The expression
meglitinide analogs was introduced in 1995 to cover new molecules proposed as non-sulfonylurea insulinotropic agents and displaying structural analogy with
meglitinide, such as
repaglinide,
nateglinide, and
mitiglinide.
Meglitinide analogs display, as judged by conformation analysis, a U-shaped configuration similar to that of
antihyperglycemic sulfonylureas such as
glibenclamide (
glyburide) and
glimepiride. In rat pancreatic islets incubated in the presence of 7.0 mmol/L
D-glucose,
repaglinide and
mitiglinide demonstrate comparable concentration-response relationships for stimulation of
insulin release, with a threshold value < 10 nmol/L and a maximal secretory response at about 10 nmol/L. Several findings indicate that
meglitinide analogs provoke the closing of
adenosine triphosphate-sensitive
potassium channels, with subsequent gating of voltage-sensitive
calcium channels. The effects of
meglitinide analogs upon the binding of [3H]
glibenclamide to islet cells membranes reinforces this concept. At variance, however, with other
meglitinide analogs, the ionic and secretory response to
repaglinide (10 micromol/L) is not rapidly reversible in perifused rat islets. In experiments conducted in vivo in control and diabetic rats,
repaglinide provokes a greater and more rapid increase in plasma
insulin concentration and an earlier fall in glycemia than
glibenclamide or
glimepiride. Onset of effect is also more rapid and duration of effect shorter with
nateglinide versus
glibenclamide. In clinical studies, single or repeated daily administration of
repaglinide increased plasma
insulin concentration in a dose-dependent manner, with an incremental peak reached about 2 hours after
repaglinide intake. Plasma concentrations of
repaglinide are about 5.0 microg/L 2-2.5 hours after oral intake of the
drug. Despite the slow reversibility of
repaglinide action in vitro, this
drug offers advantages over
glibenclamide in terms of the possible occurrence of
hypoglycemia if a meal is missed. In volunteers receiving a single oral dose of
nateglinide (120mg) 10 minutes before a standardized 800 Kcal breakfast, the plasma
insulin concentration was higher 5, 10, and 20 minutes after meal intake than when they received a single dose of
repaglinide (0.5 or 2.0mg) or placebo 10 minutes before breakfast. Peak plasma concentrations of
nateglinide were reached within 2 hours in most volunteers. Peak plasma concentrations of
mitiglinide were reached 30 minutes after a single oral dose in a representative volunteer.
Mitiglinide significantly suppressed meal-induced elevations in
blood glucose concentrations in a study of patients with
type 2 diabetes. In conclusion, two obvious differences among these
meglitinide analogs should be underlined. First, on a molar basis,
nateglinide is somewhat less potent than
repaglinide or
mitiglinide, as an insulinotropic agent. The maximal secretory responses evoked by these three
meglitinide analogs are, however, identical to one another. Secondly, and as already mentioned, the functional effects of
nateglinide and
mitiglinide are more rapidly reversible than those of
repaglinide, for instance in perifused rat islets. The
meglitinide analogs offer the advantage over the long-acting
antihyperglycemic sulfonylurea
glibenclamide of minimizing the risk of undesirable
hypoglycemia.