Association of Glucagon-Like Peptide 1 Analogs and Agonists Administered for Obesity with Weight Loss and Adverse Events: A Systematic Review and Network Meta-Analysis

Background: Comparative effectiveness of 7 glucagon-like peptide 1 (GLP-1) agents on weight loss (WL) in obesity is unknown. Methods: Study Design: Systematic review, network meta-analysis (NMA) Data Sources: MEDLINE, EMBASE, Scopus, Cochrane Central and clinical trial registries, from inception to March 2, 2021 Prespecified Criteria for Study Inclusion: Randomized clinical trials (RCTs) of >12 weeks’ duration.    Data Appraisal and Extraction: Two investigators independently, using published reports. Main Outcomes and Statistical Methods: WL over placebo (WLOP) and adverse events (AEs) among GLP-1 agents using random-effects NMA (frequentist approach); relative ranking using surface under the cumulative ranking (SUCRA) method and certainty of evidence using GRADE. Registration: None Findings: Data Synthesis: 64 RCTs (2004-2021) had 27018 patients (medians of age, 55.1y; 57.4% women; baseline weight 94.8kg and BMI 33.0kg/m2; trial duration 26 weeks). Direct meta-analysis showed significant WLOP with: -1.44kg (95% CI, -2.14 to ‑0.74) with dulaglutide ≥1.5 mg; -1.82kg (‑2.42 to ‑1.23) with exenatide IR; -2.20kg (-4.31 to -0.08) with exenatide ER; -3.20kg (-6.53 to 0.15) with efpeglenatide; -2.72kg (‑3.35 to -2.09) with liraglutide ≤1.8mg; -4.49kg (-5.26 to -3.72) with liraglutide >1.8mg; ‑0.62kg (-1.22 to -0.02) with lixisenatide; ‑4.33kg (-5.71 to -3.00) with semaglutide SQ 1.8mg (SUCRAs 100, 86.1, 82.8 respectively). Highest SUCRAs for discontinuation due to AEs were with taspoglutide and liraglutide >1.8mg.Risk of bias was high or unclear for random sequence generation (29.7%), allocation concealment (26.6%), and incomplete outcome data (26.6%).  Heterogeneity (I  2  >50%) in WL and AEs reflected magnitude, not direction of effect. Interpretation: Semaglutide (SQ, oral) and liraglutide (SQ) were the most efficacious GLP-1 agents to induce WL during  >  12 weeks’ treatment. Funding: NIH R01-DK67071 (Camilleri) Declaration of Interest: Dr. Michael Camilleri serves on an advisory board for Phenomix Sciences regarding the company’s development of a test to predict weight loss response to obesity therapy, and he is a stockholder in the company. Phenomix Sciences has obtained an exclusive license to Dr. Michael Camilleri’s and Dr. Andres Acosta’s biomarker technology, submitted patent, and know-how to develop a biomarker to predict response to obesity pharmacotherapy. Dr. Camilleri also serves as a consultant to Kallyope for the company’s development program regarding obesity (the consulting fee is paid to his employer, Mayo Clinic). All other authors have nothing to declare.