Gastrointestinal adverse effects of GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists: A narrative expert review of approved therapies, oral formulations, and pipeline agents.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists have transformed the management of type 2 diabetes and obesity. Gastrointestinal (GI) adverse events are the most common limitation of these therapies and a leading cause of discontinuation. This narrative expert review synthesizes evidence from randomized controlled trials, observational studies, meta-analyses, and pharmacovigilance data to characterize the incidence, mechanisms, and clinical implications of GI adverse effects across approved agents and late-stage pipeline therapies. Nausea, vomiting, diarrhea, and constipation are established class effects, occurring in approximately 30%-50% of patients, typically during initiation and dose escalation. These events are generally mild to moderate and manageable with dose titration and dietary modification. Mechanisms include delayed gastric emptying, central activation of emetic pathways, altered intestinal motility, and physiologic effects of rapid weight loss itself. Randomized trial data are reassuring for acute pancreatitis, with no class-level excess risk demonstrated; pharmacovigilance signals are most plausibly explained by diagnostic misclassification rather than true causal risk. Cholelithiasis shows a probable class-level association, substantially mediated by weight loss rather than direct receptor signaling. Peri-procedural data show increased residual gastric volume without confirmed aspiration events. Preliminary data on late-stage pipeline agents (retatrutide, survodutide, and cagrilintide-semaglutide) suggest a similar GI adverse event profile to approved agents, though evidence remains largely limited. GI adverse events with GLP-1-based therapies are predictable and manageable. A proactive, patient-centered approach is essential to optimize adherence, safety, and clinical outcomes as newer agents expand the therapeutic landscape.