Nateglinide (DB00731): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Nateglinide is an orally administered, short-acting insulin secretagogue belonging to the meglitinide (or glinide) class of antidiabetic agents. Chemically, it is a D-phenylalanine derivative, distinguishing it structurally from the sulfonylurea class of drugs.[1] Its primary therapeutic application is as an adjunct to diet and exercise for the management of type 2 diabetes mellitus, specifically targeting postprandial hyperglycemia.[3] The pharmacological action of nateglinide is characterized by a unique "fast on-fast off" kinetic profile at its molecular target, the pancreatic β-cell ATP-sensitive potassium channel.[5] This property enables it to mimic the physiological first-phase insulin secretion that occurs in response to a meal, leading to rapid but transient insulin release that effectively controls post-meal glucose excursions.

The clinical use of nateglinide is governed by its rapid and short-lived action. A strict, meal-dependent dosing regimen is essential for both efficacy and safety, encapsulated by the critical patient counseling point: "skip a meal, skip a dose".[3] This approach mitigates the principal adverse effect of hypoglycemia. Pharmacokinetically, nateglinide is characterized by rapid absorption, a short half-life of approximately 1.5 hours, and extensive hepatic metabolism. Its clearance is predominantly mediated by the cytochrome P450 isozyme CYP2C9, a fact that introduces significant considerations for pharmacogenomics and drug-drug interactions, particularly in individuals who are genetically poor metabolizers of the enzyme.[7] While approved by major regulatory bodies, including the U.S. Food and Drug Administration (FDA), its marketing authorization in the European Union was withdrawn in 2022 for commercial reasons, reflecting a shift in the therapeutic landscape toward newer antidiabetic agents with more convenient