GLP-1 Receptor Agonists in Metabolic Disease: A 2025 PRISMA-Guided Systematic Review of Efficacy, Safety, and Comparative Effectiveness
Abstract Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) — including semaglutide, tirzepatide, and liraglutide — are cornerstone therapies for type 2 diabetes (T2DM) and obesity. Recent trials and regulatory updates (including oral semaglutide) have expanded their therapeutic landscape. Objective: Systematically synthesize clinical evidence on GLP-1 RAs with updated 2025 data on metabolic outcomes, cardiovascular events, and safety. Methods: A PRISMA-aligned systematic review of Phase III RCTs, cardiovascular outcome trials (CVOTs), and high-quality meta-analyses was conducted. Data sources included PubMed/MEDLINE and recent literature through December 2025. Results: GLP-1 RAs consistently improve glycemic control (HbA1c reductions ~0.8–1.8%) and promote significant weight loss (up to ~20% with tirzepatide). Recent evidence supports reductions in MACE in high-risk patients and novel data on oral formulations. Safety profiles remain dominated by gastrointestinal...