Neurological symptoms during incretin receptor agonist therapy: current evidence for metabolic and fluid-electrolyte mechanisms and testable hypotheses

This focused review examines the current evidence linking neurological symptoms during tirzepatide treatment to metabolic and fluid-electrolyte disturbances. Evidence from regulatory documents, randomised trials, human physiology, pharmacovigilance analyses, and case reports is separated according to evidentiary strength. Established findings include marked appetite suppression, frequent gastrointestinal adverse effects, low but incompletely characterised biochemical hypoglycaemia in obesity trials, and preserved acute glucagon counterregulation under controlled hypoglycaemic conditions. Reported ketoacidosis frequently occurs with marked dietary restriction or gastrointestinal loss, whereas published hyponatraemia cases represent heterogeneous water-balance phenotypes rather than a demonstrated syndrome of chronic sodium-wasting diuresis. Based on these gaps, the review derives four prospective hypotheses concerning prolonged low intake, conditional ketoacidosis, heterogeneous sodium-water disturbances, and biochemical classification of neurological symptoms. Each hypothesis is paired with a prospective test and an explicit finding that would weaken the proposed explanation.