GLP-1 receptor agonists and serious adverse events: Evidence, uncertainty and clinical implications

Glucagon-like peptide-1 (GLP-1) receptor agonists provide benefits in weight reduction, glycaemic control in Type 2 diabetes, and cardiovascular and renal outcomes. Their widespread use has given rise to concerns regarding rare but potentially serious adverse events. This narrative review appraises evidence regarding seven serious adverse events linked to GLP-1 receptor agonists: thyroid cancer, non-arteritic anterior ischaemic optic neuropathy (NAION), suicidal behaviours and self-harm, diabetic retinopathy complications, acute pancreatitis, gallbladder and biliary disease and intestinal obstruction. Evidence from mechanistic studies, spontaneous reports, randomized trials and cohort studies is considered. Gallbladder and biliary disease has the most consistent evidence supporting a causal association. Worsening of diabetic retinopathy appears most consistent with early worsening after rapid glycaemic improvement in patients with pre-existing retinopathy. For thyroid cancer, NAION, suicidal behaviour and self-harm, acute pancreatitis and intestinal obstruction, evidence regarding causality remains uncertain. Rare events, incomplete ascertainment in trials and residual confounding in observational studies limit inference. Because these events are rare, even substantial relative risk increases generally correspond to small absolute risk increases in broad populations but may become relevant in patients with high baseline risk. Treatment decisions should consider the strength and uncertainty of safety evidence, individual baseline risk, expected benefits relative to available alternatives and patient preferences.