Independent effects of companion lifestyle interventions in anti-obesity medication trials: protocol of a systematic review and meta-analysis

Abstract Background Anti-obesity medications (AOMs) are increasingly indicated in the management of overweight and obesity. Most international guidelines recommend their co-prescription with companion lifestyle interventions (CLIs), typically modelled on the high-intensity, multi-contact behavioural support evaluated in pre-pharmacotherapy trials. The assumption that this intensity is required alongside an effective AOM has not been formally tested. Service models built on this assumption are resource-intensive, capacity-limited, and represent the principal bottleneck to equitable access in many health systems. Objective This systematic review aims to (i) quantify the upper-bound contribution of CLI to weight change in the placebo arms of randomised placebo-controlled AOM trials; (ii) characterise CLI content, dose and delivery; and (iii) examine between-trial dose–response relationships between CLI intensity, contact time and modality, in order to test whether higher-intensity (“high-touch”) approaches outperform lower-intensity (“light-touch”) approaches alongside effective pharmacotherapy. Methods This protocol follows PRISMA-P guidelines. Randomised placebo-controlled trials in adults with BMI ≥ 25 kg/m 2 receiving AOMs licensed for weight management in the UK (tirzepatide, semaglutide, liraglutide, orlistat) will be included, provided that the same CLI is delivered in both arms. Searches will be conducted in four databases: MEDLINE (via PubMed), Embase (via Ovid), CENTRAL, and CINAHL. The primary outcome will be mean weight change (kg) at the longest in-trial follow-up in placebo arms receiving CLI. A secondary outcome will capture weight change at the longest available post-treatment follow-up to address sustained weight loss. CLI engagement and adherence will also be analysed. Subgroup analyses and random-effects meta-regression will examine between-trial associations between CLI characteristics (contact minutes, frequency, modality, professional mix, Behavioural Change content) and weight outcomes (subject to a minimum of ten studies per covariate). Discussion This review will provide an upper-bound estimate of CLI-attributable weight change in AOM placebo arms, characterise the behavioural content and intensity of CLIs, and test whether between-trial variation in CLI intensity predicts weight outcomes. The findings will inform whether the prevailing assumption that high behavioural intensity is required alongside AOMs is supported by trial evidence, and will identify the components and minimum effective CLI dose to prioritise in scalable models of obesity care. Systematic review registration PROSPERO 2025 CRD420251050251.