Mealtime glucose regulation with nateglinide in healthy volunteers: comparison with repaglinide and placebo.
OBJECTIVE
This study was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide, and placebo on mealtime insulin secretion and glycemic control in healthy subjects.


METHODS
Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were performed from 0 to 12 h postdose.


RESULTS
Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insulin rise of 2.3, 1.3, 1.15, and 0.8 microU x ml(-1) x min(-1), respectively, over the 0- to 30-min postmeal interval. After peaking, insulin concentrations decreased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations were delayed and returned to baseline more slowly than with nateglinide treatment. Nateglinide treatment produced lower average plasma glucose concentrations in the 0- to 2-h postdose interval than either dose of repaglinide and placebo (P < 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose concentrations returned more rapidly to predose levels with nateglinide treatment than with either dose of repaglinide. Treatment with repaglinide produced a sustained hypoglycemic effect up to 6 h postdose.


CONCLUSIONS
In this single-dose study in nondiabetic volunteers, nateglinide provided a more rapid and shorter-lived stimulation of insulin secretion than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more physiological insulin secretory response with the potential for a reduced risk of postabsorptive hypoglycemia.
Kalbag
J B
JB
Department of Clinical Pharmacology, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA.
Walter
Y H
YH
Nedelman
J R
JR
McLeod
J F
JF
D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D001835:Body Weight; D002219:Carbamates / Q000494:pharmacology; D018592:Cross-Over Studies; D003510:Cyclohexanes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005502:Food; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D000077715:Nateglinide; D010649:Phenylalanine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010919:Placebos; D013997:Time Factors
D001786:Blood Glucose; D002219:Carbamates; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; D010919:Placebos; D000077715:Nateglinide; D010649:Phenylalanine; C072379:repaglinide