Adverse Events Associated with Incretin-Based Therapies: A Narrative Review on Mechanisms, Clinical Management, and Risk Mitigation.

Background: Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), are established therapies for obesity and type 2 diabetes mellitus, providing sustained weight reduction, improved glycaemic control, cardiovascular and renal benefits. Despite these established benefits, safety concerns remain an important clinical issue because adverse events may affect treatment persistence, patient acceptability, and clinical decision-making. This review evaluates a number of safety profiles of GLP-1RAs using clinical, mechanistic, and pharmacovigilance evidence, with attention to both common adverse events and emerging safety signals. Methods: A narrative review was conducted to evaluate the safety profile of GLP-1RAs in obesity and type 2 diabetes mellitus. PubMed/MEDLINE, Embase, and Web of Science were searched for studies published between January 2005 and April 2026. Evidence from randomised controlled trials, observational studies, meta-analyses, pharmacovigilance investigations, and regulatory safety reports was synthesised qualitatively. Results: Findings from 60 studies and safety reports were included. Common adverse events were predominantly gastrointestinal, particularly nausea, vomiting, diarrhoea, and constipation, and represented the most consistently reported adverse effects and the principal cause of treatment discontinuation. Uncommon safety concerns included renal adverse events, which were reported infrequently and often occurred in clinical contexts involving gastrointestinal intolerance, volume depletion, or other predisposing factors. Gallbladder and biliary complications were also infrequent and appeared to be influenced by rapid weight loss and baseline patient risk factors. Acute pancreatitis remained rare in clinical trials, although severe cases have been reported in postmarketing settings. Human evidence did not demonstrate an increased risk of thyroid malignancy. Emerging safety signals, including early worsening of diabetic retinopathy, muscle mass reduction, psychiatric symptoms, and alopecia, were identified mainly through observational and pharmacovigilance evidence. Conclusion: GLP-1RA adverse events predominantly reflect predictable pharmacological and physiological effects rather than off-target toxicity. Safety profiles appear agent-specific, dose-dependent, and influenced by underlying mechanisms and patient characteristics. Risk-stratified prescribing should therefore align agent selection, dose escalation, and monitoring intensity with patient-specific vulnerabilities, particularly gastrointestinal tolerability, risk of renal dehydration, gallbladder history, retinopathy risk during rapid glycaemic improvement, and frailty or sarcopenia risk. Continued long-term surveillance and further evidence generation are needed to better define rare, delayed, and emerging safety signals and to optimise safe use across diverse clinical populations.