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.
No comprehensive meta-analytic studies of obesity pharmacotherapy have been published to date, but three meta-analyses have been published on single drugs. Lijesen et al1 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 circumference and visceral fat when compared to placebo. Greenway3 examined phenylpropanolamine (PPA) trials since 1973, including trials that were reviewed by previous investigators4,5 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 efficacy6 were authored by Goldstein and Potvin7 and the National Task Force on the Prevention and Treatment of Obesity.8 Goldstein and Potvin7 conducted a detailed review of 20 long-term (ie those lasting 6 months or longer) phentermine, mazindol, fenfluramine, dexfenfluramine and fluoxetine 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 Obesity8 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 hydrochloride, 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
The purpose of this study is to provide a comprehensive meta-analytic review of anti-obesity agents, both prescription and over-the-counter (OTC), and drugs that are/were FDA-approved and are/were used off-label for obesity.8 The specific aims are to evaluate the clinical efficacy of obesity medications and determine whether methodological factors (eg length of treatment, year of publication) are systematically related to treatment outcome. In addition, based on the results of this meta-analysis, suggestions for future research are discussed.
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 Obesity8 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 field of obesity research.
We retained fenfluramine and dexfenfluramine 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), bromocriptine, buspar, cimetidine, fluvoxamine, human chorionic gonadotropin, human growth hormone, leptin, naloxone/naltrexone or synthyroid. We also did not include dietary supplements, which are defined by the Dietary Supplement Health and Education Act of 19949 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, constituent, extract, or combination of any of the previously described ingredients. Examples of substances in this category include 5-hydroxytryptophan (5-HTP), ma huang (ephedrine), guarana (caffeine), chitosan, chromium (picolinate and nicotinate), dehydroepiandrosterone (DHEA), garcinia cambogia/hydroxycitric acid, pyruvate and St John's 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 participants assigned randomly, some haphazardly); (6) groups were distinguishable on relevant parameters (eg drug type, use of lifestyle intervention); (7) the study provided sufficient outcome data to compute an effect size based on weight loss (see effect size definition below); (8) the study 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 sufficient data to compute an effect size (typically these studies presented no data on outcome variability nor information where outcome variance could be estimated). 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.10,11,12 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 American 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 characteristics 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 definitions of the variables used in this review was developed (available via email in MS Word for Windows format upon request from the first author). Reliability of coding was maintained by providing intensive training of the project assistants, including 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 assistant independently verified 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 defined as:
where is the mean weight loss in the treatment group of the ith study, is the mean of the control or alternative treatment in the ith study, and is the pooled standard deviation of change for the two groups. When sufficient data were not reported to directly compute 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 estimating 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 relevant 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 insignificant where adequate data were not presented to compute an effect size were conservatively coded as zero. Hedges' correction 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 sufficient 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.
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 significantly altered the original study design and thus precluded our ability to present directly interpretable 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’ examination of long-term treatment effects were coded as follow-ups.
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 sufficient 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 benzphetamine 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%. Consistent with published guidelines, most studies used some form of lifestyle management program even though these guidelines were published long after many studies were in print.19 This partially reflects the multidisciplinary nature of obesity treatment and the recognition that successful drug interventions 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 modification, experienced greater average weight loss than patients in the placebo groups. Unweighted weight loss differences ranged from −0.80 to 3.82 kg, with most drugs demonstrating modest weight losses relative to placebo. It is interesting to note that five drugs (benzocaine, dexfenfluramine, diethylpropion hydrochloride, fenfluramine 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% confidence intervals for drug–placebo comparisons. Confidence intervals 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 various drugs generally produced comparable weight losses. However, it could be argued that amphetamine, benzphetamine, fenfluramine 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 defined in meta-analysis.20 Furthermore, fenfluramine and sibutramine produced significantly better weight losses (based on the effect size 95% confidence intervals) than five of the other drugs studied, ie benzocaine, dexfenfluramine, fluoxetine, mazindol and orlistat. Nevertheless, both drugs overlapped with amphetamine, benzphetamine, diethylpropion, phentermine and PPA, suggesting that there were no statistically significant 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 study's treatment (r=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=0.016, P=0.875), suggesting that many drugs may have their greatest impact on weight early in treatment. Seven drugs were judged to have a sufficient number of studies and variance in treatment length to be examined in within-drug analyses (ie dexfenfluramine, diethylpropion hydrochloride, fenfluramine, mazindol, orlistat, phentermine 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 subject's outcome and, because a correlation coefficient represents an effect size,21 it was a priori decided that a correlation coefficient 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 significant 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 influence phentermine's 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 significantly correlated only for dexfenfluramine (both drug and placebo) and the placebo groups in diethylpropion hydrochloride studies. Patients receiving diethylpropion hydrochloride or orlistat (or those participating in diethylpropion hydrochloride or orlistat study placebo groups) also demonstrated greater weight loss with increased treatment time, but the correlations were not statistically significant. Patients receiving placebo in both fenfluramine 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.
Effect of publication year
Overall, there was no relationship between year of publication and effect size, suggesting that the placebo-controlled outcomes of drug studies are not changing over time (r=0.055, P=0.592). Most of the seven selected drugs demonstrated no or positive, but statistically insignificant, relationships between publication year and effect size except for dexfenfluramine. The correlation between dexfenfluramine's effect size and year of publication was strong and negative, suggesting that effect size in dexfenfluramine studies decreased over time. This was also demonstrated in the negative correlation between publication year and the amount of weight (kg) lost in patients taking dexfenfluramine, suggesting that later dexfenfluramine studies that met our inclusion criteria demonstrated less weight loss than earlier studies. While the same trend was noted in patients receiving placebos in dexfenfluramine studies, the correlation was not statistically significant.
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=17.3; median 6.0). The relationship between length of follow-up and effect size was not significant (P=0.066), although the magnitude of the correlation was moderate (r=−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 periods for the majority of studies examined represent post-treatment observation periods without any extension of the treatments, not reflecting the current long-term treatment paradigm in obesity management. With the exception of amphetamine and mazindol, all drugs with follow-up 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. Dexfenfluramine 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 definition 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 modification (ie modification of diet and/or physical activity). All drug combinations produced placebo-subtracted weight loss, ranging from 0.30 kg for PPA–benzocaine to 9.60 kg for fenfluramine–phentermine. Effect sizes for phentermine–fenfluramine (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 fenfluramine and sibutramine (see Figure 1). However, these effect sizes are based on a much smaller number of studies (n=1 for most) and some of the combinations are now viewed as having significant adverse health impacts (eg fenfluramine–phentermine, methamphetamine–phenobarbatol).
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 prescription drugs it was compared with, eg mazindol and diethylpropion. In contrast, ephedrine–caffeine, another OTC, performed moderately better than dexfenfluramine. 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 identified by the National Task Force on the Prevention and Treatment of Obesity8 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, benzphetamine, fenfluramine 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 benefit 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% confidence intervals for the studied drugs overlapped, indicating that the differences in effect sizes among many of the drugs were not statistically significant. For example, sibutramine, the drug with the largest effect size, had overlapping confidence intervals with benzphetamine, diethylpropion, fenfluramine, phentermine and PPA, and the effect size for amphetamine exceeded its lower boundary. The only clearly ineffective drug was benzocaine, with a negative effect size of −0.35 and a placebo-subtracted weight loss of −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 influence 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=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 demonstrated negative relationships between treatment length and effect size (eg dexfenfluramine, diethylpropion, fenfluramine and PPA), suggesting that their effectiveness decreased with increasing treatment time, although these correlations were small and not statistically significant. While there was no overall relationship between publication year and effect size, it is interesting to note that there was a statistically significant negative correlation between publication year and effect size for dexfenfluramine, 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 insignificant 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 paradigm 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 hypertension patients, ie there is no more reason to expect that obesity medications will have significant prolonged effects than would be expected with any other chronic disease pharmacotherapy. Given this new treatment paradigm, obesity 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. Nevertheless, 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 combinations 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, fenfluramine and methamphetamine) or have been or are under consideration for removal (eg PPA, ephedra).23,24,25,26,27
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 descriptions 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 parameters 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 maintenance, 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 modification programs that typically are based in obesity treatment centers. In addition, obesity medications can result in important reductions in overall medication use and net costs associated with obesity-related comorbidites.27
Finally, more recent studies that did not meet our inclusion criteria and were not included in this meta-analysis10,11,12 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 al12 found that patients receiving sibutramine for an 18-month maintenance phase, following a 6-month 600 kcal diet+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.
Represents three independent studies.
Represents data from a single study published in multiple articles.
Represents two independent studies.
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Appendix 1: Studies included in the meta analysis
Appendix 1: Studies included in the meta analysis
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Haddock, C., Poston, W., Dill, P. et al. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes 26, 262–273 (2002). https://doi.org/10.1038/sj.ijo.0801889
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