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


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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.
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Pharmacotherapy for obesity: a quantitative analysis
of four decades of published randomized clinical trials
CK Haddock
*, WSC Poston
, PL Dill
, JP Foreyt
and M Ericsson
University of Missouri-Kansas City and Mid America Heart Institute, St Luke’s Hospital, Kansas City, Missouri, USA;
College of Medicine, USA; and
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
> 0.80;
amphetamine, benzphetamine, fenfluramine and sibutramine). The placebo-subtracted weight losses for single drugs
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
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
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,
who concluded that it was effective in reducing waist cir-
cumference and visceral fat when compared to placebo.
examined phenylpropanolamine (PPA) trials
since 1973, including trials that were reviewed by previous
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
were authored by Goldstein and Potvin
and the National
Task Force on the Prevention and Treatment of Obesity.
Goldstein and Potvin
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
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.
*Correspondence: CK Haddock, Health Research Group, University of
Missouri-Kansas City, 4825 Troost, Room 124, Kansas City, MO 64110,
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
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.
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.
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
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.
In addition, we based our selection of drugs on extensive
consultation with several experts in the eld of obesity
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
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
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
Years of publications (range)
Amphetamine (dexamphetamine)
Biphetamine II 6 1969 1974
Benzocaine Slim Mint, Trocaine OTC 1 1999
Didrex III 3 1960 1987
Redux IV 18 1989 1998
Tenuate, Tenuate Dospan IV 13 1965 1983
Pondimin IV 15 1966 1992
Prozac None 11 1987 1995
Sanorex, Mazanor IV 28 1969 1982
Desoxyn II 1 1960
Xenical None 6 1995 1999
Bontril, Plegine, Prelu-2, X-Trozine III
Phentermine (HCL and resin)
Adipex-P, Fastin, Oby trim, Ionamin IV 9 1969 1992
Phenylpropanolamine (PPA)
Dexatrim, Acutrim OTC 9 1975 1999
Zoloft None
Meridia IV 5 1991 1998
: FDA, Food and Drug Administration; DEA, Drug Enforcement Agency; OTC, over the counter.
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.
Drugs highlighted by the National Task Force on the Prevention and Treatment of Obesity (1996).
Removed from the market in 1997.
FDA-approved drugs that have been used off-label for obesity.
Approved by the FDA after the 1996 report by the National Task Force on the Prevention and Treatment of Obesity.
No studies of these drugs met our inclusionary criteria.
Obesity medication meta-analysis
CK Haddock
et al
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
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 Xc
where DX
is the mean weight loss in the treatment group
of the ith study, DX
is the mean of the control or
alternative treatment in the ith study, and DX
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.
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,
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,
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,
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.
Thus, these unweighted
raw differences between treatment groups are provided for
descriptive purposes only and should be interpreted with
Statistical analyses
Standard statistical procedures for meta-analysis were used
for data analysis.
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
International Journal of Obesity
examination of long-term treatment effects were coded as
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,
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.
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
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
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)
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)
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)
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)
: 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
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.
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,
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.
: 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
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
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)
: values in cells represent correlation coefcient and its associated
-value (in parentheses). Only drugs with a sufcient number of primary studies were included
in this table.
Table 4 Single drug
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)
(16 21)
00 0 7 3.45 7 2.5 7 0.95 0.225*
Dexfenuramine (9) 33.6
(5 116)
(5 108)
11 11 0 6.04
( 7 1.5 11.7)
(1.9 8.5)
( 7 3.6 3.5)
(0.238 0.564)
Mazindol (4) 18.3
(10 23)
(10 24)
00 0 7 0.28
( 7 6.1 2.3)
7 0.85
( 7 5.5 1.1)
( 7 0.60 1.8)
(0.329 1.019)
Phentermine (2) 16.3
(8 25)
(9 27)
0 0 0 8.23
Sibutramine (2) 31.3
(15 48)
(15 50)
50 50 0 4.87
(3.3 6.4)
(1.7 3.3)
(1.63 3.1)
: 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.
Weight losses for individual groups only reported in one of the two phentermine studies.
Obesity medication meta-analysis
CK Haddock
et al
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.
We meta-analyzed published, randomized, controlled trials
of obesity pharmacotherapies identied by the National Task
Force on the Prevention and Treatment of Obesity
as being
currently approved, those that were used off-label, recently
approved drugs that were not reviewed by the Task Force,
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
placebo: post-treatment outcomes
Drug combination components
Number at
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)
(26 28)
(23 28)
(78.6 88.5)
(67.9 78.3)
100 2.4
(2.1 2.7)
(0.9 1.9)
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
: 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
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
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.
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
post-test Female (%)
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)
(5 31)
(4 32)
(59.4 100)
(71.9 100)
78 5.47
(2.9 9.0)
(1.6 8.1)
(0.043 0.471)
(2) Amphetamine 12
(8 16)
(5 30)
(4 32)
50 4.9
(3.4 6.4)
(1.6 5.9)
(3) Diethylpropion 11.7
(11 12)
17.3 19.3 96.2
100 6.7
(2.9 9.0)
(2.0 8.0)
( 7 0.073 0.693)
(3) Phenmetrazine 5.3
(2 8)
18.3 18 91.1
(80 100)
(85.7 100)
66.7 5.1
(3.5 6.7)
(2.9 5.7)
(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)
(16 50)
(15 49)
(64 100)
(69.4 100)
100 7.1
(6.1 8.3)
(5.6 6.3)
(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
: 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.
Only one study reported data for this factor.
Obesity medication meta-analysis
CK Haddock
et al
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.
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.
Similarly, James et
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.
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.
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... 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]. ...
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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%. ...
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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. ...
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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. ...
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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.
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.
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.
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.
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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.
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.
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.
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.
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.
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.