Hypoglycaemia (revision 6)

Hypoglycaemia is abnormally low blood glucose. It is classified by level: below 3.9 mmol/L as an alert value, below 3.0 mmol/L as clinically significant, and any episode requiring assistance as severe regardless of the measured value.^[1]

Incretin agonists carry a low intrinsic risk because their action on insulin secretion is glucose-dependent: they amplify a response that glucose has initiated rather than initiating one. Below the glucose threshold for triggering, there is nothing to amplify.^[2]

Risk arises when they are combined with agents that are not glucose-dependent — insulin and sulfonylureas — and the usual response on initiating an incretin agonist alongside either is to reduce the background agent.^[1]

The beta cell distinguishes a triggering signal from an amplifying one. Glucose metabolism raises the ATP:ADP ratio, closes potassium channels and admits calcium — the trigger. Incretin signalling raises cAMP, which increases the amount of insulin released per unit of calcium — the amplifier.^[2]

Sulfonylureas act on the trigger, closing the potassium channel pharmacologically regardless of glucose, which is why they cause hypoglycaemia. Injected insulin bypasses the beta cell entirely.

This is a mechanistic argument rather than a guarantee. Reported hypoglycaemia rates on incretin monotherapy are low but not zero, and the residual reflects other contributors — missed meals, alcohol, renal impairment, and concurrent agents.^[3]