Sitagliptin, a DPP-4 inhibitor, is weight-neutral compared to sulphonylureas. The reason sitagliptin does not cause hypoglycaemia as monotherapy is:

• A Sitagliptin also blocks glucagon secretion at all times, preventing rebound hypoglycaemia
• B It enhances GLP-1-mediated insulin secretion only in response to meals (glucose-dependent), with no effect on basal insulin or glucagon when glucose is normal ✓
• C DPP-4 inhibitors increase GLP-1, which directly stimulates hepatic gluconeogenesis as a counter-regulatory mechanism
• D Sitagliptin reduces insulin receptor downregulation, improving sensitivity without increasing insulin secretion

Explanation

GLP-1 (incretin) stimulates insulin secretion and suppresses glucagon in a glucose-dependent manner — these effects are absent when blood glucose is in the normal fasting range. DPP-4 inhibitors like sitagliptin prolong endogenous GLP-1 action, inheriting this glucose-dependence. As a result, the drug amplifies insulin release only postprandially (when glucose is elevated) and does not stimulate insulin when normoglycaemic, minimising hypoglycaemia risk. This is in contrast to sulphonylureas which stimulate insulin regardless of glucose.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.