Glucagon-like peptide-1 receptor agonists (GLP-1RAs)-along with the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA tirzepatide-are widely acknowledged for their efficacy in managing both type 2 diabetes mellitus and obesity, with expanding indications in cardiometabolic risk reduction. While their glycemic, weight-lowering, and cardiovascular benefits are well established through randomized trials and meta-analyses, concerns remain regarding their safety and tolerability across diverse populations and clinical settings. Gastrointestinal (GI) adverse events-particularly nausea, vomiting, diarrhea, and constipation-are the most common side effects, generally emerging during dose escalation and resolving over time. However, accumulating evidence has identified additional GI complications, including cholelithiasis, cholecystitis, gastroparesis, and bowel obstruction, which may warrant caution in susceptible individuals. Injection-site reactions and worsening of pre-existing diabetic retinopathy are also relevant clinical concerns. Although rare, associations with nonarteritic anterior ischemic optic neuropathy, pancreatitis, medullary thyroid carcinoma, and acute kidney injury (AKI) have been reported, primarily through pharmacovigilance and case-based evidence. Importantly, large-scale randomized trials, meta-analyses, and observational studies suggest that GLP-1RAs do not significantly increase AKI risk and may even confer renal benefits in high-risk populations. There is no confirmed elevated risk of suicidality, but surveillance remains warranted. Safety data in special populations-such as pregnant or lactating women, pediatric patients, and those with advanced renal or hepatic impairment-remain limited and require further study. This state-of-the-art narrative review synthesizes current evidence from clinical trials, pharmacovigilance databases, and real-world cohorts to provide a comprehensive evaluation of the safety and tolerability of GLP-1RAs and tirzepatide. We present clinical strategies for adverse event mitigation, monitoring recommendations, contraindications, and practical considerations for treatment discontinuation or switching. Although these agents offer transformative therapeutic potential, their optimal use requires individualized care, careful patient selection, and ongoing safety surveillance. Future research should prioritize long-term safety in underrepresented populations and strategies to mitigate lean mass loss during therapy.
