Hypoglycaemia during incretin receptor agonist therapy in people without diabetes: beyond acute counterregulation

Abstract

In the pivotal tirzepatide clamp study the acute glucagon response was preserved, but absolute glucagon concentrations were lower at every plateau except the nadir; catecholamine responses at the 63 mg/dL alerting threshold were approximately 70% lower, converging with placebo at nadir; autonomic symptom scores at nadir were lower; and eight of nine spontaneous hypoglycaemic events were asymptomatic. Participants were studied after ordinary nutritional intake rather than after prolonged caloric deprivation. Published cases in users without diabetes share a different antecedent: days of vomiting and negligible intake, with ketosis and low plasma glucose occurring together — though in most reports the glucose values lie in the alert range and Whipple’s triad was not established, a limitation made explicit in a summary table. Human work after gastric bypass shows that prandial endogenous glucose production during hypoglycaemia is reduced and rises when the GLP-1 receptor is blocked, indicating that the hepatic step is modifiable by GLP-1 receptor signalling. That model is not equivalent to chronic pharmacological agonism, and the review states the limits of the extrapolation. Four feasible studies are specified, together with the findings that would refute the hypothesis. This version follows external peer review of the preceding deposit. Numerical citations were added throughout; the argument was reframed from a claimed mechanism to a delimited hypothesis; the inference from lean-mass loss to gluconeogenic capacity was made conditional; the ketosis argument was corrected; the bariatric evidence was restated more narrowly; a case-summary table and a limitations section were added. Preprint. Not yet submitted to a journal.