Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss and Cardiovascular Protection in Obesity and Type2 Diabetes: A Systematic Review and Meta-Analysis

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly recognised as dual-action therapies for obesity and type 2 diabetes, with emerging evidence of cardiovascular protection. Despite widespread use, uncertainty remains regarding long-term efficacy, safety, and potential publication bias across trials.

We conducted a systematic review and meta-analysis of major randomised controlled trials, including weight-loss studies and cardiovascular outcome trials (CVOTs). Data were pooled for weight reduction, major adverse cardiovascular events (MACE), and treatment discontinuation due to adverse events. Subgroup and sensitivity analyses assessed the influence of trial design, dose, and sponsorship. Publication bias was evaluated using funnel plots and Egger’s tests.

GLP-1 RAs produced substantial and durable weight reduction, particularly at higher doses and with longer treatment durations. Consistent reductions in MACE were observed across diverse populations, reinforcing their cardioprotective role. Gastrointestinal adverse events were the primary driver of treatment discontinuation, but serious adverse events were not consistently increased. Safety concerns regarding pancreatitis, thyroid cancer, or neoplasia were not supported by current evidence, though gallbladder events were more frequent in select trials. Funnel plots suggested modest asymmetry in weight-loss studies, largely reflecting small-study effects; however, sensitivity analyses excluding high-risk or industry-sponsored trials confirmed the robustness of findings. GLP-1 RAs provide a favourable benefit–risk profile, combining clinically meaningful weight loss with cardiovascular protection. Their integration into clinical practice has transformative potential for obesity and diabetes management. Future research should clarify long-term safety signals, optimise dosing strategies, and evaluate real-world effectiveness to guide equitable access and sustainable implementation.