The use of GLP-1 receptor agonists and co-agonists in adults without diabetes: a systematic review and network meta-analysis protocol.
This paper describes a pre-registered protocol for a systematic review and network meta-analysis (NMA) examining the comparative efficacy and safety of GLP-1 receptor agonists (GLP-1 RAs) and novel co-agonists (e.g., dual/triple agonists) for weight loss in adults with overweight or obesity who do not have diabetes. The authors plan to search PubMed, Ovid, and Cochrane CENTRAL for randomized controlled trials (RCTs) comparing these agents against placebo or each other. Trials involving participants with diabetes, specific comorbidities, or prior bariatric surgery will be excluded. The primary outcome is relative change in body weight from baseline at approximately 6 months and 1–1.5 years. Secondary outcomes include absolute weight change, total adverse events, gastrointestinal adverse events, serious adverse events, and death. Frequentist random-effects pairwise and network meta-analyses will be conducted, with treatment rankings generated via the surface under the cumulative ranking curve (SUCRA). Risk of bias will be assessed using the Cochrane RoB 2 tool and the RoB-NMA tool. Importantly, this is a protocol paper only — no data have been collected or analyzed yet — so no results or conclusions about the efficacy or safety of any specific agent are available at this stage.
Why this grade: This is a protocol-only publication with no data collected or analyzed; no evidence about the comparative efficacy or safety of GLP-1 RAs in humans can be drawn from it yet.
Background Despite the increasing clinical use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), head-to-head evidence across these agents remains limited. This systematic review and network meta-analysis (NMA) will assess the comparative efficacy and safety of GLP-1 RAs and novel co-agonists for weight loss among adults without diabetes. Methods We will systematically search the PubMed, Ovid, and Cochrane CENTRAL databases to identify randomized controlled trials (RCTs) comparing a GLP-1 RA/co-agonist to placebo or another GLP-1 RA/co-agonist. We will restrict inclusion to RCTs in adults with overweight or obesity; those including participants with diabetes, specific comorbidities or diseases, or history of bariatric surgery will be excluded. The primary outcome will be weight loss, expressed as relative change from baseline, assessed at 6 months (± 4 weeks) and 1-1.5 years (± 4 weeks). Secondary outcomes will include absolute body weight change, total adverse events, gastrointestinal adverse events, serious adverse events, and death. Pairwise meta-analyses and frequentist NMAs will be conducted using a random-effects model. Treatment rankings for efficacy and safety outcomes will be generated using the surface under the cumulative ranking curve. The validity of the results and the assumptions underlying the analyses will be evaluated using a local and global approach. Study-level quality will be assessed using the Cochrane Risk of Bias (RoB) 2 tool and overall network quality will be assessed using the RoB-NMA tool. Discussion We aim to provide an up-to-date synthesis of RCTs assessing the weight loss effects of GLP-1 RAs and co-agonists among adults without diabetes to support future clinical decision-making, guideline development, and policy decisions. Systematic review registration PROSPERO CRD420251009368.
Educational summary of published research — not medical advice. License: cc by-nc-nd. Full text is shown only where licensing permits.