Nateglinide: A structurally novel, short-acting, hypoglycemic agent

Nateglinide is a short-acting, pancreatic, beta -cell-selective, K-ATP pota ssium channel blocker that improves overall glycemic control in type 2 diab etes. Although nateglinide's mechanism of action is related to that of sulp honyl-ureas and repaglinide, important differences do exist. Nateglinide bi nds rapidly to the sulfonylurea SUR1 receptor with a relatively low affinit y, and it dissociates from it extremely rapidly in a manner of seconds. Thi s rapid association and dissociation gives nateglinide a unique "fast on-fa st off" effect. Thus, nateglinide has a rapid onset and short duration of a ction stimulating insulin secretion in vivo and providing good control of p ostprandial hyperglycemia when taken immediately prior to meals. The rapid action of nateglinide on the beta cells stimulates and restores the normal physiological first and early phase of insulin secretion, consequently redu cing postprandial hyperglycemia. This hypoglycemic effect of nate-glinide l eads to improved glycemic control, while the short duration avoids delayed hyperinsulinemia and hypoglycemia after meals. Nateglinide is not a sulfony lurea, but it shares the mechanism of action of commonly used oral hypoglyc emic agents such as glibenclamide and glipizide. Like the recently introduc ed, short-acting agent, repaglinide, it does not incorporate a sulfonylurea moiety. However, nateglinide's effects on insulin secretion and glycemic c ontrol differ significantly from the sulfonylureas and repaglinide in that it preferentially stimulates acute phase insulin, better controls postprand ial glucose excursions and spikes, and causes less hyperinsulinemia and hyp oglycemia. Compounds with such a profile should not only achieve improved o verall glucose control, but also reduce the risk of vascular complications which is the most important feature of nateglinide. Clinical studies with n ateglinide have confirmed that it acts rapidly and both restores insulin re lease and attenuates the postprandial glucose spike. Nateglinide is both ef fective and well tolerated in the treatment of type 2 diabetes. The reporte d overall profile of adverse effects appears to be superior to that of othe r K-ATP potassium channel blockers, the glucose modulator metformin and PPA R gamma agonists such as troglitazone. Clinical comparisons of these agents have shown nateglinide to be more effective in attenuating postprandial gl ucose than any other oral hypoglycemic agent, and that treatment with both nateglinide and metformin provides additive effects that afford improved co ntrol of plasma glucose levels. The administration regimen for nateglinide, immediately prior to meals, also facilitates patient compliance. (C) 2001 Prous Science. All rights reserved.