Comprehensive evaluation of GLP-1 receptor agonists: an umbrella review of clinical outcomes across multiple diseases

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were initially approved for type 2 diabetes mellitus. Recent evidence suggests their therapeutic potential in various diseases, though their efficacy and safety remain incompletely understood. Here, we conduct an umbrella review including 123 meta-analyses covering 464 outcomes from 5617 articles to comprehensively assess the effectiveness and adverse events (AEs) of GLP-1 RAs across diverse outcomes. GLP-1 RAs showed trends toward improvements in endocrine and metabolic, cardiovascular, renal, and respiratory outcomes, cognitive function, with a potential reduction in fracture risk and all-cause mortality in certain populations. However, increased risks of certain AEs, including diabetic retinopathy, ketoacidosis, gastrointestinal events, and treatment discontinuation, were also observed. AMSTAR 2 assessments indicate that the existing evidence is limited by methodological shortcomings, including incomplete reporting of excluded studies, suboptimal literature search strategies, and insufficient evaluation of how bias in primary studies may influence meta-analytic estimates. Some outcomes did not reach statistical significance in all populations, highlighting the need for further high-quality clinical research. Careful consideration of potential benefits and risks is essential for optimizing treatment outcomes and ensuring patient safety when using GLP-1 RAs in clinical practice.