The quantity, quality and findings of network meta-analyses evaluating the effectiveness of GLP-1 RAs for weight loss: a scoping review

Background Glucagon-like peptide 1 receptor agonists are a class of drug originally developed to treat type 2 diabetes but now increasingly used for weight loss, especially in people living with obesity. Despite an abundance of evidence about the effectiveness and safety of glucagon-like peptide 1 receptor agonists for weight loss, network meta-analyses are inconsistent in their quality and scope, and this is a fast-moving field. Objectives We sought to identify the most recent network meta-analyses evaluating the effectiveness of glucagon-like peptide 1 receptor agonists for weight loss; critically appraise included network meta-analyses; provide an overview of the quality and findings of existing network meta-analyses, and identify any pertinent gaps in the evidence; and consider the value of updating the most recent, comprehensive and high-quality network meta-analyses. Methods On 6 June 2023, we searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and Epistemonikos for systematic reviews with network meta-analyses published since 2020 in adults (18 or above) with body mass index ≥ 25 (or ≥ 23 for Asian populations), including at least one relevant glucagon-like peptide 1 receptor agonist and weight loss outcomes. We screened and selected reviews in duplicate and independently, and appraised reviews using a modified A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR-2) and a network meta-analysis reliability checklist. The highest-quality reviews were then extracted in depth, and the most relevant network meta-analysis models identified, focusing on weight loss and safety outcomes. A top-up search for trials published since October 2022 was also undertaken to identify relevant trials not included in published network meta-analyses. A further search for new network meta-analyses was conducted on 26 September 2024. Results Of 22 systematic reviews identified, 14 were prioritised for analysis as the remaining 8 reviews were rated as low or critically low quality. We focused on network meta-analyses of weight loss outcomes measured at 6 months, 12 months, longer than 12 months or over a mix of time points. At 6 months, subcutaneous tirzepatide was the most effective drug associated with 9 kg (at 5 mg) to 12 kg (at 15 mg) of weight loss. However, the largest effects were seen for subcutaneous semaglutide 2.4 mg, which was associated with between 11.5 and 12.5 kg of weight loss, though this came from two network meta-analyses, both informed by six trials, and both merging findings across multiple time points. The relative effectiveness among glucagon-like peptide 1 receptor agonists followed a pattern suggested by their performance against placebo, with tirzepatide and semaglutide standing out as the most effective drugs for weight loss. No network meta-analyses compared tirzepatide and semaglutide 2.4 mg. The drugs associated with the greatest weight loss, tirzepatide and semaglutide 2.4 mg, were generally associated with increased risk of safety issues compared to placebo. The update trial search identified 11 new trials, which, though largely small, could make a new network meta-analysis useful. The update search for network meta-analyses yielded 13 new includes. Among other novel comparisons, tirzepatide was indirectly compared with semaglutide 2.4 mg, outperforming it at 15 mg, but not 5 or 10 mg. Data again came from merged time points. Discussion To our knowledge, this is the first review of network meta-analyses of glucagon-like peptide 1 receptor agonists. The evidence presented regarding weight loss is in general agreement with the wider literature, though data on tirzepatide were not as resounding as reported in some meta-analyses. Limitations Current network meta-analyses of glucagon-like peptide 1 receptor agonists with weight loss outcomes often lack clarity about the network meta-analysis methods, such as which trials were included. The tendency to combine multiple doses of drugs, and to merge findings from multiple time points, limits our understanding of dose and time effects. Future work Head-to-head trials of tirzepatide versus semaglutide 2.4 mg are required to determine their relative effectiveness and safety, as the two most promising options for weight loss, as are longer-term trials to establish the effectiveness and safety of glucagon-like peptide 1 receptor agonists when taken for durations of > 72 weeks. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme as award number NIHR159924.