250 (0.275)
Orlistat 0.146 (0.782) 0.456 (0.441) 0.809 (0.097) 0.017 (0.975) 0.623 (0.262) 0.879 (0.050)
Phentermine 0.685 (0.202) 0.035 (0.956) 7 0.420 (0.482) 0.141 (0.790) 7 0.346 (0.502) 7 0.115 (0.828)
Phenylpropanolamine (PPA) 7 0.132 (0.778) 0.210 (0.651) 0.291 (0.527) 7 0.091 (0.845) 0.171 (0.713) 0.169 (0.717)
Note
: values in cells represent correlation coefcient and its associated
P
-value (in parentheses). Only drugs with a sufcient number of primary studies were included
in this table.
Table 4 Single drug
vs
placebo: follow-up outcomes
Number at follow-up
Providing booster
sessions (%) Drug
Drug (number continued kg lost kg lost Drug 7 Effect size
of studies) Drug Placebo Drug Placebo (%) with drug with placebo placebo (kg) (95% CI)
Amphetamine (2) 19.5
(19 20)
18.5
(16 21)
00 0 7 3.45 7 2.5 7 0.95 0.225*
Dexfenuramine (9) 33.6
(5 116)
33.0
(5 108)
11 11 0 6.04
( 7 1.5 11.7)
4.99
(1.9 8.5)
1.05
( 7 3.6 3.5)
0.401
(0.238 0.564)
Mazindol (4) 18.3
(10 23)
17.8
(10 24)
00 0 7 0.28
( 7 6.1 2.3)
7 0.85
( 7 5.5 1.1)
0.58
( 7 0.60 1.8)
0.674
(0.329 1.019)
Phentermine (2) 16.3
(8 25)
18.0
(9 27)
0 0 0 8.23
a
5.8
a
2.43
a
0.810*
Sibutramine (2) 31.3
(15 48)
32.5
(15 50)
50 50 0 4.87
(3.3 6.4)
2.5
(1.7 3.3)
2.37
(1.63 3.1)
1.05*
Note
: unless otherwise indicated, numbers in parentheses are the range of the distribution of values. Aggregate data based on studies that presented necessary
information. An asterisk indicates unweighted effect sizes (computed for drugs with less than three studies). Drugs not included in this table did not have studies that
met the study inclusionary criteria that also provided sufcient data to compute drug 7 placebo effect sizes. Data presented for kg lost for drug conditions, placebo
conditions, and drug minus placebo are unweighted and represent the follow-up weight of participants minus their baseline weight. Negative numbers for kg
changes indicate weight gain. Numbers in parentheses represent the number of studies contributing data to a particular row; studies may contribute data to more
than one row.
a
Weight losses for individual groups only reported in one of the two phentermine studies.
Obesity medication meta-analysis
CK Haddock
et al
267
International Journal of Obesity
periods demonstrated sustained weight loss. Phentermine
and sibutramine maintained fairly large placebo subtracted
weight losses (ie 2.43 and 2.37 kg, respectively) and had the
largest effect sizes, ranging from 0.810 to 1.05. Dexfenur-
amine had a smaller placebo-subtracted weight loss and a
more modest effect size, but results are based on a larger
number of studies than the effect sizes for phentermine and
sibutramine. Given the small number of studies providing
follow-up assessments, the effects of moderators of outcome
were not explored.
Combination drug vs placebo: post-treatment outcomes
Six studies provided comparisons of combination drugs vs
placebo and met study inclusionary criteria. None of the
combination drug trials included assessments that met our
denition of a follow-up. Outcomes for the combination
drugs are presented in Table 5.
Length of treatment for combination drug trials ranged
from 6 to 32 weeks and the majority of patients were women.
All patients in these trials received some form of lifestyle
modication (ie modication of diet and=or physical activ-
ity). All drug combinations produced placebo-subtracted
weight loss, ranging from 0.30 kg for PPA benzocaine to
9.60 kg for fenuramine phentermine. Effect sizes for phen-
termine fenuramine (1.48), PPA caffeine (2.58), and
methamphetamine phenobarbatol (5.04) were all very
large. It also should be noted that, with one exception
(PPA benzocaine), all combination drugs produced larger
effect sizes than any single drug except fenuramine and
sibutramine (see Figure 1). However, these effect sizes are
based on a much smaller number of studies (n ¼ 1 for most)
and some of the combinations are now viewed as having
signicant adverse health impacts (eg fenuramine
phentermine, methamphetamine phenobarbatol).
Drug drug comparisons
There were few drug drug comparisons to examine (ie 18 in
total). Table 6 summarizes the data, including effect sizes, for
all drug drug comparisons. Most effect sizes for the drug
drug comparisons were in the medium range with the
exception of diethylpropion vs PPA caffeine and mazindol
vs PPA caffeine. No general patterns of effectiveness
emerged based on drug pharmacology, eg PPA caffeine, an
OTC preparation, was consistently less effective than pre-
scription drugs it was compared with, eg mazindol and
diethylpropion. In contrast, ephedrine caffeine, another
OTC, performed moderately better than dexfenuramine.
Most drug drug comparison trials were relatively short
duration, ranging from 2 to 15 weeks. Overall, mazindol
was compared to other drugs more often than any of the
others that met our study inclusion criteria. Mazindol
tended to demonstrate greater weight losses than the drugs
it was compared with, with effect sizes in the medium range
in most cases.
Discussion
We meta-analyzed published, randomized, controlled trials
of obesity pharmacotherapies identied by the National Task
Force on the Prevention and Treatment of Obesity
8
as being
currently approved, those that were used off-label, recently
approved drugs that were not reviewed by the Task Force,
8
and recently removed drugs that were previously approved
by the FDA for obesity management. Overall, the studied
drugs produced medium effect sizes with only four drugs
having effect sizes greater than 0.80 (amphetamine, benz-
phetamine, fenuramine and sibutramine) and only one
exceeding 0.90 (sibutramine). As noted in Table 2, the
absolute placebo-subtracted weight losses associated with
studies of single drugs included in the meta-analysis never
exceeded 4.0 kg. Thus, the incremental benet of obesity
drug treatments, in addition to lifestyle interventions,
appears to be modest. It is interesting that there was no
drug, or class of drugs, that demonstrated clear superiority.
As can be seen in Figure 1, many of the 95% condence
intervals for the studied drugs overlapped, indicating that
the differences in effect sizes among many of the drugs were
not statistically signicant. For example, sibutramine, the
drug with the largest effect size, had overlapping condence
intervals with benzphetamine, diethylpropion, fenura-
mine, phentermine and PPA, and the effect size for amphe-
tamine exceeded its lower boundary. The only clearly
Table 5 Combination drug
vs
placebo: post-treatment outcomes
Drug combination components
Number at
Percentage
post-test Female (%) using kg lost
First drug Weeks of lifestyle kg lost with Effect
(number of studies) Second drug Third drug any treatment Drug Placebo Drug Placebo treatment with drug placebo size
PPA (2) Caffeine 6.0
(6.0 6.0)
27
(26 28)
25.5
(23 28)
83.6
(78.6 88.5)
73.1
(67.9 78.3)
100 2.4
(2.1 2.7)
1.4
(0.9 1.9)
2.58
PPA (1) Benzocaine 14 10 10 100 100 100 1.9 1.6 0.136
Fenuramine (1) Phentermine 32 58 54 75.8 72.9 100 14.2 4.6 1.481
Methamphetamine (1) Phenobarbatol 20 7 5 ——100 2.4 0.5 5.043
Amphetamine (1) Laevoamphetamine Meth-aqual-one 8 20 20 ——100 3.3 0.2 0.873
Note
: PPA, phenylpropanolamine. None of the effect sizes are presented with condence intervals due to the small number of studies providing tests of combination
drug treatments. Blank cells represent factors that were not presented in the primary study.
Obesity medication meta-analysis
CK Haddock
et al
268
International Journal of Obesity
ineffective drug was benzocaine, with a negative effect size
of 7 0.35 and a placebo-subtracted weight loss of 7 0.80 kg.
However, the outcome of benzocaine was based on one
randomized clinical trial.
Another surprising result was that treatment length and
year of publication did not inuence effect size over all drugs
studied. While longer treatments were associated with
greater weight loss, this was true for both drug and placebo
groups and the relationships were roughly equivalent (ie
r ¼ 0.430 and 0.395, respectively), suggesting that this
effect was independent of drug treatments. When examining
individual drugs, it was striking to note that several demon-
strated negative relationships between treatment length and
effect size (eg dexfenuramine, diethylpropion, fenuramine
and PPA), suggesting that their effectiveness decreased with
increasing treatment time, although these correlations were
small and not statistically signicant. While there was no
overall relationship between publication year and effect size,
it is interesting to note that there was a statistically signi-
cant negative correlation between publication year and
effect size for dexfenuramine, indicating that treatment
effectiveness (and weight loss in drug treatment groups)
decreased over the last decade of published studies. Mazindol
and PPA also had negative, but small and statistically insig-
nicant associations between effect size and publication
year.
Few drug studies provided follow-up outcome data and
those that did discontinued pharmacotherapy during this
time. This is notable given that the current treatment para-
digm emphasizes that obesity is a chronic disease requiring
sustained treatment.
22
Thus, having drug-free follow-ups in
obesity treatment should be akin to expecting sustained anti-
hypertensive effects after drug discontinuation in hyperten-
sion patients, ie there is no more reason to expect that
obesity medications will have signicant prolonged effects
than would be expected with any other chronic disease
pharmacotherapy. Given this new treatment paradigm, obe-
sity pharmacotherapy studies may need to shift from the
idea of using drug-free follow-up periods to studying long-
term continuous or intermittent drug administration. Never-
theless, some drugs continued to provide important weight
loss maintenance during drug free follow-up periods. For
example, both phentermine and sibutramine demonstrated
large effect sizes and modest placebo-subtracted weight
loss (ie 2.43 and 2.37 kg, respectively) even though
pharmacotherapy had been discontinued during the
follow-up period and PPA provided sustained weight loss
with continued administration.
With the exception of PPA benzocaine, drug combina-
tions appeared to be the most potent weight loss agents,
producing large effect sizes ranging from 0.873 to 5.043 and
placebo-subtracted weight losses ranged from 1.0 to 9.6 kg.
Unfortunately, several of the constituent drugs in these
combinations have demonstrated substantial negative side-
effects and have been removed from the market or are not
available (eg amphetamine, fenuramine and methamphe-
tamine) or have been or are under consideration for removal
(eg PPA, ephedra).
23 27
Table 6 Drug drug comparisons: post-treatment outcomes
Number at
Percentage
post-test Female (%)
using
First drug Weeks of lifestyle kg lost kg lost
(number of studies) Second drug any treatment Drug 1 Drug 2 Drug 1 Drug 2 treatment with drug 1 with drug 2 Effect size
Amphetamine (1) Amphetamine synthroid 12 53 48 96.2 97.9 100 5.2 6.7 7 0.519
Benzocaine (1) Benzocaine PPA 14 7 10 100 100 100 0.80 1.9 7 0.511
Diethylpropion (1) PPA caffeine 8 23 25 95.7 96 100 3.6 3.1 0.872
Dexfenuramine (1) Ephedrine caffeine 15 43 38 83 78 100 6.9 8.3 7 0.292
Fenuramine (1) Metformin 8 10 10 100 100 100 7.7 5.2 0.772
Fluoxetine (1) Benzphetamine 8 32 33 88 80 100 3.7 3.2 0.209
Mazindol (9) All other drugs 9
(2 16)
18.9
(5 31)
19.7
(4 32)
85.2
(59.4 100)
87.9
(71.9 100)
78 5.47
(2.9 9.0)
4.3
(1.6 8.1)
0.257
(0.043 0.471)
(2) Amphetamine 12
(8 16)
17.5
(5 30)
18
(4 32)
59.4
a
71.9
a
50 4.9
(3.4 6.4)
3.75
(1.6 5.9)
0.096
(3) Diethylpropion 11.7
(11 12)
17.3 19.3 96.2
a
90.9
a
100 6.7
(2.9 9.0)
5.1
(2.0 8.0)
0.310
( 7 0.073 0.693)
(3) Phenmetrazine 5.3
(2 8)
18.3 18 91.1
(80 100)
91.9
(85.7 100)
66.7 5.1
(3.5 6.7)
4.2
(2.9 5.7)
0.034
(0.342 0.410)
(1) Phentermine 2 15 17 100 100 100 6.7 5.5 0.114
(1) PPA caffeine 6 28 27 82.1 88.9 100 4.1 3.7 0.870
Phentermine (2) All Other Drugs 7
(2 14)
33
(16 50)
32
(15 49)
82
(64 100)
84.7
(69.4 100)
100 7.1
(6.1 8.3)
5.95
(5.6 6.3)
0.446
(1) Phenmetrazine 2 16 15 64 69.4 100 6.1 5.6 0.050
(1) Diethylpropion 12 50 49 64 69.4 100 8.3 6.3 0.574
Sibutramine (1) Dexfenuramine 12 112 112 90.2 93 100 4.5 3.2 0.347
Notes
: PPA, phenylpropanolamine. There were nine total studies comparing Mazindol to other drugs. Individual comparisons of Mazindol to a particular drugaddto
10 because one study contributed to more than one group of these comparisons.
a
Only one study reported data for this factor.
Obesity medication meta-analysis
CK Haddock
et al
269
International Journal of Obesity
Prior to conducting this meta-analysis, several moderator
variables were hypothesized to affect the outcomes of the
clinical trials but were not included in this review. For
instance, the effects of drug side effects and attrition due
to side effects was a primary interest of the meta-analysis
team. However, few studies provided useable data on either
patterns of or attrition due to side effects. Further, many
studies provided only scant description of controls used to
ensure the internal validity of the trial or codeable descrip-
tions of lifestyle components. As with all meta-analyses, we
were limited to coding factors that are presented in primary
studies. Therefore, standards for reporting important para-
meters in obesity drug clinical trials are needed to increase
the utility of future reviews of this literature.
The results of this meta-analysis have several important
implications for obesity pharmacotherapy. First, increasing
length of drug treatment does not lead to more weight loss;
thus, longer treatments appear to promote weight mainte-
nance, but further weight loss beyond the typical plateau at
6 months is unlikely. In addition, the amount of weight lost
above and beyond that achieved in placebo treatments, most
of which included some form of lifestyle management (ie
diet, exercise, or both) is typically modest (ie usually greater
than 2 kg) and never exceeded 4 kg in the single drug vs
placebo comparisons. Some may argue that this is a very
small incremental improvement given the costs and risks
associated with drug therapies; however, this amount of
weight is important (ie nearly or exceeding 1 BMI unit)
and drug treatments often can be more accessible and
easier to use than structured lifestyle modication programs
that typically are based in obesity treatment centers. In
addition, obesity medications can result in important reduc-
tions in overall medication use and net costs associated with
obesity-related comorbidites.
27
Finally, more recent studies that did not meet our inclu-
sion criteria and were not included in this meta-analysis
10 12
suggest that pharmacotherapy may be particularly helpful in
promoting long-term weight maintenance. For example,
75% of patients taking sibutramine following a 4-week very
low calorie diet (VLCD) maintained 100% of their initial
weight loss 1 y after completing the VLCD, compared with
only 42% of placebo-treated patients.
10
Similarly, James et
al
12
found that patients receiving sibutramine for an 18-
month maintenance phase, following a 6-month 600 kcal
diet þ sibutramine weight loss segment, maintained a greater
amount of their initial weight loss when compared to
patients randomized to receive a placebo. Thus, 43% of the
drug-treated patients maintained 80% of their initial weight
loss as compared to only 16% of the placebo-treated patients.
Future studies should examine the effectiveness of drug
therapies as long-term weight maintenance agents.
Acknowledgements
This paper was supported by a faculty research grant from
the University of Missouri-Kansas City awarded to Dr Had-
dock and a minority scientist development grant from the
American Heart Association, awarded to Dr Poston.
References
1 Lijesen GK, Theeuwen I, Assendelft WF, Van Der Wal G. The
effect of human chorionic gonadotropin (HCG) in the treatment
of obesity by means of the Simeons therapy: a criteria-based
meta-analysis. Br J Clin Pharmac 1995; 40: 237 243.
2 Van Gaal LF, Wauters MA, Peiffer FW, De Leeuw IH. Sibutramine
and fat distribution: is there a role for pharmacotherapy in
abdominal=visceral fat reduction? Int J Obes Relat Metab Disord
1998; 22(Suppl): S38 S40.
3 Greenway FL. Clinical studies with phenylpropanolamine: a
meta-analysis. Am J Clin Nutr 1992; 55: 203S 205S.
4 Scoville BA. Review of amphetamine like drugs by the Federal
Drug Administration: clinical data and value judgments. In: G
Bray (ed). Obesity in perspective, DHEW publication no. (NIH)
75 708. US Government Printing Ofce: Washington, DC;
1973.
5 Weintraub M. Phenylpropanolamine as an anorexiant agent
weight control: a review of published and unpublished studies.
In: JD Morgan, DV Kagan, JS Brody (eds). Phenylpropanolamine:
risks, benets, and controversies. Praeger: New York; 1985. pp 53
79.
6 Committee on Nutrition, Massachusetts Medical Society. Obesity
treatment using drug therapy. White paper. The Massachusetts
Medical Society: Waltham, MA; 1998.
7 Goldstein DJ, Potvin JH. Long-term weight loss: the effect of
pharmacological agents. Am J Clin Nutr 1994; 60: 647 657.
8 National Task Force on the Prevention and Treatment of Obesity.
Long-term pharmacotherapy in the management of obesity.
JAMA 1996; 276: 1907 1915.
9 Dietary Supplement Health and Education Act of 1994 (DSHEA).
Public Law 103 417: 103rd Congress, 2nd Session Senate,
Report 103 410 Washington, DC; pp, 1 49.
10 Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leute-
negger E. Long-term maintenance of weight loss after a very-
low-calorie diet: a randomized blinded trial of the efcacy and
tolerability of sibutramine. Am J Med 1999; 106:179 184.
11 Wadden TA, Bartlett SJ, Foster GD, Greenstein RA, Wingate BJ,
Stunkard AJ, Letizia KA. Sertraline and relapse prevention train-
ing following treatment by very-low-calorie diet: a controlled
clinical trial. Obes Res 1995; 3: 549 557.
12 James WPT, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S,
Saris WHM, Van Gaal LF. Effects of sibutramine on weight
maintenance after weight loss: a randomized trial. Lancet 2000;
356: 2119 2125.
13 Rosenthal R. Parametric measures of effect size. In: H Cooper, LV
Hedges (eds). The handbook of research synthesis. Russell Sage:
New York; 1994. pp 231 244.
14 Lipsey MW, Wilson DB. The efcacy of psychological, educa-
tional, and behavioral treatment: conrmation from meta-ana-
lysis. Am Psychol 1993; 48: 1181 1209.
15 Shadish, WR, Haddock, CK. Combining estimates of effect size.
In: H Cooper, LV Hedges (eds). The handbook of research synthesis.
Russell Sage: New York; 1994. pp 261 281.
16 Hedges LV. Estimation of effect size from a series of independent
experiments. Psychol Bull 1982; 92:490 499.
17 Hedges LV, Olkin I. Statistical methods for meta-analysis. Academic
Press: San Diego, CA; 1985.
18 Cooper H, Hedges LV. The handbook of research synthesis (Part VI).
Russell Sage: New York; 1994.
19 Cohen J. A power primer. Psychol Bull 1992; 112: 155 159.
20 National Institutes of Health (NIH), National Heart, Lung, and
Blood Institute (NHLBI). Clinical guidelines on the identication,
evaluation, and treatment of overweight and obesity: the evidence
report. US Government Press: Washington DC; 1998.
21 Ozer DJ. Correlation and the coefcient of determination.
Psychol Bull 1985; 97: 307 315.
Obesity medication meta-analysis
CK Haddock
et al
270
International Journal of Obesity
22 Kopelman PG. Obesity as a medical problem. Nature 2000; 404:
635 643.
23 Kernan WN, Viscoli CM, Brass LM, Broderick JP, Brott T, Feld-
mann E, Mogenstern LB, Wilterdink JL, Horwitz RI. Phenylpro-
nanolamine and the risk of hemorrhagic stroke. New Engl J Med
2000; 343: 1826 1832.
24 Kolanowski J. A risk benet assessment of anti-obesity drugs.
Drug Safety 1999; 20:119 131.
25 Scheen AJ, Lefebvre PJ. Pharmacological treatment of obesity:
present status. Int J Obes Relat Metab Disord 1999; 23:47 53.
26 Haller CA, Benowitz NL. Adverse cardiovascular and central
nervous system events associated with dietary supplements
containing ephedra alkaloids. New Engl J Med 2000; 343:
1833 1838.
27 Greenway FL, Ryan DH, Bray GA, Rood JC, Tucker EW, Smith SR.
Pharmaceutical cost savings of treating obesity with weight loss
medications. Obes Res 1999; 7: 523 531.
Appendix 1: Studies included in the meta analysis
References
1 Abramson R, Garg M, Cioffari A, Rotman PA. An evaluation of
behavioral techniques reinforced with an anoretic drug in a
double-blind weight loss study. J Clin Psychiatry 1980; 41:
234 237.
2 Alger S, Larson K, Boyce VL, Seagle H, Fontvielle A, Ferraro R,
Rising R, Ravussin E. Effect of phenylpropanolamine on energy
expenditure and weight loss in overweight women. Am J Clin
Nutr 1993; 57: 120 126.
3 Allen GS. A double-blind clinical trial of diethylpropion hydro-
chloride, mazindol, and placebo in the treatment of exogenous
obesity. Curr Ther Res 1997; 22: 678 685.
4 Altschuler S, Conte A, Sebok M, Marlin R, Winick C. Three
controlled trials of weight loss with phenylpropanolamine. Int
J Obes Relat Metab Disord 1982; 6: 549 556.
5 Altschuler S, Frazer DL. Double-blind clinical evaluation of the
anorectic activity of phenylpropanolamine hydrochloride drops
and placebo drops in the treatment of exogenous obesity. Curr
Ther Res 1986; 40: 211 217.
6 Atkinson RL, Greenway FL, Bray GA, Dahms WT, Molitch ME,
Hamilton K, Rodin J. Treatment of obesity: comparison of
physician and nonphysician therapists using placebo and anor-
ectic drugs in a double-blind trial. Int J Obes Relat Metab Disord
1977; 1: 113 120.
7 Bacon GE, Lowery GH. A clinical trial of fenuramine in obese
children. Curr Ther Res 1967; 9:626 630.
8 Baird IM, Howard AN. A double-blind trial of mazindol using a
very low calorie formula diet. Int J Obes Relat Metab Disord 1977;
1: 271 278.
9 Bandisode MS, Boshell BR. Double blind clinical evaluation of
mazindol (42 548) in obese diabetics. Curr Ther Res 1975; 18:
816 824.
10 Bolding OT. Diethylpropion hydrochloride: an effective appetite
suppressant. Curr Ther Res 1974; 16:40 48.
11 Bradley MH, Raines J. The effects of phenylpropanolamine
hydrochloride in overweight patients with controlled stable
hypertension. Curr Ther Res 1989; 46:74 84.
12 Bray GA, Ryan DH, Gordon D, Heidingsfelder S, Cerise F, Wilson
K. A double-blind randomized placebo-controlled trial of sibu-
tramine. Obes Res 1996; 4: 263 270.
13 Breum L, Astrup A, Andersen T, Lammert O, Nielsen E, Garby L,
Quaade F. The effect of long-term dexfenuramine treatment on
24-hour energy expenditure in man: a double-blind placebo
controlled study. Int J Obes Relat Metab Disord 1990; 14: 613
621.
14 Breum L, Pedersen JK, Ahlstrom F, Frimodt-Moller J. Comparison
of an ephedrine=caffeine combination and dexfenuramine in
the treatment of obesity: a double-blind multicentre trial in
general practice. IntJObesRelatMetabDisord1994; 18:99 103.
15 Brightwell DR, Naylor CS. Effects of a combined behavioral and
pharmacologic program on weight loss. Int J Obes Relat Metab
Disord 1979; 3: 141 148.
16 Brodbin P, OConnor CA. A double-blind clinical trial of an
appetite depressant, fenuramine, in general practice. Practi-
tioner 1967; 198: 707 710.
17 Brun LD, Bielmann P, Gagne C, Moorjani S, Nadeau A, Lupien,
PJ. Effects of fenuramine in hypertriglyceridemic obese sub-
jects. Int J Obes Relat Metab Disord 1988; 12:423 431.
18 Campbell CJ, Bhalla IP, Steel JM, Duncan LJP. A controlled trial
of phentermine in obese diabetic patients. Practitioner 1977; 218:
851 855.
19 Connolly VM, Gallagher A, Kesson CM. A study of uoxetine in
obese elderly patients with type 2 diabetes. Diabetic Med 1995;
12: 416 418.
20 *Conte A. Evaluation of Sanorex-a new appetite suppressant.
J Obes Bariat Med 1973; 2: 104 107.
21 *Conte A. Evaluation of Sanorex-a new appetite suppressant.
J Obes Bariat Med 1973; 2: 104 107.
22 *Conte A. Evaluation of Sanorex-a new appetite suppressant.
J Obes Bariat Med 1973; 2: 104 107.
23 Crommelin RM. Nonamphetamine, anorectic medication for
obese diabetic patients: controlled and open investigations of
mazindol. Clin Med 1974; 81:20 24.
24 Dahms WT, Molitch ME, Bray GA, Greenway FL, Atkinson RL,
Hamilton K. Treatment of obesity: cost benet assessment of
behavioral therapy, placebo, and two anorectic drugs. Am J Clin
Nutr 1978; 31: 774 778.
25 Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted
CH, Heber D, Heimburger DC, Lucas CP, Robbins DC, Chung J,
Heymseld SB. Weight control and risk factor reduction in obese
subjects treated for 2 y with orlistat: a randomized controlled
trial. JAMA 1999; 281: 235 242.
26 DeFelice EA, Chaykin LB, Cohen A. Double-blind clinical eva-
luation of mazindol, dextroamphetamine and placebo in treat-
ment of exogenous obesity. Curr Ther Res 1973; 15: 358 366.
27 DeFelice E, Bronstein S, Cohen A. Double-blind comparison of
placebo and 42 548, a new appetite suppressant, in obese
volunteers. Curr Ther Res 1969; 11: 256 262.
28 Drent ML, Larsson I, William-Olsson T, Quaade F, Czubayko F,
von Bergmann K, Strobel W, Sjostrom L, van der Veen EA.
Orlistat (RO 18-0647), a lipase inhibitor, in the treatment of
human obesity: a multiple dose study. Int J Obes Relat Metab
Disord 1995; 19: 221 226.
29 Elliott BW. A collaborative investigation of fenuramine: anor-
exigenic with sedative properties. Curr Ther Res 1970; 12: 502
515.
30 Elmaleh, MK, Miller, J. Controlled clinical evaluation of a new
anorectic agent in obese adults. Pa Med 1974; 77:46 50.
31 Enzi G, Baritussio A, Marchiori E, Crepaldi G. Short-term and
long-term clinical evaluation of a non-amphetaminic anorex-
iant (mazindol) in the treatment of obesity. J Int Med Res 1976; 4:
305 318.
32 Enzi G, Crepaldi G, Inelmen EM, Bruni R, Baggio B. Efcacy and
safety of dexfenuramine in obese patients: a multi-center
study. Clin Neuropharmac 1988; 11(Suppl): S173 S178.
33 Ferguson JM, Feighner JP. Fluoxetine induced weight loss in
overweight non-depressed humans. Int J Obes Relat Metab Disord
1987; 11: 163 170.
34 Finer N, Finer S, Naoumova RP. Prolonged use of a very low
calorie diet (Cambridge diet) in massively obese patients attend-
ing an obesity clinic: safety, efcacy, and additional benet from
dexfenuramine. Int J Obes Relat Metab Disord 1989; 13:91 93.
35 Galloway DB, Logie AW, Petrie JC. Prolonged action fenura-
mine in nondiabetic patients with refractory obesity. Postgrad
Med J 1975; 51:155 157.
*Represents three independent studies.
Obesity medication meta-analysis
CK Haddock
et al
271
International Journal of Obesity
36 Goldrick RB, Hevnstein N, Whyte HM. Effects of caloric restriction
and fenuramine on weight loss and personality proles of pati-
ents with long-standing obesity. Austr NZ J Med 1973; 3:131 141.
37 Goldstein DJ, Rampey AH, Potvin JH, Fludzinski LA. Fluoxetine
in obese patients with noninsulin-dependent diabetes mellitus.
Clin Res 1992; 40: 240A (abstract).
38 {Holman SL, Goldstein DJ, Enas GG. Pattern analysis method
for assessing successful weight reduction. Int J Obes Relat Metab
Disord 1994; 18: 281 285.
39 Goldstein DJ, Rampey AH Jr, Enas GG, Potvin JH, Fludzinski LA,
Levine LR. Fluoxetine: a randomized clinical trial in the
treatment of obesity. Int J Obes Relat Metab Disord 1994; 18:
129 135.
40 Gray DS, Fujioka K, Devine W, Bray GA. A randomized double-
blind clinical trial of uoxetine in obese diabetics. Int J Obes
Relat Metab Disord 1992; 16:S67 S72.
41 {Greenway F, Herber D, Raum W, Morales S. Double-blind,
randomized, placebo-controlled clinical trials with non-pre-
scription medications for the treatment of obesity. Obes Res
1999; 7: 370 378.
42 {Greenway F, Herber D, Raum W, Morales S. Double-blind,
randomized, placebo-controlled clinical trials with non-pre-
scription medications for the treatment of obesity. Obes Res
1999; 7: 370 378.
43 Guy-Grand B, Apfelbaum M, Crepaldi G, Gries A, Lefebvre P,
Turner P. International trial of long-term dexfenuramine in
obesity. Lancet 1989; 2: 1142 1144.
44 {Pfohl M, Luft D, Blomberg I, Schmulling R-M. Long-term
changes of body weight and cardiovascular risk factors after
weight reduction with group therapy and dexfenuramine. Int
J Obes Relat Metab Disord 1994; 18: 391 395.
45 Hanotin C, Thomas F, Jones SP, Leutenegger E, Drouin P. Efcacy
and tolerability of sibutramine in obese patients: a dose-ranging
study. Int J Obes Relat Metab Disord 1998; 22:32 38.
46 Hanotin C, Thomas F, Jones SP, Leutenegger E, Drouin P. A
comparison of sibutramine and dexfenuramine in the treat-
ment of obesity. Obes Res 1998; 6: 285 291.
47 Heber KR. Double-blind trial of mazindol in overweight
patients. Med J Aust 1975; 2: 566 567.
48 Hill JO, Hauptman J, Anderson JW, Fujioka K, ONeil PM, Smith
DK, Zavoral JH, Aronne LJ. Orlistat, a lipase-inhibitor, for weight
maintenance after conventional dieting: a 1-y study. Am J Clin
Nutr 1999; 69: 1108 1116.
49 Hoebel BG, Krauss IK, Cooper J, Willard D. Body weight
decreased in humans by phenylpropanolamine taken before
meals. J Obes Bariat Med 1975; 4: 200 206.
50 Holdaway IM, Wallace E, Westbrooke L, Gamble G. Effect of
dexfenuramine on body weight, blood pressure, insulin resis-
tance, and serum cholesterol in obese individuals. Int J Obes
Relat Metab Disord 1995; 19: 749 751.
51 Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T,
Weiss SR, Crockett SE, Kaplan RA, Comstock J, Lucas CP, Lodewick
PA, Canovatchel W, Chung J, Hauptman J. Role of orlistat in the
treatment of obese patients with type 2 diabetes: a 1-year rando-
mized double-blind study. Diabetes Care 1998; 21:1288 1294.
52 Hooper ACB. Comparison of fenuramine (with ad libitum food
intake) with 1000 calorie diet in obesity. J Irish Med Assoc 1972;
65:35 37.
53 Johnson WG, Hughes JR. Mazindol: its efcacy and mode
of action in generating weight loss. Addict Behav 1979; 4: 237
244.
54 Kaplan NM, Jose A. Thyroid as an adjuvant to amphetamine
therapy of obesity: a controlled double-blind study. Am J Med Sci
1970; 260: 105 111.
55 Kolanowski J, Younis LT, Vanbutsele R, Detry JM. Effect of
dexfenuramine treatment on body weight, blood pressure
and noradrenergic activity in obese hypertensive patients. Eur
J Clin Pharmac 1992; 42: 599 606.
56 {Kornhaber A. Obesity-depression: clinical evaluation with a
new anorexigenic agent. Psychosomatics 1973; 14: 162 167.
57 {Kornhaber A. Obesity-depression: clinical evaluation with a
new anorexigenic agent. Psychosomatics 1973; 14: 162 167.
58 Kutnowski M, Daubresse J, Friedman H, Kolanowski J, Krzen-
towski G, Scheen A, van Gaal L. Fluoxetine therapy in obese
diabetic and glucose intolerant patients. Int J Obes Relat Metab
Disord 1992; 16(Suppl): S63 S66.
59 Lafreniere F, Lambert J, Rasio E, Serri O. Effect of dexfenur-
amine treatment on body weight and postprandial thermogen-
esis in obese patients: a double-blind placebo-controlled study.
Int J Obes Relat Metab Disord 1993; 17:25 30.
60 Langlois KJ, Forbes JA, Bell GW, Grant GF Jr. A double-blind
clinical evaluation of the safety and efcacy of phentermine
hydrochloride (Fastin) in the treatment of exogenous obesity.
Curr Ther Res 1974; 16: 289 296.
61 Lawson AAH, Roscoe P, Strong JA, Gibson A, Peattie P. Compar-
ison of fenuramine and metformin in the treatment of obesity.
Lancet 1970; i: 437 441.
62 Levine LR, Rosenblatt S, Bosomworth J. Use of a serotonin re-
uptake inhibitor, uoxetine, in the treatment of obesity. Int J
Obes Relat Metab Disord 1987; 11: 185 190.
63 Levine LR, Enas GG, Thompson WL, Byyny RL, Dauer, AD, Kirby
RW, Kreindler TG, Levy B, Lucas CP, Mcllwain HH, Nelson EB.
Use of uoxetine, a selective serotonin-uptake inhibitor, in the
treatment of obesity: a dose response study. Int J Obes Relat
Metab Disord 1989; 13: 635 645.
64 Lucas CP, Sandage BW. Treatment of obese patients with dexfen-
uramine: a multicenter, placebo-controlled study. Am J Ther
1995; 2: 962 967.
65 Marbury TC, Angelo JE, Gulley RM, Krosnick A, Sugimoto DH,
Zellner SR. A placebo-controlled dose-response study of dexfen-
uramine in the treatment of obese patients. Curr Ther Res 1996;
57:663 674.
66 Mathus-Vliegen EMH, van de Voorde K, Kok AME, Res AMA.
Dexfenuramine in the treatment of severe obesity: a placebo-
controlled investigation of the effects on weight loss, cardiovas-
cular risk factors, food intake, and eating behavior. J Intern Med
1992; 232: 119 127.
67 Mathus-Vliegen LMH, Res AMA. Dexfenuramine inuences
dietary compliance and eating behavior, but dietary instruction
may overrule its effect on food selection in obese subjects. JAm
Diet Assoc 1993; 93: 1163 1165.
68 Mathus-Vliegen EMH. Prolonged surveillance of dexfenura-
mine in severe obesity. Neth J Med 1993; 43: 246 253.
69 McKay RHG. Long-term use of diethylpropion in obesity. Curr
Med Res Opin 1973; 1: 489 493.
70 McQuarrie HG. Clinical assessment of the use of an anorectic
drug in a total weight reduction program. Curr Ther Res 1975; 17:
437 443.
71 Miach PJ, Thomson W, Doyle AE, Louis WJ. Double-blind cross-
over evaluation of mazindol in the treatment of obese hyper-
tensive patients. Med J Aust 1976; 2: 378 380.
72 Munro JF, Seaton DA, Duncan LJP. Treatment of refractory
obesity with fenuramine. Br Med J 1966; 2: 624 625.
73 Murphy JE, Donald JF, Molla AL, Crowder D. A comparison of
mazindol (Teronac) with diethylpropion in the treatment of
exogenous obesity. J Int Med Res 1975; 3: 202 206.
74 Noble RE. A controlled study of a weight reduction regimen.
Curr Ther Res 1971; 13: 685 691.
75 Nolan GR. Use of an anorexic drug in a total weight reduction
program in private practice. Curr Ther Res 1975; 18: 332 337.
76 OConnor HT, Richman RM, Steinbeck KS, Caterson ID. Dexfen-
uramine treatment of obesity: a double blind trial with post
trial follow-up. Int J Obes Relat Metab Disord 1995; 19: 181 189.
77 OKane M, Wiles PG, Wales JK. Fluoxetine in the treatment of
obese type 2 diabetic patients. Diabetic Med 1994; 11: 105 110.
{Represents data from a single study published in multiple
articles.
{Represents two independent studies.
Obesity medication meta-analysis
CK Haddock
et al
272
International Journal of Obesity
78 Oster HL, Medlar RE. A clinical pharmacologic study of benz-
phetamine (Didrex
1
), a new appetite suppressant. Arizona Med
1960; 17: 398 404.
79 Persson I, Andersen U, Deckert T. Treatment of obesity with
fenuramine. Eur J Clin Pharmacol 1973; 6:93 97.
80 Petrie JC, Bewsher PD, Mowat JA, Stowers, JM. Metabolic effects
of fenuramine-a double-blind study. Postgrad Med J 1975; 51:
139 144.
81 Pijl H, Koppeschaar HPF, Willekens FLA, de Kamp IO,
Veldhuis HD, Meinders AE. Effect of serotonin re-uptake
inhibition by uoxetine on body weight and spontaneous
food choice in obesity. Int J Obes Relat Metab Disord 1991; 15:
237 242.
82 Recasens MA, Barenys M, Sola R, Blanch S, Masana L, Salas-
Salvado J. Effect of dexfenuramine on energy expenditure in
obese patients on a very-low-calorie-diet. Int J Obes Relat Metab
Disord 1995; 9: 162 168.
83 Sainani GS, Fulambarkar AM, Khurana BK. A double blind trial
of fenuramine in the treatment of obesity. Br J Clin Pract 1973;
27: 136 138.
84 Schteingart DE. Effectiveness of phenylpropanolamine in the
management of moderate obesity. Int J Obes Relat Metab Disord
1992; 16: 487 493.
85 Schwartz LN. A non-amphetamine anorectic agent: preclinical
background and a double-blind clinical trial. J Int Med Res 1975;
3: 328 332.
86 Seagle HM, Bessesen DH, Hill JO. Effects of sibutramine on
resting metabolic rate and weight loss in overweight women.
Obes Res 1998; 6: 115 121.
87 Sebok M. A double-blinded, placebo-controlled, clinical study of
the efcacy of a phenylpropanolamine=caffeine combination
product as an aid to weight loss in adults. Curr Ther Res 1984;
28: 701 708.
88 Sedgwick JP. Mazindol in the treatment of obesity. Practitioner
1975; 214: 418 420.
89 Silverstone JT, Solomon T. The long-term management of obe-
sity in general practice. Br J Clin Pract 1965; 19: 395 398.
90 Simkin BWL. A controlled clinical trial of benzphetamine
(Didrex
1
) in the management of obesity. Curr Ther Res 1960;
2:33 38.
91 Simkin B, Wallace L. Some quantitative observations on a
methampetamine phenobarbital anorexic compound in obese
outpatients. Am J Med Sci 1960; 239: 533 538.
92 Sirtori C, Hurwitz A, Azarnoff DL. Hyperinsulinemia secondary
to chronic administration of mazindol and d-amphetamine. Am
J Med Sci 1971; 261: 341 349.
93 Sjostrom L, Rissanen A, Andersen T, Boldrin M, Golay A, Kop-
peschaar HPF, Krempf M. Randomised placebo-controlled trial
of orlistat for weight loss and prevention of weight regain in
obese patients. Lancet 1998; 352: 167 172.
94 Sonka J, Limanova Z, Zbirkova A, Kratochvil O. Effects of diet,
exercise, and anorexigenic drugs on serum thryoid hormones.
Endokrinologie 1980; 76:351 356.
95 Sproule BC. Double-blind trial of anorectic agents. Med J Aust
1969; 1: 394 395.
96 Stewart DA, Bailey JD, Patell H. Tenuate dospan as an appetite
suppressant in the treatment of obese children. Appl Ther 1970;
12:34 36.
97 Stewart GO, Stein GR, Davis TME, Findlater P. Dexfenuramine
in type II diabetes: effect on weight and diabetes control. Med J
Austr 1993; 158: 167 169.
98 Swinburn BA, Carmichael HE, Wilson MR. Dexfenuramine
as an adjunct to a reduced-fat, ad libitum diet: effects on
body composition, nutrient intake, and cardiovascular risk
factors. Int J Obes Relat Metab Disord 1996; 20: 1033
1040.
99 Thorpe PC, Isaac PF, Rodgers J. A controlled trial of mazindol
(Sanorex
1
, Teronao
1
) in the management of the obese rheu-
matic patients. Curr Ther Res 1975; 17:149 155.
100 Truant AP, Olon LP, Cobb S. Phentermine resin as an adjunct in
medical weight reduction: a controlled, randomized, double-
blind prospective study. Curr Ther Res 1972; 14: 726 738.
101 Valle-Jones JC, Brodie NH, OHara H, OHara J, McGhie RL. A
comparative study of phentermine and diethylpropion in the
treatment of obese patients in general practice. Pharmatherapeu-
tica 1983; 3: 300 304.
102 Van Gaal LF, Broom JI, Enzi G, Toplak H. Efcacy and tolerability
of orlistat in the treatment of obesity: a 6-month study dose-
ranging study. Eur J Clin Pharmac 1998; 54:125 132.
103 Vernace BJ. Controlled comparative investigation of mazindol,
d-amphetamine and placebo. J Obes Bariat Med 1974; 3: 124
129.
104 Visser M, Seidell JC, Koppeschaar PF, Smits P. The effect of
uoxetine on body weight, body composition and visceral fat
accumulation. Int J Obes Relat Metab Disord 1993; 17:247 253.
105 Waal-Manning HJ, Simpson FO. Fenuramine in obese patients
on various antihypertensive drugs: Double-blind controlled
trial. Lancet 1969; 2: 1392 1395.
106 Walker BR, Ballard IM, Gold JA. A multicentre study comparing
mazindol and placebo in obese patients. J Int Med Res 1977; 5:
85 90.
107 Wallace AG. AN 448 Sandoz (mazindol) in the treatment of
obesity. Med J Aust 1976; 1: 343 345.
108 Weintraub M. Long-term weight control: the National Heart,
Lung, and Blood Institute funded multimodal intervention
study. Clin Pharmac Ther 1992; 51: 581 585.
109 {Weintraub M, Sundaresan PR, Madan M, Schuster B, Balder A,
Lasagna L, Cox C. Long-term weight control study I (weeks 0 to
34): the enhancement of behavior modication, caloric restric-
tion, and exercise by fenuramine plus phentermine versus
placebo. Clin Pharmacol Ther 1992; 51: 586 594.
110 {Weintraub M, Sundaresan PR, Schuster B, Ginsberg G, Madan
M, Balder A, Stein EC, Byrne L. Long-term weight control study
II (weeks 34 104): an open-label study of continuous fenur-
amine plus phentermine versus targeted intermittent medica-
tion as adjuncts to behavior modication, caloric restriction,
and exercise. Clin Pharmac Ther 1992; 51: 595 601.
111 {Weintraub M, Sundaresan PR, Schuster B, Moscucci M, Stein
EC. Long-term weight control study III (weeks 104 to 156): an
open-label study of dose adjustment of fenuramine and phen-
termine. Clin Pharmac Ther 1992; 51: 602 607.
112 {Weintraub M, Sundaresan PR, Schuster B, Averbuch M, Stein
EC, Cox C. Long-term weight control study IV (weeks 156 to
190): the second double-blind phase. Clin Pharmac Ther 1992;
51: 608 614.
113 {Weintraub M, Sundaresan PR, Schuster B, Averbuch M, Stein
EC, Byrne L. Long-term weight control study V (weeks 190 to
210): follow-up of participants after cessation of medicine. Clin
Pharmac Ther 1992; 51: 615 618.
114 {Weintraub M, Sundaresan PR, Cox C. Long-term weight con-
trol study VI: individual participant response patterns. Clin
Pharmac Ther 1992; 51: 619 633.
115 {Weintraub M, Sundaresan PR, Schuster B. Long-term weight
control study VI (weeks 0 to 210): serum lipid changes. Clin
Pharmac Ther 1992; 51: 634 641.
116 {Weintraub M. Long-term weight control study: conclusions.
Clin Pharmac Ther 1992; 51: 642 646.
117 Weintraub M, Rubio A, Golik A, Byrne L, Scheinbaum ML.
Sibutramine in weight control: a dose-ranging, efcacy study.
Clin Pharamc Ther 1991; 50: 330 337.
118 Wise PJ. Clinical experience with a new dosage form of phen-
termine hydrochloride. J Obes Bariat Med 1975; 4: 102 105.
Obesity medication meta-analysis
CK Haddock
et al
273
International Journal of Obesity
... Currently, some of the US-FDA approved antiobesity active pharmaceutical ingredients, i.e., phentermine, lorcaserin, naltrexone, orlistat, and liraglutide are clinically tested (Table 1) and available in the market [74]. e long-term safety and efficacy of newly developed drugs should also be evaluated in the management of obesity, which often requires continuous treatment to achieve and maintain weight loss, though the rigidity of a regulatory committee for the approval of novel antiobesity drugs and the regulatory guidelines for antiobesity therapy represents a significant limitation to developing drugs [75,76]. ...
Article
Full-text available
The incidence of obesity and over bodyweight is emerging as a major health concern. Obesity is a complex metabolic disease with multiple pathophysiological clinical conditions as comorbidities are associated with obesity such as diabetes, hypertension, cardiovascular disorders, sleep apnea, osteoarthritis, some cancers, and inflammation-based clinical conditions. In obese individuals, adipocyte cells increased the expression of leptin, angiotensin, adipocytokines, plasminogen activators, and C-reactive protein. Currently, options for treatment and lifestyle behaviors interventions are limited, and keeping a healthy lifestyle is challenging. Various types of phytochemicals have been investigated for antiobesity potential. Here, we discuss pathophysiology and signaling pathways in obesity, epigenetic regulations, regulatory mechanism, functional ingredients in natural antiobesity products, and therapeutic application of phytochemicals in obesity.
... 57 Phentermine is widely prescribed, mainly in the USA, but in spite of its widespread use, the longest published placebo-controlled trial of phentermine lasted 36 weeks. 58 Orlistat has been approved for obesity treatment for more than 20 years. Its modest weightreducing effect results from reducing absorption of ingested fat by approximately 30%. ...
Article
Full-text available
Obesity is now recognised as a disease that is associated with serious morbidity and increased mortality. One of its main metabolic complications is type 2 diabetes, as the two conditions share key pathophysiological mechanisms. Weight loss is known to reverse the underlying metabolic abnormalities of type 2 diabetes and, as such, improve glucose control; loss of 15% or more of bodyweight can have a disease-modifying effect in people with type 2 diabetes, an outcome that is not attainable by any other glucose-lowering intervention. Furthermore, weight loss in this population exerts benefits that extend beyond glycaemic control to improve risk factors for cardiometabolic disease and quality of life. We review the evidence supporting the role of weight loss in the management of type 2 diabetes and propose that many patients with type 2 diabetes would benefit from having a primary weight-centric approach to diabetes treatment. We discuss the logistical challenges to implementing a new weight-centric primary treatment goal in people with type 2 diabetes.
... hence, it is used as an off-label drug for the treatment of obesity. 24 suffering from hypothalamic obesity also led to promising results. 28 In all patients, dexamphetamine was started at 5 mg per day and gradually increased to up to 20 mg per day. ...
Article
Full-text available
Non-alcoholic fatty liver disease (NAFLD) is one of most frequent causes of chronic liver disease. Global prevalence of NAFLD and nonalcoholic steatohepatitis (NASH) with advanced fibrosis is increasing day by day. Patients with NAFLD are more susceptible to encounter cardiovascular morbidity and mortality. Apart from lifestyle changes and dietary modifications, no effective pharmacotherapy is available to prevent the progression of NAFLD to NASH and advanced stages of hepatic fibrosis and cirrhosis. Dexamphetamine is the d-isomer of amphetamine, which acts by inhibiting monoamine reuptake and direct stimulation of dopamine and noradrenaline release. Presently, dexamphetamine is indicated for the treatment of attention deficit hyperactivity disorder and narcolepsy, but since its use was found to be associated with weight loss, it is also now used as an off-label drug for the treatment of obesity. Direct or indirect evidence is present in the form case reports, case series and from effects of related drugs to support the potential role of dexamphetamine in NAFLD. There is an urgent need to initiate preclinical and clinical studies involving robust methodology and adequate sample sizes to explore the potential of dexamphetamine in patients with NAFLD. In this review, we will discuss the therapeutic potential of dexamphetamine for the treatment of NAFLD.
... It is not approved in Europe due to its pharmacological similarities with amphetamine. A meta-analysis has estimated that treatment with phentermine (30 mg/day) for about 3 months results in a mean weight loss of about 3 kg relative to a placebo [113]. Among the side effects of phentermine are dry mouth and constipation, in addition to agitation and insomnia in some cases. ...
Article
Full-text available
Numerous combinations of diets and pharmacological agents, including lifestyle changes, have been launched to treat obesity. There are still ambiguities regarding the efficacies of different approaches despite many clinical trials and the use of animal models to study physiological mechanisms in weight management and obesity comorbidities, Here, we present an update on promising diets and pharmacological aids. Literature published after the year 2005 was searched in PubMed, Medline and Google scholar. Among recommended diets are low-fat (LF) and low-carbohydrate (LC) diets, in addition to the Mediterranean diet and the intermittent fasting approach, all of which presumably being optimized by adequate contents of dietary fibers. A basic point for weight loss is to adopt a diet that creates a permanently negative and acceptable energy balance, and prolonged dietary adherence is a crucial factor. As for pharmacological aids, obese patients with type 2 diabetes or insulin resistance seem to benefit from LC diet combined with a GLP-1 agonist, e.g. semaglutide, which may improve glycemic control, stimulate satiety, and suppress appetite. The lipase inhibitor orlistat is still used to maintain a low-fat approach, which may be favorable e.g. in hypercholesterolemia. The bupropion-naltrexone-combination appears promising for interruption of the vicious cycle of addictive over-eating. Successful weight loss seems to improve almost all biomarkers of obesity comorbidities. Until more support for specific strategies is available, clinicians should recommend an adapted lifestyle, and when necessary, a drug combination tailored to individual needs and comorbidities. Different diets may change hormonal secretion, gut-brain signaling, and influence hunger, satiety and energy expenditure. Further research is needed to clarify mechanisms and how such knowledge can be used in weight management.
Article
Background: Innovations in drug therapy for obesity have had a limited impact on the body mass index, prevalence of medical complications, quality of life, and work potential of a substantial majority of affected persons. Study question: What are the milestones of the changes in the expert approach to the pharmacological management of obesity in the past century? Study design: To determine the changes in the experts' approach to the management of obesity, as presented in a widely used textbook in the United States. Data sources: The primary sources were chapters describing the management of obesity in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. Secondary sources were publications retrieved from Medline that clarified technical issues related to the development, regulatory approval, and use of the drugs mentioned in the Cecil Textbook of Medicine. Results: Pharmacological interventions aimed at increasing caloric expenditures through thermogenesis were recommended from 1927 through 1943. Thyroid extracts were prescribed even in the absence of demonstrated hypothyroidism or decreased basal metabolic rate throughout this period. Dinitrophenol was mentioned in 1937, but was banned soon thereafter. Appetite suppression with amphetamine was considered useful from 1943 through 1988, after which the drug was replaced with other centrally acting molecules, such as fenfluramine in 1988, sibutramine in 2000, and rimonabant in 2008, which were in turn withdrawn because of major adverse effects. In the past decade, obesity has been treated with the appetite suppressants phentermine-topiramate, bupropion-naltrexone, lorcaserin, and liraglutide, and with orlistat, a drug promoting fat malabsorption. The change in weight produced by these drugs is generally modest and transient. Conclusions: The pharmacological management of obesity has remained frustratingly inefficient. The reasons for the relative lack of success may reside in the ever-growing access to dense, palatable, and relatively inexpensive food, coupled with the decrease in energy expenditure created by a sedentary lifestyle.
Article
Background This “Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association Clinical Practice Statement 2022” is intended to provide clinicians an overview of Food and Drug Administration (FDA) approved anti-obesity medications and investigational anti-obesity agents in development. Methods The scientific information for this Clinical Practice Statement (CPS) is based upon published scientific citations, clinical perspectives of OMA authors, and peer review by the Obesity Medicine Association leadership. Results This CPS describes pharmacokinetic principles applicable to those with obesity, and discusses the efficacy and safety of anti-obesity medications [e.g., phentermine, semaglutide, liraglutide, phentermine/topiramate, naltrexone/bupropion, and orlistat, as well as non-systemic superabsorbent oral hydrogel particles (which is technically classified as a medical device)]. Other medications discussed include setmelanotide, metreleptin, and lisdexamfetamine dimesylate. Data regarding the use of combination anti-obesity pharmacotherapy, as well as use of anti-obesity pharmacotherapy after bariatric surgery are limited; however, published data support such approaches. Finally, this CPS discusses investigational anti-obesity medications, with an emphasis on the mechanisms of action and summary of available clinical trial data regarding tirzepatide. Conclusion This “Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association Clinical Practice Statement 2022” is one of a series of OMA CPSs designed to assist clinicians in the care of patients with pre-obesity/obesity.
Chapter
Obesity is often incorrectly viewed as a self‐inflicted consequence of personal lifestyle choices, and as a result, people commonly delay or avoid seeking medical advice or treatment. Before considering pharmacotherapy, initial management strategies should focus on diet, exercise, and behavioral support. Rather than to replace this first line management, the role of anti‐obesity drugs is as an adjunct to lifestyle and behavioral modification when these methods alone do not achieve clinically meaningful weight loss and/or to help maintain weight loss. The potential use of glucagon‐like peptide 1 analogs in the management of obesity is discussed in the future therapies section of this chapter. Currently, a number of medications and therapeutic targets are being considered in the management of obesity. Some of these are currently licensed for the management of conditions other than obesity but have incidentally been shown to have a positive impact on weight loss.
Article
Full-text available
Weight loss is a therapeutic solution for many metabolic disorders, such as obesity and its complications. Bariatric surgery aims to achieve lasting weight loss in all patients who have failed after multiple dietary attempts. Among its many benefits, it has been associated with the regression of non-alcoholic fatty liver disease (NAFLD), which is often associated with obesity, with evidence of substantial improvement in tissue inflammation and fibrosis. These benefits are mediated not only by weight loss, but also by favorable changes in systemic inflammation and in the composition of the gut microbiota. Changes in microbial metabolites such as short-chain fatty acids (SCFAs), capable of acting as endocrine mediators, and bile acids (BAs) as well as modifications of the gut-brain axis, are among the involved mechanisms. However, not all bariatric surgeries show beneficial effects on the liver; those leading to malabsorption can cause liver failure or a marked worsening of fibrosis and the development of cirrhosis. Nevertheless, there are still many unclear aspects, including the extent of the benefits and the magnitude of the risks of bariatric surgery in cirrhotic patients. In addition, the usefulness and the safety of these procedures in patients who are candidates to or who have undergone liver transplant need solid supporting evidence. This paper aims to review literature data on the use of bariatric surgery in the setting of chronic liver disease.
Article
Objective: Mexico has the second largest prevalence of obesity among adults worldwide, a condition especially affecting the low-income population. There is a pressing need to improve therapeutic options for weight loss. Phentermine is an old and low-cost agent given as an adjuvant therapy for obesity for a 12-week period, at an initial dose of 15 mg or 30 mg. However, there are no precise guidelines on the suitability of both the starting dose and the continuation of treatment for 6 months. The aim of this study was to evaluate the 3- and 6-month efficacy and safety of phentermine in obese Mexican patients to elucidate the aforementioned. Materials and methods: In this prospective, multi-center, open-label study, 932 obese adults received 15 mg or 30 mg phentermine once daily for 6 months. Results: 30 mg phentermine was more effective than 15 mg phentermine in improving anthropometric variables in the 3-month follow-up, but not after completing the 6-month treatment period. Nearly 40% of 3-month non-responders reached a body weight reduction of at least 5% at 6 months. Conversely, ~ 65% and 25% of 3-month responders maintained or improved, respectively, their body weight reduction with long-term phentermine. Potential tolerance as weight regain was ~ 10% from 3 to 6 months. None of the doses increased cardiovascular risk, although mild-to-moderate adverse events were more frequent with 30 mg phentermine. Conclusion: 30 mg phentermine was more effective than 15 mg phentermine after 3 months, but not at 6 months of treatment. An important number of subjects could benefit following the therapy from 3 to 6 months.
Obesity is a chronic disease which is often relapsing and progressive due in part to the physiology of energy homeostasis in people with obesity, rendering them with the challenge of attaining adequate weight loss and weight maintenance after successful weight loss. Depending on the presence, types and severity of the obesity-related comorbidities (ORCs), some patients will require an amount of weight loss beyond what lifestyle and behavioural modification can achieve. Even after bariatric surgery, patients may not lose the expected amount of weight or experience weight regain. Anti-obesity medications may be required to support them further. Hence, the use of pharmacotherapy in obesity management remains an important adjunct to lifestyle and behavioural modifications and even to bariatric surgery, particularly in those with more severe ORCs and with a high body mass index. This article discusses the general approach to the use of pharmacotherapy in obesity management and the various anti-obesity medications currently approved.
Article
In a double-blinded, placebo-controlled, six-week study of 70 obese adults, the efficacy of the combination of 35 mg phenylpropanolamine (PPA) and 140 mg caffeine, given twice daily as an adjunct to a low-calorie diet plan, was assessed. During the course of the study, more weight loss was seen in the PPA/caffeine group than in the control group. As the study progressed, nine patients given the combination and 12 given placebo dropped out. Compared with the control group, the group given the PPA/caffeine combination consistently lost more weight as determined both in pounds and in percent of initial body weight. The difference between the two groups with respect to overall trends in mean percent weight loss was significant (p < 0.05). Half (13/26) of the group taking the combination lost at least six pounds, whereas only 22% (5/23) of the placebo group lost this much weight; this difference approached the 0.05 level of significance. Thirty-one percent (8/26) of the group given the PPA/caffeine combination lost at least 5% of their initial body weight; only four percent (1/23) of the placebo group lost this much; this difference also was significant (p < 0.05). Side effects were mild; the nature and frequency of complaints were similar for the two groups.
Article
Preclinical data suggesting potential advantages for mazindol prompted the design of a double-blind comparative trial with 60 obese patients. In it, mazindol, 2 mg once a day, was compared for 12 weeks to placebo. Weight loss was significantly greater with mazindol than placebo throughout the trial. After the 12 weeks, the mazindol patients had lost an average of 18.5 lbs compared to 2.4 lbs with placebo. Constant efficacy at the fixed once-daily dosage was obtained with no signs of tolerance. No significant adverse effects or other signs of toxicity to mazindol were encountered. Extensive clinical evaluation of this drug in relation to the established anorectics is strongly recommended.
Article
The safety and efficacy of phenylpropanolamine hydrochloride (PPA) were investigated in subjects who were 10% to 55% overweight with stable, controlled hypertension in two six-week studies. In a pilot study, 12 patients received 25-mg PPA plus 100-mg caffeine three times daily for the first two weeks, placebo tablets daily for the next two weeks, and sustained-release 75-mg PPA once daily for the final two weeks. In the main study, 72 patients received either 25-mg PPA or placebo three times daily in a double-blind protocol. Vital signs were measured and clinical and laboratory data obtained. Acute dosing effects on blood pressure and pulse rate were measured at 0.5, 1, 2, and 4 hours after the daily initial dose of medication at two-week intervals in the pilot study and once at the start of the main study. No statistically significant main treatment effects upon either blood pressure or pulse rate were observed during weeks, 2, 4, or 6 of the pilot or main studies as compared with baseline. PPA produced no significant changes in laboratory values. There were some statistically significant changes in vital signs during the acute dosing in the pilot and main studies, but because of their magnitude they were judged to be clinically insignificant. No subjective side effects were attributed to PPA administration. Both studies found that PPA suppressed hunger and produced more weight loss in comparison with placebo. The pilot study showed mean cumulative weight loss of 1.9 lb/week with 25-mg PPA plus caffeine, 1.4 lb/week with 75-mg PPA sustained-release, and 0.63 lb/week with placebo. The main study reported a mean cumulative weight loss of 0.79 lb/week for the PPA group and 0.50 lb/week in the placebo group. Based on these findings, it may be concluded that PPA is a safe and effective diet aid, even for patients with stable, controlled hypertension.
Article
This randomized, placebo-controlled, double-blind study was designed to evaluate the safety and efficacy of dexfenfluramine (Dfen). Dfen 15 mg BID, and placebo were administered for 12 weeks to 337 moderately obese patients on calorically restricted diets. Patients were monitored for an additional 4 weeks. Efficacy was evaluated in 321 patients who were an average of 52% in excess of ideal body weight. Dfen-treated patients lost significantly more weight than did those treated with placebo (p less-than-or-equal 0.001). Small nonsignificant fluctuations in body weight were observed during the 4-week posttreatment period in both groups. The most common drug-related side effects were diarrhea, asthenia, dry mouth, and thirst (p less-than-or-equal 0.05 compared with placebo). Dexfenfluramine may become a valuable addition to weight loss and weight management programs.