Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials Haddock C K, Poston W S, Dill P L, Foreyt J P, Ericsson M

Authors' objectives To assess the clinical effectiveness of medications for obesity.

Searching Reports published in peer-reviewed journals before December 1999 were sought. Studies were identified by searching databases such as MEDLINE and PsycINFO, and by examining the reference sections of journals, abstracts, previous reviews, past empirical studies, and relevant book chapters. In addition, recent issues of journals that publish obesity research (e.g. 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) were reviewed. Individuals who regularly publish in obesity journals were contacted for details of their personal list of obesity studies involving pharmaceutical agents. Only studies for which an English language version was available were included.

Study selection Study designs of evaluations included in the review Randomised controlled trials (RCTs), in which the randomisation was not broken during the study, were eligible if the groups were distinguishable on intervention details such as drug type and lifestyle modification.

Specific interventions included in the review Anti-obesity agents that are, or were, approved by the Food and Drug Administration (FDA) for the treatment of obesity were eligible. These included prescription medication, over-the-counter drugs, and drugs that are FDA approved and are used off-label. In addition, fenfluramine and dexfenfluramine (both were removed from the market in 1997) were eligible. Experimental anti-obesity agents, dietary supplements, and drugs used for weight maintenance following obesity treatment, were excluded.

The following drugs were compared either with each other or with a control therapy: amphetamine, benzocaine, benzphetamine, dexfenfluramine, diethylpropion, fenfluramine, fluoxetine, mazindol, methamphetamine, orlistat, phendimetrazine, phentermine, phenylpropanolamine, sertraline and sibutramine. Most studies also used some form of lifestyle management programme. Combinations of the above listed drugs, either with each other or with caffeine, phenobarbitol or laevoamphetamine and meth-aqual-one, were also included. The duration of treatment ranged from 1.6 to 76 weeks. In the post-treatment phase, all studies discontinued drug treatment and most studies did not provide booster sessions.

Participants included in the review Obese individuals were eligible. Most of the patients were female; the proportion of females in the individual studies ranged from 57.6 to 88.5%. The mean age of the participants ranged from 5 to 77 years (mean: 40.7 years).

Outcomes assessed in the review Studies that provided sufficient data to calculate an effect size based on weight loss were eligible. Weight loss was assessed at the end of treatment and, where possible, after a follow-up period without treatment. The follow-up periods ranged from 1 to 136 weeks post-treatment.

How were decisions on the relevance of primary studies made? The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.

Page: 1 / 4 Assessment of study quality The included studies were restricted to RCTs. No formal validity assessment was performed.

Data extraction The data were extracted and coded by intensively trained project assistants, with another project assistant independently verifying all coding. The authors state that details of the coding definitions are available from the first author on request. When the drug dose varied during the study, an average value was coded. For each study, a standardised mean difference (d) on reduction in weight was calculated. Where more than one relevant effect size was presented in a single study, all the within-study effect sizes were aggregated. Results described as insignificant, with insufficient data to estimate an effect size, were coded as having an effect size of zero. Hedges' correction for small sample size bias was applied to all effect sizes (see Other Publications of Related Interest).

Methods of synthesis How were the studies combined? The studies were categorised as single-drug versus placebo, combination drug versus placebo, and between-drug comparisons. For each group, the mean values of the following were tabulated for each drug included in the review: the duration of treatment; the number of patients post-test by intervention group; the proportion of females; and the daily drug dosage. The studies were initially combined in a narrative review. Subsequently, where more than one study evaluated a drug, a pooled effect size was calculated with weighting by the inverse of the sample variance.

How were differences between studies investigated? The influence of year of publication and length of treatment on study outcome was explored, both overall and separately, for any drug examined in a sufficient number of studies.

Results of the review One hundred and eight RCTs were included. It was not possible to calculate the number of participants included in the review.

The methodological flaws included scant description of controls, and the lack of sufficient useable data on either patterns of or attrition due to side-effects.

Single drug versus placebo: post-treatment outcomes.

Apart from benzocaine, the patients in the drug therapy groups experienced greater average weight loss than those in the placebo group. The unweighted difference in weight loss between the drug treatment and placebo ranged from -0.80 to 3.82 kg. Most drug treatments were associated with modest weight loss in comparison with placebo. The drugs associated with a statistically-significantly greater weight loss than placebo treatment were: amphetamine (2 RCTs), with a d-value of 2.7 kg (95% confidence interval, CI: 2.1, 3.3); benzphetamine (3 RCTs), d of 3.3 kg (95% CI: 1.7, 5.3); fluoxetine (11 RCTs), d of 3.3 kg (95% CI: 0.20, 7.4); orlistat (6 RCTs), d of 2.08 kg (95% CI: 0.30, 4.2); phentermine (6 RCTs), d of 3.6 kg (95% CI: 0.6, 6.0); phenylpropanolamine (7 RCTs), d of 0.89 kg (95% CI: 0.30, 2.0); and sibutramine (4 RCTs), d of 3.5 kg (95% CI: 2.4, 5.1). There was no statistically-significant correlation (r) between treatment length and effect size, either overall (r=0.016, p=0.875) or for any of the following seven drugs: dexfenfluramine, diethylpropion, fenfluramine, mazindol, orlistat, phentermine and phenylpropanolamine. There was also no statistically-significant correlation between year of publication and effect size, either overall (r=0.055, p=0.592) or for any of these seven drugs.

Single drug versus placebo: follow-up outcomes (19 RCTs).

Overall, there was no statistically-significant correlation between treatment length and effect size (r = -0.43, p=0.066).

Dexfenfluramine (9 RCTs; d=0.401, 95% CI: 0.238, 0.564), phentermine (2 RCTs; d=0.810) and sibutramine (2 RCTs; d=1.05) demonstrated a sustained weight loss. Amphetamine (2 RCTs) and mazindol (4 RCTs) did not show sustained weight loss. Page: 2 / 4 Combination drug versus placebo: post-treatment outcomes (6 RCTs).

Only one of the five drug combinations was assessed in more than one RCT. The 95% CIs for the effect sizes were not reported, hence interpretation of the results is difficult. Several of the constituents have been removed from the market or are unavailable.

Drug-drug comparisons (18 RCTs).

Most comparisons were relatively short (2 to 15 weeks), and all but 2 drugs were only compared in one RCT. Mazindol was the drug most frequently compared with other included drugs; the d-value against all other comparator drugs (9 RCTs) was 0.257 (95% CI: 0.043, 0.471).

Authors' conclusions The conclusions appear to be that the amount of weight lost, above and beyond that achieved in placebo treatments, is typically modest and that increasing the length of drug treatment does not appear to increase weight loss.

CRD commentary The aims were stated clearly, and the inclusion criteria were defined in terms of the study design, participants, intervention and outcome. Several relevant sources of literature were searched, but the methods used to select the studies were not described. By restricting the included studies to those published in the English language in peer- reviewed journals, other relevant studies may have been omitted. The possibility of publication bias was raised. The eligible studies were restricted to randomised controlled studies but no formal validity assessment was undertaken.

The methods used to extract coded data were described. Some relevant aggregated information was tabulated, but no details were provided on the characteristics of the populations studied or the lifestyle interventions employed in the individual studies. A pooled effect size was calculated where more than one study examined the effectiveness of a single drug, but statistical heterogeneity was not tested. In addition, clinical heterogeneity was not discussed, and it was unclear whether the analysis was conducted on an intention to treat basis. The influence of length of treatment and year of publication on the study outcome was explored.

The review would have been strengthened by a formal validity assessment of the included studies, more comprehensive information on the characteristics of the populations studied, and an examination of clinical and statistical heterogeneity among the studies.

Aside from these reservations, the evidence presented does appear to support the authors' conclusions.

Implications of the review for practice and research Practice: The authors state that increasing the length of drug treatment does not appear to increase weight loss, and that weight loss associated with drug therapy is usually modest.

Research: The authors state that future studies should examine the effectiveness of drug therapies as long-tem weight maintenance agents. They also state that standards for reporting important parameters in obesity drug clinical trials need to increase.

Funding University of Missouri-Kansas City; the American Heart Association.

Bibliographic details Haddock C K, Poston W S, Dill P L, Foreyt J P, Ericsson M. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. International Journal of Obesity 2002; 26(2): 262-273

Page: 3 / 4 PubMedID 11850760

DOI 10.1038/sj.ijo.0801889

Other publications of related interest Brodin P, O'Connor CA. A double-blind clinical trial of an appetite depressant, fenfluramine, in general practice. Practitioner 1967;198:707-10.

Indexing Status Subject indexing assigned by NLM

MeSH Amphetamines /therapeutic use; Anti-Obesity Agents /therapeutic use; Benzphetamine /therapeutic use; Cyclobutanes /therapeutic use; Fenfluramine /therapeutic use; Humans; Obesity /prevention & control; Randomized Controlled Trials as Topic

AccessionNumber 12002000408

Date bibliographic record published 31/03/2003

Date abstract record published 31/03/2003

Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

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