The placebo response rate and nocebo events in obesity pharmacological trials. A systematic review and meta-analysis.

Background: There is a growing number of trials examining the effectiveness of pharmacotherapies for obesity, however, little is known about placebo and nocebo effect in these trials. Hence, we sought to examine the effect of placebo in obesity trials, to better understand the potential factors affecting clinical endpoints in them.
Methods: Medline, Embase, and Cochrane CENTRAL were searched for articles examining weight-loss RCTs examining patients with overweight or obesity in placebo-controlled arms from inception till 25 June 2022. This paper was registered online with PROSPERO (CRD42022302482). A single arm meta-analysis of proportions was used to estimate the primary outcomes, ≥5%, ≥10%, and ≥15% total weight loss - and the adverse effects that patients experienced during the trial. A meta-analysis of means was used to estimate the pooled mean differences of the secondary outcomes including, body weight measurements, lipid levels, glycemic indices, and blood pressure over time.
Findings: A total of 63 papers involving 20,454 patients and 69 trials were included. The proportion of patients that had ≥5%, ≥10%, and ≥15% weight loss was 20·4% (CI:16·1% to 25·0%), 8·3% (CI:6·1% to 10·9%), and 6·2% (CI:3·8% to 9·7%), respectively. Analysis by duration of trials showed stepwise increase in proportion of patients with ≥5% and ≥10% weight loss with increasing duration of study. Analysis of secondary outcomes found modest improvement in all analyses. The pooled average rate of overall AEs, serious AEs, and discontinuation was 73·7% (CI:68·0% to 79·0%), 3·4% (CI:2·4% to 4·5%), and 5·2% (CI:4·0% to 6·5%), respectively. In psychiatric complications, the pooled rates of anxiety and depression were 2·7% (CI:1·8% to 3·7%) and 2·5 (CI:1·7% to 3·3%).
Interpretation: Our meta-analysis of placebo-treated participants in weight-loss RCTs indicate a significant placebo and nocebo effect. These findings are important to quantify their effect and may inform the design of future RCTs.
Funding: This research did not receive additional support from organizations beyond the authors' academic institutions.
Competing Interests: Mark Y. Chan: Speaker's fees and research grants Astra Zeneca, Abbott Technologies and Boston Scientific. Gemma A Figtree: G.A.F. receives funding from the National Health and Medical Research Council (Australia), New South Wales Office of Health and Medical Research, and Heart Research Australia. She reports personal consulting fees from CSL, Janssen, Amgen and Boehringer Ingelheim and grants from Abbott Diagnostic outside the submitted work. In addition, G.A.F. has a patent Biomarkers and Oxidative Stress awarded USA May 2017 (US9638699B2) issued to Northern Sydney Local Health District. Vincent Wong: V.W. has served as an advisory board member or consultant for 3 V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Inventiva, Merck, Novartis, Novo Nordisk, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns and is on the speaker's bureau for Abbott, AbbVie, Echosens, Gilead Sciences, and Novo Nordisk; he has received a grant from Gilead Sciences for fatty liver research and is a cofounder of Illuminatio Medical Technology Limited. Mazen Noureddin: M.N. has been on the advisory board for 89BIO, Gilead, Intercept, Pfizer, Novo Nordisk, Blade, EchoSens, Fractyl, Terns, Siemens and Roche diagnostic; he has received research support from Allergan, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Madrigal, Novartis, Pfizer, Shire, Viking and Zydus; he is a minor shareholder or has stocks in Anaetos, Rivus Pharma and Viking. Arun Sanyal: A.J.S. is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect and Galmed. He has served as a consultant to Astra Zeneca, Nitto Denko, Enyo, Ardelyx, Conatus, Nimbus, Amarin, Salix, Tobira, Takeda, Jannsen, Gilead, Terns, Birdrock, Merck, Valeant, Boehringer-Ingelheim, Lilly, Hemoshear, Zafgen, Novartis, Novo Nordisk, Pfizer, Exhalenz and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Affimune, Chemomab, Zydus, Nordic Bioscience, Albireo, Prosciento, Surrozen and Bristol Myers Squibb. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, Astra Zeneca, Malinckrodt, Cumberland and Norvatis. He receives royalties from Elsevier and UptoDate. David E. Cummings: D.E.C. is on the Scientific Advisory Boards of GI Dynamics, Endogenex, and Gila Therapeutics. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2022 The Author(s).)