Effect of glucagon-like peptide-1 receptor agonists on glycemic control, and weight reduction in adults: A multivariate meta-analysis

PLOS ONE RESEARCH ARTICLE Effect of glucagon-like peptide-1 receptor agonists on glycemic control, and weight reduction in adults: A multivariate metaanalysis Tzu-Lin Yeh ID1,2, Ming-Chieh Tsai2,3,4, Wen-Hsuan Tsai4, Yu-Kang Tu2, KuoLiong Chien ID2,5* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Department of Family Medicine, Hsinchu MacKay Memorial Hospital, Hsinchu, Taiwan, 2 Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan, 3 Department of Medicine, MacKay Memorial College, New Taipei City, Taiwan, 4 Division of Endocrinology, Department of Internal Medicine, MacKay Memorial Hospital, New Taipei City, Taiwan, 5 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan * Abstract OPEN ACCESS Citation: Yeh T-L, Tsai M-C, Tsai W-H, Tu Y-K, Chien K-L (2023) Effect of glucagon-like peptide-1 receptor agonists on glycemic control, and weight reduction in adults: A multivariate meta-analysis. PLoS ONE 18(1): e0278685. https://doi.org/ 10.1371/journal.pone.0278685 Editor: Ming-Chang Chiang, Fu Jen Catholic University, TAIWAN Received: September 12, 2022 Accepted: November 22, 2022 Published: January 25, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0278685 Copyright: © 2023 Yeh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Aims To explore the effect of glucagon-like peptide-1 receptor agonist (GLP-1 RAs) on glycemic control and weight reduction in adults. Methods Databases were searched from August 2021 to March 2022. Data were analyzed using mean difference (MD) values with 95% confidence intervals (CIs). Both random-and fixedeffect models were employed. Heterogeneity was explored using pre-specified subgroup analyses and meta-regression. Structural equation modeling fitting was used for the multivariate meta-analysis. Results A total of 31 double-blind randomized controlled trials with 22,948 participants were included in the meta-analysis. The MD and 95% CI of the pooled GLP1-RA-induced change in the glycated hemoglobin level was -0.78% (-0.97%, -0.60%) in the random-effects model and -0.45% (-0.47%, -0.44%) in the fixed-effect model, with a high heterogeneity (I2 = 97%). The pooled body weight reduction was -4.05 kg (-5.02 kg, -3.09 kg) in the random-effects model and -2.04 kg (-2.16 kg, -1.92 kg) in the fixed-effect model (I2 = 98%). The standardized pooled correlation coefficient between HbA1c levels and body weight was -0.42. A negative correlation between glycemic control and weight reduction was obtained. Conclusion Long-acting GLP-1 RAs significantly reduced the glycated hemoglobin level and body weight in adults. PLOS ONE | https://doi.org/10.1371/journal.pone.0278685 January 25, 2023 1 / 14 PLOS ONE Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Effects of glucagon-like peptide-1 agonists Introduction Glucagon-like peptide 1, an incretin secreted from the gut, exerts metabolic effects through glucose-dependent stimulation of insulin secretion, delayed gastric emptying, inhibition of appetite, and increased natriuresis [1]. Glucagon-like peptide receptor agonists (GLP-1 RAs) have been used to treat patients with diabetes since 2007 [2]. and have been approved as antiobesity drugs since 2014 [3]. However, long-acting GLP-1 RAs have attracted increasing interest due to their better efficacy in diabetes and obesity treatment [4]. Long-acting GLP-1 RA treatment was shown to be associated with a pooled glycated hemoglobin (HbA1c) reduction of 0.99% and a pooled body weight reduction of 2.69 kg (heterogeneity, approximately 90%) [5]. The high heterogeneity can be partially explained by differences in the underlying conditions of participants [6] and the GLP-1 RA interventions [7]. Moreover, participant age and the baseline glycemic level may interact with the results in children [6], indicating the existence of potential effect modifiers. However, further analysis to explore the high heterogeneity and potential effect modifiers in adults is lacking [8, 9]. Glycemic control is intertwined with the weight reduction caused by long-acting GLP-1 RAs through insulin resistance and metabolic changes [10]. Thus, these two outcomes of interest should not be independently estimated. However, previous randomized controlled trials (RCTs) rarely reported the correlation coefficients at the within-study level [11], and to the best of our knowledge, no correlation coefficient was reported in between-study-level metaanalysis [12, 13]. Thus, to explore the high heterogeneity and possible effect modifiers associated with these findings, we performed further univariate meta-analyses of the glycemic control and weight reduction caused by long-acting GLP-1 RAs in adults. Considering the correlation between these outcomes, our study used the structural equation modeling approach for multivariate meta-analysis to jointly estimate the effect sizes for glycemic control and weight reduction in one model and to investigate the associations between these two outcomes of long-acting GLP-1 RA treatment. Materials & methods Search strategy and selection criteria We searched the Medline, Ovid EMBASE, Cochrane Library and ClinicalTrials.gov databases for relevant studies from August 2021 to March 2022 by using the following keywords: “Glucagon-Like Peptide 1” OR “GLP-1” OR “Placebo” OR “Body Weights” OR “Glucose” OR “Glycosylated Hemoglobin A” OR “Trials, Randomized Clinical.” The PRISMA checklist and detailed search strategies are shown in Supplement and S1 Table. To enable a comprehensive search, we did not include limiting parameters for language, article type, year of publication, animal or human subjects, and age of participants. We included all eligible publications that met the following inclusion criteria: (1) adult participants older than 18 years, either from the general population or including patients with a specific disease; (2) intervention with U.S. Food and Drug Administration approved long-acting GLP-1 RAs, including liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide, which were administered orally or subcutaneously, either in same or different doses; (3) comparison with a placebo; (4) glycemic or anthropometric changes as either primary or secondary outcome (...truncated)